CN1177962A - Novel process for preparing 2, 3 -lihydro-benzofuranol derivatives - Google Patents

Abstract

This invention relates to a novel process for preparing 2, 3-dihydro-benzofuranol derivatives and to the novel intermediates produced thereby.

Description

Process for preparing 2, 3-dihydro-benzofuranol derivatives

Background

The present invention relates to a novel process for the preparation of 2, 3-dihydro-benzofuranol derivatives and intermediates produced thereby.

2, 3-dihydro-benzofuranol exhibits radical scavenger properties. Examples of diseases that can be ameliorated by free radical scavengers include stroke, nervous system trauma or reperfusion injury, as more fully described in patent application WO93/20057 filed 3/10, 1993 and in corresponding U.S. patent application No. 08/318,633 filed 12/22, 1994, which are incorporated herein by reference.

More particularly, the present invention relates to a novel process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers, optically active forms and racemic mixtures thereof, or pharmaceutically acceptable salts thereof:wherein R is₂Is C_1-4Alkyl radical, each R₂Part being independent C_1-4Alkyl or two R₂Part of which forms C together with the carbon atom to which it is attached_5-6A cycloalkyl moiety; r₄Is C_1-6An alkyl group; r₅Is H or C (O) R, R is H or C_1-9An alkyl group; r₆Is C_1-6An alkyl group; r₇Is H or C_1-6An alkyl group; x is COOR₈、CH₂OH, halomethyl, C (O) A or CH₂A; a is NR₇R₉、-N^R₆R₆R₆-Q^○Pyrrolidino, piperidino, morpholino or

R₈Is H, C_1-6Alkyl or- (CH)₂)_m-a, m is 2,3 or 4; r₉Is H, C_1-4Alkyl, aryl, heteroaryl, and heteroaryl,N is 1, 2,3 or 4, p is 1, 2 or 3; r₁₀Is H, C_1-8Alkyl radical, C_2-6Alkenyl radical, C_4-6Cycloalkyl, cyclohexylmethyl, hydroxyalkyl (C)_2-6) Dihydroxyalkyl (C)_3-6)、C_2-9Acyloxyalkyl (C)_2-6)、C_1-4Alkoxyalkyl (C)_1-6)、-(CH₂)_2-6-O-(CH₂)_2-4-OH、t is 0, 1 or 2, or pyrimidinyl, with the proviso that R is not H when Y is not H₁₀Is H; y is H, CH₃Or COOR₇；R₁₁Is H, C_1-4Alkoxy radical, C_1-4Alkyl or halogen; r₁₂Is in the ortho position C_1-4Alkoxy radical, ortho-C_1-4Alkyl or para-halo; and Q is a halogen or sulfonate ion^○-SO₃R₁，R₁Is H, C_1-6Alkyl, aryl or aralkyl.

Summary of The Invention

The present invention provides a novel process for the preparation of benzofuranol derivatives of formula (I), including stereoisomers, enantiomers, optically active forms and racemic mixtures thereof, or pharmaceutically acceptable salts thereof:

wherein R is₂Is C_1-4Alkyl radical, each R₂Part being independent C_1-4Alkyl or two R₂Part of which forms C together with the carbon atom to which it is attached_5-6A cycloalkyl moiety; r₄Is C_1-6An alkyl group; r₅Is H or C (O) R, R is H or C_1-9An alkyl group; r₆Is C_1-6An alkyl group; r₇Is H or C_1-6An alkyl group; x is COOR₈、CH₂OH, halomethyl, C (O) A or CH₂A；A is NR₇R₉、-N^㊉R₆R₆R₆-Q^㊀Pyrrolidino, piperidino, morpholino orR₈Is H, C_1-6Alkyl or- (CH)₂)_m-a, m is 2,3 or 4; r₉Is H, C_1-4Alkyl, aryl, heteroaryl, and heteroaryl,n is 1, 2,3 or 4, p is 1, 2 or 3; r₁₀Is H, C_1-8Alkyl radical, C_2-6Alkenyl radical, C_4-6Cycloalkyl, cyclohexylmethyl, hydroxyalkyl (C)_2-6) Dihydroxyalkyl (C)_3-6)、C_2-9Acyloxyalkyl (C)_2-6)、C_1-4Alkoxyalkyl (C)_1-6)、-(CH₂)_2-6-O-(CH₂)_2-4-OH、t is 0, 1 or 2, or pyrimidinyl, with the proviso that R is not H when Y is not H₁₀Is H; y is H, CH₃Or COOR₇；R₁₁Is H, C_1-4Alkoxy radical, C_1-4Alkyl or halogen; r₁₂Is in the ortho position C_1-4Alkoxy radical, ortho-C_1-4Alkyl or para-halo; and Q is a halogen or sulfonate ion^○-SO₃R₁，R₁Is H, C_1-6An alkyl, aryl or aralkyl group, the method comprising: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,

with 2-halo-2- (C)_1-4) Alkyl radical (C)_1-6) Acid halides or of the formula R₂-C(W)(R₂) 2-halo-2- (C) of C (O) V_1-4) Alkyl radical (C)_1-6) Acid reaction, wherein R₂W is hydrogen or halogen such as iodine, bromine, chlorine or fluorine, preferably bromine or chlorine, and V is halogen or hydroxy as defined above, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6) wherein R is₂、R₄、R₆And R₇As defined above, the above-mentioned,

(b) protecting the 5-hydroxy moiety of the resulting benzofuranone (6) with a suitable protecting group to convert the ketone moiety to an exomethylene group to give a benzofuran of formula (8) wherein R₂、R₄、R₆And Pg is as defined above, and,

(c) converting the exomethylene group of the resulting benzofuran of formula (8) into a hydroxymethyl group by hydroboration/oxidation to give a compound of formula (9), wherein R₂、R₄、R₆、R₇And Pg is as defined above, and,

optionally, (d) resolving the alcohol (9) to give (R) and (S) optically active compounds (9), optionally (e) deprotecting the 5-hydroxy group of the compound of formula (9) to give benzofuranols of formula (I) which are useful as anti-inflammatory agentsWherein X is CH₂OH and R₅Is H, optionally (f) oxidizing the 3-hydroxymethyl group of formula (9) to the 3-carboxylic acid of formula (12),

optionally (g) resolving the racemic acid of formula (12) to give (S) and (R) the optically active compound (12), optionally (h) deprotecting the 5-hydroxy group of acid (12) to give the benzofuranol of formula (I) wherein X is COOH and R₅(ii) is H, optionally (I) esterifying a formic acid of formula (12) and optionally deprotecting the hydroxy group to give a benzofuranol of formula (I) wherein X is COOR₈And R₅(ii) optionally, (j) reacting the desired amino group with a carboxylic acid of formula (12) and optionally deprotecting the hydroxy group to give a benzofuranol of formula (I) wherein X is C (O) A and R₅(ii) reduction of formic acid of formula (12) with H, optionally (k), to give a compound of formula (9), optionally (l) deprotection of the hydroxy group of the compound of formula (9) and conversion of the hydroxy group of the 3-hydroxymethyl group to halogen, to give a benzofuranol of formula (I) wherein X is halomethyl and R is₅(ii) is H, optionally, (m) optionally deprotecting the hydroxy group of the compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a leaving group to give a benzofuranol of formula (10),optionally, (n) substituting the leaving group of compound (10) with the desired amino group and optionally deprotecting the hydroxy group to provide a product of formula (I) wherein X is CH₂A and R₅Is H, optionally (o) esterified wherein R₅The 5-hydroxy group of the compound of formula (I) being H, to give a compound of formula (I) wherein R is₅Is COR, R is C_1-9Alkyl, and optionally converting said product into a pharmaceutically acceptable salt thereof.

As used in the description of the invention: (a) the term "alkyl" refers to a monovalent group (-R). It includes straight and branched chain saturated aliphatic hydrocarbon moieties of a specified number of carbon atoms. For example, the term "C_1-9Alkyl "and" C_1-8Alkyl "refers to saturated straight and branched chain hydrocarbon radicals containing from 1 to 8 and from 1 to 9 carbon atoms, respectively, preferably from 1 to 6 carbon atoms (" C_1-6Alkyl group "), more preferably containing 1 to 4 carbon atoms (" C_1-4Alkyl "). Included within the scope of this term are methyl, ethyl, n-butylPropyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, 2, 3-dimethyl-2-butyl, heptyl, 2-dimethyl-3-pentyl, 2-methylhexyl, octyl, 4-hexyl-3-heptyl, nonyl and the like. Likewise, C_1-6Alkyl is preferably C_1-4An alkyl group. Including the foregoing preferred embodiments, all C_1-4The alkyl group may have any arrangement of 1, 2,3 or 4 carbon atoms. (b) The term "alkylene" refers to a saturated divalent alkyl group (-R-). Likewise, the term "alkylene" includes straight or branched chain moieties. Some examples of branched alkylene groups are ethylene, 2-methyltrimethylene, 2-dimethyltrimethylene and the like. E.g. C₃Alkylene may mean

(c) The term "alkenyl" refers to an unsaturated monovalent group. Including straight and branched chain unsaturated aliphatic hydrocarbon groups of a specified number of carbon atoms. For example, the term "C_2-6Alkenyl "means an unsaturated straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms. Included within the scope of this term may be ethenyl, propenyl, 2-methyl-2-propenyl, butenyl and the like; (d) formula-c (o) -or-CO-means a carbonyl group of the formula:the term-C (O) R includes where R is H or C_1-9Those of alkyl moieties such as formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like. The term-COOR includes where R is H or C_1-6Those alkoxycarbonyl groups of the alkyl moiety, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like. Alkoxycarbonyl groups in which R is other than H are also known as esters; (e) NR (nitrogen to noise ratio)₇R₈Part of which comprises a compound containing R as defined above₇And R₈Amino, mono-substituted amine and di-substituted amine of (a); (f) the term "Bn" refers to a benzyl group of the formula:

(g) the term "aralkyl" refers to a moiety of the formula wherein m ═ 1, 2,3, or 4

Including benzyl, phenethyl, phenylpropyl, or phenylbutyl moieties; wherein the phenyl moiety may be allowed to have a substituent selected from C at the ortho, meta or para positions_1-41, 2,3 substituents of alkyl (preferably methyl) or halogen (preferably chlorine, but including bromine and iodine); (h) in mono-and dihydroxy-substituted alkyl moieties, the alkyl moiety may be allowed to contain one or two OH groups (instead of two hydroxyl groups on one carbon atom), preferably with a hydroxyl group on the terminal carbon atom; (i) at C_2-9Acyloxyalkylene (C)_2-6) In which the acyloxy moiety contains 2 to 9 carbon atoms and the alkylene moiety contains 2 to 6 carbon atoms, e.g. -CH₂CH₂-OC(O)CH₃；(j)-C_2-6alkylene-O- (CH)₂)_2-4The moieties each have a divalent carbon atom moiety bonded to oxygen (O). Oxygen is also attached to the 2-4 carbon atom moiety terminating in a hydroxyl moiety, an example of which is-CH₂CH₂OCH₂CH₂CH₂OH; (k) piperidino refers to a compound of the formula:(l) Pyrrolidino refers to a compound of the formula:

(m) piperazino means a compound of the formula:

(n) morpholino refers to a compound of the formula:

(o) formulaRefers to hydroquinone, substituted hydroquinone, it being understood that R may be attached to any position at the 2,3, 5 or 6 position; (p) formulaRefers to a benzofuran derivative, a substituted benzofuran, with the understanding that R may be attached to any of the 2,3, 4, 5, 6 or 7 positions; benzofuranol derivatives refer to 5-hydroxybenzofuran derivatives; and (q) formula

Refers to benzofuranones, substituted benzofuranones, it being understood that R can be attached to any position of 2, 4, 5, 6 or 7.

The symbol "-" refers to a bond that extends out of the plane of the paper.

The symbol "- - - - -" refers to a bond extending into the plane of the paper.

The term "pharmaceutically acceptable salts" includes acid addition salts derived by reaction with acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic carboxylic acids such as acetic, propionic, glycolic, maleic, tartaric, citric, salicylic, 2-acetoxybenzoic or organic sulfonic acids such as methanesulfonic, 4-toluenesulfonic and naphthalenesulfonic acid. Of course, other acids well known in the pharmaceutical art may be used. The term "pharmaceutically acceptable salt" may also include hydrates.

The stereoisomers of the compounds of formula (I) are a general term for all isomers of the compounds, which differ only in the spatial orientation of the carbon atoms. It includes geometric (cis/trans) isomers as well as isomers of compounds containing more than one chiral center that are not mirror images of each other (diastereomers or diastereomers). The term "enantiomer" refers to two stereoisomers whose mirror images are not superimposable on each other. The term "chiral center" refers to a carbon atom that is attached to four different groups. The Nomenclature of the term R/S is as described in the Joint Commission on Biochemical Nomenclature (IUPAC-IUB Joint Commission on Biochemical Nomenclature), see the European journal of biochemistry (Eur.J. biochem.), 138: 9-37(1984). Chiral materials may contain equal amounts of the R and S isomers, which are referred to herein as "racemic", or unequal amounts of the R and S isomers, which are referred to herein as "optically active" or "non-racemic".

The mixture may be resolved or isolated according to conventional standard procedures well known in the art; for example chromatographic separation of chiral stationary phases, fractional crystallization of addition salts formed by reagents used for this purpose using optically active esters (see "Enantiomers, racemates and resolution" (Enantiomers, racemases and solutions), j.jacques, a.collet and s.h.wilen, Wiley (1981)), enzymatic resolution and the like. The resolution of stereoisomers is carried out on the intermediates of formula (I) or the final products of formula (I). The term "resolution" refers to the separation of a racemic mixture into optically active components. Alternatively, enantiomers can be prepared by using enantioselective or asymmetric syntheses well known to those skilled in the art. The term "enantioselectivity" or "asymmetry" refers to the ability to produce an optically active form of a product.

Should be used forIt will be appreciated that the compounds of formula (I) may exist in various forms of stereoisomeric configurationAt this point. It is to be further understood that the compounds of the present invention include compounds of formula (I) that exist in their various structures and stereoisomeric configurations, which may be single isomers or mixtures of isomers. The term "enantiomeric excess" or ee refers to the percentage of excess of one enantiomer, E1, in a mixture of two enantiomers, E1 plus E2, and therefore $\frac{(E1-E2)}{(E1+E2)}\×100\%=\mathrm{ee}$ The symbol (+) -means the positive (plus) enantiomer and (-) -means the negative (minus) enantiomer.

"Pg" refers to an appropriate protecting group. "protected hydroxy" means a protecting group (Pg) in place of H and attached to the oxygen atom of the hydroxy group. Suitable protecting groups can be found in the following references: greene and P.Wuts, Protective groups in organic synthesis, second edition, published by John Wiley & Sons Inc., New York (1991), which is incorporated herein by reference. For convenience, Pg in the scheme may be a hydrogen atom.

In the prior art, the compounds of formula (I) have been synthesized as described in scheme I below in patent application WO93/20057 filed 3/10, 1993.Route I: presynthesizing

Fires rearrangement of the substituted acrylic acid diester (3) of hydroquinone (2) at elevated temperatures, e.g., 120 ℃ and 150 ℃ gives the 6-membered ring (protected 6-hydroxy-3, 4-dihydro-1, 2H-benzopyran-4-one) (4). The enolizable ketone obtained was subjected to a cyclodepsipercation reaction with thallium (III) nitrate in trimethyl orthoformate/methanol to obtain compound (5). The acid moiety of (5) is then reduced to its corresponding alcohol, the resulting alcohol is converted to a halogen, which is then substituted with an amino group to provide the desired 2, 3-dihydro-benzofuranol (I). Thallium (III) nitrate is used in the ring reduction step and must be handled with care, since this compound is very toxic. Further, the use of such salts can cause waste products, solvents and all materials in contact with the salts to be troublesome to handle. The large scale preparation of 2, 3-dihydro-benzofuranol is not feasible due to a number of inconveniences.

After extensive experimentation, the present invention discloses a novel preparation method which avoids the ring-shrinking step and does not use thallium (III) nitrate. This new process uses the Friedel-crafts reaction (defined below) to obtain the intermediate 5-membered ring (6) directly from the starting hydroquinone instead of the 6-membered ring (4) obtained in the previous scheme I. The novel intermediates are useful for preparing stereoisomers of 2, 3-dihydro-benzofuranol derivatives (I) or mixtures thereof.

As described in scheme II below, racemates or optically active derivatives can be obtained.Route II, step a:

in the present invention, the aryl group used in the Friedel-crafts reaction is a substituted hydroquinone of formula (2) wherein R is₄、R₆And R₇As defined above.

2, 6-dimethylhydroquinone (R)₇Hydrogen) and 2,3, 5-trimethylhydroquinone are commercially available. Other substituted hydroquinones (2) can be readily prepared by methods well known in the art, as described in "Methoden der Organischen Chemie" Houben Weyl, band VII/3a chinone, teil 1 and J.T.Gupton et al, J.Org.Chem., 1983, 48, 2933-J.2936, which are incorporated herein by reference.

The hydroxyl group of the trialkylhydroquinone (2) is optionally protected with a suitable protecting group (Pg) to give the protected hydroquinone (3). Many protecting groups commonly used for alcohols are also suitableIn phenol. Ethers and esters are the most commonly used protecting groups used. By ether is meant an ether capable of forming an-OR group wherein R is an alkyl group, such as methyl, cyclohexyl, isopropyl, tert-butyl OR methoxymethyl, benzyloxymethyl, 2- (trimethylsilyl) -ethoxymethyl, tetrahydropyranyl, allyl, benzyl OR silyl including trimethylsilyl, tert-butyldimethylsilyl. By ester is meant capable of forming an ester (-OCOR), such as an acetate (-OCOCH)₃) Levulinic acid ester (CH)₃COCH₂CH₂CO₂-, pivalate ((CH)₃CCO₂-) benzoate ester (-OCOC)₆H₅) Carbonates such as methyl carbonate (-OCOCH)₃) Aryl carbonate, benzyl carbonate (-OCOCH)₂C₆H₅) Carbamates (-OCONHR), phosphonates such as dimethylphosphoryl ester ((CH)₃)₂P (O) O-, sulfonates such as methanesulfonate or methanesulfonyl (-OSO)₂CH₃) Or tosylate or tosyl (-OSO)₂C₆H₄-p-CH₃)。Route II

The present inventors have found that protecting groups may affect the formation of five-membered rings. As the protecting group, an alkyl group is preferable, and a methyl group is more preferable.

Preferably, the trialkylhydroquinone (2) is protected by conventional reactions, for example by treating the trialkylhydroquinone (2) with dimethyl sulphonate or methyl iodide in a solvent such as a ketone, an alcohol (e.g. methanol, ethanol) in the presence of a base such as potassium carbonate, sodium hydroxide, potassium hydroxide, the reaction preferably being carried out at reflux. The protected hydroquinone (3) is isolated according to methods well known in the art.Route II, step B:

the novel intermediates (6) are prepared by Friedel-crafts acylation as described in Methoden der Organi schen Chemie, (Houben Weyl, band VII/3 achhinone, teil I, 1973) or Friedel-crafts and related reactions (Interscience, New York, 1963-. The Friedel-crafts reaction is involved in catalysisReaction between an aryl halide and an acid halide, carboxylic acid, anhydride or ketene in the presence of an agent. For the acid halide, all four halides (Cl, Br, I, F) can be used. In the present invention, the reagent for completing the formation (6) is preferably of the formula R₂-C(W)(R₂) C (O) 2-halo-2- (C) of V (wherein W is hydrogen or halogen such as iodine, bromine, chlorine or fluorine, more preferably bromine or chlorine, and V is halogen or hydroxy (-OH) as defined above)_1-4) Alkyl radical (C)_1-6) Acid halides or 2-halo-2- (C)_1-4) Alkyl radical (C)_1-6) And (4) acid.

As an example, when R₂In the case of methyl or ethyl, 2-bromo-2-methylpropanoyl bromide (propionicbromide) or 2-bromo-2-ethylpropionyl bromide, respectively, are commercially available. When R is₂In the case of propyl, commercially available 2-propylpentanoic acid can be converted to 2-halo-2- (C) by using a halide instead of α -hydrogen_1-4) Alkyl radical (C)_1-6) More preferably, "α -hydro" is replaced by iodide, bromide or chloride "α -hydro" refers to hydrogen attached to the carbon atom directly adjacent to the carbonyl. α -hydro may be replaced by bromide or chloride by methods well known in the art, such as with bromine or chlorine with phosphorus oxyhalide as the catalyst (this reaction is known as the Hell-Volhard-zelinski reaction, and chlorosulfonic acid may also be used as the catalyst to give α -iodination and α -chlorinated or α -brominated carboxylic acids), with N-bromosuccinimide or N-chlorosuccinimide and bromic or chloric acid, with cuprous chloride in a polar inert solvent to make α -chlorinated carboxylic acid, with iodine and a small amount of iodic acid to make α -iodinated acid chloride.

The Friedel-Crafts reaction is most commonly carried out in or without a solvent such as methylene chloride, dichloroethane, tetrachloroethane, chlorobenzene, nitromethane or carbon disulfide. The catalyst is a lewis acid. "Lewis acids" are a class of materials having an energetic orbital. The most commonly used catalysts are ferric chloride, iodine, zinc chloride, aluminum chloride and iron, more preferably aluminum chloride and ferric chloride are used. Preferably, the proportion of catalyst is from 0.1 to 2 per mole of reagent.

More preferably, in the temperature range of-10 ℃ to 100 ℃, as catalyzed by Lewis acidsUsing R in the presence of an agent (aluminium chloride or ferric chloride) in a solvent such as dichloromethane, dichloroethane, tetrachloroethane₂-C (halo) (R)₂) C (O) halide-treated hydroquinone (3). The resulting benzofuranones are isolated and optionally deprotected using methods well known in the art.

1, 4-bis- (2-halo-2-alkyl-acetoacetoxy) -2, 3, 5-trialkylhydroquinone may be formed as a by-product in the reaction, and the mixture may require a supplementary saponification step to obtain the desired product. The mixture is thus treated by basic conditions such as potassium hydroxide or sodium hydroxide in a mixed solvent such as aqueous methanol/tetrahydrofuran at a temperature in the range of 40 ℃ to 80 ℃. More preferably, an aqueous solution of sodium hydroxide is added to the crude product dissolved in methanol/tetrahydrofuran 1/1 and the reaction is carried out at 60 ℃ for 3 to 5 hours. The novel benzofuranones are isolated by conventional methods.Route II, step C:

the 5-hydroxy group of the resulting benzofuranone is protected using an appropriate protecting group as described above. More preferably, reagents such as 2-methyl-propionyl halide, methyl halide or benzyl halide are used. More preferably, 2-methyl-propionyl chloride is added to the solution of benzofuranone (6) in a solvent such as dichloromethane; the mixture is stirred in an inert atmosphere at a temperature in the range of-5 ℃ to 10 ℃. The protected compound (7) was isolated by extraction in quantitative yield and was used without further purification in the next step.

Further, more preferably, benzyl bromide or benzyl chloride is added to a solution of benzofuranone (6) in a solvent such as acetone, dichloromethane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, potassium hydroxide, sodium hydride or sodium amide. More preferably, benzyl bromide is added to the acetone solution of benzofuranone (6) in the presence of potassium carbonate and the mixture is stirred at a temperature in the range of 5 ℃ to 65 ℃. The protected compound is isolated by filtration or by methods well known in the art.Route II, step D:

conversion of the keto group of benzofuranone (7) to exomethylene (exomethyl refers to divalent C) using methods well known in the art₁The radical being in the form of a side chainAre linked, rather than included in a ring); the known process is the Wittig reaction or a two-step process involving alkylation with methyllithium or methylmagnesium halide followed by acidic catalytic elimination of tertiary alcohols.

In the Wittig reaction, a phosphonium ylide (also referred to as phosphorane, which refers to a carbonate ion in it) is usedSubstances bound to hetero atoms having a high positive charge, i.e. -C^--X⁺) The keto group of benzofuranone (7) is treated to give an olefin as described by Johnson in ylium Chemistry (school Chemistry), Academic Press, New York, 1966, which is incorporated herein by reference. The ylides of phosphines are usually prepared by treatment of a phosphonium salt with a base, which is commercially available or is usually prepared from a phosphine and an alkyl halide. The most common method is to convert the phosphonium salt to the ylide by treatment with a strong base such as butyllithium, sodium or potassium amide, sodium or potassium hydride, sodium or potassium alkoxide. Generally, a solvent such as tetrahydrofuran can be used. The reaction is carried out in an inert atmosphere at a temperature in the range of-5 ℃ to 35 ℃.

More preferably, an alkoxide such as potassium tert-butoxide is added in portions to an anhydrous tetrahydrofuran suspension of benzofuranone (7) and methylphosphonium halide at about 0 ℃ under an inert atmosphere. The mixture is then worked up using methods well known in the art to give the product in high yield. The quality of the alkoxide, for example potassium tert-butoxide, is very important for increasing the yield of the olefin (8).

In addition, in the alkylation/elimination process, the ketone (7) is treated with methylmagnesium halide such as methylmagnesium chloride, methylmagnesium bromide or methylmagnesium iodide. More preferably, the ketone is treated with methylmagnesium chloride in an ether solvent such as diethyl ether, tetrahydrofuran at a temperature in the range of-5 ℃ to 50 ℃ to give the intermediate tertiary alcohol. The addition of an acid such as concentrated sulfuric acid causes elimination to give the desired olefin (8), which can be further purified by methods known in the art, such as crystallization.Route II, step E

The exomethylene group of (8) in the methyl-alcohol group can be converted by hydroboration/oxidation. The olefin is treated with borane in an ether solvent, typically a commercially available borane complex containing tetrahydrofuran, dimethyl sulfoxide or a tertiary amine is used. Boranes may also be prepared in situ by methods well known in the art, for example by reacting sodium borohydride with boron trifluoride.

More preferably, olefin (8) is treated with borane-methyl sulfide complex in a solvent such as chloroform, dichloromethane or an ether (e.g. diethyl ether, tert-butyl methyl ether, tetrahydrofuran) under an inert atmosphere at about 0 ℃. Borane is added to the olefin to form an oxidized intermediate. The organoborane produced can be oxidized to primary alcohols (primary alcohols refer to alcohols in which the carbon attached to the hydroxyl group is attached to one alkyl group or not attached to an alkyl group and at least two hydrogen atoms) using sodium hydroxide-hydrogen peroxide, which is well known in the art. The alcohol (9) produced was used without further purification.Scheme III, step A

Optionally, racemic 3-hydroxymethyl-benzofuran (9) may be resolved or isolated according to conventional standard methods well known in the art, including chromatographic separation on a chiral stationary phase, fractional crystallization using an optically active ester, addition salts formed by reagents used for this purpose, enzymatic resolution and the like. More preferably, 3-hydroxymethyl-benzofuranol is resolved using an enzyme. More preferably enzymatic transacylation is used for the resolution of alcohols, wherein one enantiomer is reactive and acylated while the other enantiomer remains unchanged.

Commonly used enzymes include microbial lipases such as Candida cylindracea, Rhizopus arrhizus, Chromobacterium violaceum, Pseudomonas cepacia, Mucor miehei, Aspergillus niger, enzymes derived from mammalian liver such as porcine pancreatic lipase, or chiral enzymes (Chirazyme) L-1, L-2, L-3, L-5 or L-6 from Boehringer Mannheim. The enzymes used may be in their crude or purified form, sometimes on solid supports on agar or red kieselguhr chromatographic supports. The acylation reaction is carried out by transferring and esterifying ester and alcohol in an organic solvent by using enzyme; the esters include methyl acetate, acetic anhydride, vinyl acetate, isopropenyl acetate, 2, 2, 2-trifluoroethyl acetate; the organic solvent includes ethers such as diethyl ether, t-butyl methyl ether, tetrahydrofuran or other solvents such as benzene. More preferably, the 3-hydroxymethylbenzofuran (9) is resolved using Candida cylindracea microbial lipase. More preferably, the reaction is carried out with vinyl acetate in an ether solvent such as t-butyl methyl ether at room temperature or at a temperature in the range of 0 ℃ to 50 ℃.

The optically active acetyl derivative of (9) and the inert alcohol can be isolated by methods well known in the art. For example, the mixture is filtered, concentrated to weight under reduced pressure, and the residue is chromatographed on silica gel to give the acylated isomer and the isomer which remains unchanged. Other methods such as HPLC (high purity liquid chromatography) or crystallization may also be used. The acetyl isomer may be de-esterified by methods well known in the art, wherein, for example, the acetyl isomer is dissolved in methanol and treated with basic conditions such as potassium carbonate at a temperature in the range of 15 ℃ to 60 ℃. The recovered desired optically active alcohol (9) can be purified by a method known in the art, such as crystallization.

The undesired optically active alcohol (9) can be recycled one or more times. More preferably, the 3-hydroxymethyl group is converted to a leaving group, more preferably to a mesylate, by conventional methods well known in the art. Elimination of the resulting leaving group produces an alkene (8) which may be included in the present process. The elimination reaction can be carried out by a method known to those skilled in the art. More preferably, the leaving group is eliminated in tetrahydrofuran under basic conditions such as potassium tert-butoxide at room temperature.

The 5-hydroxy group of compound (9) can be further deprotected using methods known to those skilled in the art. More preferably, if isobutyryl is used to protect the 5-hydroxy group, it may be between 70 ℃ and 85 DEGBasic conditions such as sodium hydroxide are used in a solvent mixture such as water/methanol/tetrahydrofuran at deg.C.Route III Route III, step B:

the primary alcohol of the obtained 3-hydroxymethyl-2, 3-dihydro-benzofuran derivative (9) is converted into a leaving group, which is a group that can be easily substituted with a nucleophile. For example, the leaving group includes tosylate, p-bromobenzenesulfonate, nosylate, mesylate, triflate, nonaflatate, tresylate, or halide.

More preferably, the hydroxyl group is converted to a halide or mesylate. When a hydroxyl group is converted into a halide, a commonly used reagent is a halogen acid or thionyl halide, phosphorus pentahalide, phosphorus trihalide, phosphorus oxyhalide, trialkylphosphoryl halide, triphenylphosphine halide, or the like (wherein halogen means chlorine (Cl), bromine (Br), or iodine (I)).

More preferably, the hydroxy group is converted to the bromide using triphenylphosphine bromide, which may be generated in situ, in a solvent such as dichloromethane at a temperature in the range of-5 ℃ to 10 ℃. Alcohol (9) was added to this mixture at this temperature, and then allowed to warm to room temperature. This mixture was processed in a manner known in the art to give product (10) in quantitative yield.

Another method is to convert the hydroxyl group to the mesylate salt. The reaction is carried out at room temperature under basic conditions such as pyridine; more preferably, it is carried out in tetrahydrofuran in the presence of a base such as triethylamine, e.g., at a temperature in the range of-5 ℃ to 20 ℃.Route III, step C:

to obtain a compound in which X is CH₂A (A is as defined above) using the desired amino-NR₇R₈Pyrrolidino, piperidino, morpholino or piperazino in place of the leaving group.

Desired amine HNR₇R₈Synthetic Organic Chemistry (Chapter 1.3, Synthesis of amines and ammonium salts, Trost-Fleming, PergamonPress, 1991), which is commercially available or readily synthesized by methods well known in the art as described in the literature, which is incorporated herein by reference. The most common reaction involves the reaction between the desired alkyl group and ammonia:

more preferably, for the synthesis of primary amines, reduction of azides is used; the azides are obtained by substitution of alkyl halides or by the Gabriel reaction, see for example e.f.v.seven and k.tumbell, chemical reviews (chem.rev.), 1988, 88297 (see this document)Incorporated by reference) which comprises reacting phthalimide ions with a suitable alkylating agent followed by removal of the phthaloyl group. Pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine, 2-methylpiperazine, piperazinecarboxylic acid are commercially available.

Substituted piperazines of the formula

The amine HNR can be synthesized as described above₇R₈Is easily synthesized.

Wherein Y is COOR₇Piperazines of the above formula can be readily synthesized by esterifying commercially available piperazinecarboxylic acids with the desired alkyl reagents using general esterification procedures well known to those of ordinary skill in the art.

The reaction of substituting the leaving group of compound (10) with the desired amino group can be carried out using procedures well known in the art, such as in acetonitrile, dimethylformamide, methanol, ethanol or isopropanol at reflux temperature. After extraction, the final product (I) can be isolated by column chromatography or crystallization. Crystallization appears to give higher yields than column chromatography. Optionally, the 5-hydroxy group may be deprotected according to methods well known in the art. Using the 5-hydroxy protected intermediate (9), the diastereoisomers R- (I) and S- (I) can be obtained by resolution of the acid (12) of scheme IV.Scheme IV, step a:

preferably, the 5-hydroxy group may be protected by an alkyl group such as methyl or by a benzyl group using the methods described above. The 3-hydroxy moiety of 3-hydroxymethyl-5-protected hydroxy-2, 3-dihydro-benzofuran (9) is oxidized to carboxylic acid to give compound (12).

Primary alcohols can be oxidized by many strong oxidizing agents such as permanganate and nitric acid. More preferably, the primary alcohol may also be converted to a carboxylic acid by a two-step process via an aldehyde. The conventional method for obtaining aldehydes is to treat the alcohol with dimethyl sulfoxide, Dicyclohexylcarbodiimide (DCC) and anhydrous phosphoric acid. Similar oxidation reactions were carried out using dimethylsulfoxide or other reagents in place of DCC; the other reagents include: acetic anhydride, sulfur trioxide-pyridine-triethylamine, trifluoroacetic anhydride, chlorosulfonyl isocyanate, oxalyl chloride, peroxyMolybdenum oxide, tosyl chloride, chlorine, bromine, silver tetrafluoroborate and triethylamine, trifluoromethanesulfonic acid anhydride, potassium iodide and sodium bicarbonate, methanesulfonic acid anhydride and the like.Route IV

More preferably, the 3-hydroxy moiety of 3-hydroxymethyl-5-protected hydroxy-2, 3-dihydro-benzofuran (9) may be oxidized to the aldehyde using Swern oxidation conditions as described in A.J. Mancuso and D.Swern, Synthesis (Synthesis), p165, 1981, which is incorporated herein by reference. The Swern oxidation involves the use of, for example, oxalyl chloride, dimethyl sulfoxide and a base such as triethylamine as reagents. The reaction can be carried out in a solvent such as dichloromethane at a temperature in the range of-78 ℃ to 0 ℃.

The aldehyde can be further oxidized to carboxylic acid. The oxidation of aldehydes to carboxylic acids is well known in the art, as is Selection of Oxidants in the synthesis (p7-11, Chinn, Marcel Dekker, New York, 1971), which is incorporated herein by reference. Oxidation of aldehydes can be carried out using permanganate under acidic, basic or neutral conditions, chromic acid, bromine and silver oxide.

More preferably, aldehydes are oxidized to acids using sodium chlorite and sodium dihydrogen phosphate, such as b.s.bal, w.e.childers and h.w.pinnick, journal of Tetrahedron (Tetrahedron), 1981, 37, 2091, which are incorporated herein by reference. The reaction is carried out in an alcoholic solvent such as tert-butanol, acetonitrile in the presence of 2-methyl-2-butane at a temperature ranging from 0 to 25 ℃. This gives protected 5-hydroxy-2, 3-dihydrobenzofuran-3-carboxylic acid (12).

Alternatively, protected 5-hydroxy-2, 3-dihydrobenzofuran-3-carboxylic acid (12) can be obtained from benzofuranone (7) by using the following steps: the ketone is reduced to the corresponding alcohol, the 3-hydroxy group of the alcohol is converted to a leaving group, the leaving group is replaced by a cyano group, and hydrolysis is carried out to yield the corresponding protected 5-hydroxy-2, 3-dihydrobenzofuran-3-carboxylic acid (12).

Optionally, the racemate (12) may be cleaved or separated according to methods well known in the art, such as chromatographic separation, fractional crystallization, use of optically active esters or optically active bases, enzymatic resolution, and the like.

More preferably, the acid (12) can be isolated by chemical resolution. For chemical resolution, the 5-hydroxy group is preferably protected by an ester group such as an acetate group, and if the 5-hydroxy group is protected by an alkyl group such as methyl or benzyl, prior deprotection is required.

Deprotection of the hydroxyl group protected to a methoxy group can be carried out using conventional deprotection reagents such as trimethylsilyl iodide, boron tribromide, boron trifluoride, trimethylsilylmethyl sulfide or trimethylsilylphenyl sulfide, aluminum halide (halogen is chlorine or bromine), according to methods well known in the art.

Deprotection of the hydroxy group protected to a benzyloxy group can be routinely carried out by catalytic or chemical reduction using palladium on carbon in ethanol, sodium in ammonia or ethanol, trimethylsilyl iodide in dichloromethane, and the like.

The 5-hydroxy group is then protected by an ester such as acetate. The reaction can be carried out using acetic anhydride or acetyl chloride. More preferably, the most common method of introducing the acetate is to use acetic anhydride in pyridine at a temperature of 0 ℃ to 25 ℃. This gives the 5-hydroxy protected compound (12) which is purified by standard methods in the art.

More preferably, the enantiomer 5-acetoxy-2, 3-dihydrobenzofuran-3-carboxylic acid (12) may be separated using an optically active base, any optically active base, natural or synthetic, such as morpholine, ephedrine, brucine, strychnine and some other (α) -methylbenzylamine.

More preferably, S (-) - (α) -methylbenzylamine is used in a solvent mixture such as alcohols (methanol, ethanol, isopropanol), ethers (diethyl ether, tetrahydrofuran), ethyl acetate, and 5-acetoxy-2, 3-dihydro-benzofuran-3-carboxylic acid (12) is cleaved, more preferably a mixture of isopropanol and ethyl acetate the first diastereomeric salt is obtained as a crystal, which can be separated from the other diastereomers by filtration, the filtrate is then treated with acidic conditions such as hydrochloric acid to recover the free acid of the second enantiomer, the free acid is extracted with an organic solvent such as ethyl acetate, the second enantiomer is obtained by crystallization using R (+) - (α) -methylbenzylamine, and the second enantiomer is recovered by treating the salt under acidic conditions, as described above, and this resolution gives the two enantiomers R-5-acetoxy-2, 3-dihydro-benzofuran-3-carboxylic acid R- (12) and S-5-acetoxy-2, 3-dihydro-benzofuran-3-carboxylic acid S- (12).

Each carboxylic acid thus obtained may be reduced to its corresponding primary alcohol. They can be readily reduced by using lithium aluminum hydride or other hydride reagents such as sodium borohydride or boron complexes such as dimethylsulfide, tetrahydrofuran containing complexes. More preferably borane dimethylsulfide is used in tetrahydrofuran at reflux.

In order to obtain optically active 2, 3-dihydrobenzofuranol derivatives (I) from R-5-acetoxy-2, 3-dihydro-benzofuran-3-carboxylic acid and S-5-acetoxy-2, 3-dihydrobenzofuran-3-carboxylic acid, respectively, various optically active compounds can be treated according to the method for treating racemates described above.

Optionally, the acid (12) may be esterified to give a compound in which X is COOR₇A compound of formula (I). The esterification reaction can be carried out by procedures known in the art, such as advanced organic Chemistry, Jerry March, John Wiley&Sons, New York, 0-24, p348-353, 1989, or patent application WO93/20057, 3/10, 1993,these documents are incorporated herein by reference.

Optionally, the acid (12) may be converted to an amide of formula (I) wherein X is C (O) A (A is as defined above). Amide formation can be carried out using procedures well known in the art, such as Advanced Organic Chemistry (Advanced Organic Chemistry), Jerry March, John Wiley & Sons, New York, 0-24, p371-373, 1989, or U.S. patent application No. WO93/20057, filed 3/10, 1993 and corresponding U.S. patent application No. 08/318,633, filed 12/22, 1994, which are incorporated herein by reference. Optionally, the 5-hydroxy group of the compound of formula (I) may be esterified using the methods described above.

The process of the invention is preferably used for the synthesis of compounds of formula (I)Wherein: r₂' is C_1-4Alkyl radical, each R₂Part being independent C_1-14An alkyl group; r₄Is C_1-6An alkyl group; r₅' is H; r₆Is C_1-6An alkyl group; r₇Is H or C_1-6An alkyl group; x' is CH₂A 'and A' are

R₁₀' is H, C_1-3An alkyl group.

As an example, the racemate and optically active 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl]Preferred synthetic methods for the (E) -2, 3-dihydro-1-benzofuran-5-ol derivatives are described in scheme V, scheme VI and scheme VII below, respectively. The following compound designations correspond to those of similar compounds claimed above, with addition of V, VI or VII indicating a route.Route V: synthesis of racemic 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methano [ ] Base of]-2, 3-dihydro-1-benzofuran-5-ol Route V: racemic 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino)-methyl ] -2, 3-dihydro-1-benzofuran-5-ol

Route V (continuation)

Scheme VI: synthesis of optically active 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl ] -2, 3-dihydro-1-benzofuran-5-ol by chemical resolution of acidScheme VI: (continuation)

Route VII: synthesis of optically active 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methyl) by alcohol resolution Piperazino) -methyl]-2, 3-dihydro-1-benzofuran-5-ol

Route VII: (continuation)

The following examples represent typical syntheses as described in scheme V, VI and scheme VII, which are to be understood as being illustrative only and not limiting the scope of any invention, as used herein, the following terms mean "g" means g "," mmol "means mmol", "ml" means ml "," bp "means boiling point", "mp" means melting point "," deg.C "means temperature", "mmHg" means mmHg mercury column "," Pa "means Pascal", "μ l" means microliter "," μ g "means microgram", "μ M" means micromolar "," TLC "means thin layer chromatography purification", "M" means molar concentration "," N "means equivalent concentration", "α]_D ²⁰"refers to the D-line helicity of sodium at 20 ℃ in a 1 cm cell; "GC" refers to gas chromatography; and "Rf" refers to retention factor.

Example 11, 4-dimethoxy-2, 3, 5-trimethylhydroquinone

A mixture of trimethylhydroquinone (60.87g, 0.4mol), dimethyl sulfate (151.36g, 1.2mol) and potassium carbonate (221g, 1.6mol) in acetone (1.6L) was refluxed for 3 hours under a nitrogen atmosphere. After cooling, 10% sodium hydroxide (400ml) was added and most of the acetone was evaporated. The black mixture was dissolved in heptane (800ml) and the organic phase was separated and washed with 10% sodium hydroxide (2X 200ml), water (200ml) and brine (200 ml). Drying (magnesium sulfate) and evaporation of the solvent under reduced pressure gave a yellow oil. Purification on a small pad of silica gel eluting with heptane/ethyl acetate 95: 5 gave 57.4g (80%) of 1, 4-dimethoxy-2, 3, 5-trimethylhydroquinone as a colourless oil which slowly crystallised.

To avoid the formation of large amounts of 2,3, 5-trimethyl-1, 4-benzoquinone, nitrogen gas should be blown into the acetone for 30 minutes in advance. The 1, 4-dimethoxy-2, 3, 5-trimethylhydroquinone can be purified by distillation.

Example 25-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one

Aluminum chloride (25g, 188mmol) was added dropwise to a solution of 1, 4-dimethoxy-2, 3, 5-trimethylhydroquinone (33.83g, 188mmol) and 2-bromo-2-methylpropanoyl bromide (129.46g, 563mmol) in tetrachloroethane (188mmol) at 0 ℃ under a nitrogen atmosphere. The dark solution was then heated at 70 ℃ until TLC (heptane/ethyl acetate 90: 10) indicated completion of the reaction (3-5 days). Ice was carefully added to stop the reaction. The black mixture was acidified to pH1 with concentrated hydrochloric acid and extracted with dichloromethane (2X 150 ml). The organic phase was washed with water (150ml), 10% potassium bicarbonate (2X 150ml), dried (magnesium sulphate) and evaporated to dryness. The residue was triturated with heptane (106g) to precipitate 1, 4-bis- (2-bromo-2-methylpropanoyloxy) -2, 3, 5-trimethylhydroquinone formed in the reaction, which was then filtered off (30.15 g). The filtrate was evaporated to dryness and the residue (66.37g) was passed over a small pad of silica gel eluting with heptane/ethyl acetate 95: 5to give 39.78g of crude 5- (2-bromo-2-methylpropanoyloxy) -2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (Rf ═ 0.4, heptane/ethyl acetate 90: 10). The yellow solid was dissolved in a methanol/tetrahydrofuran (400ml, 1: 1) mixture and added dropwise to sodium hydroxide (20g, 500mmol) in water (100ml) under a nitrogen atmosphere. The solution was stirred at 60 ℃ for 4 hours and at room temperature overnight. The black mixture was then acidified with concentrated hydrochloric acid. Most of the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (300 ml). The organic phase was washed with water (150ml), 10% sodium bicarbonate (2X 150ml), brine, dried (magnesium sulfate) and evaporated to dryness to give 22.39g of crude 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one as a yellow powder. The sample was recrystallized from heptane/diisopropyl oxide mp 142-144 ℃ and Rf 0.29 (heptane/ethyl acetate 80: 20).

Example 35- (2-methylpropionyloxy) 2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one

A solution of 2-methylpropanoyl chloride (isobutyryl chloride, 8.05g, 75.55mmol) in dichloromethane (10ml) was added dropwise to a solution of 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (12.8g, 58.11mmol) and pyridine (5.97g, 61mmol) in dichloromethane (58ml) at 0 ℃ under a nitrogen atmosphere. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. Water (10ml) was added and the organic phase was washed with 2N hydrochloric acid (100ml), water (100ml), 10% sodium bicarbonate (100ml) and brine. The solution was dried (magnesium sulfate) and evaporated to dryness to give 17g (100%) of 5- (2-methylpropanoyloxy) -2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one as an oil which was used without purification in the next step. Rf 0.5 (heptane/ethyl acetate 90: 10).

Example 43-methylene-5- (2-methylpropionyloxy) -2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

Potassium tert-butoxide (1.53g, 13.68mmol) was added dropwise to a suspension of methyltriphenylphosphonium bromide (49g, 13.68mmol) in anhydrous tetrahydrofuran (57ml) at 0 ℃ under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 hour. 5- (2-Methylpropionyloxy) -2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (3.31g, 11.4mmol) in dry tetrahydrofuran (20ml) was added dropwise to the yellow suspension at 0 ℃ and the reaction mixture was stirred at room temperature overnight. Water was added and most of the tetrahydrofuran was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried (magnesium sulfate) and the solvent was evaporated to dryness. Flash chromatography, eluting with heptane/ethyl acetate 95: 5 then 90: 10, afforded 2.8g (85%) of 3-methylene-5- (2-methylpropanoyloxy) -2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran as a yellow oil. Rf 0.79 (heptane/ethyl acetate 70: 30).

Example 55-hydroxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

10M borane dimethyl sulfide complex (6.1ml, 61mmol) was added dropwise to a solution of 3-methylene-5- (2-methylpropanoyloxy) -2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (11.7g, 57mmol) in tetrahydrofuran (40ml) at 0 ℃ under a nitrogen atmosphere, and the solution was stirred at room temperature for 3 hours. Water (10ml) was carefully added followed by 3N sodium hydroxide (30ml) and 30% hydrogen peroxide (10.1 ml). After stirring at room temperature for 2 hours, most of the tetrahydrofuran was evaporated and the residue was extracted with ethyl acetate. The organic phase was washed with 10% sodium sulphite (10ml), water (100ml), brine, dried (magnesium sulphate) and evaporated to dryness to give 13.29g of a mixture of 5-hydroxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (Rf ═ 0.37, heptane/ethyl acetate 50: 50) and the corresponding 5-isobutyryl ester (Rf ═ 0.57, heptane/ethyl acetate 50: 50). The residue was then treated with sodium hydroxide (6.5g, 162mmol) in a water/methanol/tetrahydrofuran 40: 20 mixture at 80 ℃ for 2 h. Hydrochloric acid was added until pH1 and most of the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with water, brine, dried (magnesium sulfate) and evaporated to dryness. Flash chromatography, eluting with heptane/ethyl acetate 80: 20 to 50: 50, afforded 5-hydroxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran as a yellow oil, which slowly crystallized. The sample was recrystallized from ethyl acetate/heptane, mp 89-90 ℃.

Example 63-bromomethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-5-ol

To an ice-cooled solution of triphenylphosphine (41.89g, 160mmol) in dichloromethane (120ml) was added dropwise a solution of bromine (24.33g, 152mmol) in dichloromethane (40ml), and the resulting mixture was stirred at 0 ℃ for 1 hour to give a white precipitate free from bromine color. To this mixture was added 5-hydroxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (34.26g, 145mmol), and the resulting mixture was warmed to room temperature and stirred for 18 hours. The solution was concentrated to a small volume and chromatographed on silica gel, eluting with dichloromethane/hexane 1: 2. The product-containing fractions were combined and evaporated to give 43.28g (99%) of 3-bromomethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-5-ol as an oil. The sample was recrystallized from ethyl acetate/heptane, mp 79-80 ℃.

Example 72, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl]-2, 3-dihydro-1-benzofuran-5-ol dihydrochloride hydrate

A solution of 3-bromomethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-5-ol (81g, 270mmol), phenol (26.75, 284mmol) and N-methylpiperazine (28.47g, 284mmol) in acetonitrile (300ml) was stirred at reflux temperature for 60 hours. The precipitate formed was collected, washed with acetonitrile and slurried in 10% sodium bicarbonate solution. The product was extracted twice with ethyl acetate, washed with water and brine, dried (magnesium sulfate) and evaporated. The resulting solid was dissolved in ethanol (150ml) and 2N hydrochloric acid (150ml) and evaporated to near dryness. The resulting solid was recrystallized from ethanol/ethyl acetate, dried at 60 ℃ under 13Pa and equilibrated in an aqueous atmosphere for 24 hours to give 48.60g (44%) of 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl ] -2, 3-dihydro-1-benzofuran-5-ol dihydrochloride hydrate, mp ═ 172-3 ℃ (decomposed). Column chromatography on silica gel purified the free base and eluted with dichloromethane/methanol 9: 1 to give 19.63g of 2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl ] -2, 3-dihydro-1-benzofuran-5-ol dihydrochloride hydrate as second crop (total 63% yield).

Example 85-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one

A mixture of phenol 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (7.16g, 32.54mmol), dimethyl sulfide (6.16g, 48.8mmol) and potassium carbonate (13.5g, 97.63mmol) in acetone (160ml) was refluxed for 3 days under a nitrogen atmosphere. After cooling, 3N sodium hydroxide (100ml) was added and most of the acetone was evaporated under reduced pressure. The mixture was extracted with ethyl acetate (200ml) and the organic phase was washed with 3N sodium hydroxide (2 × 100ml), water, brine, dried (magnesium sulphate) and evaporated to dryness to give 7.52g (99%) of 5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one as a yellow solid which was used without purification in the next step. Rf 0.4 (heptane/ethyl acetate 90: 10).

Example 95-methoxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

Potassium tert-butoxide (4g, 35.5mmol) was added dropwise to a suspension of methyltriphenylphosphonium bromide (12.7g, 35.5mmol) in anhydrous tetrahydrofuran (120ml) at 0 ℃ under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 hour. 5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (5.55g, 23.7mmol) in anhydrous tetrahydrofuran (40ml) was added dropwise to the yellow suspension at 0 ℃ and the reaction mixture was stirred at room temperature overnight. Water (50ml) was carefully added and most of the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200ml), washed with brine, dried (magnesium sulfate) and evaporated to dryness. Purification on silica gel pad using dichloromethane as solvent gave 5.47g of 5-methoxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (99%) as a yellow oil. Rf 0.48 (heptane/ethyl acetate 90: 10).

Example 103-hydroxymethyl-5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

10M borane dimethyl sulfide complex (2.08ml, 20.8mmol) was added dropwise to a solution of 5-methoxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (4.03g, 17.35mmol) in anhydrous tetrahydrofuran (35ml) at 0 ℃ under a nitrogen atmosphere, and the solution was stirred at room temperature for 2 hours. Water (10ml) was carefully added to the solution followed by 3N sodium hydroxide (5.78ml) and hydrogen peroxide (5.78 ml). After 2 hours at room temperature, most of the tetrahydrofuran was evaporated to dryness and the residue was extracted with ethyl acetate (2X 100 ml). The combined organic phases were washed with 10% sodium sulfite, water, brine, dried (magnesium sulfate) and evaporated to dryness to give 4.2g of crude alcohol. Flash chromatography, eluting first with heptane/ethyl acetate 70: 30 and then 60: 40, afforded 4g (92%) of 3-hydroxymethyl-5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran as a white powder. The sample was recrystallized from hexane, mp-79-81 ℃. Rf 0.28 (heptane/ethyl acetate 70: 30).

Example 115-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid a) Swern Oxidation

Dimethyl sulfoxide (687mg, 8.8mmol) in dichloromethane (10ml) was added dropwise to a solution of oxalyl chloride (558mg, 4.4mmol) in dichloromethane (20ml) at-60 ℃ under a nitrogen atmosphere. After stirring and reacting for 5 minutes, 3-hydroxymethyl-5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (1g, 4mmol) was added dropwise to dichloromethane (10 ml). After stirring for 15 minutes, triethylamine (2.02g, 30mmol) was added dropwise to the solution. The cooling bath was removed and the solution was stirred at room temperature for 2 hours. Water (40ml) was added. The organic phase was dried (magnesium sulfate) and evaporated to dryness to give the crude aldehyde (1g, 100%) which was used without purification in the next step. b) Oxidation of aldehydes to carboxylic acid 5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid

Following the procedures described in b.s.bal, w.e.childers and h.w.pinnick in Tetrahedron (Tetrahedron), 1981, 37, 2091, with only minor modifications. The crude aldehyde (1g, 4mmol) was dissolved in t-butanol (83ml) and 2-methyl-2-butene (13.22g, 188.5 mmol). A solution of sodium chlorite (3.31g, 36.6mmol) and sodium dihydrogen phosphate monohydrate (3.81g, 27.64mmol) in water (33ml) was added dropwise over 10 minutes. The pale yellow reaction mixture was stirred at room temperature for 1 hour. Then, volatile components were removed under reduced pressure, and the residue was dissolved in diethyl ether (30ml) and extracted with 10% potassium carbonate (3X 30 ml). The combined aqueous phases were acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2X 30 ml). The organic phase was washed with brine, dried (magnesium sulfate) and evaporated to dryness to give 440mg (41%) of 5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid as a white solid.

The sample was recrystallized from heptane/ethyl acetate, mp 185-187 ℃.

Example 125-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-carboxylic acid

Boron tribromide (0.42ml of a 1M solution in dichloromethane, 0.42mmol) was added dropwise to a solution of 5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid (100mg, 0.38mmol) in dichloromethane (4ml) at-78 ℃ under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was stopped by addition of water (10ml) and extracted with dichloromethane (2X 20 ml). The organic phase was dried (magnesium sulfate) and evaporated to dryness to give 90mg of 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid as a white solid. The sample was recrystallized from heptane/ethyl acetate, mp 182 ℃ -184 ℃.

Example 135-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid

Scheme VI

To a solution of 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid (25.03g, 100mmol) in pyridine (200ml) was added acetic anhydride (100ml), and the mixture was stirred at room temperature for 24 hours. Water and ice were added and the mixture was stirred at about 30 ℃ for 30 minutes. The mixture was cooled in ice and 6N hydrochloric acid (450ml) was added. The resulting solid was collected, washed with water, and dissolved in ethyl acetate. The organic layer was washed with 2N hydrochloric acid and water, dried (magnesium sulfate) and evaporated to dryness. Recrystallization from ethyl acetate gave 23.6g (81%) of 5-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid (mp 187 ℃ -188 ℃).

Example 14Example 13 chemical resolution of carboxylic acid derivatives

A solution of 5-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid (15.27g, 52.3mmol) and S (-) - α -methylbenzylamine (6.65g, 54.9mmol) in a mixture of isopropanol (100ml), water (2ml) and ethyl acetate (300ml) was evaporated to a volume of about 100ml and the crystalline material obtained after standing at room temperature was recrystallized twice from the same solvent mixture to give 6.02g (56%) of the diastereomeric salt [ α%]_D ²⁵The combined filtrates were suspended in water and 2N hydrochloric acid (50ml) was added and the mixture was extracted twice with ethyl acetate, the extracts were washed with 2N hydrochloric acid, brine, dried (magnesium sulfate) and evaporated to give 11.34g of an oil to which R (+) - α -methylbenzylamine (4.7g, 38.8mmol) was added, crystallisation was carried out using the same solvent as above and two recrystallisations gave 7.9g (73%) of the other diastereomeric salt, [ α% ]]_D ²⁵-14.21 (0.99 in methanol) and ee-99.9%.

The various diastereomeric salts can be converted into the free acids and reduced to the corresponding alcohol 3-hydroxymethyl-5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran using borane-dimethylsulfide complex, converted to 3-bromomethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-5-ol using triphenylphosphine/bromine and reacted with N-methylpiperazine under the same conditions as described above.

Using R (+) - α -methylbenzylamine, R (+) - (2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl ] can be obtained from the diastereomeric salt of 5-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid]-2, 3-dihydro-1-benzofuran-5-ol), mp 265 ℃ (decomposition) [ α ℃]_D ²⁰+20.68 (1.18 in water, pH 1.4). Loss on heating (40 ℃/min, 40 ℃ to 175 ℃) 4.22% ═ 1.02mmol of water.

Using S (-) - α -methylbenzylamine, S (-) - (2, 2, 4, 6, 7-pentamethyl-3- [ (4-methylpiperazino) -methyl ] can be obtained from the diastereomeric salt of 5-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid]-2, 3-dihydro-1-benzofuran-5-ol), mp 267 ℃ (decomposition) [ α ℃]_D ²⁰-20.66 (1.66 in water, pH 1). Loss on heating (40 ℃/min, 40 ℃ to 175 ℃) 3.95% ═ 0.97mmol of water.

X-ray crystallography indicates that the salt of the R- (+) -amine has the S configuration. Due to the nomenclature, the enantiomer derived from a carboxylic acid has the R configuration.

Example 155-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one

Potassium carbonate (720g) was added to a solution of 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (453g, 2.1mmol) in acetone (2L), and a solution of benzyl bromide (423g, 2.5mmol) in acetone (200ml) was added portionwise over 10 minutes. A small exotherm was observed. After 3 hours, the mixture was heated to reflux. After 39 hours, TLC indicated complete conversion to product. The mixture was cooled to 50 ℃ and the solid in the flask was removed by filtration through 1.5L of ethyl acetate. The solid was washed with ethyl acetate (1.5L), the filtrate was concentrated, and the resulting solid was dissolved in ethyl acetate (7L). The solution was washed with water, dried (magnesium sulfate) and concentrated. The resulting solid was placed on a tray and air dried. Two days later 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (638g, 99%) was collected, mp ═ 114 ℃ -115 ℃.

Example 165-benzyloxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

A3.0M solution of methylmagnesium chloride in tetrahydrofuran (800ml, 2.4mol) was added to a solution of 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (500g, 1.6mol) in tetrahydrofuran at 0 ℃ over 1 hour. The mixture was warmed to room temperature. After 15 h, TLC and GC showed complete conversion to 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-ol. The mixture was cooled to 0 ℃ and a saturated ammonium chloride solution (300ml) was added very carefully and concentrated sulfuric acid (300ml) was added dropwise over 1 hour. TLC indicated conversion to 5-benzyloxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one. Water (1.5L), ethyl acetate (1.5L) and ammonium chloride solution (1L) were added to dissolve the salts. The organic phase was dried (magnesium sulfate) and concentrated. The crude oil was transferred to a crystallization dish with minimal ethyl acetate and seeded. Complete crystallization occurred in about 30 minutes. The solid was placed in a tray and air dried. Two days later 5-benzyloxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (492g, 99%) was collected. mp is 55-57 ℃.

Example 175-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

A solution of borane-dimethyl sulfide (2.0M) complex in tetrahydrofuran (950ml, 1.9mol) was added to a solution of 5-benzyloxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (492g, 1.6mol) in tetrahydrofuran (1.6L) over 2 hours under a nitrogen atmosphere and cooled with an ice bath. The temperature of the reaction kettle is maintained at 0-5 ℃. The solution was warmed to room temperature. After 15 hours the solution was cooled in an ice bath and water (900ml) was carefully added (evolution of hydrogen stopped after addition of approximately 30ml of water). Sodium hydroxide solution (3.0M, 530ml) was added over 30 minutes, maintaining the temperature of the reaction kettle below 10 ℃. 30% hydrogen peroxide (530ml) was introduced while maintaining the temperature of the reaction kettle below 20 ℃. After 3 hours, water (1L), ethyl acetate (1L) was added and many solids formed (all solids were readily dissolved with acidification of the aqueous waste, which may be where acidification would make the salt better soluble). The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and concentrated. The oily residue was poured into hexane (1L) using hexane (800ml) to form white crystals. The solid was discharged from the side and shaken to increase the crystallization. The solid was collected and air-dried to give 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (371 g). The mother liquor was boiled to 700ml and activated carbon was added. After filtration through celite, the seeding crystals were added. Nitrogen was blown to evaporate the hexane. The oil on the solid was washed off with hexane. The solid was collected and washed with hexane to give 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (28 g). The mother liquor was concentrated. The resulting oil was plug filtered through 1.8L of gravity silica gel and collected as 4 (500mL) fractions of 00% hexane, 6 (500mL) fractions of 5% ethyl acetate/hexane, 4 (500mL) fractions of 10% ethyl acetate/hexane and 4 (500mL) fractions of 20% ethyl acetate/hexane. The fractions containing the desired product were concentrated. The oil was transferred to an Erlenmeyer flask using hexane (300 ml). After standing overnight, 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (42g) was collected. The combined fractions and the above mother liquor were concentrated and 2 (250ml) fractions of 100% hexane, 8 (250ml) fractions of 5% ethyl acetate/hexane, 10 (250ml) fractions of 10% ethyl acetate/hexane and 10 (250ml) fractions of 20% ethyl acetate/hexane were collected by 1L gravity silica plug filtration. Fractions containing the desired product were combined. The residue was dissolved in hexane (100 ml). After standing overnight, 10g of 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran were collected. All of 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (451g, 87%) was collected.

Example 18R-5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

A mixture of 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (40.1g, 0.12mol), lipase/Candida cylindracea (132g), vinyl acetate (35.0g, 0.41mol) and tert-butyl methyl ether (1800ml) was combined and stirred for 24 hours. The mixture was filtered and the filtrate was concentrated (60 ℃/15tor) to constant weight. The residue was chromatographed on silica gel (hexane: ethyl acetate 4: 1) to give a first fraction containing the desired acetic acidEster (19.7g, e.e.87%, R configuration.) the resulting acetate ester (19.7g, 0.053mol) was dissolved in 400ml methanol and treated with potassium carbonate (2.0g, 0.014 mol.) the mixture was stirred at room temperature for 5 hours (TLC; no starting material present), then the solvent was evaporated (60 ℃/15 tor.) the residue was dissolved in ether/water, the ether extract was washed with brine, dried over magnesium sulfate, the solvent was evaporated to give 17.0g of an oily residue, which was dissolved in 800ml hexane, crystallization occurred within 48 hours, the solvent was decanted from the crystal mass without affecting the crystal mass, cold hexane (150ml) was added and shaken gently, the hexane was decanted and added an additional 150ml of cold hexane, R-5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran was collected, dried to give 10.9g (27%) of a white solid (e.98%, α% methanol [ e 4.4% ], α% ]]_D ²⁰＝+7.9)。C₂₁H₂₅O₃Elemental analysis: calculated values: c, 77.27; h, 8.03. Measured value: c, 77.35; h, 7.96. A process for the cyclization of S-5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran.

Methanesulfonyl chloride (13.3g, 116mmol) was added dropwise to a solution of S-5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (31.6g, 97mmol) and triethylamine (11.8g, 116mmol) in tetrahydrofuran (300ml) at 0 ℃ over 30 minutes, and the mixture was warmed to room temperature. After 3 hours potassium tert-butoxide (39g, 348mmol) in tetrahydrofuran (200ml) was added over 30 minutes and the solution warmed to room temperature. Ethyl acetate was added after 1 hour. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated. The oil was transferred to a crystallization dish with a minimum amount of hexane and complete crystallization occurred after 30 minutes. The solid was air dried overnight to give 30.2g (98%) of 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran which was then recycled. The total yield of 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran after three cycles was 65%.

Example 19R-5-benzyloxy-3- (methylsulfonyl) -2, 3-dihydro-2, 2, 4, 6, 7-pentamethyl-1-benzofuran

Methanesulfonyl chloride (8.4g, 74mmol) was added dropwise to a solution of R-5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (20g, 61mmol) and triethylamine (7.5g, 74mmol) in tetrahydrofuran (200ml) at 0 ℃ over 15 minutes, after which the mixture was warmed to room temperature after 30 minutes and after 3 hours the mixture was washed with 5% hydrochloric acid (200ml) using ethyl acetate (100ml) and the organic phase was washed with brine, dried (magnesium sulfate) and concentrated to give 24.7g (99%) of R-5-benzyloxy-3- (methanesulfonyl) -2, 3-dihydro-2, 2, 4, 6, 7-pentamethyl-1-benzofuran-3-methanol as a white solid mp-]_D ²⁰(methanol) + 10.5.

Example 20R-5-hydroxy-3- [ (4-methylpiperidino) -methyl]-2, 3-dihydro-2, 2, 4, 6, 7-pentamethyl-1-benzofuran dichloride hydrate

A mixture of R-5-benzyloxy-3- (methylsulfonyl) -2, 3-dihydro-2, 2, 4, 6, 7-pentamethyl-1-benzofuran (13.3g, 33mmol), 4-methylpiperazine (6.6g, 66mmol) and potassium carbonate (18g, 0.13mol) in acetonitrile (200ml) was refluxed for 18 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in water/chloroformIn, extracting with chloroformAn aqueous phase. The combined organic phases were dried (magnesium sulfate) and concentrated to give crude R-5-hydroxy-3- [ (4-methylpiperidino) -methyl]-2, 3-dihydro-2, 2, 4, 6, 7-pentamethyl-1-benzofuran (16 g). The crude product was dissolved in ethanol (50ml) and acetic acid (50ml), 1.0g of 10% palladium on carbon was added to a Parr bottle, and the mixture was placed in a Parr shaker under 345kPa hydrogen for 18 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated. TLC indicated the absence of starting material. The residue was dissolved in ethanol (50ml) and acetic acid (50ml) and 2.0g of 10% palladium on carbon was added to a Parr bottle. After 18 hours, the mixture was filtered through celite and concentrated. Of the crude product¹H NMR indicated complete debenzylation. To the crude product was added a dilute solution of hydrochloric acid (8 ml of concentrated hydrochloric acid in 20ml of water) followed by ethanol (20 ml). The solution was concentrated to dryness. The residue was dissolved in hot isopropanol (100ml) and about 1g of activated carbon was added. After filtration through celite, the solution was allowed to stand for 2 days. The white solid was collected, washed with isopropanol and air dried for 2 days. After being placed on a vacuum oven at 45 ℃ for 2 days, R-5-hydroxy-3- [ (4-methylpiperidino) -methyl group was collected]-2, 3-dihydro-2, 2, 4, 6, 7-pentamethyl-1-benzofuran dichloride hydrate (9.0g, 68%) [ α ]]_D ²⁰(water) + 20.9.

Example 215-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-ol

Sodium borohydride (12.2g, 0.324mol) was added dropwise over 45 minutes to a solution of 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one (32g, 0.108mol) in methanol (300 ml). After 2 hours the reaction was stopped by adding aqueous citric acid. The solution was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated to give 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-ol (28g, 83%) as a white solid.

Example 225-benzyloxy-3-cyano-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran

Acetic anhydride (0.5g, 4.8mmol) and triethylamine (1ml) were added to a solution of 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-ol (1.0g, 3.2mmol) and dimethylaminopyridine (10mg) in dichloromethane (15ml), and the mixture was stirred for 1 hour. The reaction was stopped with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and washed sequentially with hydrochloric acid, sodium bicarbonate and brine. Dried over sodium sulfate and concentrated. The 5-benzyloxy-3-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (1.03g, 91%) was solidified in a frozen state.

Diethylaluminum cyanide (1.2ml, 1.2mmol) was added to a solution of 5-benzyloxy-3-acetoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (0.4g) in toluene (5 ml). The toluene solution was stirred for 1 hour, the reaction was stopped with an aqueous potassium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated to give 5-benzyloxy-3-cyano-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (0.35g, 90%) as a white solid.

Example 235-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid

A10% aqueous potassium hydroxide solution (5ml) and a 30% aqueous hydrogen peroxide solution (5ml) were added to a solution of 5-benzyloxy-3-cyano-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran (300 mg). After stirring at room temperature for 15 minutes, the solution was heated under reflux for 3 days. The solution was cooled to room temperature and extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solution was concentrated to give a solid which was dissolved in dioxane (5ml) and treated with hydrochloric acid (5 ml). The solution was heated at reflux for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The ethyl acetate solution was washed with brine and dried over sodium sulfate. The solution was concentrated to give 5-benzyloxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-carboxylic acid (206mg, 65%) as an oil.

The compounds of the present invention are free radical scavengers as disclosed in patent application WO93/20057 filed 3/10, 1993 and in corresponding U.S. patent application No. 08/318,633 filed 12/22, 1994. Pathologically, free radical reactions affect more than 50 human diseases. Free radicals or other reactive oxygen species are constantly formed in the human body by synthesis (e.g., by activation of phagocytes) and chemical side reactions. They can be removed by enzymatic or non-enzymatic antioxidant defense systems. Stress reactions that occur when antioxidants are poorly protected can damage fat, protein, carbohydrate, and DNA. Many clinical manifestations are caused by stress, and more often, this stress is caused by disease and is apparently due to disease pathology. For a more detailed review, see journal of medicine (Drugs), 1991, 24, 569-.

There is increasing information about the body that oxygen radical induced fat peroxidation plays an important pathological role after ischemia or hemorrhagic central nervous system trauma or stroke. A decrease in the concentration of intrinsic antioxidants and an increase in the production of fat peroxidation in brain tissue has been observed. Inhibitors of brain fat peroxidation counteract and reduce brain tissue damage and extend the life of injured animals. These findings have been disclosed in the following documents: hall and J.M.Braughler, Free radial biology and Medicine, 1989, 6, 303-313. In addition, m.miyamoto et al, (j.pharmacol.exp.ther., 1989, 250, 1132) reported that neurotoxicity caused by excessive glutamate release was similarly reduced by antioxidants. They propose that brain fat peroxidation can be inhibited using agents for the treatment of neurodegenerative diseases such as Huntington's disease and Alzheimer's disease, in which release of excessive glutamic acid is observed. M.r. hori et al (chem.pharm.bull.1991, 39, 367) reported anti-amnesic activity of inhibitors of brain fat peroxidation in rats.

The role of oxygen radicals in parkinson's disease has recently been reviewed (Free radial biol. med., 1991, 10, 161-169), and the clinical use of Free Radical scavengers has been tested with some success (fundam. clin. pharmacol.1988, 2, 1-12).

Ischemia after reperfusion results in the formation of free radicals derived from oxygen and increases fat peroxidation and results in tissue damage. Administration of free radical scavengers to animals undergoing ischemia/reperfusion may reduce their effects in heart, lung, kidney, pancreas, brain and other tissues.

The process of inflammation is well known and involves the release of superoxide radicals from phagocytes, which causes some symptoms of rheumatoid arthritis and other inflammatory diseases such as ulcerative trigonitis. Free radical scavengers such as the compounds of the present invention may also be useful in the treatment of these diseases.

Smoking can lead to lung injury due to an increase in the pulmonary microvasculature and pulmonary edema. This process is accompanied by an increase in fat peroxidation in lung tissue. Min et al (j.med.cell.pla, 1990, 5, 176-. They propose the use of antioxidants to treat smoking lung injury, adult respiratory stress syndrome and pulmonary edema.

Reactive oxygen species also have a role in foam cell formation in the atherosclerotic plaque (reviewed by d. steinberg et al, New engl.j.med., 1989, 320, 915-. Degenerative retinal damage and diabetic retinopathy are also targeted for treatment with free radical scavengers (see J.W.Baynes, Diabetes, 1991, 40, 405. sup. 412; S.P.Wolff et al, FreeRad.biol.Med., 1991, 10, 339. sup. 352.).

Since free radicals derived from oxygen are identified as causative factors, the compounds of the invention are also useful in the treatment of cancer and degenerative diseases associated with aging, stroke and head injury, see b.halliwell and c.guttteridge, bilchem.j., 1984, 219, 1-14; TINS 1985, 22-6. Antioxidants have also been shown to be useful in the treatment of cataracts, Free rad.biol.med., 12: 251-261(1992).

The in vitro and in vivo activity of the compounds of the invention can be determined using standard experiments which reveal free radical scavenging properties, affinity for cardiac tissue and cardioprotective properties; and compared to known reagents having utility for these purposes. An experimental example for determining the radical scavenging activity of the compounds of the invention is shown by in vitro inhibition of fat peroxidation in rat brain homogenate.

The free radical scavenging properties of a compound can be readily assessed by using standard and well-established methods used in the art. For example, the radical scavenging properties can be evaluated by the following assays: peroxide radicals are generated by 4mU xanthine oxidase in the presence of 0.1mM xanthine and detected in spectrophotometric assays by reduction of 40 μm NBT (nitro blue tetrazolium) to the dimethyl Formazan dye as described by C.Beauchamp and I.Fridovick (Analyt. biochem.1971, 44, 276-287). 30U superoxide dismutase inhibited the reduction by 90% due to the presence of peroxide radicals. In the presence of a peroxide scavenger (test compound), there is competition for peroxide radicals, whereby a decrease in the colour formation of NBT indicates the peroxide radical scavenging properties of the test compound.

Inhibition of the fat peroxidation process can be determined by measuring the tissue homogenate for antioxidant activity of biological fluids using the method of J.stocks et al (Clin.Sci.mol.Med., 1974, 47, 215-222). Brain tissue homogenates of treated adult Sprague Dawley rats were used in the method.

A total volume of 1ml of diluted brain homogenate sample and scavenger with appropriate dilution were incubated. Samples without incubation were considered background. Samples without scavenger were control and samples with buffer only were considered blank. After incubation at 37 ℃ for 30 minutes 200. mu.l of 35% perchloric acid are added, the sample is centrifuged and 800. mu.l of the supernatant, mixed with 200. mu.l of thiobarbituric acid active material, is developed in a boiling water bath at 100 ℃ for 15 minutes and the absorption is observed at 532 nm.

For in vitro inhibition of tissues including heart or brain tissue, lipoxidation can be used in mice to illustrate the compound's ability to penetrate and in the brain to act as a free radical scavenger. The experiment included pre-treatment of male CDI mice with test compounds by subcutaneous administration. After 1 hour the brains were excised and homogenized 1+9(w/v) in 20mM potassium phosphate buffer at pH 7.3(0.14M KCl) and incubated for 30-120 minutes at 37 ℃ in 1ml of 1/100 strength buffer. At the end of the incubation, 200. mu.l of 35% perchloric acid was added and the protein was removed by centrifugation. To 800ml of the supernatant was added 200. mu.l of 1% TBA and the sample was treated to 100 ℃ for 15 minutes. The TBA-adduct is extracted into 2 times 1ml of n-butanol. The fluorescence relative to a standard sample made from malondialdehyde dimethylacetal was measured at an excitation wavelength of 515nm and an emission wavelength of 553 nm.

At the same time, they also release proteolytic enzymes such as elastase, which are also microbicides but potentially threatening the connective tissue of the host₁-protease inhibitors (α)₁P_i) Normally protect host tissues from proteolytic digestion however α₁P_iInactivation by leukocyte-derived oxidants α₁P_iIs the indication of the radical scavenger disclosed α₁P_iConcentration required to protect 50% of elastase inhibitory ability (PC)₅₀) Depending on the amount of stimulated leukocytes present.Methods described by Skosey and Chow (see J.L.Skosey and D.C.Chow, Handbook of Methods for Oxygen chemical Research (Greenwald, R.A. eds.) 1985, 413-416, CRC Press, Boca Raton.) briefly, human α was cultured using zymosan-stimulated human peripheral blood leukocytes in the presence or absence of scavenger agents₁P_iProtection α₁P_iThe amount of protection against oxidative inactivation is determined by its residual elastase inhibitory capacity.

Substances associated with inflammation have been reviewed by Weiss (see s.j.weiss, n.england j.med.1989, 320, 365-.Emphysema and α₁P_iFurther increase the incidence of disease by the inhaled oxidants during smoking, which can lead to α in lung tissue₁P_iOxidative inactivation of (see j. travis and g.s. savesen, annu. rev. biochem., 1983, 52, 655-709.) oxidized α₁P_iHave also been isolated from rheumatoid synovial fluid (see p.s.wong and j.travis, biochem. biophysis roc. comm.1980, 06, 1440-one 1454). Degradation of hyaluronic acid, a macromolecule that determines synovial fluid viscosity, is caused by peroxyl groups released in human leukocytes in vitro (see r.a. greenwald and s.a. moak, Inflammation, 1986, 10, 15-30). Further, non-steroidal anti-inflammatory drugs have been shown to inhibit the release of peroxy groups from leukocytes (see h.strom and i.ahnfelt-ron, Agents and dactinons, 1989, 26, 235-and m.roch-arveiler, v.revelent, d.pharm Huy, l.maman, j.fontagne j.r.j.sorenson and j.p.giroud, Agents and Actions, 1990, 31, 65-71), and 5-aminosalicylic acid can have therapeutic activity on inflammatory bowel disease through a free radical scavenger mechanism (see i.ahnfelt-ron, o.h.nielsen, a.christensen, e.langz, v.binder and p.ris, Gastroenterology, 1990, 98, 1162 1169). It is therefore believed that the compounds of the present invention may be useful in the above mentioned pathological conditions, and inflammatory bowel disease is a particular target. Immunostimulation of antioxidants has also been reported (r.anderson and p.t.lukey, ann.n.y.acad.sci., 1987, 498, 229-fla 247); they are able to enhance the activity of lymphocytes in the presence of leukocytes elicited in vitro and after in vitro pretreatment of volunteers.

Thus, using standard and well-known methods and in comparison with useful known compounds, it was found that the compounds of the present invention are useful in the prevention and treatment of diseases associated with neurotoxicity due to excessive release of glutamate, Huntington-related diseases, Alzheimer's disease and other homologous dysfunctions (such as memory, learning and attention deficit), amnesia and parkinson's disease, as well as in the treatment and prevention of histological damage to heart, lung, kidney, pancreas and brain tissue caused by ischemia/reperfusion, and in the alleviation of acute blood loss caused by hemorrhagic stroke.

The compounds of the invention are particularly useful in treating patients suffering from stroke, nervous system trauma and reperfusion injury. As used herein, these terms have the following meanings:

a) stroke refers to cerebrovascular disease, including cerebral insufficiency caused by temporary disturbance of blood flow, infarction and arteriovenous malformations, and arteriovenous malformations causing focal, infarction or hemorrhage.

b) Nervous system trauma refers to injury to the head or spine. Such as those occurring by cranial or spinal penetrations, or those occurring by rapid brain acceleration or deceleration that may damage tissue at the impact site, at the opposite end thereof, or in the frontal or temporal lobes. The damage may include damage to neural tissue, blood vessels, and/or meninges that can cause neurological disorders, ischemia, and/or edema. And

c) reperfusion injury refers to injury that can occur in any blood lost tissue, any part of the body, depending on reintroduction of blood supply. Such as reperfusion of ischemic areas of the myocardium or brain layer.

The compounds of the invention are useful both prophylactically and therapeutically. The amount of active ingredient therapeutically administered may vary widely depending on factors such as the species of mammal in need of treatment, its age, health, sex, body weight, characteristics and severity of the disease for which treatment is desired.

The term "patient" refers to warm-blooded animals such as rats, mice, dogs, cats, guinea pigs, primates, and humans. Generally, therapeutically effective dosages of the active ingredient administered will vary from about 0.1mg/kg to 30mg/kg of body weight per day. For prophylactic administration, relatively low doses may be used. Preferably, the compounds of the present invention are administered to a patient in combination with a pharmaceutically acceptable carrier, which refers to any substance that assists in the administration of the compounds of the present invention without substantially affecting the function of the treatment.

More preferably, the compounds are administered intravenously, particularly in emergency situations where the therapeutic agent is required to reach the site of its action as quickly as possible, such as emergencies caused by coronary infarction, stroke, and surgery, and situations that can cause severe reperfusion injury.

The compounds of the invention may be administered orally, preferably with more active ingredient per day than parenterally, preferably in 3 to 4 divided doses per day. Enteral administration after a hazardous situation, in particular after discharge, is preferred. The compounds of the present invention may be employed in standard dosage unit forms such as tablets, capsules, dragees, lozenges, elixirs, emulsions, suspensions, and preferably by suppositories or sublingual administration for topical application. Tablets and capsules containing 100mg to 400mg are preferred forms of enteral administration. Of course, in treating inflammation, the preferred method of administration is direct injection of the agent to the site of inflammation followed by enteral administration.

In the preparation of solid dosage forms such as tablets, the active ingredient is generally mixed with conventional pharmaceutical carriers or excipients such as gelatin, various starches, lactose, calcium phosphate or powdered sugar. The pharmaceutical carrier used herein also includes a lubricant for increasing the flow rate of the tablet particles and preventing sticking of the tablet material to the tablet die and the drill. Suitable lubricants include, for example, talc, stearic acid, calcium stearate, magnesium stearate and zinc stearate. Also included in the pharmaceutical carrier used are disintegrants which are added to help break down and dissolve the tablet after administration; colorants and/or flavorants may also be included to enhance the sensory quality of the tablet and make it more acceptable to the patient.

Suitable liquid excipients for the preparation of liquid dosage unit forms include water and alcohols such as ethanol, benzyl alcohol and polyethylene glycol, with or without the addition of surfactants. In general, preferred liquid excipients (particularly for injectable formulations) include water, physiological saline solutions, dextrose and glycol solutions such as aqueous propylene glycol or polyethylene glycol solutions. To reduce or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in such formulations is from about 5% to 15% by weight. The surfactant may be a single component having the above-identified HLB, or a mixture of two or more components having the desired HLB. Examples for parenteral formulations are surfactants which are polyoxyethylene sorbitol fatty acid esters such as sorbitol monooleate and a large molecular weight adduct of ethylene oxide with a hydrophobic base, the adduct being formed by the condensation of propylene oxide and ethylene oxide. In certain topical and parenteral formulations, various oils may be employed as carriers or excipients. Examples of such oils include mineral oils, glyceride oils such as lard, cod liver oil, peanut oil, sesame oil, cottonseed oil and soybean oil. For insoluble compounds, suspending agents may be added as well as agents to control viscosity, such as magnesium aluminum silicate or carboxymethylcellulose. In addition to these excipients, buffers, preservatives and emulsifiers may be added. Typical enemas using small volume retention enemas are generally much smaller than about 150ml for adults, with typical volumes of only a few milliliters being preferred. Of course, the excipients and solvents used in retention enema should be selected to avoid intestinal irritation and to minimize absorption of the various agents.

The compounds of the present invention may also be administered topically. This is accomplished by simply preparing a solution of the compound to be administered, preferably using a known solvent that promotes transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO), which may or may not contain other excipients. Preferred topical administration is accomplished by using a reservoir and a membrane patch (patch) of the porous membrane type or solid matrix type.

Some suitable transdermal drug delivery devices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, and 4,031,894. These devices generally comprise a backing film defining a facial surface; an active agent permeating the adhesive layer, the adhesive layer defining another surface of the device; and at least one active agent-containing reservoir interposed between the two surfaces. Alternatively, the active agent may be contained in a plurality of microcapsules distributed throughout the osmotic binding layer. In both cases, the active agent is continuously delivered through the membrane from the reservoir or microcapsule to the active agent permeating the adhesive layer, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of active agent is carried into the recipient. In the case of microcapsules, the encapsulated agent may also serve as a membrane.

In another device for transdermal administration of a compound of the invention, the pharmaceutically active compound is contained in a matrix from which the compound is delivered at a desired gradual, constant and controlled rate. The matrix is permeable and releases the compound by diffusion or microporous flow, the rate of release being controlled. Such a system that does not require a membrane is described in us patent 3,921,636. There are at least two possible modes of release in this system. When the matrix is a non-porous material, the pharmaceutically effective compound is then released by diffusion, dissolving in the matrix and diffusing through the matrix itself. When the pharmaceutically effective compound is delivered from the liquid phase through the pores of the matrix, it can be released by micropore flow.

The compounds of the present invention may be formulated into aerosol formulations by methods well known to those of ordinary skill in the art. Aerosol formulations can be prepared for topical aerosol use or for inhalation use. Aerosol formulations may be in the form of solutions and suspensions, and may contain other ingredients such as solvents, propellants and/or dispersants. Typical examples of aerosol formulations are disclosed in the following documents: remington's pharmaceutical Sciences, 18 th edition, Mack Publishing Company, Estonpennsylvania, pp1694-1712 (1990). This document is incorporated herein by reference.

Certain subclasses and certain specific compounds are more preferred with other compounds based on the fact that most types of compounds are suitable or can be used as therapeutic agents. In this case, R is preferably₂、R₄、R₆And R₇The moiety is methyl. Preferably R₅Is H or an acyl moiety such as formyl and acetyl. X is preferably CH₂A. A is preferably the following group:

wherein Y is preferably H; r₁₀Preferably C_1-6Alkyl, more preferably C_1-3Alkyl groups, more preferably methyl groups. Other preferred forms of R₁₀Is acyloxyalkylene, especially-CH₂-O-C(O)CH₃Hydroxyalkyl (C)_2-6) (particularly- (CH)₂)₂-OH) and pyrimidinyl.

Claims (13)

1. A process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof:wherein R is₂Is C_1-4Alkyl radical, each R₂Part being independent C_1-4Alkyl or two R₂Part of which forms C together with the carbon atom to which it is attached_5-6A cycloalkyl moiety; r₄Is C_1-6An alkyl group; r₅Is H or C (O) R, R is_HOr C_1-9An alkyl group; r₆Is C_1-6An alkyl group; r₇Is H or C_1-6An alkyl group; x is COOR₈、CH₂OH, halomethyl, C (O) A or CH₂A; a is NR₇R₉、-N^㊉R₆R₆R₆-Q^㊀Pyrrolidino, piperidino, morpholino or

R₈Is H, C_1-6Alkyl or- (CH)₂) m-A, m is 2,3 or 4; r₉Is H, C_1-4Alkyl, aryl, heteroaryl, and heteroaryl,

n is 1, 2,3 or 4, p is 1, 2 or 3; r₁₀Is H, C_1-8Alkyl radical, C_2-6Alkenyl radical, C_4-6Cycloalkyl, cyclohexylmethyl, hydroxyalkyl (C)_2-6) Dihydroxyalkyl (C)_3-6)、C_2-9Acyloxyalkyl (C)_2-6)、C_1-4Alkoxyalkyl (C)_1-6)、-(CH₂)_2-6-O-(CH₂)_2-4-OH、t is 0, 1 or 2, or pyrimidinyl, with the proviso that R is not H when Y is not H₁₀Is H; y is H, CH₃Or COOR₇；R₁₁Is H, C_1-4Alkoxy radical, C_1-4Alkyl or halogen；R₁₂Is in the ortho position C_1-4Alkoxy radical, ortho-C_1-4Alkyl or para-halo; and Q is a halogen or sulfonate ion^㊀-SO₃R₁，R₁Is H, C_1-6An alkyl, aryl or aralkyl group, the method comprising: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,

with 2-halo-2- (C)_1-4) Alkyl radical (C)_1-6) Acid halides or of the formula R₂-C(W)(R₂) 2-halo-2- (C) of C (O) V_1-4) Alkyl radical (C)_1-6) Acid reaction, wherein R₂W is hydrogen or halogen such as iodine, bromine, chlorine or fluorine, preferably bromine or chlorine, and V is halogen or hydroxy as defined above, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6) wherein R is₂、R₄、R₆And R₇As defined above, the above-mentioned,(b) protecting the 5-hydroxy moiety of the resulting benzofuranone (6) with a suitable protecting group to convert the ketone moiety to an exomethylene group to give a benzofuran of formula (8) wherein R₂、R₄、R₆And Pg is as defined above, and,(c) converting the exomethylene group of the resulting benzofuran of formula (8) into a hydroxymethyl group by hydroboration/oxidation to give a compound of formula (9), wherein R₂、R₄、R₆、R₇And Pg is as defined above, and,

optionally, (d) resolving the alcohol (9) to give (R) and (S) an optically active compound (9), optionally (e) deprotecting the 5-hydroxy group of the compound of formula (9) to give a benzofuranol of formula (I) wherein X is CH₂OH and R₅Is H, optionally (f) oxidizing the 3-hydroxymethyl group of formula (9) to a 3-carboxylic acid of formula (12),optionally, (g) resolving the racemic acid of formula (12) to give (S) and(R) an optically active compound (12), optionally (h) deprotecting the 5-hydroxy group of acid (12) to give a benzofuranol of formula (I) wherein X is COOH and R₅Is a compound of formula (I) in the formula (H),optionally, (I) esterifying a carboxylic acid of formula (12) and optionally deprotecting the hydroxy group to give a benzofuranol of formula (I) wherein X is COOR₈And R₅(ii) optionally, (j) reacting the desired amino group with a carboxylic acid of formula (12) and optionally deprotecting the hydroxy group to give a benzofuranol of formula (I) wherein X is C (O) A and R₅(ii) for H, optionally (k) reducing a carboxylic acid of formula (12) to give a compound of formula (9), optionally (l) optionally deprotecting the hydroxy group of the compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a halogen to give a benzofuranol of formula (I) wherein X is a halomethyl group and R is₅(m) optionally deprotecting the hydroxy group of the compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a leaving group to give a benzofuranol of formula (10),

optionally, (n) substituting the leaving group of compound (10) with the desired amino group and optionally deprotecting the hydroxy group to provide a product of formula (I) wherein X is CH₂A and R₅Is H, optionally (o) esterified wherein R₅The 5-hydroxy group of the compound of formula (I) being H, to give a compound of formula (I) wherein R is₅Is COR, R is C_1-9Alkyl, and optionally converting said product into a pharmaceutically acceptable salt thereof.

2. A process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof, according to claim 1:

wherein: r₂' is C_1-4Alkyl radical, each R₂Part being independent C_1-14An alkyl group; r₄Is C_1-6An alkyl group; r₅' is H; r₆Is C_1-6An alkyl group; r₇Is H or C_1-6An alkyl group; x' is CH₂A 'and A' are

R₁₀' is H, C_1-3An alkyl group, the method comprising: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,with 2-halo-2- (C)_1-4) Alkyl radical (C)_1-6) Acid halides or of the formula R₂-C(W)(R₂) 2-halo-2- (C) of C (O) V_1-4) Alkyl radical (C)_1-6) Acid reaction, wherein R₂W is hydrogen or halogen such as iodine, bromine, chlorine or fluorine, preferably bromine or chlorine, and V is halogen or hydroxy as defined above, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6) wherein R is₂、R₄、R₆And R₇As defined above, the above-mentioned,

(b) protecting the 5-hydroxy moiety of the resulting benzofuranone (6) with a suitable protecting group to convert the ketone moiety to an exomethylene group to give a benzofuran of formula (8) wherein R₂′、R₄、R₆And Pg is as defined above, and,

(c) converting the exomethylene group of the resulting benzofuran of formula (8) into a 3-hydroxymethyl group by hydroboration/oxidation to give a compound of formula (9), wherein R₂′、R₄、R₆、R₇And Pg is as defined above, and,

optionally, (d) resolving the alcohol (9) to give (R) and (S) optically active compounds (9), optionally (e) oxidizing the 3-hydroxymethyl group of compounds (9) to the 3-carboxylic acid of formula (12),optionally, (f) resolving the racemic acid of formula (12) to give (S) and (R) optically active compound (12), optionally, (g) reducing the carboxylic acid of formula (12) to give compound of formula (9), (h) optionally deprotecting the hydroxy group of compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a leaving group to give benzofuranol of formula (10),(i) use the instituteThe desired amino group replaces the leaving group of compound (10) and optionally deprotects the hydroxy group to provide a product of formula (I) wherein X' is CH₂A', and optionally converting said product into a pharmaceutically acceptable salt thereof.

3. A process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof, according to claim 1:

wherein: r ″)₂、R″₄、R″₆And R ″)₇Is methyl, R₅' is H; x' is CH₂A ', A' isR″₁₀Is methyl, the method comprises: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,with 2-halo-2-methylpropyl halide or 2-halo-2-methylpropionic acid, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6) wherein R ″₂、R″₄、R″₆And R ″)₇As defined above, the above-mentioned,(b) protecting the resulting hydroxy moiety of benzofuranone (6) with an appropriate protecting group to convert the ketone moiety to an exomethylene moiety to provide a benzofuran of formula (8) wherein R ″₂、R″₄、R″₆、R″₇And Pg is as defined above, and,(c) converting the exomethylene group of the resulting benzofuran of formula (8) into a 3-hydroxymethyl group by hydroboration/oxidation to give a compound of formula (9),

optionally, (d) resolving the alcohol (9) to give (R) and (S) optically active compounds (9), optionally (e) oxidizing the 3-hydroxymethyl group of formula (9) to a 3-carboxylic acid of formula (12),

optionally (f) resolving the racemic acid of formula (12) to give (S) and (R) optically active compound (12), optionally (g) reducing the carboxylic acid of formula (12) to give compound of formula (9), optionally (h) optionally deprotecting the hydroxy group of compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a leaving group to give benzofuranol of formula (10),(i) substitution of the leaving group of compound (10) with the desired amino group and optional deprotection of the hydroxyl group gives the product of formula (I) wherein X' is CH₂A ", and optionally converting said product into a pharmaceutically acceptable salt thereof.

4. A process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof, according to claim 3:

wherein: r ″)₂、R″₄、R″₆And R ″)₇Is methyl, R₅' is H; x' is CH₂A ', A' isR″₁₀Is methyl, the method comprises: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,

with 2-halo-2-methylpropyl halide or 2-halo-2-methylpropionic acid, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6) wherein R ″₂As defined above, the above-mentioned,

(b) protecting the hydroxyl moiety of the resulting benzofuranone (6) with a suitable protecting group, converting the ketone moiety to an exomethylene moiety to give a benzofuran of formula (8),

(c) the exomethylene group of the benzofuran of formula (8) produced is reacted by hydroboration/oxidationConversion to 3-hydroxymethyl to give a compound of formula (9),

optionally, (d) resolving the alcohol (9) to give (R) and (S) an optically active compound (9), (e) optionally deprotecting the hydroxy group of the compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group into a leaving group to give the benzofuranol of formula (10),(f) substitution of the leaving group of compound (10) with the desired amino group and optional deprotection of the hydroxyl group gives the product of formula (I) wherein X' is CH₂A ", and optionally converting said product into a pharmaceutically acceptable salt thereof.

5. A process for resolving an optically active isomer compound of formula (9),

wherein R ″)₂、R″₄、R″₆And R ″)₇Is methyl and Pg is H or a suitable protecting group, which process comprises: (a) reacting a compound of formula (9) with lipase/candida cylindracea and vinyl acetate, (b) separating the respective isomers, (c) optionally deprotecting the 5-hydroxy group.

6. Preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), according to claim 3, including the sameA process for the preparation of stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof:wherein: r ″)₂、R″₄、R″₆And R ″)₇Is methyl, R₅' is H; x' is CH₂A ', A' is

R″₁₀Is methyl, the method comprises: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,

with 2-halo-2-methylpropyl halide or 2-halo-2-methylpropionic acid, optionallyThe resulting compound is saponified or deprotected to give a benzofuranone of formula (6) wherein R ″₂As defined above, the above-mentioned,

(b) protecting the hydroxyl moiety of the resulting benzofuranone (6) with a suitable protecting group, converting the ketone moiety to an exomethylene moiety to give a benzofuran of formula (8),

(c) converting the exomethylene group of the resulting benzofuran of formula (8) into a 3-hydroxymethyl group by hydroboration/oxidation to give a compound of formula (9),(d) oxidizing the compound (9), 3-hydroxymethyl group, to a 3-carboxylic acid of formula (12),

optionally, (e) resolving the racemic acid of formula (12) to give (S) and (R) optically active compound (12), (f) reducing the carboxylic acid of formula (12) to give compound of formula (9), (g) optionally deprotecting the hydroxy group of compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a leaving group to give benzofuranol of formula (10),

(h) substitution of the leaving group of Compound (10) with the desired amino group and optional deprotection of the hydroxyl groupProtecting to obtain the product of formula (I) wherein X' is CH₂A ", and optionally converting said product into a pharmaceutically acceptable salt thereof.

7. A process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof:

wherein R is₂Is C_1-4Alkyl radical, each R₂Part being independent C_1-4Alkyl or two R₂Part of which forms C together with the carbon atom to which it is attached_5-6A cycloalkyl moiety; r₄Is C_1-6An alkyl group; r₅Is H or C (O) R, R is H or C_1-9An alkyl group; r₆Is C_1-6An alkyl group; r₇Is H or C_1-6An alkyl group; x is COOR₈、CH₂OH, halomethyl, C (O) A or CH₂A; a is NR₇R₉、-N^㊉R₆R₆R₆-Q^㊀Pyrrolidino, piperidino, morpholino or

R₈Is H, C_1-6Alkyl or- (CH)₂)_m-a, m is 2,3 or 4; r₉Is H, C_1-4Alkyl, aryl, heteroaryl, and heteroaryl,

n is 1, 2,3 or 4, p is 1, 2 or 3; r₁₀Is H, C_1-8Alkyl radical, C_2-6Alkenyl radical, C_4-6Cycloalkyl, cyclohexylmethyl, hydroxyalkyl (C)_2-6) Dihydroxyalkyl (C)_3-6)、C_2-9Acyloxyalkyl (C)_2-6)、C_1-4Alkoxyalkyl (C)_1-6)、-(CH₂)_2-6-O-(CH₂)_2-4-OH、

t is 0, 1 or 2, or pyrimidinyl, with the proviso that R is not H when Y is not H₁₀Is H; y is H, CH₃Or COOR₇；R₁₁Is H, C_1-4Alkoxy radical, C_1-4Alkyl or halogen; r₁₂Is in the ortho position C_1-4Alkoxy radical, ortho-C_1-4Alkyl or para-halo; and Q is a halogen or sulfonate ion^㊀-SO₃R₁，R₁Is H, C_1-6An alkyl, aryl or aralkyl group, the method comprising: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,with 2-halo-2- (C)_1-4) Alkyl radical (C)_1-6) Acid halides or of the formula R₂-C(W)(R₂) 2-halo-2- (C) of C (O) V_1-4) Alkyl radical (C)_1-6) Acid reaction, wherein R₂W is hydrogen or halogen such as iodine, bromine, chlorine or fluorine, preferably bromine or chlorine, and V is halogen or hydroxy as defined above, optionally saponifying or deprotecting the resulting compound to give a benzofuran of formula (6)Furanones of the formula wherein R₂、R₄、R₆And R₇As defined above, the above-mentioned,

(b) optionally protecting the 5-hydroxy group of benzofuranone (6), reducing the ketone to its corresponding alcohol, converting the 3-hydroxy group to a leaving group, replacing the leaving group with a cyano group, hydrolyzing the resulting cyano group to give an acid of formula (12), and partially converting to exomethylene groups to give a benzofuran of formula (8), wherein R is₂、R₄、R₆And Pg is as defined above, and,optionally (c) resolving the racemic acid of formula (12) to give (S) and (R) the optically active compound (12), optionally (d) deprotecting the 5-hydroxy group of acid (12) to give the benzofuranol of formula (I) wherein X is COOH and R₅Is H, optionally (e) esterifying a carboxylic acid of formula (12) and optionally deprotecting the hydroxy group to give a benzofuranol of formula (I) wherein X is COOR₈And R₅Optionally, (f) reacting the desired amino group with a carboxylic acid of formula (12) and optionally deprotecting the hydroxy group to give a benzofuranol of formula (I) wherein X is C (O) A and R₅(ii) optionally, (g) reducing the carboxylic acid of formula (12) to give a compound of formula (9),

optionally, (h) optionally deprotecting the hydroxy group of a compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a halogen to give a benzofuranol of formula (I) wherein X is a halomethyl group and R₅Is H, optionally (i) optionally deprotecting the hydroxy group of the compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group to a leaving group to give a benzofuranol of formula (10),(j) substitution of the leaving group of compound (10) with the desired amino group and optional deprotection of the hydroxy group affords a product of formula (I) wherein X is CH₂A and R₅Is H, optionally (k) esterification wherein R is₅The 5-hydroxy group of the compound of formula (I) being H, to give a compound of formula (I) wherein R is₅Is COR, and optionally converting said product into a pharmaceutically acceptable salt thereof.

8. A process for the preparation of 2, 3-dihydro-benzofuranol derivatives of formula (I), including stereoisomers, enantiomers and optically active and racemic mixtures thereof, or pharmaceutically acceptable salts thereof, according to claim 7:

wherein: r ″)₂、R″₄、R″₆And R ″)₇Is methyl, R₅' is H; x' is CH₂A ', A ' is (inserted into the original text P100, structure formula ①); R ')₁₀Is methyl, the method comprises: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,

with 2-halo-2-methylpropyl halide or 2-halo-2-methylpropionic acid, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6) wherein R ″₂、R″₄、R″₆And R ″)₇As defined above, the above-mentioned,

(b) optionally protecting the 5-hydroxy group of benzofuranone (6), reducing the ketone to its corresponding alcohol, converting the 3-hydroxy group to a leaving group, replacing the leaving group with a cyano group, hydrolyzing the resulting cyano group to give an acid of formula (12),

optionally, (c) resolving the racemic acid of formula (12) to give (S) and (R) the optically active compound (12), (d) reducing the carboxylic acid of formula (12) to give the compound of formula (9),(e) optionally deprotecting the hydroxy group of the compound of formula (9) and converting the hydroxy group of the 3-hydroxymethyl group into a leaving group to give the benzofuranol of formula (10),(f) substitution of the leaving group of compound (10) with the desired amino group and optional deprotection of the hydroxy group affords a product of formula (I) wherein X is CH₂A and R₅Is H, and optionally converting said product into a pharmaceutically acceptable salt thereof.

9. A process for the preparation of derivatives of formula (6), including stereoisomers, enantiomers and optically active and racemic mixtures thereof or pharmaceutically acceptable salts thereof:wherein R is₂Is C_1-4Alkyl, or two R₂Part of which forms C together with the carbon atom to which it is attached_5-6A cycloalkyl moiety; r₄Is C_1-6An alkyl group; r₆Is C_1-6An alkyl group; and R₇Is H or C_1-6An alkyl group, the method comprising: (a) using Friedel-Crafts reaction conditions, a hydroquinone of formula (3), wherein R is₄、R₆And R₇As defined above and Pg is hydrogen or a suitable protecting group,with 2-halo-2- (C)_1-4) Alkyl radical (C)_1-6) Acid halides or of the formula R₂-C(W)(R₂) 2-halo-2- (C) of C (O) V_1-4) Alkyl radical (C)_1-6) Acid reaction, wherein R₂W is hydrogen or halogen such as iodine, bromine, chlorine or fluorine, preferably bromine or chlorine, and V is halogen or hydroxy (-OH) as defined above, optionally saponifying or deprotecting the resulting compound to give a benzofuranone of formula (6),

10. the compound 5-hydroxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran-3-one.

11. The compound 5-hydroxy-3-methylene-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydrobenzofuran.

12. The compound 5-benzyloxy-3-hydroxymethyl-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran.

13. The compound 3-hydroxymethyl-5-methoxy-2, 2, 4, 6, 7-pentamethyl-2, 3-dihydro-1-benzofuran.