WO2011116491A1

WO2011116491A1 - Preparation method for nortropine benzilate and its salts and intermediates used in said method

Info

Publication number: WO2011116491A1
Application number: PCT/CN2010/000347
Authority: WO
Inventors: 罗宣德; 刘玉忠; 叶光; 张铭锡
Original assignee: 北京世纪迈劲生物科技有限公司
Priority date: 2010-03-22
Filing date: 2010-03-22
Publication date: 2011-09-29
Also published as: DE112010005112T5; CN102333775A

Abstract

Preparation method for nortropine benzilate or its salts, intermediates used in said method and nortropine benzilate or its salts prepared are disclosed. The preparation method for nortropine benzilate comprises the following steps: using tropine as starting material, forming tropine benzilate by transesterification of tropine with diphenyl hydroxy acetyl imidazole and demethylating tropine benzilate to obtain nortropine benzilate.

Description

Process for preparing diphenyl glycolic acid dehydrobenzoate and its salt and technical field thereof

This invention relates to a novel process for the preparation of decanoic acid esters of diphenylglycolic acid and salts thereof, and to novel intermediates for use in the process.

Background technique

There is a literature on the synthesis of decanthoyl glycolate. VH Batholde et al. (Arzneim. - Forsch, 17, 719-726, 1967) reported the use of tropine as a starting material, cbz protection, and esterification with ct-chloro-diphenylacetyl chloride in the presence of pyridine. α-Chloro-diphenylacetic acid-cbz N-deetropine ester; then, after hydrolysis of the chlorine to a hydroxyl group, the deprotection group is hydrogenated at 10 W / C to obtain nortropine diphenylglycolate. This method is characterized by the removal of cbz by hydrogenation with Pd-C to achieve the purpose of dethiolation, and the acid chloride used for esterification is prepared by using PC1 ₅ . The disadvantage is that the reagents used (PC1 ₅ , pyridine) cause serious pollution to the environment, and the Alpha chlorine is hydrolyzed into a hydroxyl group in the process, which is extremely inconvenient to operate, high in cost, and difficult to purify the product.

Recently, Xu Rongsen et al. (CN 101003535A, 2007-07-25) discloses an improved method with a high yield and a total yield of about 60%. This method starts from a top product, is esterified with a-hydroxy-CC-phenylphenylacetate, and is deaminated with ethyl chlororuthenate and HBr/HAc to obtain a deuterated ester of diphenylglycolic acid. However, the reaction conditions of the method are too severe, it is difficult to control the tropine ester to be not destroyed, and the intermediate bromide is still subjected to the hydrolysis step to obtain the product, which is complicated in operation and difficult to control, and is not suitable for industrial production.

Therefore, there is a need in the art for a novel process for the preparation of diterpene glycolate and its salts. The process is simple in operation, high in yield, low in environmental pollution, and easy to control in quality of finished products, and is suitable for industrialized production.

Summary of the invention

One of the objects of the present invention is to provide a novel method for preparing a diphenylglycolic acid deuterated ester of the following formula (1) and a salt thereof.

The method has the characteristics of mild reaction condition, simple operation, short reaction time, high yield, less environmental pollution, easy control of finished product quality, and is suitable for industrial production.

A second object of the present invention is to provide a novel intermediate for the preparation of the diphenylglycolic acid deuterated ester of the formula (1) and a salt thereof, and a process for the preparation of the intermediate.

Detailed description of the invention

The method of the invention comprises the following steps:

(A) using the following formula (2)

Reacting with diphenylhydroxyacetimidazole of the following formula (3) in a solvent

The diphenyl glycolate hydrazine of the following formula (4) is obtained:

(B) reacting a compound of the formula (4) with a chlorodecanoate to obtain an intermediate of the following formula (5),

Wherein R represents dC ₄ alkyl, halo d-C ₄ alkyl or phenyl; Hal represents hydrogen, chlorine or bromine; optionally isolating the intermediate of formula (5), followed by hydrolysis or alcoholysis to give (1) a diphenyl alcohol acetate deuterated ester; and optionally a compound of the formula (1) is reacted with an acid to obtain a salt of the compound of the formula (1).

According to the present invention, the benzoate of the formula (4) is prepared according to the method described by R. Banholzer et al. (Arzneim. - Forsch, 36 (II), 8, 1161-1166, 1986); Further reacting with chlorophthalic acid ester at 0-100 ° C to obtain an intermediate of formula (5), separating the intermediate and then performing hydrolysis or alcoholysis reaction, or directly purifying the intermediate, directly proceeding to the next step The hydrolysis or alcoholysis reaction gives the diphenyl alcohol acetate deuterated ester of the formula (1); then, the compound of the formula (1) is optionally reacted with an acid to obtain a salt thereof. The reaction process is as follows:

(1) The transesterification of the oxime of the formula (2) and the diphenyl hydroxyacetimidazole of the formula (3) for the transesterification of the benzoic acid ester of the formula (4) in a common inert solvent, preferably an inert solvent From acetone, mercaptoethyl ketone, butanone, tetrahydrofuran, dichloroethane, benzene, toluene, dinonylbenzene, and mixtures thereof. More preferred inert solvents are acetone, butanone, tetrahydrofuran, benzene, and mixtures thereof. The reaction temperature is from room temperature to 11 CTC, preferably from room temperature to 80 °C, more preferably from room temperature to 60 °C. The reaction is from 30 minutes to 10 hours, preferably from 2 to 6 hours.

The reaction of the compound of the formula (4) with chlorodecanoate to prepare a compound of the formula (5) is also carried out in an inert solvent. The inert solvent is selected from the group consisting of chloroform, dichloro-decane, 1,2-dichloroethane, benzene, toluene, diphenylbenzene, and mixtures thereof. Among the preferred solvents are chloroform, dichlorodecane, 1,2-dichloroethane and mixtures thereof.

The reaction temperature is 0-110 ° C, and the preferred reaction temperature is room temperature to 60 ° C. Reaction time is 4 to 20 hours, preferably 10 to 15 hours.

The chlorophthalic acid ester used in the reaction is selected from the group consisting of: benzyl chlorate, ethyl chlorohydrazide, 1-chloroethyl chloroantimonate, 1-bromoethyl chloroantimonate, propyl chloroformate, chloroformic acid 1 -chloropropyl ester, 1-bromopropyl chloroantimonate, butyl chloroantimonate, 1-chlorobutyl chlorate, 1-bromobutyl chlorate, 2, 2, 2-trichloroethane Esters and mixtures thereof. Preference is given to benzyl chloroantimonate, ethyl chloroantimonate, 1-chloroethyl chlorate, propyl chloroformate, butyl chloroantimonate, 1-chloropropyl chloroantimonate and mixtures thereof.

The chlorophthalic acid ester is used in the reaction in an amount of usually 1 to 10 equivalents, preferably 1 to 5 equivalents to the compound of the formula (4).

In a preferred embodiment of the present invention, the above reaction produces an alkoxy or substituted alkoxycarbonyl deuterated intermediate of the formula (5), which is directly subjected to hydrolysis or alcoholysis without isolation to obtain a formula (1). ) compound.

The hydrolysis reaction is a conventional acid hydrolysis reaction, and the acid used is a usual organic or inorganic acid, preferably hydrochloric acid, sulfuric acid, acetic acid, glacial acetic acid and a mixture thereof. More preferred are concentrated hydrochloric acid, aqueous acetic acid and mixtures thereof. The reaction temperature is 10-10 (TC, preferably room temperature to 7 (TC; the reaction time is 5-20 hours, preferably 8-12 hours).

The alcoholysis reaction is a conventional alcoholysis reaction condition. Preferred solvents are decyl alcohol, ethanol, or mixtures thereof or mixtures thereof with water. The reaction temperature is from 10 to 85 ° C, preferably from room temperature to 60 ° C; and the reaction time is from 0.5 to 8 hours, preferably from 1 to 4 hours.

Salts of the compounds of formula (1) include pharmaceutically acceptable salts with organic or inorganic acids. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and the like. Examples of the organic acid include acetic acid, citric acid, citric acid, tartaric acid, ascorbic acid and the like.

The method of the present invention disclosed above has mild reaction conditions, short reaction time, short reaction process, high operation rate, high yield, and easy purification of the finished product. In particular, the desulfurization reaction is extremely mild, the yield is high, the cost is low, and the environment is non-polluting, which is very suitable for industrialized large-scale production.

Another aspect of the invention also provides a novel intermediate of the following formula (5)

(5)

Wherein R represents a dC alkyl group, a halogenated d_C ₄ alkyl group or a phenyl group, and Ha l represents hydrogen, chlorine or bromine. Among the compounds of the formula (5) of the present invention, a particularly preferred compound of the formula (5) is a compound wherein R represents a methyl group and Ha l represents hydrogen or chlorine.

detailed description

The following specific examples are illustrative of the invention and are not to be construed as limiting.

Example 1

Preparation of benzoic acid benzoate (formula 4 compound):

a) Preparation of diphenyl hydroxyacetimidazole (compound of formula 3)

The glycyl imidazole 38. 9 g (0.24 mol) was dissolved in 130 ml of dichloromethane, and the phenylglycolic acid was added in portions, 54. 8 g (0.24 mol), at 15-20. C was stirred and mixed, and after precipitation, the reaction was continued for 2-5 hours. Filtration, washing with dichloromethane (30 ml X 2 ), drying to give diphenylcarbamic acid imide 52 g (94.5%), mp 38-139 ° C (dec), recrystallized from acetone, mp 47-148 ° C.

b) Preparation of benzoic acid benzoate (formula 4 compound)

The pharmaceutically acceptable product of formula (2) 14. lg (0.1 mol) was dissolved in acetone 60 ml, and diphenyl hydroxyacetimidazole (compound of formula 3) 27. 8 g (0.1 mol) was added in portions, as described above. In the solution. After the product was precipitated, the mixture was refluxed for 5 h, cooled to 0 ° C, filtered, washed with acetone, and then dried to give the title compound (3) of benzene benzoate (31.73 g) (yield 90.0%).

Example 2 Preparation of diphenylglycolic acid decodone ester (compound of formula 1):

a) Put benzoic acid tropine ester (formula 4 compound) 512g ( 1.46mol), dissolved in 5L of dichloroethane, and add 1.4L (0.8kg, 7.3mol) of ethyl chloroantimonate at room temperature. , 5 eq.), added, stirred under reflux for 4 h, and concentrated to give a white solid, N- (ethoxycarbonyl) dehydrazide (Compound 5 compound), quantitative yield (100%), recrystallized to yield ( Mp.137- 138 ° C).

Η-匪R (ARX-400, CDC1 ₃ , δ (ppm): 7.33-7.41 (m, 10H), 5.25-5.28 (t, 1H), 4.24 (S, 1H), 4.08—4.12 (m, 4H) , 2.13-2.15 (d, 2H), 1.68-1.71 (d, 2H), 1.61-1.63 (t, 2H), 1.23-1.26 (m, 5H)].

The above pure product lOg (0.024mol), concentrated hydrochloric acid 75ml, glacial acetic acid 50ml, stirred at 95-100 °C, 1 Oh, concentrated, the residue was added with chloroform 50ml, sterol 30ml and water 40ml, with stirring The concentrated NaOH reaction adjusted the pH to 14. Then, the mixture was stirred for 0.5 h, filtered, and the filtrate was partitioned. After stirring with acetonitrile (15 ml) for 0.5 h, it was filtered, washed with acetonitrile and dried to give a white solid, <RTI ID=0.0>>

b) benzoic acid tropine ester (4) 51.2g (0.146mol), soluble in 1,2-dichloroethane

In 500 ml, 140 ml (159.6 g, 1.47 mol) of ethyl chloroantimonate was added thereto with stirring, and reflux reaction was added for 24 hours; the solvent was concentrated to remove and recrystallized to give an intermediate of hydrazine-ethoxycarbonyl dehydrazone.

[Ή-NMR (ARX-400, CDC1 ₃ , δ (ppm): 7.32- 7.42 (m, 10H), 5.26-5.28 (t, lH), 4.24 (S, 1H), 4.08-4.13 (m, 4H) , 2.13-2.16 (d, 2H), 1.67-1.70 (d, 2H), 1.60-1.62 (t, 2H), 1.20-1.25 (m, 5H) ].

To the above intermediate, 450 ml of concentrated hydrochloric acid and 300 ml of glacial acetic acid were added, and the mixture was reacted at 95-100 ° C for 15 hours with stirring, and concentrated. To the residue was added 400 ml of chloroform and 200 ml of water, and alkalized with sodium hydroxide solution with stirring. The organic layer was washed with water (200 ml) and concentrated to dryness to afford white solid, diphenylglycolic acid, decantamine (compound of formula 1), 30.0 g, yield 61%. MS: [M+1] +338.1. c) Put benzoic acid benzoate (Compound 4) 120 kg of 10.2 kg, 1,2-dichloroethane into a 300 L reaction kettle, stir, add 31.8 kg of ethyl chloroantimonate, and heat and reflux for 24 h. After completion of the reaction, the mixture was concentrated to dryness to give N- ethoxycarbonyl dehydrazide intermediate 11.9 kg.

The intermediate 11.9 kg, concentrated hydrochloric acid 100 kg, and acetic acid acetic acid 62.4 kg were put into a 300 L reaction kettle, stirred, heated at 95-100 ° C for 14 h, and the reaction solution was concentrated to dryness; chloroform 88.6 kg, water was added to the residue. 47.6 kg. The mixture was alkalized with aqueous sodium hydroxide solution with thorough stirring, stirred for 30 minutes, and allowed to stand for stratification. The lower layer was washed with 30 kg of water, and concentrated to dryness to obtain diphenyl glycolic acid to remove the ester (1) 6.25 kg, yield 50%. The content of HPLC was determined to be 99.2%;

MS: [M+U+338.1 ₀ ['H-NMR (ARX-400, CDC1 ₃ , δ (ppm): 9.56 (S, 2H), 7.31-7.39 (m, 10H), 5.24-5.26 (t, 1H ), 3.83 (S, 2H), 2.58-2.64 (m, 2H), 1.79-1.87 (m, 4H), 1.19-1.27 (m, 2H) ].

d) benzoic acid tropine ester (compound of formula 4) 35. lg (0. lmol) is dissolved in 350 ml of 1,2-dichloroethane, and benzyl chloride chlorate (25.65 g (0.15 mol) is added under (TC) The reaction mixture was stirred at room temperature overnight, until the reaction was completed by TLC, and the solvent was evaporated under reduced pressure to give the crude product of N-(benzyloxycarbonyl) dehydrazide intermediate. 150 ml of decyl alcohol, stirred at room temperature 2h, until TLC detected the reaction was completed, methanol was evaporated, and the residue was dissolved in 80 ml of tert-butyl oxime ether, filtered, and the insolubles were removed, and the solvent was evaporated to give 38.81 g of toltolide of diphenylglycolate in a yield of 90%. Example 3

Preparation of Diphenylglycolic Acid Dehydrotropin (Compound of Formula 1):

a) The decanoic acid ester of diphenylglycolate obtained in Example 2b (1) is treated with a solution of hydrogen chloride or a solution of guanidinium chloride to obtain a hydrochloride salt of decanoic acid (formula 1).

b) Diphenyl glycolic acid tropine ester (4) 35. lg (0. lmol) is dissolved in 350 ml of 1,2-dichloroethane, and 54.0 ml of chloropuric acid-1-chloroethyl ester (about 71.5 g, 0.5 mol, 5. Oeq.); The reaction mixture was heated under reflux for 5 h, and the solvent was concentrated to give N-(l-chloroethoxycarbonyldehydrazide ester intermediate, recrystallized to yield pure product.

['H-NMR, (ARX-400, CDC1 ₃ , δ (ppm): 7.26-7.42 (m, 10H), 6.56-6.59 (t, 1H), 5.27-5.29 (t, 1H), 4.13-4.22 ( m, 3H) , 2.17-2.18(m, 2H), 1.75-2.18 (m, 2H) , 1.75-1.79 (m, 5H) , 1.709-1.714 (m, 2H), 1.91-1.24 (m, 2H) ].

To the above intermediate, 150 ml of decyl alcohol was added, and the mixture was stirred at room temperature for 2 hr. The decyl alcohol was evaporated, and the residue was dissolved in diethyl ether (80 ml), filtered, and the insolubles were removed, and the solvent was evaporated to give diphenylglycolic acid. g, yield 75.0%, determined by HPLC, content 99.6%.

[Ή-NMR (ARX-400, CDC1 ₃ , δ (pm): 9.56 (S, 2H), 7.31-7.39 (m, 1 OH)

5.24-5.26 (t, 1H), 3.84-4.30 (1H), 3.83 (S, 2H), 2.58-2.64 (m, 2H), 1.79-1.87 (m, 4H), 1.19-1.27 (m, 2H) ] .

c) 50 kg of phenyl benzoate, 313 kg of 1,2-dichloroethane, put into a 500 L reaction kettle, stir and dissolve, add 40.8 kg of chloroantimonic acid 1-chloroethyl ester, temperature control 75 ° C The reaction was stirred for 6 h. After completion of the reaction, the mixture was concentrated, crystals were precipitated, 142 kg of decyl alcohol was added, and the reaction was stirred at 25 ° C for 1 h, and a solution of hydrogen hydrazide (25%) 20.8 kg was added, and the mixture was stirred for 1 hour, and concentrated to dryness. Add 130kg of absolute ethanol, stir and stir to dissolve, and filter out insoluble matter. The filtrate is stirred and cooled to precipitate solid. It is cooled to room temperature at about 20 °C for 4h, then reduced to 5 °C, suction filtered, with 0-5 °C. After washing with ethanol, after drying, it was dried at 50 ° C to obtain 42.6 kg of diphenyl glycolic acid dehydrobenzoate hydrochloride, and the yield was 80%.

d) diphenyl glycolate (4) 35. lg (0. lmol) is dissolved in 400 ml of 1,2-dichloroethane, and chloric acid-2, 2, 2-3 is added at 0 °C. Chloroethyl ester 27.5 ml (about 42.4 g, 0.2 mol, 2 eq.). The reaction mixture was stirred at room temperature overnight until the reaction was completed, the solvent was removed to give N-2,2,2-trichloroethoxycarbonyl dehydrazide ester intermediate; 200 ml of decyl alcohol, stirred at room temperature for 2 h, evaporated The sterol was dissolved in 100 ml of diethyl ether, filtered, and the insoluble material was removed, and the solvent was evaporated to give 31.7 g of diphenylglycolic acid decanoate (1) in a yield of 85%.

e) Dissolving the diphenyl glycolic acid tropate of formula (4) 35. lg (0.1 mol) in 350 ml of 1,2-dichloroethane, adding 1-chloropropyl chlorohydrate 32.8 The reaction mixture was stirred at room temperature overnight, until the reaction was completed by TLC, and the solvent was removed under reduced pressure to give crude N-(l-chloropropoxycarbonyl)-dehydrazide intermediate. 150 ml of ethanol was added and stirred at room temperature for 2 h, and the reaction was completed by TLC. Ethanol was evaporated under reduced pressure, and the residue was dissolved in 80 ml of tert-butyl oxime ether, filtered to remove insolubles, and the solvent was evaporated to give diphenylglycolic acid. The ester was 38.38 g, and the yield was 89%. The solution was treated with a hydrochloric acid/ethanol solution to obtain a diphenyl glycolic acid dehydrobenzoate ester.

Claims

1. A method for preparing a diglycolic acid decodone ester of the following formula (1) or a salt thereof:

(1 )

The method includes:

(A) using the following formula (2)

(2)

Reaction with diphenyl hydroxyacetimidazole of the following formula (3) in an inert solvent

(3)

Obtaining Diphenylglycolic Acid Trotine I of the following formula (4)

(4);

(B) reacting a compound of the formula (4) with a chlorophthalic acid ester in an inert solvent to obtain a middle formula (5)

Wherein R represents dC ₄ alkyl, dC ₄ alkyl or benzyl; Ha l represents hydrogen, chlorine or bromine; the intermediate of formula (5) is isolated and then subjected to hydrolysis or alcoholysis, or is not isolated (5) The intermediate is directly subjected to hydrolysis or alcoholysis to obtain a diphenyl alcohol acetate deuterated ester of the formula (1); and optionally a compound of the formula (1) is reacted with an acid to obtain a salt of the compound of the formula (1) .

The method according to claim 1, wherein the chlorophthalic acid ester used in the step (B) is selected from the group consisting of benzyl chlorate, ethyl chlorohydrazide, 1-chloroethyl chlorate, and chlorodecanoic acid 1- Bromoethyl ester, propyl chloroantimonate, 1-chloropropyl chloroantimonate, 1-bromopropyl chloroformate, butyl chloroantimonate, 1-chlorobutyl chloroantimonate, 1-bromobutyl chlorate , 2, 2, 2-trichloroethyl chlorodecanoate and mixtures thereof.

3. The method of claim 2, wherein the chlorophthalic acid ester is selected from the group consisting of: benzyl chlorate, ethyl chloroacetate, 1-chloroethyl chloroantimonate, propyl chloroantimonate, chloranil Butyl acrylate, 1-chloropropyl chloroformate and mixtures thereof.

4. The method of claim 1, wherein the inert solvent used in the step (B) is selected from the group consisting of: chloroform, dichlorodecane, 1,2-dichloroethane, benzene, toluene, diphenylbenzene, and the like mixture.

The method according to claim 1, wherein the intermediate of the formula (5) obtained in the step (B) is not isolated and purified, and is directly subjected to an alcoholysis reaction to obtain a diphenyl alcohol acetate deuterated ester of the formula (1).

6. The process of any of claims 1-5, wherein the alcoholysis reaction is carried out in ethanol, decyl alcohol or a mixture thereof, and optionally in the presence of HCl / HAc.

The method according to any one of claims 1 to 5, wherein the reaction of the step (B) is carried out at a temperature of from room temperature to 60 °C.

8. The method of any one of claims 1 to 5, wherein the salt of the compound of formula (1) is the hydrochloride salt thereof.

9. Compounds of the following formula (5):

(5)

Wherein R represents (^-(: ₄ alkyl, substituted - C ₄ alkyl or phenyl, and Hal represents hydrogen, chlorine or bromine.

10. A compound of claim 9 wherein R represents methyl and Hal represents hydrogen or chlorine.

A nordroxanol nortropin or a salt thereof prepared by the method according to any one of claims 1-8.