CN1115315A - Intermediate of pyrido-benzoxazine derivative and prepn. method - Google Patents
Intermediate of pyrido-benzoxazine derivative and prepn. method Download PDFInfo
- Publication number
- CN1115315A CN1115315A CN94107432A CN94107432A CN1115315A CN 1115315 A CN1115315 A CN 1115315A CN 94107432 A CN94107432 A CN 94107432A CN 94107432 A CN94107432 A CN 94107432A CN 1115315 A CN1115315 A CN 1115315A
- Authority
- CN
- China
- Prior art keywords
- compound
- base
- alkyl
- chemical formula
- hydrogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
A new N-isopropylphenylamine derivant and the process for preparing said derivant and preparing benzoxazine dervant using N-isopropylphenylamine derivant are disclosed.
Description
The present invention relates to racemization and optical activity N-isopropyl benzene sulfonamide derivatives and preparation method thereof; Relate to application racemization or optical activity N-isopropyl benzene sulfonamide derivatives and prepare racemization or optical activity pyrido-benzoxazine derivative important intermediate 3,4-dihydrobenzo oxazine derivative.The present invention be more particularly directed to the optical activity Ofloxacine USP 23, as Levofloxacin, and the useful intermediates of analogue and preparation method thereof.
European patent EP 47005 discloses the Ofloxacine USP 23 of following chemical formula (IX), and (oflox-acin) is as efficient, wide spectrum synthetic antibacterial drug.Ofloxacine USP 23 is in listing of many countries and clinical use.
Above-mentioned bibliographical information, 7,8-difluoro-3,4-dihydro-3 methyl-2H-[1,4] benzoxazine is the intermediate of synthetic Ofloxacine USP 23.
Day disclosure special permission 83-210092 reports, 6,8-dichloro-7 fluorine-3-methyl-3,4-dihydro-2H-[1,4] benzoxazine also is the intermediate of synthetic Ofloxacine USP 23.
European patent EP 206283A2 discloses the Levofloxacin (levofloxacin or (S)-(-)-ofloxacin), it is than the antibiotic work of Ofloxacine USP 23 of following chemical formula (X) again
The property strong, toxicity is low and water-soluble big.At present, Levofloxacin is gone on the market in Japan.
(S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine is the useful important intermediate of the optical activity pyrido-benzoxazine derivative (pyridobenzoxazine derivatives) of synthetic Levofloxacin and other anti-microbial activity.
Preparation (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[method of 1,4] benzoxazine has:
1, Split Method: EP206283 for example; EP304684; Day disclosure special permission 90-31695.7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine obtains S-(-) isomer to these methods, but yield is not higher than 50%, and its by product R-(+) isomer needs racemization, complicated operation by splitting.7,8-difluoro-3,4-dihydro-3-methyl-2H-[preparation of 1,4] benzoxazine need be used sublimability and strong 2,3-difluoro-6-nitrophenols intermediate and the strong Mono Chloro acetone of tearing property of contaminative.
2, asymmetric synthesis method: EP273399 report is by asymmetric reduction 7,8-difluoro-3-methyl-2H-[1,4] benzoxazine makes corresponding (S)-(-) isomer.This method needs valuable chiral reduction reagent, and also uses 2,3-difluoro-6-nitrophenols and Mono Chloro acetone.
3, synthesis method: the EP322815 of chirality unit, the method of EP368410 and day disclosure special permission 90-218648 all is and chiral reagent generation etherification reaction, through 3,4-difluoro-2-[(R)-and 2-hydroxyl propoxy-] synthetic S-(-)-7 of oil of mirbane intermediate, 8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine.Several intermediates of these literature methods are oily matter, and wherein functional group position isomerism, separation and purification difficulty easily take place under acid-base function 3,4-difluoro-2-[(R)-2-hydroxyl propoxy-] oil of mirbane.
4, biotransformation method: day disclosure special permission 93-68577 methods that provide are with micro-reduction 2-acetone oxygen base-3,4-difluoro nitrobenzene, generate 3,4-difluoro-2-[(R)-and 2-hydroxyl propoxy-] the oil of mirbane intermediate, there is easy isomerization equally in this intermediate, the separation and purification difficult problem.And 2-acetone oxygen base-3,4-difluoro nitrobenzene is by 2,3-difluoro-6-nitrophenols and Mono Chloro acetone preparation.
In order to solve the problem that above-mentioned literature method exists, the invention provides the racemization of following chemical formula (I) or optically active compound and preparation method thereof, and the racemization of the chemical formula V of the conduct of using preparation or the intermediate of optically active compound, particularly as preparation (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[the intermediate of 1,4] benzoxazine
X wherein
1, X
2And X
3Can be identical or different, each represents halogen atom or X
1, X
2, X
3One of them is a hydrogen atom, and all the other are halogen atom, and Y is a halogen atom, and A is-CH
2OR base (R is the protecting group of hydrogen atom or hydroxyl) or-COOR
3Base (R
3Be hydrogen atom, the alkyl of 1 to 6 carbon or the protecting group of carboxyl), R
1And R
2Both one of for containing the alkyl of 1 to 4 carbon, another is a hydrogen atom, Z is a hydrogen atom ,-CH=C (COOR
4)
2Base (R
4Be the alkyl of 1 to 6 carbon) ,-SO
2R
5The base or-COR
5Base, (R
5Be alkyl or substituted hydrocarbon radical).Z is specifically :-CH=C (COOEt)
2, p-toluenesulfonyl, benzenesulfonyl, methylsulfonyl, phenacyl alkylsulfonyl, trifluoromethyl sulfonyl, benzoyl, carbobenzoxy, formyl radical, ethanoyl, trifluoroacetyl group etc.Preferably p-toluenesulfonyl or benzoyl.
The racemization or the optically active compound of chemistry formula V can be made through figure below reactions steps by the racemization or the optically active compound of chemical formula (I):
In the above-mentioned chemical formula (I), if A is-CH
2The OR base, wherein R is that the general protecting group of hydroxyl (comprises the aliphatic radical such as the tertiary butyl; Acyl group is formyl radical for example, ethanoyl, trifluoroacetyl group, benzene oxygen ethanoyl; Ethers such as THP trtrahydropyranyl, methoxyl methyl, 1-ethoxyethyl; Virtue aliphatic radical such as benzyl are to methoxybenzyl, to nitrobenzyl or trityl etc.Benzyl preferably.), then (I) formula compound needs deprotection base R to make the compound of chemical formula (VII).
If A is-COOR
3Base (R
3Be hydrogen atom, the alkyl of 1 to 6 carbon or the protecting group of carboxyl.Preferably methyl or ethyl), the compound of chemical formula (I) need be reduced into the compound of chemical formula (VIII).
By the compound and the intermediate (I) thereof of the prepared chemical formula V of the inventive method, (VIII) or (I) can be applied to prepare racemization or optical activity pyrido-benzoxazine derivative, particularly Levofloxacin.The compound of following chemical formula (VII),
X wherein
1, X
2, X
3, Y, R
1And R
2Have above-mentioned implication, Z represents hydrogen atom ,-CH=C (COOR
4)
2Base (R
4Be the alkyl of 1 to 6 carbon) ,-SO
2R
5The base or-COR
5Base (R
5Be alkyl or substituted hydrocarbon radical), can by chemical formula the halogenated nitrobenzene derivative of (XI),
X wherein
1, X
2, X
3Have implication as mentioned above with Y, the several reactions steps by following reaction synoptic diagram (A) obtain: a) nitro-reduction reaction; B) amido protecting; C) N-alkylation reaction; D) (d1) dehydroxylation protecting group or (d2) ester or acid are reduced into the primary alconol reaction.
Reaction synoptic diagram (A)
X wherein
1, X
2, X
3, Y, Z, R
1, R
2And R
3Have implication as mentioned above, R is a hydroxyl protecting group, and C is-CH=C (COOR
4)
2Base (R
4Be the alkyl of 1-6 carbon) ,-SO
2R
5The base or-COR
5Base, B is-SO
2R
5Base (R
5Be alkyl or substituted hydrocarbon radical).
Describe each the step reaction in the reaction synoptic diagram (A) below in detail:
Reactions steps is nitro-reduction reaction a)
Nitro in the compound of chemical formula (XI) uses the catalyst hydro-reduction such as Raney nickel, palladium charcoal, platinum oxide to become amino, thereby obtains the compound of chemical formula (XII).Perhaps use such as the metal one sour restoring system of iron powder with hydrochloric acid nitroreduction is become amino.Reaction solvent comprises lower alcohol such as methyl alcohol, ethanol and propyl alcohol.Temperature of reaction is in the boiling spread of room temperature to solvent.Catalytic hydrogenation can be carried out under condition of high voltage at normal pressure.Generally at synthesis under normal pressure.
Reactions steps b); Amido protecting
Amino available-SO in the compound of chemical formula (XII)
2R
5Base ,-COR
5Base (R
5Be alkyl or substituted hydrocarbon radical) or-CH=C (COOR
4)
2Base (R
4Be the alkyl of 1 to 6 carbon) protection.Use R
5SO
2Cl, R
5COCl (or other acylating agent such as active ester, acid anhydrides, acid add DCC etc.) carries out acylation reaction to the compound of chemical formula (XII).Perhaps chemical formula is Q-CH=C (COOR
4)
2Compound, wherein Q representation alkoxy, halogen or-N (R
4)
2Compound generation condensation reaction with chemical formula (XII).Thereby obtain the compound of chemical formula (III).
Acylation reaction is preferably in alkali and exists down, uses the R such as Tosyl chloride
5SO
2Cl or the R such as Benzoyl chloride
5COCl is to the compound acylation of chemical formula (XII).Alkali used herein comprises such as triethylamine, tri-n-butylamine, N, N-diisopropylethylamine and so on tertiary amine and such as pyridine, lutidine, the heterocyclic bases of N-methylmorpholine and so on.
Reacting suitable solvent is aprotic solvent, comprises ethers such as tetrahydrofuran (THF), 1,2-glycol dimethyl ether etc. and halo alkanes such as methylene dichloride, chloroform, 1,2-ethylene dichloride etc.
Temperature of reaction at 0 ℃ between the solvent boiling point.Be preferably between 0 ℃ to 50 ℃.
Reactions steps c): N-alkylation reaction
(wherein C is-SO the compound of chemical formula (III)
2R
5The base or-COR
5Base, R
5Be alkyl or substituted hydrocarbon radical) with the racemization of following chemical formula (XIII) or have optically active compound,
R wherein
1And R
2Both one of for containing the alkyl of 1 to 4 carbon, another be a hydrogen atom, R is the protecting group of hydroxyl, X comprises optional mesyloxy for reacting leavings group, trifluoro-methanesulfonyl oxy, phenylsulfonyloxy, tolysulfonyl oxygen base, halogen, chemical formula are Ph
3PO-triphenyl phosphine oxygen base etc.,
N-alkylation reaction takes place to be generated the racemization of chemical formula (VI) or have optically active N-isopropyl benzene sulfonamide derivatives,
The perhaps racemization of (III) formula compound and following chemical formula (XIV) or have optically active propanoic derivatives,
R wherein
1, R
2Have the above implication, R with X
3It is for example benzyl of the suitable protecting group of the alkyl of 1 to 6 carbon or carboxyl.
In the presence of alkali and phase-transfer catalyst, N-alkylation reaction takes place, generate the racemization of chemical formula (VIII) or have optically active compound.
Alkali used herein refers to mineral alkali or organic bases.Mineral alkali comprises alkali hydroxide metal such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Comprise carbonic acid basic metal such as Quilonum Retard, yellow soda ash, salt of wormwood.Organic bases comprises tertiary amine such as triethylamine, tri-n-butylamine, N, N-diisopropylethylamine; Comprise quaternary ammonium hydroxide such as tetraethylammonium hydroxide, hydroxide dimethyl decyl benzyl ammonium, hydroxide trimethylammonium ammonium in the last of the ten Heavenly stems; Comprise sodium alkoxide or potassium alcoholate such as sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide etc.
Phase-transfer catalyst used herein refers to the crown ether such as 18-crown ether, quaternary salt or quaternary ammonium salt such as bromination hexadecyl tributyl salt.Quaternary ammonium salt comprises 4-n-butyl ammonium hydrogen sulfate, bromination tetra-n-butyl ammonium, chlorination triethyl benzyl ammonium, bromination dodecyl dimethyl benzyl ammonium, cetyl trimethylammonium bromide, Alaquat336 etc.
The solvent that N-alkylation reaction uses comprises hydrocarbon such as benzene, toluene etc.; Comprise ether such as tetrahydrofuran (THF), dioxane, 1,2-glycol dimethyl ether etc.; Comprise acid amides and N, N-dimethyl formamide etc.; Comprise aprotic polar solvent such as dimethyl sulfoxide (DMSO) etc.; Comprise alkyl chloride such as methylene dichloride, chloroform, tetracol phenixin, 1,1-ethylene dichloride, 1,2-ethylene dichloride, 1,1,2,2-tetrachloroethane etc.
Temperature of reaction in room temperature between the solvent boiling point.
(wherein C is-CH=C (COOR the compound of chemical formula (III)
4)
2Base, R
4Be the alkyl of 1 to 6 carbon) and the compound (wherein X is a hydroxyl) of chemical formula (XIII) or the compound (wherein X is a hydroxyl) of chemical formula (XIV), at 0-50 ℃, and such as ether, tetrahydrofuran (THF) and 1, (see O.Mitsunobn with 1-1.5 times of molar Mitsnnobn reagent in the solvent of 2-glycol dimethyl ether and so on, Synthesis, 1:28 (1981)) handle, thereby N-alkylation reaction takes place, (wherein C is-CH=C (COOR the compound of generation chemical formula (VI)
4)
2Base) or generate the compound of chemical formula (VIII) (wherein C is-CH=C (COOR
4)
2Base, (R
4Be the alkyl of 1 to 6 carbon).
The compound of chemical formula (XIV) can be made by 2-hydroxycarboxylic acid ester derivative.For example produce from lactate.The compound of chemical formula (XIII) can be made by 1,2-alkyl diol derivative.1,2-alkyl diol derivative is to be obtained or reduction obtains as 1-pyruvic alcohol by 1-hydroxyketone-2 derivative by 2-hydroxycarboxylic acid esters reduction.In 2-hydroxycarboxylic acid ester derivative and 1, the 2-alkyl diol derivative 2-position hydroxyl can for example be converted into the leavings group that replaces sulfonyloxy or halogen and so on replacement SULPHURYL CHLORIDE or sulfur oxychloride reaction by currently known methods in the presence of alkali.
2-hydroxycarboxylic acid or its ester comprise optically pure isomer or two kinds of enantiomeric mixture such as raceme, can be bought by market obtain.1,2-alkyl diol derivative of optical purity or two kinds of enantiomeric mixture is perhaps prepared from 1-hydroxyketone-2 derivative by asymmetric reduction or biological enzyme reduction method by corresponding 2-hydroxycarboxylic acid esters of reduction or acid preparation.
After it should be noted that the compound of the compound of chemical formula (III) and chemical formula (XIII) or with the compound of chemical formula (XIV) N-alkylation reaction taking place, the configuration generation Walden (Walden) of 2 asymmetric carbons of chiral centre transforms in the compound of the compound of chemical formula (XIII) or chemical formula (XIV).The for example compound of (2R)-2-tolysulfonyl oxygen base ethyl propionate and chemical formula (III) reaction, thus corresponding (S) configuration chemical formula (VIII) compound (R wherein generated
1=Me; R
2=H; R
3=Et)
Reactions steps d): the compound of preparation chemical formula (VIII)
(d1): the dehydroxylation protecting group
Hydroxyl protecting group R in the compound of chemical formula (VI) changes the H atom into by usual method deprotection base.For example R is that the protecting group of benzyl can be with palladium charcoal or platinum charcoal catalytic hydrogenolysis at normal temperatures.
(d2): ester or acid are reduced into the primary alconol reaction
Chemical formula (VIII) (B=SO
2R
5, R
5Be alkyl or substituted hydrocarbon radical) ester or its hydrolysate acid, can be reduced into the alcohol of chemical formula (VIII) by currently known methods.For example the ester of chemical formula (VIII) is reduced into primary alconol with copper-chromium (Copper chromite) catalytic hydrogenation or with Lithium Aluminium Hydride, lithium borohydride.The hydrolysate acid of chemical formula (VIII) becomes primary alconol with borane reduction.In the reduction reaction process, the chiral centre of compound (VIII) keeps configuration.
(d3) deaminizating protecting group reaction
(VI) formula and (VII) in the formula compound, Z is that the compound of hydrogen atom can be-SO by Z
2R
5The base or-COR
5Base (R wherein
5Be alkyl or substituted hydrocarbon radical) compound deaminizating protecting group obtain.
The invention provides the racemization of following chemical formula (1) or optical activity N-isopropyl benzene sulfonamide derivatives and preparation method thereof,
X wherein
1, X
2, X
3, Y, Z, R
1, R
2Has implication as mentioned above with A.If A is-CH
2OR base (wherein R is the protecting group of hydroxyl) then is the compound of chemical formula (VI), if A is-CH
2The OH base then is the compound of chemical formula (VIII); If A is-COOR
3Base (R
3Be the alkyl or the suitable protecting group of carboxyl of 1 to 6 carbon), then be the compound of chemical formula (VIII).
The compound of the chemical formula (VII) that makes by the several reactions steps of above-mentioned reaction synoptic diagram (A), the two step reactions steps of passing through following reaction synoptic diagram (B) again are converted into the racemization of chemical formula (XV) or have optical activity 3-alkyl-3,4-dihydro-2H-[1,4] benzo-oxazine derivative:
Reaction synoptic diagram (B)
X wherein
1, X
2, X
3, Y, R
1And R
2Have implication as mentioned above, Z is a hydrogen atom ,-CH=C (COOR
4)
2Base (R
4Alkyl for 1-6 carbon) ,-SO
2R
6The base or-COR
5(R
5Be alkyl or replace hydro carbons), p-toluenesulfonyl for example, benzenesulfonyl, methylsulfonyl, phenacyl alkylsulfonyl, trifluoromethyl sulfonyl etc.; Perhaps as benzoyl, carbobenzoxy, formyl radical, ethanoyl, trifluoroacetyl group etc.Preferably p-toluenesulfonyl or benzoyl.
Reactions steps e): ring-closure reaction
Compound cyclization in the presence of alkali of chemical formula (VII) becomes the compound of chemical formula V.Suitable alkali comprises metal hydride such as hydrolith, sodium hydride, potassium hydride KH etc.; Comprise metal alkyl oxide such as potassium tert.-butoxide etc.; Comprise alkaline carbonate such as yellow soda ash, salt of wormwood etc.; Also comprise fluorochemical such as Potassium monofluoride, tetrabutylammonium.Ring-closure reaction is such as dimethyl sulfoxide (DMSO), N, and N-dimethyl formamide, 1,2-glycol dimethyl ether, two (2-methoxyl group) ether, tetrahydrofuran (THF) in the aprotic solvent of dioxane and chlorobenzene and so on, and carries out in the boiling temperature scope in room temperature.
Through ring-closure reaction, the asymmetric chiral carbon configuration in chemical formula (VII) compound does not change.So, can make the optically active compound of the chemical formula V of same chiral configuration from the compound of optical activity chemical formula (VII).
Reactions steps f) deaminizating protecting group reaction
(Z is-SO the amino protecting group Z of chemistry formula V compound
2R
3The base or-COR
5Base) under corresponding known deprotection method condition, leaves away.For example under acid hydrolysis or reductive cleavage condition, amino p-toluenesulfonyl can be sloughed and dissociate amino.It should be noted that in taking off alkylsulfonyl protecting group reaction process, the compound chirality configuration of chemical formula V is constant.Thereby can make the compound of the chemical formula (XV) of same chiral configuration from the compound of optical activity chemistry formula V.
Therefore, the invention provides the racemization of chemical formula (XV) or chemical formula V or have preparation method's (see reaction synoptic diagram (A) and (B)) of the novelty of optically active compound, comprising Levofloxacin intermediate (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (XV, X
1=X
2=F, X
3=H, R
1=Me, R
2=H) preparation method.
With compound of the present invention (I) as intermediate preparation (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazines are compared with background technology, have overcome the shortcoming in the background technology, and nearly all intermediate at room temperature is a solid in the inventive method, easily separated and purifying, no column chromatography operation, easy to use, help scale operation.
Following examples will the invention will be further described, rather than to its restriction.
Embodiment 1:
2,3,4-trifluoromethyl aniline hydrochloride [(XII) HCl, X
1=X
2=Y=F, X
3=H] preparation
2,3, the mixture of 4-trifluoronitrobenzene (20g), ethanol (200ml) and 5% palladium charcoal (8.3g) is in room temperature normal pressure catalytic hydrogenation, and after reaction absorbed calculated amount hydrogen, elimination palladium charcoal added concentrated hydrochloric acid (10.3ml), concentrates, and reclaims ethanol.Resistates petroleum ether, suction filtration obtain light green title compound (20.57g).Fusing point is 101.5-110 (decomposition).This product does not need further refining next step reaction that is used for.
Embodiment 2:
2,3,4-trifluoro-N-p-toluenesulfonyl aniline (III, X
1=X
2=Y=F, X
3=H, C=Ts)
In ice bath and under agitation condition, (4.15g) joins 2,3 in batches with Tosyl chloride, in the solution of 4-trifluoromethyl aniline hydrochloride (4g), pyridine (7.1ml) and methylene dichloride (40ml).This mixture stirring reaction 20 hours.Add dilute hydrochloric acid solution.Organic layer extracts with dilute sodium hydroxide.The extraction liquid washed with dichloromethane neutralizes with dilute hydrochloric acid again.Obtain white solid, suction filtration, washing obtains title compound (5.86g) after the drying.Molten point is 120.5-121.3 ℃.
1H nucleus magnetic resonance (CCl
4) δ: 2.40 (3H, s) .6.65-7.10 (1H, m), 7.10-7.50 (1H, m), 7.25 (2H, d, J=9Hz), 7.7 (2H, d.J=9Hz).
Embodiment 3:
N-(1-ethoxycarbonyl-ethyl)-N-(2,3,4-trifluorophenyl) 3-para toluene sulfonamide (VIII, X
1=X
2=Y=F, X
3=H, B=Ts, R
1+ R
2=Me+H, R=Et)
In 2; 3; (100mg adds toluene (10ml), tetra-n-butyl ammonium bromide (30mg) and 2-(tolysulfonyl oxygen base) ethyl propionate (90mg) to 4-trifluoro-N-p-toluenesulfonyl aniline in 2N sodium hydroxide (0.175ml) and water (0.6ml) mixing solutions.Reaction mixture stirring and refluxing 18.5 hours under nitrogen protection.After the cooling, filter insoluble substance, filtrate is used dilute hydrochloric acid respectively, dilute sodium hydroxide liquid and water washing, and the organic layer anhydrous magnesium sulfate drying concentrates and obtains title compound (107mg).
1H nucleus magnetic resonance (CCl
4) δ: 1.25 (3H, t, J=7Hz) .1.26 (3H, d, J=7Hz), 2.46 (3H, s), 4.10 (2H, q, J=7Hz), 4.86 (1H, q, J=7Hz) 6.65-7.10 (1H, m), 7.10-7.50 (1H, m), 7,25 (2H, d, J=8.5Hz), 7.62 (2H, d, J=8.5Hz).
Embodiment 4:
(R)-(-)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3, a 4-trifluorophenyl) para toluene sulfonamide (VIII, X
1=X
2=Y=F, X
3=H, B=Ts, R
1=H, R
2=Me, R
3=Et)
Press embodiment 3 working method, 2,3,4-trifluoro-N-para toluene sulfonamide (10.0g) and (S)-(-)-2-(tolysulfonyl oxygen base) ethyl propionate (9.04g) ([α]
D 23-28.16, N-alkylation reaction CHCl3) takes place and generates title compound (12.27g) in C=2.2.[α]
D 22.5—1.345，(C＝4.4，CHCl
3)。
Embodiment 5:
(S)-(+)-N-(1-ethoxycarbonyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (VIII, X
1=X
2=Y=F, X
3=H, B=Ts, R
1=Me, R
2=H, R
3=Et)
Press embodiment 3 working method, 2,3,4-trifluoro-N-para toluene sulfonamide (15.0g) and (R)-(+)-2-(tolysulfonyl oxygen base) ethyl propionate (13.56g) ([α]
D 2035.35, C=2, CHCl
3) N-alkylation reaction takes place obtain title compound (16.7g).
Embodiment 6:
N-(1-methyl-2-benzyloxy ethyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (VI, X
1=X
2=Y=F, X
3=H, Z=Ts, R
1+ R
2=Me+H, R=PhCH
2)
By similar embodiment 3 working method, 2,3, N-alkylation reaction (106mg) takes place with 1-benzyloxy-2-tolysulfonyl oxygen base propane (44.5-46 ℃ of fusing points) and obtains title compound (115mg) in 4-trifluoro-N-para toluene sulfonamide (100mg).Fusing point is 94.5-96.5 ℃.
Embodiment 7:
N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (VIII, X
1=X
2=Y=F, X
3=H, Z=Ts, R
1+ R
2=Me+H)
Under agitation condition, absolute ether (2ml) solution of the product (460mg) that dropping embodiment 3 obtains in the muddy liquid of past Lithium Aluminium Hydride (76mg) and absolute ether (2ml).Stir under this mixture room temperature after 2 hours, add Na
2SO410H
2O filters, filtrate concentrate light yellow crystal.Use 95% ethanol, one sherwood oil (30-60 ℃) recrystallization again, thereby obtain the title compound (313mg) of white crystal.Fusing point is 124-126 ℃.
1H nucleus magnetic resonance (CDCl
3) δ: 0.97 (d, 3H, J=7Hz), 2.00 (s, 1H), 2.43 (S, 3H), 3.00～3.65 (m, 2H), 4.35 (m, 1H), 6.70-7.32 (m, 2H), 7.30 (d, 2H, J=8.5Hz), 7.72 (d, 2H, J=8.5Hz)
Embodiment 8:
N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (VIII, X
1=X
2=Y=F, X
3=H, Z=Ts, R
1+ R
2=Me+H)
The mixture of product (50mg), ethyl acetate (10ml) and 5% palladium charcoal (30mg) that embodiment 6 obtains, the room temperature normal pressure leads to hydrogen.After hydrogenolysis was intact, elimination palladium charcoal reclaimed solvent and gets white solid, and with sherwood oil (30-60 ℃) washing, suction filtration obtains title compound (35mg).Fusing point is 124.5-126.5 ℃.
The Rf value of its TLC is the same with the product Rf value of embodiment 7.
Embodiment 9:
(R)-(-)-N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (VII, X
1=X
2=Y=F, X
3=H, Z=Ts, R
1=H, R
2=Me)
Press embodiment 7 working method, the product (5.00g) that makes with Lithium Aluminium Hydride (678mg) reduction embodiment 4, thus obtain title compound (2.82g).Fusing point is 83-85.5 ℃.[α]
D 23—47.7(C＝2，CHCl
3)。
Embodiment 10:
(S)-(+)-N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (VIII, X
1=X
2=Y=F, X
3=H, Z=Ts, R
1=Me, R
2=H).
Press embodiment 7 working method, the product (11g) that makes with Lithium Aluminium Hydride (1.4g) reduction embodiment 5, thus obtain title compound (6.57g).Fusing point is 81.5-83.2 ℃, [α]
D 19.551.43 (C=2, CHCL
3).
Embodiment 11:
7,8-difluoro-3,4-dihydro-3-methyl-4 one p-toluenesulfonyls-2H-[1,4] benzoxazine (V, X
1=X
2=F, X
3=H, Z=Ts, R
1+ R
2=Me+H).
7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazines (0.25g) are (by 2-acetone oxygen base-3,4-difluoro nitrobenzene is pressed EP47005 method preparation), the mixture stirring of methylene dichloride (5ml) and pyridine (0.81g) 15 minutes, add Tosyl chloride (0.26g) again.Reaction solution under agitation refluxed 20 hours.Cooling is with dilute hydrochloric acid and washed several times with water.Tell organic layer, with concentrating behind the anhydrous magnesium sulfate drying.Residue (0.305g) is separated out crystallization, gets title compound (0.190g) with tetracol phenixin-sherwood oil recrystallization.Fusing point is 121-122.5 ℃.Mass spectrum: 339 (M
+).
1H nucleus magnetic resonance (CDCl
3) δ: 1.23 (d, 3H, J=7H2), 2.41 (s, 3H), 3.2 (dd, 1H, J
1=3Hz, J
2=11Hz), 3.96 (d, 1H, J=11Hz), 4.5 (m, 1H), 6.4-7.1 (m, 1H), 7.25 (d, 2H, J=8.5Hz), 7.52 (d, 2H, J=8.5Hz), 7.55-7.93 (m, 1H).
Embodiment 12:
7,8-difluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X
1=X
2=F, X
3=H, Z=Ts, R
1+ R
2=Me+H).
N under 120 ℃ temperature-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-para toluene sulfonamide (75mg) (product that obtains by embodiment 7), N, the mixture stirring reaction of N-dimethyl formamide (7.5ml) and salt of wormwood (58mg) 1 hour 20 minutes, the elimination insoluble substance is concentrated filtrate then.The residue that is generated ethanol-sherwood oil (30-60 ℃) crystallization, thus white title compound (62mg) obtained.Fusing point is 122-123.5 ℃.Mass spectrum: 339 (M
+)
1The product that H-NMR collection of illustrative plates and embodiment 11 obtain
1H-NMR collection of illustrative plates is the same.
Embodiment 13:
(R)-(+)-7,8-difluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X
1=X
2=F, X
3=H, Z=Ts, R
1=H, R
2=Me
Press embodiment 12 working method, ring-closure reaction takes place in the product that embodiment 9 makes (0.74g), thereby obtains title compound (0.55g).Fusing point is 128.5-131 ℃.Mass spectrum: 33.9 (M
+).
Embodiment 14:
(S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X
1=X
2=F, X
3=H, Z=Ts, R
1=Me, R
2=H)
Press embodiment 12 working method, ring-closure reaction takes place in the product that embodiment 10 makes (1g), thereby obtains title compound (0.73g).Fusing point is 128-131 ℃, [α]
D 27-114.96 (C=1, CHCl
3).
Embodiment 15;
7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (XV, X
1=X
2=F, X
3=H, R
1+ R
2=Me+H)
Under logical nitrogen and agitation condition, drip the solution that naphthalene (840mg) and glycol dimethyl ether (3ml) form in the mixture of past granular metal sodium (152mg) and glycol dimethyl ether (3ml).Reaction solution becomes dark green and black.Continue to stir 1 hour 40 minutes, drip the solution of product (30mg) in glycol dimethyl ether (3ml) that embodiment 12 makes then.Mixture stirred after 2 hours, added entry (0.12ml) and concentrated hydrochloric acid (0.55ml) successively, concentrated again.Resulting residue through ether (after 5 * 2ml) washings, extract with ethanol (7ml), the elimination insolubles, filtrate concentrates, the enriched material water dissolution, the elimination insolubles extracts then with dilute sodium hydroxide accent filtrate alkalize, and with benzene again.Organic layer washes with water, uses anhydrous magnesium sulfate drying again, concentrates then, thereby obtains title compound (10mg).
The Rf of its TLC and
1The H nuclear magnetic resonance data is with to press the EP47005 method the same by the Rf and the 1H nuclear magnetic resonance data of 2-acetone oxygen base-title compound that 3,4-difluoro nitrobenzene makes.
1H nucleus magnetic resonance (CCl
4) δ: 1.20 (d, 3H, J=6Hz), 3.2-3.67 (m, 2H), 3.8 (t, 1H, J
1=8Hz), 4.23 (dd, 1H, J
1=2Hz, J
2=10Hz), 6.2 (m, 1H), 6.5 (m, 1H).
Embodiment 16:
(R)-(+)-7.8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (XV, X
1=X
2=F, X
3=H, R
1=H, R
2=Me)
Press embodiment 15 working method, the product that embodiment 14 makes (0.400g) deaminize protecting group, the amine that dissociates, thus obtain title compound (0.199g).[α]
D 17＋8.199(C＝1.66，CHCL
3)。Mass spectrum: 185 (M
+).
Embodiment 17:
(S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (XV, X
1=X
2=F, X
3=H, R
1=Me, R
2=H)
Press embodiment 15 working method, the product that embodiment 15 makes (0.250g) deaminize protecting group, the amine that dissociates, thus obtain title compound (0.110g).[α]
D 27—7.85(C＝2.2，CHCl
3)。
Repeat top-operation, the product (0.235g) that makes from embodiment 15 prepares title compound (0.100g).
1H nucleus magnetic resonance (CCl
4): δ 1.183 (d, 3H, J=6Hz), 3.183-3.6 (m, 2H), 3.73 (t, 1H, J
1=10Hz, J
2=8Hz), 4.2 (dd, 1H, J
1=10Hz, J
2=2.5Hz), 6.2 (m, 1H), 6.5 (m, 1H).
Claims (17)
1, racemization or have optically active compound, its chemical formula is:
X wherein
1And X
2And X
3Can be identical or different, each represents halogen atom or X
1, X
2, X
3One of them is a hydrogen atom, and all the other are halogen atom, and Y is a halogen atom, and A is-CH
2The OR base, wherein R is the protecting group of hydrogen atom or hydroxyl, or A is-COOR
3Base, R
3The expression hydrogen atom, the alkyl of 1 to 6 carbon or the protecting group of carboxyl, R
1And R
2Both one of for containing the alkyl of 1 to 4 carbon, another is a hydrogen atom, Z is a hydrogen atom ,-CH=C (COOR
4)
2Base, wherein R
4Be the alkyl of 1 to 6 carbon, or Z is-SO
2R
5The base or-COR
5Base, R
5Be alkyl or substituted hydrocarbon radical.
2, by the compound of claim 1, wherein Z is-SO
2R
5Base, R
5Be alkyl or substituted hydrocarbon radical.
3, by the compound of claim 2, wherein A is-CH
2OR base, R are the protecting group of hydrogen atom or hydroxyl.
4, by the compound of claim 2, wherein A is-COOR
3Base, R
3Be hydrogen atom, the alkyl or the carboxyl-protecting group of 1 to 6 carbon.
5, by the compound of claim 3, chemical name is (S)-(+)-N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-right-toluol sulfonamide.
6, by the compound of claim 3, chemical name is (R)-(-)-N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-to a toluol sulfonamide.
7, by the compound of claim 3, chemical name is (±)-N-(1-methyl-2-hydroxyethyl)-N-(2,3,4-trifluorophenyl)-right-toluol sulfonamide.
8, by the compound of claim 3, chemical name be (±)-N-(1-methyl-2-benzyloxy ethyl)-N-(2,3,4-trifluorophenyl-to a toluol sulfonamide.
9, by the compound of claim 4, chemical name is (S)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3,4-trifluorophenyl)-to a toluol sulfonamide.
10, by the compound of claim 4, chemical name is (R)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3,4-trifluorophenyl)-right-toluol sulfonamide.
11, by the compound of claim 4, chemical name is (±)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3,4-trifluorophenyl)-right-toluol sulfonamide.
12, racemization or have optically active compound, its chemical formula is:
Wherein, X
1, X
2And X
3Can be identical or different, each represents halogen atom or X
1, X
2And X
3One of them is a hydrogen atom, and all the other are halogen atom, R
1And R
2Both one of for containing the alkyl of 1 to 4 carbon, another is a hydrogen atom, B is-SO
3R
5Base (R
5Be alkyl or substituted hydrocarbon radical).
13, by the compound of claim 1, chemical name is (±)-7,8-difluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine.
14, by the compound of claim 12, chemical name is (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine.
15. by the compound of claim 12, chemical name is (R)-(+)-7,8-difluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine.
16, the method for (I) formula compound of preparation claim 1,
X wherein
1, X
2, X
3, Y, A, R
1, R
2Identical with the Z implication with claim 1, it is characterized in that compound with chemical formula (III),
X wherein
1, X
2, X
3Have implication as mentioned above with Y, C is-CH=C (COOR
4)
2Base (R
4Be the alkyl of 1 to 6 carbon) ,-SO
2R
5The base or-COR
5Base (R
5Be alkyl or substituted hydrocarbon radical),
Compound with chemical formula (IV)
R wherein
1, R
2Having as mentioned above, implication D is-CH
2The OR base, wherein R is that the protecting group or the D of hydroxyl are-COOR
3Base, R
3Expression, the alkyl of 1-6 carbon or the protecting group of carboxyl, X comprises mesyloxy for the reaction leavings group, trifluoro-methanesulfonyl oxy, phenylsulfonyloxy, tolysulfonyl oxygen base, halogen, triphenyl phosphine oxygen base etc.,
Reaction in the presence of alkali and phase-transfer catalyst, generating Z is not hydrogen, R is not hydrogen, R in the A group
3It is not (I) formula compound of hydrogen.
(I) in the formula compound, Z is a hydrogen atom, and R is hydrogen atom, R in the A group
3Being the compound of hydrogen atom, is not that R is not hydrogen, R in hydrogen, the A group by Z
3Do not go protecting group to obtain for (I) formula compound of hydrogen.
17, with (I) formula compound (V) formula compound,
X wherein
1, X
2, X
3, R
1, R
2Identical with the Z implication with claim 1.It is characterized in that compound with chemical formula (VI),
X wherein
1, X
2, X
3, Y, Z, R
1, R
2Implication is identical with claim 1, and R is a hydroxyl protecting group, and the dehydroxylation protecting group obtains the compound of chemical formula (VII);
Or, make the compound of chemical formula (VII) with going back original reagent,
X wherein
1, X
2, X
3, Y, R
1And R
2Implication is identical with claim 1, R
3Be hydrogen atom or alkyl, B is-SO
2R
5Base, R
5Be alkyl or substituted hydrocarbon radical,
Be reduced into wherein Z=SO of chemical formula (VII)
2R
5Compound
The compound of the chemical formula (VII) that above-mentioned two kinds of methods make, wherein X
1, X
2, X
3, R
1, R
2, Y is identical with claim 1 with the Z implication, has the reaction that issues living molecule inner ring condensation at alkali, makes the compound of chemical formula V,
(V) in the formula compound, Z is the compound of hydrogen atom, can also be-SO by Z
2R
5Or-COR
5Compound, R wherein
5Be alkyl or substituted hydrocarbon radical, protecting group obtains in the denitrogenation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94107432A CN1066136C (en) | 1994-07-21 | 1994-07-21 | Intermediate of pyrido-benzoxazine derivative and prepn. method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94107432A CN1066136C (en) | 1994-07-21 | 1994-07-21 | Intermediate of pyrido-benzoxazine derivative and prepn. method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1115315A true CN1115315A (en) | 1996-01-24 |
| CN1066136C CN1066136C (en) | 2001-05-23 |
Family
ID=5033041
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94107432A Expired - Fee Related CN1066136C (en) | 1994-07-21 | 1994-07-21 | Intermediate of pyrido-benzoxazine derivative and prepn. method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1066136C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009221209A (en) * | 1999-09-08 | 2009-10-01 | Daiichi Sankyo Co Ltd | Method for producing benzoxazine derivative and production intermediate thereof |
| TWI616440B (en) * | 2013-04-30 | 2018-03-01 | ３Ｍ新設資產公司 | Process for preparing poly (benzoxazines) |
-
1994
- 1994-07-21 CN CN94107432A patent/CN1066136C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009221209A (en) * | 1999-09-08 | 2009-10-01 | Daiichi Sankyo Co Ltd | Method for producing benzoxazine derivative and production intermediate thereof |
| JP2009235077A (en) * | 1999-09-08 | 2009-10-15 | Daiichi Sankyo Co Ltd | Method and intermediate for producing benzoxazine derivative |
| TWI616440B (en) * | 2013-04-30 | 2018-03-01 | ３Ｍ新設資產公司 | Process for preparing poly (benzoxazines) |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1066136C (en) | 2001-05-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1119319C (en) | Asymmetric synthesis of (-) 6 -chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1, 4dihydro-2H-3, 1-benzoxazin-2-one | |
| KR960003810B1 (en) | Process for producing optically active benzene-sulfonamide derivatives | |
| CN1680340A (en) | Novel triazolo pyrimidine compounds | |
| CN1106396A (en) | Intermediates useful in the production of aromatic amino-alcohol derivatives having anti-diabetic an21443/o1besity properties | |
| CN1353692A (en) | Betz 2-adrenoceptor agonists | |
| CN1430603A (en) | Novel bicyclic compounds | |
| JP2005505617A (en) | Novel β-phenyl-α-oxy substituted propionic derivatives, processes for their preparation and their use in the production of pharmaceutically important compounds | |
| CN1239487C (en) | Internediate for preparing quetiapin and preparation method of the intermediate | |
| CN87105516A (en) | Phenyl crotonamide compound that replaces and preparation method thereof | |
| CN101062897A (en) | Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof | |
| CN1578762A (en) | Process for resolution of tamsulosin and compounds, compositons, and processes associated therewith | |
| CN1688588A (en) | Process and intermediates for the preparation of thienopyrrole derivatives | |
| CN1066136C (en) | Intermediate of pyrido-benzoxazine derivative and prepn. method | |
| CN1120041A (en) | Novel benzobiulkyl, preparation of same and parmaceutical composition of same | |
| CN1125815C (en) | Method for the synthesis of quinoline derivatives | |
| CN1125073C (en) | Process for preparing (-) pyridobenzoxazine carboxylic acid derivatives | |
| CN1025857C (en) | Process for preparing thiazolo [5, 4-b ] [1, 5] benzodiazepines having pharmacological properties | |
| CN1067391C (en) | Piperidyl methyl oxazolidinone | |
| CN1042531C (en) | Corbostyril derivatives and pharmaceutical compostions contaiming same | |
| WO2006090768A1 (en) | Process for production of optically active ppar-activating compound and intermediate of the same | |
| CN1229359C (en) | Catalytic process for prepn. of thiazole derivatives | |
| CN1083843C (en) | 2-(aminomethyl)-3,4,7,-9-tetrahydro-2H-pyrano-[2,3-e] indol-8-ones and derivatives | |
| CN1914213A (en) | Process for the preparation of thiazolopyrimidines | |
| CN1100094A (en) | Process for the enantioselective synthesis of alkylated oxindoles used as intermediates in the preparation of physostigmine | |
| CN1037179C (en) | 1,4-benzoxazino derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: China Medicine Research and Development Centre Document name: Deemed a waiver of a patent claim |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |