阅读说明：本技术 一种制备(1r,3s)-3-氨基环戊醇盐酸盐的方法 (Method for preparing (1R,3S) -3-aminocyclopentanol hydrochloride ) 是由 费安杰 叶伟平 周章涛 王杨 程冰心 于 2020-12-17 设计创作，主要内容包括：一种制备(1R,3S)-3-氨基环戊醇盐酸盐的方法,属于有机化学合成领域,为改善现有的价格较贵、手性控制不易等缺点,本发明提供的工艺路线:1)碳酸叔丁酯羟胺在氯化铜与2-乙基-2-唑啉催化下,被氧化成碳酸叔丁酯亚硝酰,然后原位与环戊二烯进行杂狄尔斯-阿尔德反应；2)锌粉-醋酸反应体系下,选择性还原氮-氧键；3)在脂肪酶催化下,与醋酸乙烯酯作用,光学选择性实现手性拆分；4)通过钯碳氢化还原双键；5)在氢氧化锂-甲醇的碱性条件下,脱乙酰基保护；6)在乙酰氯与异丙醇原位制备的氯化氢-异丙醇酸性溶液中,脱碳酸叔丁酯保护,并原位成盐酸盐得目标产物。本发明的有益效果在于本发明合成方法具有路线新颖简短、光学纯度高、成本低等特点。(A method for preparing (1R,3S) -3-amino cyclopentanol hydrochloride belongs to the field of organic chemical synthesis, and aims to overcome the defects of high price, difficult chiral control and the like in the prior art, the provided process route comprises the steps of 1) oxidizing tert-butyl hydroxylamine carbonate into tert-butyl nitrosyl carbonate under the catalysis of copper chloride and 2-ethyl-2-oxazoline, and then carrying out a hetero Diels-Alder reaction with cyclopentadiene in situ; 2) under a zinc powder-acetic acid reaction system, selectively reducing nitrogen-oxygen bonds; 3) under the catalysis of lipase, the chiral separation is realized by the optical selectivity under the action of vinyl acetate; 4) reducing the double bond by palladium on carbon hydrogenation; 5) performing deacetylation protection under the alkaline condition of lithium hydroxide-methanol; 6) in a hydrogen chloride-isopropanol acidic solution prepared by acetyl chloride and isopropanol in situ, carrying out protection on tert-butyl ester by decarburization, and forming hydrochloride in situ to obtain a target product. The method has the advantages of novel and short route, high optical purity, low cost and the like.)

1. A process for preparing (1R,3S) -3-aminocyclopentanol hydrochloride, characterized in that it comprises the steps of:

1) under the catalysis of a catalyst (0.1-0.2 eq.) and a ligand 2-ethyl-2-oxazoline (0.1-0.2 eq.), tert-butyl hydroxylamine carbonate (1.0eq.) is oxidized into tert-butyl nitrosyl carbonate, and then the tert-butyl nitrosyl carbonate and cyclopentadiene (1.5-2.0 eq.) undergo a hetero Diels-Alder reaction in situ to obtain cis-2-oxa-3-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid tert-butyl ester, wherein the reaction temperature is 20-30 ℃;

2) selectively reducing nitrogen-oxygen bonds under a reaction system of a reducing agent (2.0-3.0 eq.) and acetic acid (5.0-15.0 eq.) to obtain an intermediate cis-N- [ 4-hydroxycyclopent-2-en-1-yl ] carbamic acid tert-butyl ester (1.0eq.) of an intermediate cis-2-oxa-3-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid tert-butyl ester;

3) the cis-N- [ 4-hydroxycyclopent-2-en-1-yl ] carbamic acid tert-butyl ester (1.0eq.) reacts with vinyl acetate (3.0-6.0 eq.) under the catalysis of lipase (1-10 wt.%) catalyst, so that cis- (+) -N- [ 4-hydroxyacetyl ester cyclopent-2-en-1-yl ] carbamic acid tert-butyl ester is obtained in an optical selectivity manner, and chiral resolution is realized;

4) hydrogenating and reducing double bonds of cis- (+) -N- [ 4-hydroxyacetyl ester cyclopentyl-2-en-1-yl ] carbamic acid tert-butyl ester through 10% palladium-carbon (5-10 wt%) to obtain an intermediate (1R,3S) -3-carbamic acid tert-butyl ester-1-cyclopentyl-hydroxyacetyl ester;

5) deacetyling and protecting the intermediate (1R,3S) -3-carbamic acid tert-butyl ester-1-cyclopentyl-hydroxyacetyl ester (1.0eq.) under the alkaline condition of alkali (1.5-2.5 eq.) methanol (1.5-2.5 Vol.) to obtain (1R,3S) -3-carbamic acid tert-butyl ester cyclopentanol;

6) and (3) carrying out protection on tert-butyl ester by using the intermediate (+) -3(1.0eq.) in a hydrogen chloride-alcohol solvent acidic solution prepared in situ by using acetyl chloride (1.5-2.5 eq.) and an alcohol solvent (5.0-7.0 Vol.), and carrying out in situ hydrochloride to obtain the target product (1R,3S) -3-aminocyclopentanol hydrochloride.

2. The process for preparing (1R,3S) -3-aminocyclopentanol hydrochloride according to claim 1, wherein the catalyst required in step 1) is cupric chloride and/or cuprous chloride.

3. The process for preparing (1R,3S) -3-aminocyclopentanol hydrochloride according to claim 1, wherein the reducing agent required in step 2) is zinc powder, iron powder and/or manganese powder.

4. The method for preparing (1R,3S) -3-aminocyclopentanol hydrochloride according to claim 1, wherein the Lipase catalyst required in step 3) is Novozym 435, Lipozyme TL, Lipozyme RM, Lipozyme40086 and/or Lipase PS "Amano" SD.

5. The process for preparing (1R,3S) -3-aminocyclopentanol hydrochloride according to claim 1, wherein the base required in step 5) comprises lithium hydroxide, sodium hydroxide, potassium hydroxide and/or cesium hydroxide.

6. The (1R,3S) -3-aminocyclopentanol hydrochloride characterized in that the (1R,3S) -3-aminocyclopentanol hydrochloride is prepared by the method according to any one of claims 1 to 5.

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing (1R,3S) -3-aminocyclopentanol hydrochloride.

Background

The method of (1R,3S) -3-aminocyclopentanol hydrochloride is a key chiral intermediate of an anti-AIDS drug Bictegravir.

(1R,3S) -3-aminocyclopentanol hydrochloride structural formula

Currently, there are three main synthetic routes for this intermediate. As shown in a synthetic route 1, a chiral source (-) -Vince with high price is used, a target product is obtained through five steps of reactions, chiral control is advantageous, but cost control of the route is difficult due to the high price of starting materials, and certain safety risk is caused when a format reagent is used in the process of scale-up production.

In the synthetic route 2, CbzCl is adopted to protect hydroxylamine hydrochloride, then the hydroxylamine hydrochloride is mixed with cyclopentadiene, and a Diels-Alder reaction is carried out under the action of a sodium periodate oxidant to obtain a cycloaddition intermediate. The intermediate can complete double bond reduction, ring opening and deprotection to obtain racemate through one-step reaction. However, this patent only reports the synthesis of the racemate and does not give an optically active product. And sodium periodate is expensive, making cost control difficult.

The scheme of resolving mandelic acid is adopted in the synthetic route 3, but the synthesis of the mesomer in the patent adopts a low-efficiency method, so that the cost of starting materials is higher, the resolving efficiency is lower, the overall cost is higher, and the industrial production is not facilitated.

In conclusion, the development of the pharmaceutical industry needs a key chiral pharmaceutical intermediate (1R,3S) -3-aminocyclopentanol hydrochloride, however, the current process route has a larger space for improvement.

Disclosure of Invention

Provides a method for synthesizing (1R,3S) -3-amino cyclopentanol hydrochloride, and adopts a novel process route to solve the problems.

In order to overcome the defects that the starting material of (1R,3S) -3-aminocyclopentanol hydrochloride is expensive and the chiral control is not easy, the invention develops a new process route, and the synthetic route is shown as follows. The method specifically comprises the following reaction steps:

1) tert-butyl carbonate hydroxylamine is oxidized into tert-butyl carbonate nitrosyl under the catalysis of a catalyst and 2-ethyl-2-oxazoline, and then the tert-butyl carbonate nitrosyl is subjected to a heteroDiels-Alder reaction in situ with cyclopentadiene to obtain (+/-) -2; wherein the reaction temperature is 20-30 ℃;

2) the intermediate (+/-) -2 is subjected to selective reduction of a nitrogen-oxygen bond in a reducing agent (zinc powder) -acetic acid reaction system to obtain an intermediate (+/-) -3;

3) the intermediate (+/-) -3 reacts with vinyl acetate under the catalysis of lipase, and a key intermediate (+) -4 is obtained through optical selectivity, so that chiral resolution is realized;

4) the intermediate (+) -4 is subjected to hydrogenation reduction of double bonds through palladium-carbon to obtain an intermediate (+) -5;

5) under the alkaline condition of alkali (lithium hydroxide) -methanol, performing deacetylation protection on the intermediate (+) -5 to obtain (+) -3;

6) the intermediate (+) -3 is protected by decarbonized tert-butyl ester in hydrogen chloride-isopropanol acidic solution prepared in situ from acetyl chloride and isopropanol, and is salified in situ to obtain a target product (+) -6.

The catalyst required in the step 1) is copper chloride and cuprous chloride, preferably copper chloride; the oxidant is oxygen, air or hydrogen peroxide, preferably air.

The reducing agent needed in the step 2) is zinc powder, iron powder and manganese powder, and preferably zinc powder.

The Lipase catalyst in the step 3) is Novozym 435, Lipozyme TL, Lipozyme RM, Lipozyme40086 and Lipase PS 'Amano' SD, and preferably the Lipozyme-40086.

Step 5) the base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, preferably lithium hydroxide.

In the acidification reaction condition of the step 6), the used solvent is methanol, ethanol and isopropanol, wherein the isopropanol is preferred.

The corresponding substances in each step are as follows:

the method has the advantages that the (1R,3S) -3-aminocyclopentanol hydrochloride is synthesized by the method, a novel process route is adopted in the process, and the method has the characteristics of novel and short route, high optical purity, low cost and the like.

Detailed Description

Example 1

(1) Synthesis of cis-2-oxa-3-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid tert-butyl ester

In a 3L reaction flask, tert-butyl carbonate-protected hydroxylamine (280g, 2.1mol) and 2-methyltetrahydrofuran (1L) were added in this order. Then starting stirring, adding cyclopentadiene (208g, 3.2mol), 2-ethyl-2-oxazoline (17g, 0.20mol) and copper chloride (14g, 0.10mol) into the reaction bottle in sequence, and stirring for 10 minutes under the condition of keeping the internal temperature of the reaction bottle at 20-30 ℃. Air (286g, 2.5mol) was then slowly bubbled into the above reaction flask and the whole system was stirred under these conditions for an additional 12 hours. Then adding water to dilute the system, separating the solution to obtain an organic phase, and extracting the aqueous phase by ethyl acetate. The combined organic phases were washed with saturated brine, dried and evaporated under reduced pressure to remove the organic solvent, yielding 330g of a pale yellow oil with a yield of 80%.

(2) Synthesis of cis-N- [ 4-hydroxycyclopent-2-en-1-yl ] carbamic acid tert-butyl ester

Adding the intermediate obtained in the last step into a 3L reaction bottle, then adding ethanol (1L) and acetic acid (1L) into the reaction bottle, adding zinc powder (214g, 2.0eq.) in batches under the stirring condition, and then heating and refluxing for 8 hours. The reaction progress was monitored by HPLC, after completion of the reaction, the temperature was lowered to room temperature, and the reaction solution was filtered through Celite (50g) to remove solids such as unreacted zinc powder. The filtrate was concentrated under reduced pressure, the concentrate was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate, and the extracted organic phase was concentrated to (+/-) -3(307g) with a yield of 90%.

(3) Synthesis of cis- (+) -N- [ 4-Hydroxyacetyl ester cyclopent-2-en-1-yl ] carbamic acid tert-butyl ester

The intermediate (+/-) -3 from the previous step was added to a 3L reaction flask, followed by the sequential addition of dichloromethane (830mL), vinyl acetate (680g, 8.0mol, 5equiv.) and Lipase PS "Amano" SD (16 g). The whole reaction system was stirred at room temperature (25 ℃ C.) for 72 hours. The enzyme catalyst was removed by filtration, and then the filtrate was further concentrated by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (elution machine: n-hexane/ethyl acetate mixed system) to give optically pure intermediate (+) -4 of about 160g, yield 43%, ee > 97%.

(4) Synthesis of (1R,3S) -3-carbamic acid tert-butyl ester-1-cyclopentyl-hydroxyacetyl ester

The chiral intermediate obtained above was dissolved in 200mL of methanol, and after the reaction system was replaced with nitrogen, 10% palladium on carbon (8g, 5 wt%) was added, followed by replacement of the system with hydrogen (0.2 MPa). Thereafter, the whole was stirred at room temperature (25 ℃ C.) for 6 hours. The palladium-carbon catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to remove methanol to give 159g with a yield of over 99%.

(5) Synthesis of (1R,3S) -3-carbamic acid tert-butyl ester cyclopentanol

The intermediate obtained above was dissolved in 250mL of methanol, and then lithium hydroxide (19g, 0.79mol, 1.2equiv.) was added to the mixture. The whole was stirred at room temperature (25 ℃ C.) for 12 hours. Vacuum concentrating to remove methanol, extracting the residue with water-ethyl acetate system twice, washing the combined organic phase with saturated saline solution, and drying with anhydrous sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure to obtain 120g with a yield of 90%.

(6) Synthesis of (1R,3S) -3-aminocyclopentanol hydrochloride

340mL of isopropanol was added to the dried reaction flask, and acetyl chloride (70g, 0.89mol, 1.5equiv.) was added dropwise to the reaction flask under nitrogen protection while cooling in an ice bath, maintaining the temperature of the system at not more than 25 ℃ and generating a solution of hydrogen chloride in isopropanol in situ. After the preparation of the hydrogen chloride in isopropanol solution, the intermediate (+) -V of the previous step is dissolved in 340mL of isopropanol and added dropwise to the hydrogen chloride in isopropanol solution. After the completion of the dropwise addition, the whole was allowed to react at room temperature (25 ℃ C.) for another 12 hours. The system is cooled to 0 ℃ for crystallization, and 65g of white solid of the target product (1R,3S) -3-amino-cyclopentanol hydrochloride is obtained by filtration, with the yield of 80%.

Example 2

Steps 1 to 2 and steps 4 to 6 in this example were the same as in example 1.

(3) Synthesis of cis- (+) -N- [ 4-Hydroxyacetyl ester cyclopent-2-en-1-yl ] carbamic acid tert-butyl ester

The intermediate (+/-) -3 obtained in the third step was charged into a 3L reaction flask, and then methylene chloride (830mL), vinyl acetate (680g, 8.0mol, 5equiv.) and Lipozyme40086(22g) were sequentially added to the reaction flask. The whole reaction system was stirred at room temperature (25 ℃ C.) for 48 hours. The enzyme catalyst was removed by filtration through celite, and then the filtrate was further concentrated by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (elution machine: n-hexane/ethyl acetate mixed system) to give about 158g of optically pure intermediate III, with a yield of 41% and an ee value of > 99%.

Example 3

Steps 1 to 5 in this example are the same as in example 1.

(6) Synthesis of (1R,3S) -3-aminocyclopentanol hydrochloride

250mL of methanol was added to the dried reaction flask, and acetyl chloride (70g, 0.89mol, 1.5equiv.) was added dropwise to the reaction flask under cooling with an ice bath under a nitrogen blanket, while maintaining the temperature of the system at not more than 25 ℃ to generate a methanol solution of hydrogen chloride in situ. After preparation of a methanolic solution of hydrogen chloride, the intermediate was dissolved in 250mL of methanol and added dropwise to the methanolic solution of hydrogen chloride. After the completion of the dropwise addition, the whole was allowed to react at room temperature (25 ℃ C.) for another 12 hours. After the reaction is finished, the crude product of brown oily matter is obtained by distillation and concentration under the reduced pressure, and the crude product is recrystallized by isopropanol to obtain 70g of the target product (1R,3S) -3-amino-cyclopentanol hydrochloride white solid with the yield of 86 percent.