CN110563687B

CN110563687B - Preparation method of 4- (aminomethyl) chroman-3-ol

Info

Publication number: CN110563687B
Application number: CN201910664472.XA
Authority: CN
Inventors: 何燕平; 任文武; 周强; 刘胜攀; 汪冬冬; 刘月领; 徐富军; 焦家盛; 安自强; 王瑞琪; 余沛东; 张莉莉; 陈佩; 于凌波; 马汝建
Original assignee: Shanghai SynTheAll Pharmaceutical Co Ltd
Current assignee: Shanghai SynTheAll Pharmaceutical Co Ltd
Priority date: 2019-07-23
Filing date: 2019-07-23
Publication date: 2022-09-30
Anticipated expiration: 2039-07-23
Also published as: CN110563687A

Abstract

The invention relates to a preparation method of 4- (aminomethyl) chroman-3-ol, which mainly solves the technical problem that no industrial synthesis method is available at present. The synthesis method comprises four steps of firstly, generating a compound 2 by a compound 1 and a compound sodium cyanide in a solvent N-dimethylformamide, then reacting the compound 2 with ethyl bromoacetate in acetone to obtain a compound 3, then reacting with sodium in acetone to obtain a compound 4, and then reacting with ammonia water and Raney nickel in acetone under the condition of introducing hydrogen to obtain a final compound 5.

Description

Preparation method of 4- (aminomethyl) chroman-3-ol

Technical Field

The invention relates to a synthesis method of 4- (aminomethyl) chroman-3-ol (MFCD 28636717).

Background

4- (aminomethyl) chroman-3-ols and related derivatives have wide applications in medicinal chemistry and organic synthesis. At present, the synthesis of 4- (aminomethyl) chroman-3-ol is very little, and similar literature reactions have certain dangers, long routes and low yield. Therefore, it is necessary to develop a synthesis method with easily available raw materials, convenient operation, easy control of the reaction and suitable overall yield.

Disclosure of Invention

The invention aims to develop a synthetic method of 4- (aminomethyl) chroman-3-ol, 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 of the invention is as follows: the invention relates to a preparation method of 4- (aminomethyl) chroman-3-alcohol, which comprises the following steps of dividing compound 1 into four steps, firstly generating compound 2 by compound sodium cyanide in a solvent of N-dimethylformamide, then reacting with ethyl bromoacetate in acetone to obtain compound 3, then reacting with sodium in acetone to obtain compound 4, and then reacting with ammonia water and Raney nickel in acetone under the condition of introducing hydrogen to obtain final compound 5.

The reaction formula is as follows:

the reaction temperature of the first step is 120 ℃, and the stirring reaction is carried out for 4 hours; the second step is at 25-120 deg.C, and stirring for 4 hr; the third step is that the reaction temperature is 110 ℃ and the reaction lasts for 4 hours; fourth, 50psi hydrogen pressure is applied, the reaction temperature is 50 deg.C, and the reaction time is 4 hours.

The invention has the beneficial effects that: the invention provides a method for synthesizing 4- (aminomethyl) chroman-3-ol, which has the advantages of short route, high yield up to 3.4%, 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(20.00 g, 161.11 mmol) and NaCN (8.69 g, 177.22 mmol) were dissolved in N-dimethylformamide (200.00 mL). The reaction was stirred at 120 ℃ for 4 hours. TLC (petroleum ether/ethyl acetate volume ratio = 2/1) showed the reaction was complete. The reaction was poured into water (600 mL) and the aqueous phase was extracted with ethyl acetate (100 mL x 6). The organic phases are combined, dried over sodium sulfate, filtered and concentrated by distillation under reduced pressure to give the crude product. The crude product was purified by silica gel column (dichloromethane/methanol volume ratio = 10/1) to give compound 2(3.5 g) as yellow oil in 16.32% yield.

b. Compound 2(1.50 g, 11.27 mmol) and ethyl bromoacetate (1.88 g, 11.27 mmol) were dissolved in acetone (30.00 mL) and then potassium carbonate (4.67 g, 33.80 mmol) was added in portions and the reaction solution was slowly raised to 25-120 ℃ and stirring was continued for 4 hours. TLC (petroleum ether/ethyl acetate volume ratio = 3/1) showed the reaction was complete. And filtering the reaction solution, and concentrating the filtrate by reduced pressure distillation to obtain a crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate vol = 10/1) to give compound 3(2.00 g, 9.12 mmol) as a yellow oil in 89.4% yield.

c. Sodium blocks (288.37 mg, 12.54 mmol) were shear-suspended in acetone solution (20.00 mL). The temperature was controlled and stirred for 10 minutes at 110 ℃. Then, compound 3 (2.50 g, 11.40 mmol) was dissolved in toluene (20.00 mL), and compound 3 was added dropwise to the reaction mixture at 110 ℃ while controlling the temperature, and the reaction was continued for 4 hours. TLC (petroleum ether/ethyl acetate volume ratio = 2/1) showed the reaction was complete. The reaction was cooled to 20 ℃ and poured into 10% aqueous acetic acid (100 mL) and extracted twice with ethyl acetate (30 mL x 2). The combined organic phases were washed with water (50 mL) and dried over sodium sulfate, filtered and concentrated by distillation under reduced pressure to give the crude compound 4(1.70 g, crop) as a brown solid. The crude product was used in the next step without purification.

d. Compound 4(300.00 mg, 1.73 mmol) was dissolved in acetone and then ammonia (60.64 mg, 1.73 mmol) and Raney nickel (1.48 g, 17.30 mmol) were added sequentially under nitrogen. Replacing with hydrogen for 3 times, controlling temperature at 50 deg.C, and H ₂ (50 psi) for 4 hours. The reaction turned to yellow TLC (petroleum ether/ethyl acetate volume ratio = 3/1) indicating the end of the reaction. And filtering the reaction solution, and concentrating by reduced pressure distillation to obtain a crude product. The crude product was purified by HPLC (column: Agela Durashell C18150 x 255 u; mobile phase: [ water (0.05% ammonia hydroxide v/v) -ACN]5% -60% of B%, 12min) to obtain red solid compound 5(80.00 mg, 446.38 umol) with a yield of 25.80%.

δ (DMSO) 7.16 (d, J=7.5 Hz, 1H), 7.05 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 4.07 - 4.00 (m, 2H), 3.96 - 3.88 (m, 1H), 2.91 - 2.84 (m, 1H), 2.71 - 2.64 (m, 1H)。

Claims

1. A preparation method of 4- (aminomethyl) chroman-3-ol is characterized by comprising the following steps: the method comprises the following steps of firstly, generating a compound 2 from a compound 1 and a compound sodium cyanide in a solvent of nitrogen-dimethyl formamide, secondly, reacting the compound 2 with ethyl bromoacetate in acetone to obtain a compound 3, thirdly, reacting the compound 3 with sodium in acetone to obtain a compound 4, and fourthly, reacting the compound 4 with ammonia water and raney nickel in acetone under the hydrogen pressure of 50psi to obtain a compound 5; the reaction formula is as follows:

。

2. the process according to claim 1, wherein the reaction mixture comprises the following components: the reaction temperature in the first step is 120 ℃, and the reaction is stirred for 4 hours.

3. The process according to claim 1, wherein the reaction mixture comprises the following components: the second step reaction temperature is 25-120 ℃, and the reaction is carried out for 4 hours under stirring.

4. The process according to claim 1, wherein the reaction mixture comprises the following components: the third step is at 110 deg.C for 4 hours.

5. The process according to claim 1, wherein the reaction mixture comprises the following components: fourth step 50psi hydrogen pressure, reaction temperature 50 deg.C, reaction for 4 hours.