CN110551129A

CN110551129A - preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester

Info

Publication number: CN110551129A
Application number: CN201910664445.2A
Authority: CN
Inventors: 刘月领; 任文武; 周强; 徐富军; 王瑞琪; 陈佩; 张莉莉; 李贺山; 安自强; 杨芳; 何燕平; 刘胜攀; 于凌波; 马汝建
Original assignee: Changzhou Hequan Pharmaceutical Co Ltd
Current assignee: Changzhou Hequan Pharmaceutical Co Ltd
Priority date: 2019-07-23
Filing date: 2019-07-23
Publication date: 2019-12-10
Anticipated expiration: 2039-07-23
Also published as: CN110551129B

Abstract

₂The invention relates to a preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester, which mainly solves the technical problem that no industrial synthesis method is available at present.

Description

Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester

Technical Field

The invention relates to a preparation method of 2-tert-butyl dihydropyrrolodiazepine dicarboxylate, namely a synthesis method of 2-tert-butyl 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylate (CAS: 1251017-62-5).

Background

4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester and related derivatives have wide application in pharmaceutical chemistry and organic synthesis, and are important medical intermediates. At present, few reports about the synthesis of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester exist, the reaction route is long like the literature, the yield is low, and the method is not suitable for large-scale production in factories. Therefore, it is necessary to develop a synthesis method with easily available raw materials, convenient operation, easily controlled reaction and suitable overall yield.

Disclosure of Invention

The invention aims to develop a synthetic method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester, which has the advantages of easily obtained raw materials, convenient operation, easily controlled reaction and higher yield. Mainly solves the technical problem that no industrial synthesis method is available at present.

The technical scheme includes that the preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester comprises the following steps of firstly dissolving a compound 1 in acetonitrile to react with the compound 2 under the action of potassium carbonate at room temperature to generate a compound 3, secondly, adding sodium borohydride into ethanol to reduce and amine the compound 2 and benzylamine and closing a ring to obtain a compound 4, then adding 10% palladium into an ethanol solution of the compound 4 to remove a benzyl protection group of the compound 4 through hydrogen to obtain a compound 5, then reacting with BOC ₂ O in a methanol solution of the compound 5 to obtain a compound 6, and finally adding sodium hydroxide into a mixed solvent of methanol and water to hydrolyze the compound 6 to obtain a final product 7, wherein the reaction formula is as follows:

The reaction temperature of the first step is 20 ℃, and the reaction time is 12 hours; the second step is that the reaction is carried out for 1 hour at 20 ℃ and then for 12 hours at 80 ℃; the third step is that the reaction is carried out for 20 hours under the conditions of 40 ℃ and 50 psi; the fourth step is reaction at 20 ℃ for 12 hours; the fifth step is carried out at 20 ℃ for 1 hour.

The invention has the beneficial effects that: the invention provides a method for synthesizing 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester, which has the advantages of short synthetic route, 16.8% yield, easy amplification of reaction, convenient operation and industrial application prospect.

Detailed Description

The reaction formula of the invention is as follows:

Example 1: a. compound 1 (100.00 g, 1.05 mol) was dissolved in acetonitrile (500 mL), potassium carbonate (218.00 g, 1.58 mol) was added and stirred for half an hour, then Compound 2 was added dropwise slowly at 0 ℃ and the reaction was stirred for 12 hours at 20 ℃ after the completion of the addition. TLC (petroleum ether/ethyl acetate volume ratio = 2/1) showed the reaction was complete. Water was added to the reaction system, followed by extraction with ethyl acetate three times, and the combined organic phases were purified by silica gel column chromatography to give compound 3 (186.83 g, 901.56 mmol) with a yield of 85.86%.

b. compound 3 (186.83 g, 901.56 mmol) and benzylamine (106.26 g, 991.71 mmol) are dissolved in ethanol (500 mL) and reacted at 20 ℃ for half an hour, followed by addition of sodium borohydride (20.46 g, 540.94 mmol) and stirring at 20 ℃ for an additional 30 minutes. TLC (petroleum ether/ethyl acetate volume ratio =5/1) showed complete consumption of starting material. The reaction solution was heated to 80 ℃ and stirred at that temperature for 12 hours. The reaction solution was quenched with water (200 mL), and distilled under reduced pressure to give a crude product, which was then purified by silica gel column chromatography to give compound 4 (52.00 g, 174.27 mmol) as a white solid in 19.33% yield.

c. Compound 4 (47.90 g, 160.53 mmol) was dissolved in ethanol (800 mL), 10g of 10% palladium on carbon was added, hydrogen gas was substituted 3 times, and the reaction was carried out at 40 ℃ under 50 psi for 20 hours. TLC (petroleum ether/ethyl acetate volume ratio =5/1) showed the starting material was reacted. The reaction was filtered and the filtrate was concentrated under reduced pressure to give crude compound 5, which was used directly in the next step.

d. Compound 5 (33.43 g, 160.52 mmol) was dissolved in ethanol (500 mL) and tert-butoxycarbonylanhydride (38.54 g, 176.57 mmol) was added dropwise. The reaction solution was stirred at 20 ℃ for 12 hours. TLC (dichloromethane/methanol volume ratio = 10/1) showed the reaction was complete. The reaction was concentrated under reduced pressure, water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound 6(60.00 g, crude) as a yellow oil, which was used directly in the next step.

e. Compound 6 (41.40 g, 134.25 mmol, 1.00 Eq) was dissolved in methanol (210 mL) and water H ₂ O (70 mL), sodium hydroxide (26.85 g, 671.25 mmol) was added to the reaction system, stirring was carried out at 20 ℃ for 1 hour TLC (petroleum ether/ethyl acetate volume ratio =5/1) showed the reaction was complete the reaction solution was concentrated under reduced pressure, then washed with ethyl acetate (200 mL), the aqueous phase was dissolved with 1M dilute hydrochloric acid to adjust pH to 4-5, then extracted with dichloromethane (200 mL x 3), the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give the desired compound 4, 5-dihydro-1H, 3H-pyrrolo [1,2-a ] [1,4] diazepine-2, 4-dicarboxylic acid 2-tert-butyl ester as a white solid (33.20 g, 118.44 mmol, 88.22% yield).

δ6.62 (s, 1 H), 6.24-5.91 (m, 2 H), 4.73 (d, J=15.44 Hz, 1 H), 4.32 (d, J=14.11 Hz, 2 H), 4.29-3.93 (m, 2 H), 3.57-3.25 (m, 1 H), 2.92 (s, 1 H),1.54-1.36 (m, 9 H)。

Claims

1. A preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester is characterized by comprising the following steps of firstly dissolving a compound 1 in acetonitrile to react with a compound 2 under the action of potassium carbonate at room temperature to generate a compound 3, secondly adding sodium borohydride to ethanol for reductive amination and ring closing to obtain a compound 4, thirdly adding 10% palladium carbon to ethanol solution of the compound 4 to remove a benzyl protection group of the compound 4 through hydrogen introduction to obtain a compound 5, fourthly reacting with BOC ₂ O in methanol solution of the compound 5 to obtain a compound 6, and fifthly adding sodium hydroxide to the compound 6 in a mixed solvent of methanol and water to hydrolyze the compound 6 to obtain a final product 7, wherein the reaction formula is as follows:

。

2. The method of claim 1, wherein the preparation method comprises the following steps: the reaction temperature of the first step is 20 ℃, and the reaction time is 12 hours.

3. The method of claim 1, wherein the preparation method comprises the following steps: in the second step, the reaction was carried out at 20 ℃ for 1 hour and then at 80 ℃ for 12 hours.

4. The method of claim 1, wherein the preparation method comprises the following steps: in the third step, the reaction is carried out for 20 hours at the temperature of 40 ℃ and under the condition of 50 psi.

5. The method of claim 1, wherein the preparation method comprises the following steps: the fourth step is carried out at 20 ℃ for 12 hours.

6. The method of claim 1, wherein the preparation method comprises the following steps: the reaction temperature in the fifth step was 20 ℃ and the reaction time was 1 hour.