WO2010094210A1

WO2010094210A1 - Preparation method of (4s,5r)-half-ester

Info

Publication number: WO2010094210A1
Application number: PCT/CN2010/000188
Authority: WO
Inventors: 陈芬儿; 熊非
Original assignee: 帝斯曼知识产权资产管理有限公司; 复旦大学
Priority date: 2009-02-18
Filing date: 2010-02-11
Publication date: 2010-08-26
Also published as: CN102325779A

Abstract

The method for preparing the (4S,5R)-half-ester which is the important intermediate of synthesizing the (+)-biotin is provided, which comprises reacting cycloanhydride with alcohol through enantioselective ring opening reaction in the presence of 9-sulfonamide epiquinine catalyst to obtain (4S,5R)-half-ester(I). The materials of reaction are cheap and easy to obtain, the reaction time is short, the operation is simple and the catalyst can be quantificationally recovered. This method has high yield and enantioselectivity, and is suitable for industrial production.

Description

TECHNICAL FIELD OF THE INVENTION The present invention belongs to the field of organic chemistry, and in particular provides a process for the preparation of a (4&5R)-halfester (I).

Wherein R ¹ is hydrogen, ~C ₆ alkyl, phenyl, p-tolyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 3, 4, 5-trimethyl Phenyl, 3, 4, 5-trimethoxyphenyl, p-chlorophenyl, Ar is phenyl, p-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxy Phenyl, 3, 4, 5-trimethylphenyl, 3, 4, 5-trimethoxyphenyl, p-chlorophenyl, thienylphenyl, furyl or naphthyl; R ² is CH 3⁄4 alkyl, C ₃ ~ C ₆ cycloalkyl, C ₂ ~ C ₆ alkenyl, aryl fluorenyl or aralkenyl. Background technique

(4S, 5R)-half ester (I) is an important intermediate for the synthesis of (+)-biotin (( + ) -Biotin, vitamin H).

This compound was first reported by Gerecke et al. (He/v Chim Acta, 1970, 53, 991), which monoesterified cyclic anhydride (II) with cyclohexanol to form racemic cyclic acid monocyclohexanol ester and then pseudoephedrine. (4 & 5i?)-half ester (I) required for the preparation of direct enantiomorphous crystallization; thereafter German Patent 2058234, Chinese Patent 106365, European Patent 92194 and Chen Fener , _2WS1 , 12, U4V) reported by dehydroabietylamine, substituted chiral diphenylethylamine and chloramphenicol by-product (IS, 2S) - threo-p-nitrophenyl) -1, 3- The propylene glycol is a resolving agent for the preparation of (4S, 5R)-half esters (I.) Unfortunately, the above methods all have the common problems of splitting methods such as low single resolution, complicated operation and high cost.

Gerecke et al. (Helv Chim Acta, 1970, 53, 991) reported the reaction of cholesteryl as a chiral auxiliary with a cyclic anhydride (Π) to form a diastereomeric cyclic acid half ester, which was isolated by recrystallization (4 & 5i?)-half ester (I); European Patent 92194 prepared (4S, 5i?)-half ester (I) by optically active substitution of chiral secondary alcohol and tert-butanol as chiral auxiliary agents; Sexual adjuvants are expensive, difficult to prepare, and inconvenient to recycle.

European Patent 84892, Chen Fener et al. Advanced Synthesis & Catalysis, 2005, 3^7, 549) respectively reported the stereoselective hydrolysis of internal diester diesters using pig liver esterase and polymerized pig liver esterase as catalysts. Preparation of (4 & 5i?)-half esters (I); Chinese patents 1473832, 101157655, 101279947 reported the use of chiral amines (1 & 25)-1-(4-nitrophenyl)-2-N, N- Dimethylamino-3-trityloxy-1-propanol, 9-propargylquinine, (1& 2 -3-trimethylsilyloxyamino alcohol as a chiral catalyst for the catalyzed cyclic anhydride ( II ) Asymmetric alcoholysis to prepare (4 & 5i?)-half ester (I), however, all of the above methods are required for the reaction temperature Demanding harshness is not conducive to industrial production.

Chinese Patent 101284832 reports a method for preparing (4 & 5i?)-half ester (I) with high yield and high selectivity at room temperature with 9-equinic urea as a chiral catalyst, which solves the asymmetry The catalytic cyclic anhydride (II) alcoholysis has a severe defect on the reaction temperature, but there are still defects in the reaction time. Summary of the invention

SUMMARY OF THE INVENTION The object of the present invention is to overcome the deficiencies of the prior art and to provide a method for preparing (4 & 5i?)-half ester (I) with mild reaction conditions, short time, high yield and high stereoselectivity.

In the present invention, the cyclic anhydride (II) is subjected to enantioselective ring-opening with an alcohol under the catalysis of a 9-equivalent sulfonamide catalyst (A) to obtain a 5?)-half ester (I total yield > 90%, ee >99%. The synthetic route is as follows:

Wherein R ¹ is hydrogen, C^ fluorenyl, phenyl, p-tolyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethylbenzene , 3, 4, 5-trimethoxyphenyl, p-chlorophenyl, Αι: phenyl, p-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxy Phenyl, 3, 4, 5-trimethylphenyl, 3, 4, 5-trimethoxyphenyl, p-chlorophenyl, thienylphenyl, furyl or naphthyl;

C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, aralkyl or aralkenyl.

In the asymmetric monoesterification of the present invention, the catalyst is a 9-epiquine sulfonamide compound having a structure such as (A), which enables the reaction to be prepared at room temperature under high yield and high stereoselectivity. (4 & 5/?)-half ester (I), the method has a short reaction time, and the chiral catalyst (A) is convenient to synthesize, has a wide range of raw materials, and can be quantitatively recovered, and is suitable for industrial production.

In some embodiments of the invention, the catalyst (A) (R ³ is ethyl, vinyl; R ⁴ is 3, 5-bistrifluoromethylphenyl; R ⁵ is -OR ⁶ , R ⁶ is a methyl group) is a known compound, and a synthesis method thereof is known in the art or synthesized according to a method known to a person skilled in the art.

In some embodiments of the invention, the catalyst (A) (R ³ is ethyl, vinyl; R ⁴ is 4-trifluoromethylphenyl, 4-nitrophenyl, 3, 5 - bis nitrophenyl or cyclohexyl group; R ⁵ is -OR ^{^6,} R ⁶ is methyl) is a new synthesis of the compounds, their synthesis is known in the art or synthesized according to methods known to those skilled in the art.

Wherein R ³ is hydrogen, Ce alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ⁴ is hydrogen, d-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ ~ a C ₆ alkynyl group, a C ₃ -C ₆ cycloalkyl group, an aryl group or a substituted derivative of any of the above groups; R ⁵ is -H or -OR ⁶ , and R ⁶ is a ~C ₆ alkyl group, a C ₃ -C ₆ ring An alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ acyl group, a benzyl group, a benzoyl group, a cinnamyl group or a substituted derivative of any of the above groups.

The alcohol used in the present invention is a ~C ₆ fatty alcohol, a C ₃ -C ₆ cycloalkyl alcohol, a C ₂ -C ₆ enol, an aralkyl alcohol, an aryl enol or an optionally substituted derivative of the above alcohol, such as: Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, cyclohexanol, allyl alcohol, benzyl alcohol, cinnamyl alcohol and the like can be used for the asymmetric monoesterification reaction. These alcohols are inexpensive and readily available, with a wide range of sources. The organic solvent used is a halogenated hydrocarbon (such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.); an aliphatic hydrocarbon (such as hexanyl, heptane, octane, decane, acetonitrile, acetic acid) Ethyl esters, etc.; aromatic hydrocarbons (such as benzene, toluene, xylene, nitrobenzene, etc.); various halogenated aromatic hydrocarbons (such as chlorobenzene, etc.); ether solvents (such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran) Or 1, 4-dioxane, etc.). These solvents come from a wide range of sources, are inexpensive and readily available, and are easy to recycle. The molar ratio of the cyclic anhydride ( Π ) / alcohol / chiral catalyst is 1: 1~10: 0.01 - 2.2, and the reaction can be successfully completed. The reaction temperature is controlled between -20 ° C and 50 ° C, and the reaction time is controlled between 0.5 and 180 min. The reaction is completed.

In the present invention, in the 9-epiquinine sulfonamide catalyst (A), R ³ is ethyl or vinyl; R ⁴ is 3, 5-bistrifluoromethylphenyl; R ⁵ is -OR ⁰ , and R ⁶ is The methyl 9-epiquine sulfonamide catalyst is a preferred chiral catalyst, and the catalyst has the advantages of convenient synthesis, wide source of raw materials, and easy recovery.

In the present invention, the alcohol used is methanol, which is widely available and inexpensive.

In the present invention, the organic solvent used is preferably methyl tert-butyl ether (MTBE), which is environmentally friendly, widely available, and inexpensive.

In the present invention, the molar ratio of the cyclic anhydride (Π) / alcohol / chiral catalyst is preferably 1:3 to 10:0.01 to 1.1. In the present invention, the reaction temperature is preferably in the range of 0 to 25 °C.

In the present invention, the reaction time is preferably from 0.5 to 30 min.

The invention has the advantages of mild reaction condition, short reaction time, simple operation, easy availability of raw materials, high yield and high stereoselectivity of the obtained product, and the catalyst can be quantitatively recovered and applied, and the cost is low, and is suitable for industrial production. detailed description

The following embodiments better illustrate the contents of the present invention, but those skilled in the art will understand that the definition is limited. The scope of the present invention is the claims of the present invention, and is not limited to the embodiments described below.

Example 1 cis-1,3-dibenzylimidazolidin-2-one-2H-furo[3,4-d]Pmazole-2,4,6-trione (33.6 g, 0·10) Ιηο1), Catalyst A (R ³ =-CH=CH ₂ ; R ⁴ =3,5-(CF ₃ ) ₂ C ₆ H _{3 ;} R ⁵ =-OR ⁶ , R ⁶ =CH ₃ ) (6.0 g, 0.01 Mol), methyl tert-butyl ether (1 L) was placed in a dry reaction flask, and anhydrous methanol (40.4 mL, 1 mol) was added dropwise at 25 ° C and stirring was continued for 5 min. After the completion of the reaction, 2M hydrochloric acid (400 mL) was added to the residue, and the mixture was stirred and evaporated to dryness. Filtration, the filtrate was evaporated under reduced pressure to give a white crystalline powder IO--H, Ax Ph, R ² = -CH ₃ , 34.2 g, 93 %), mpl 49 to 150 ° C, [a] _D ²² = +2.74 ° ( c 0.20, CHC1 ₃ )

IR (KBr) : v=2979, 2384, 2281, 1742, 1463, 1229, 1169, 767cm" ¹ .

1H NMR (CDC1 ₃ ): 5=3.54 (s, 1H, OC3⁄4), 4.00-4.04 (m, 2H, C _6a -H, C _3a -H) , 4.16-4.80 (dddd, 4H, 2xCH ₂ C ₆ H ₅ ) , 7.19-7.53 (m, 10H, 2xArH) ppm.

EI-MS: (m/z, %) = 368 (M+, 37), 323 (46), 309 (59), 265 (44), 154 (8), 136 (18), 91 (100) .

Catalyst recovery: The separated aqueous hydrochloric acid layer was adjusted to pH 14 with a 20% NaOH solution, and the precipitated white solid was filtered, and the catalyst was quantitatively recovered by drying.

Example 2 cis-1,3-dibenzylimidazolidin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol), catalyst A (R ³ =-CH=CH ₂ ; R ⁴ =3,5-(N0 ₂ ) ₂ C ₆ H ₃ ; R ⁵ =-OR ⁶ , R ⁶ =CH ₃ ) (5.8 g, 0.01 mol), 1 4-Dioxane (1 L) was placed in a dry reaction flask at 25. C Add propargyl alcohol (58.2 mL, 1 mol) and stir for 5 min. After completion of the reaction, 2 M hydrochloric acid (40 mL) was added to the residue and the mixture was stirred for 10 min, and the organic layer was separated and dried over anhydrous sodium sulfate. Filtration, the filtrate was evaporated under reduced pressure to give a white crystalline powder I-H, Ax= -Ph, R ² =propargyl, 37.2 g, 95%), mpl32.7~135.8 °C, [a] _D ²⁵ = +14.3 ° (c 1.0, CHC1 ₃ ).

Example 3 cis-1,3-dibenzylimidazolidin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol), catalyst A (R ³ =-CH=CH ₂ ; R ⁴ =2-N0 ₂ C ₆ H ₄ ; R ⁵ =-OR ⁶ , ⁶ =CH ₃ ) ( 5.1 g, 0.01 mol), 1, 4-dioxane The ring (0.5 L) was placed in a thousand dry reaction flask, and anhydrous methanol (40.4 mL, 1.0 mol) was added dropwise at 25 ° C, and stirring was continued for 5 min. After completion of the reaction, 2 M hydrochloric acid (400 mL) was added to the residue, and the mixture was stirred for 10 min, and the organic layer was separated and dried over anhydrous sodium sulfate. Filtration, the filtrate was evaporated under reduced pressure to give white crystalline powder IU^-H, Ax=-Ph, R ² ^ -CH ₃ , 33.2 g, 90%), mpl 48-150 ° C, [o;] _D ²² = +2.70. (c 0.20, CHC1 ₃ ).

Example 4 cis-1,3-dibenzylimidazolidin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol), catalyst A (R ³ =-CH=C3⁄4; R ⁴ =4-FC ₆ H ₄ ; R ⁵ =-OR ⁶ , R ⁶ =CH ₃ ) (4.8 g, 0.01 mol), tetrahydrofuran (0.5 L) placed in a dry In the reaction flask, anhydrous methanol (40.4 mL, 1.0 mol) was added dropwise at 25 ° C, and stirring was continued for 24 hours. After completion of the reaction, 2 M hydrochloric acid (400 mL) was added to the residue and stirred for 10 min. Filtration, the filtrate was evaporated under reduced pressure to give a white crystalline powder I-H, Ax=-Ph, R ² = -CH ₃ , 33.5 g, 91%), mpl47~150 °C, [a] _D = +2.70° (c0.20, CHC1 ₃ ).

Example 5 cis-1,3-dibenzylimidazolidin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione (33.6 g, 0.10 mol), catalyst A (R ³ =-CH=CH ₂ ; R=3,5-(CF ₃ ) ₂ C ₆ H ₃ ; R ⁵ =-O ⁶ , R ⁶ =CH ₃ ) (66.0 g, 0.11 mol), methyl The tert-butyl ether (1 L) was placed in a dry reaction flask, and anhydrous methanol (40.4 mL, 1 mol) was added dropwise at 25 ° C and stirring was continued for 0.5 min. After the reaction was completed, 2M hydrochloric acid (400 mL) was added to the residue, and the mixture was stirred for 10 min, and the organic layer was separated and dried over anhydrous sodium sulfate. The filtrate solvent was recovered under reduced pressure to give a white crystalline powder I {R ^ -H, Ax = -Ph, R 2 = -CHs, 33.0 g, 90%), mpl49 ~ 150 ° C, [a] D 22 = + 2.74° (c0.20, CHC1 ₃ ).

Claims

Claim

1, (4 & 5 ?)-half ester (I) preparation method -

R ¹ 9 R ¹

Ar", Ν' N', Ar

H 〉 (-H

R ² 0 ₂ C C0 ₂ H

(I) characterized in that the cyclic anhydride (II) is subjected to enantioselective ring opening with an alcohol in the presence of a 9-epiquinine sulfonamide catalyst (A) to obtain a (4 & 5 ?)-halfester (I):

(II)

Wherein R ¹ is hydrogen, ~C ₆ fluorenyl, phenyl, p-tolyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 3, 4, 5-trimethyl Phenyl, 3,4,5-trimethoxyphenyl, p-chlorophenyl, Ar is phenyl, p-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxy Phenyl, 3, 4, 5-trimethylphenyl, 3, 4, 5-trimethoxyphenyl, p-chlorophenyl, thienylphenyl, furyl or naphthyl; R ² is d~C ₆ An alkyl group, a C ₃ ～C ₆ cycloalkyl group, a C ₂ ～C ₆ alkenyl group, an aryl fluorenyl group or an arylalkenyl group;

The structure of the 9-epiquine sulfonamide catalyst is as shown in A:

A

Wherein R ³ is hydrogen, C^alkyl, C ₂ -C ₆ alkenyl or C ₂ ～C6 alkynyl; R ⁴ is hydrogen, ~C ₆ alkyl, C ₂ ～C ₆ alkenyl, C ₂ ~C ₆ alkynyl, substituted derivatives of C ₃ ~ C ₆ cycloalkyl embankment group, an aryl group or a group of any of the above; R ⁵ is -H or -OR ^{^6,} R ⁶ is Q ~ C ₆ alkyl group, C ₃ ~ C ₆ cycloalkyl a mercapto group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ acyl group, a benzyl group, a benzoyl group, a cinnamyl group or a substituted derivative of any of the above groups;

The alcohol is a fatty alcohol, a C ₃ -C ₆ cycloalkyl alcohol, a C ₂ -C ₆ enol, an aralkyl alcohol, an aryl enol or an optionally substituted derivative of the above alcohol.

The method of claim 1 wherein said cyclic anhydride (II) / alcohol / chiral catalysis The molar ratio of the agent is 1: 1~10: 0.01~2.2; the reaction temperature is -20 ° C ~ 50 ° C; the reaction time is 0.5 ~

3. Process according to claim 1, characterized in that the alcohol used is methanol, allyl alcohol, cyclohexanol, benzyl alcohol or cinnamyl alcohol.

4. The method according to claim 1, wherein the organic solvent is one or more of a halogenated hydrocarbon, an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether solvent.

The method according to claim 4, wherein the organic solvent is toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane.

The method according to claim 1, wherein the cyclic anhydride (II) / alcohol / chiral catalyst has a molar ratio of from 1:3 to 10: 0.01 to 1.1.

7. Process according to claim 1, characterized in that the reaction temperature for the preparation of the half ester (I) from the cyclic anhydride (II) is from 0 to 25 °C.

8. Process according to claim 1, characterized in that the reaction time for the preparation of the half ester (I) from the cyclic anhydride (?) is from 0.5 to 30 min.

The method according to claim 1, wherein R ³ of the quinidine sulfonamide catalyst (A) used is ethyl or vinyl; R ⁴ is an aryl group and a derivative thereof; and R ⁵ is - OR ⁶ and R ⁶ are methyl groups.

10. The method of claim 9, wherein R ⁴ is 3, 5-bistrifluoromethylphenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 3, 5-double Nitrophenyl or cyclohexyl.

The method according to claim 1, wherein the reaction is carried out in an organic solvent at a normal temperature, under normal pressure, under pressure or under reduced pressure.