Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
  • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
  • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/63—Esters of sulfonic acids
  • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals

Definitions

• the present invention relates to a process for preparing S- and R-enantiomers of substituted 3-aryloxy-2- hydroxypropylamines used as beta-receptor-blocking substances (hereinafter called beta blockers) and with the following respective formulae:
• beta blockers can be prepared via intermediates in the form of the S- or R-enantiomers of the amines defined below.
• R 3 will be hydrogen or a protecting group which can be easily removed by means of hydrogenolysis, for example an optionally substituted benzyl radical with one or more identical or different substituents, for example methyl, alkyl, methoxy, alkoxy, hydroxyl or nitro, it being preferable, however, for the protecting group to consist of an unsubstituted benzyl radical.
• R A will be hydrogen or a protecting group which can be easily removed by means of hydrogenolysis, for example an optionally substituted benzyl radical with one or more identical or different substituents, for example methyl, alkyl, methoxy, alkoxy, hydroxyl or nitro, it being preferable, however, for the protecting group to consist of an unsubstituted benzyl radical.
• Ar x substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character.
• Beta blockers are used as drugs primarily for cardiovascular diseases, such as hypertension, angina pectoris and certain arrhythmias, and for glaucoma (an ophthalmic disease) .
• Most beta blockers consist of substituted 3-aryloxy-2-hydroxypropylamines. These have a chiral centre at carbon atom number 2, as a result of which each of them can exist as two enantiomers, the R-form and the S-form.
• Those substances consisting of equal parts of R-form and S-form will hereinafter be called racemic or racemate, and those which consist principally of one of these two forms will be called homochiral.
• beta blockers In the case of some beta blockers, it is known that it is their S-form which possesses the pharmacological effect which is desirable in cardiovascular diseases, while the same beta blocker's R-form is virtually inactive. In contrast, both the enantiomers have been found to be approximately equally effective against glaucoma (Keates, E U, Stone, R: Am J Ophthalmol 9_8, 73 (1984)). It has therefore been proposed to use these R-beta blockers against glaucoma in order to prevent any effect on the cardiovascular system, while the S-form should be used for cardiovascular diseases. There is therefore considerable interest in establishing the simplest possible synthesis routes for preparing both the S- and R-forms of homochiral beta blockers.
• beta blockers which contain a substituted benzene radical instead of a substituted naphthalene radical.
• Ar 2 will therefore be con ⁇ sidered, as earlier on page 1, as representing both substituted benzene and naphthalene radicals.
• GB Patent 1,269,776 describes a method for preparing such beta blockers taking as a starting point certain specific amines hereinafter designated 2a, 2b, 3a and 3b, in accordance with the general method defined below (Scheme II).
• R- alkyl radical
• R 2 hydrogen or an alpha- arylalkyl radical
• Z a halogen atom.
• the present invention now includes, inter alia, a process for preparing any desired enantiomers of amines 8a or 8b and 9a or 9b (see page 2) from easily accessible raw materials.
• the amines 9a, 9b, 8a and 8b are included in the general formulae for the amines
• the raw materials which can be employed include commercially available substances such as R- or S-glycidol, or esters thereof, for example R-glycidyl butyrate, which can be converted, by means of techniques known to the person skilled in the art, to 10a or 10b, respectively, accord ⁇ ing to the following scheme:
• Ar- is a substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character, for example one or more chlorine, bromine or iodine atoms, one or more nitroso, nitro, cyano, trifluoromethyl, trichloromethyl or tri- bromomethyl groups, one or more optionally substituted sulphinyl, sulphonyl, phosphonyl, phosphoryl or carbonyl groups, or combinations of these atoms and groups, at any chosen positions on the benzene or naphthalene rings, it being preferable for Ar x to be a substituted benzene radical in which at least one substituent is a nitro, an optionally substituted sulphonyl or an optionally sub ⁇ stituted carbonyl group at any chosen position on the benzene ring.
• Ar x is a substituted benzene radical in which at least one substituent is a nitro, an
• the glycidyl sulphonates 10a and 10b can be prepared starting from allyl alcohol which, by means of enantioselective epoxidation, is converted to S- or R-glycidol, which is then reacted to give 10a or 10b, respectively, again using the known technique (cf., for example, Klunder, J M, Ko, S Y, Sharpless, K B: J Org Chem 5i, 3710 (1986)).
• the amines 9a and 9b can be completely or partially converted to amines 8a and 8b, respectively, by treatment with a base, for example hydroxides, alkoxides or car ⁇ bonates of lithium, sodium, potassium, calcium or magne ⁇ sium and optionally substituted ammonia, it being prefer ⁇ able for the base to consist of sodium or potassium hydroxide or of sodium or potassium alkoxide, for example methoxide, ethoxide or tertiary butoxide, optionally in the presence of a phenol, as is clear from the relevant part of Scheme V.
• a base for example hydroxides, alkoxides or car ⁇ bonates of lithium, sodium, potassium, calcium or magne ⁇ sium and optionally substituted ammonia
• the base it being prefer ⁇ able for the base to consist of sodium or potassium hydroxide or of sodium or potassium alkoxide, for example methoxide, ethoxide or tertiary butoxide, optionally in the presence of a phenol
• the invention furthermore relates to new routes for the preparation of S- and R-beta blockers. These routes are via the amines 9a or 9b and 8a or 8b, for which reason the starting substances for this part of the invention too are R- and S-glycidyl esters of sulphonic acids (10a or 10b) which are reacted to give the amines 9a or 9b. These amines are then further treated in accordance with the following scheme.
• R 3 and R 4 have the same meanings as above.
• Ar 2 is any one of the radicals given in Table 1 below.
• Ar 2 is any one of the radicals according to Table 2.
• the S- or R-form of the beta blockers is thus obtained.
• the advantage of adding this new reaction step is the following.
• the chloropropanediol sulphonates 11a and lib have been found to give lower proportions of by-products, in the form of C3-aminated by-products, than corres ⁇ ponding glycidyl sulphonates 10a and 10b.
• This is very important since the presence of a C3-aminated impurity in amines 8a, 8b, 9a or 9b leads to formation of impurities in the homochiral beta blockers prepared from these and consisting of the same beta blockers of the opposite chiral form (R-beta blocker as an impurity in an S-beta blocker or S- as an impurity in an R-). Impurities which are related to the main component in this way are generally difficult to remove.
• Ar. will contain at least one group of electron-attracting character is likewise that a lower proportion of C3- aminated by-product is in this way obtained.
• R-glycidyl 4-nitrobenzenesulphonate certain S- or R-glycidyl esters of sulphonic acids of formulae 10a or 10b in which Ar x has the meaning given earlier, and S- or R-3-chloro-l,2-propanediol 1-sulphonates of formulae 11a or lib, for example, S- or R-3-chloro-l,2-propanediol 1-(4-nitrobenzenesulphonate) .
• solvents which are suitable in connection with the process according to the invention, mention may be made of dichloromethane, tetrahydrofuran, dimethyl sulphoxide, methanol, water, toluene and ethyl acetate.
• concentrations are expediently chosen between about 0.1 M and the saturation concentrations in the reaction mixtures in question, and the temperatures are chosen between about -20°C and 150 ⁇ C and the pressure between 0.01 and 20 bar.
• Purity according to HPLC about 98%.
• the greatest impurity may be a product formed by the opposite opening of the epoxide ring.
• Example 5 (without conversion of epoxy group to 1,2- chlorohydrin group) .
• a product containing S-2-hydroxy-3-chloropro ⁇ yl- isopropylamine (9a; R 3 - isopropyl, R 4 H) prepared in accordance with Example 7 (46.1 g) was suspended in methanol (22 ml), and a solution of potassium hydroxide (16.6 g) in methanol (95 ml) was added. After heating for one hour at 40°C, volatile constituents were stripped off, water was added, and the mixture was extracted with dichloromethane.

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• Chemical & Material Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1990
  • 1990-01-22 SE SE9000206A patent/SE468211B/sv not_active IP Right Cessation
• 1991
  • 1991-01-15 JP JP91503496A patent/JPH05506008A/ja active Pending
  • 1991-01-15 WO PCT/SE1991/000022 patent/WO1991010642A1/en not_active Application Discontinuation
  • 1991-01-15 CA CA002074075A patent/CA2074075A1/en not_active Abandoned
  • 1991-01-15 EP EP91903459A patent/EP0512020A1/en not_active Ceased
  • 1991-01-15 AU AU72249/91A patent/AU638801B2/en not_active Ceased
• 1992
  • 1992-07-20 FI FI923305A patent/FI923305A0/fi not_active Application Discontinuation

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