阅读说明：本技术 一种反式-3-氨基丁醇的合成方法 (Synthesis method of trans-3-aminobutanol ) 是由 费安杰 叶伟平 周章涛 黄志宁 唐建 陈润林 王俊敬 于 2020-12-15 设计创作，主要内容包括：一种反式-3-氨基丁醇的合成方法,本发明属于有机化学合成领域,为改善现有路线的安全性低,收率低,难以得到高纯度产品等问题,提供一种合成反式-3-氨基环丁醇的新方法。具体包括以下反应步骤：1)式II化合物与羧酸类物质在缩合剂的作用下发生mitsunobu反应,成盐,生成式III化合物；2)式III化合物在碱性条件下水解,得到式IV化合物；3)式IV化合物在催化剂的作用下脱除苄基,得到式I化合物。采用本发明合成方法合成反式-3-氨基环丁醇,工艺路线新颖,总摩尔收率大于70％,具有路线简短、化学纯度高、易于生产方法的特点。(The invention discloses a method for synthesizing trans-3-aminobutanol, belongs to the field of organic chemical synthesis, and provides a novel method for synthesizing the trans-3-aminobutanol in order to solve the problems of low safety, low yield, difficulty in obtaining high-purity products and the like of the existing route. The method specifically comprises the following reaction steps: 1) carrying out mitsunobu reaction on the compound of the formula II and carboxylic acid substances under the action of a condensing agent to form salt, and generating a compound of a formula III; 2) hydrolyzing the compound of formula III under alkaline conditions to obtain a compound of formula IV; 3) and removing benzyl from the compound shown in the formula IV under the action of a catalyst to obtain the compound shown in the formula I. The synthesis method for synthesizing the trans-3-aminocyclobutanol has the characteristics of novel process route, total molar yield of more than 70 percent, short route, high chemical purity and easy production method.)

1. The method for synthesizing the trans-3-aminobutanol is characterized by comprising the following steps of:

1) cis-3-dibenzyl amino butyl alcohol and carboxylic acid substances are subjected to mitsunobu reaction under the action of a condensing agent to generate hydrochloride of trans-3-dibenzyl amino butyl carboxylate;

2) hydrolyzing hydrochloride of the carboxylic acid trans-3-dibenzyl cyclobutyl ester under an alkaline condition to obtain trans-3-dibenzyl cyclobutanol;

3) and removing benzyl from the trans-3-dibenzyl cyclobutanol under the action of a catalyst to obtain the trans-3-amino cyclobutanol.

2. The method for synthesizing trans-3-aminobutanol according to claim 1, wherein the step 1) comprises: adding 5-12 volumes of tetrahydrofuran, cis-3-dibenzyl cyclobutanol, triphenylphosphine and 1.01-1.3 equivalents of carboxylic acid substances into a reaction kettle, cooling to 0-10 ℃ under the protection of nitrogen, preserving heat, dropwise adding 1.6-2.3 equivalents of condensing agent, and removing tetrahydrofuran after the reaction is finished;

then adding ethyl acetate, filtering, washing a filter cake with ethyl acetate, and adjusting the pH of the filtrate to 2-3 by using a hydrogen chloride methanol solution;

filtering, pulping the filter cake with a small amount of ethyl acetate, and drying to obtain the hydrochloride of the carboxylic acid trans-3-dibenzyl cyclobutyl ester.

3. The method for synthesizing trans-3-aminobutanol according to claim 2, wherein the condensing agent in the step 1) is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate and/or di-tert-butyl azodicarboxylate.

4. The method for synthesizing trans-3-aminobutanol according to claim 2, wherein the carboxylic acid in the step 1) is selected from benzoic acid and/or p-nitrobenzoic acid.

5. The method for synthesizing trans-3-aminobutanol according to claim 1, wherein the step 2) comprises: adding hydrochloride of trans-3-dibenzyl cyclobutyl carboxylate, tetrahydrofuran, water and alkali into a reaction kettle, and heating and refluxing for reaction;

distilling to remove tetrahydrofuran and dichloromethane for extraction, drying by anhydrous sodium sulfate, concentrating, crystallizing by a small amount of isopropanol, and drying to obtain the trans-3-dibenzylcyclobutanol.

6. The method for synthesizing trans-3-aminobutanol according to claim 5, wherein the alkali required for the basic condition in the step 2) is sodium hydroxide and/or potassium hydroxide.

7. The method for synthesizing trans-3-aminobutanol according to claim 1, wherein the step 3) comprises: adding trans-3-dibenzyl cyclobutanol, an alcohol solvent and a catalyst into a hydrogenation kettle, vacuumizing, replacing with nitrogen, then replacing with hydrogen, pressurizing the hydrogen to 0.5-1.5MPa, and heating to 30-45 ℃ for reaction; filtering after the reaction is finished, and concentrating the filtrate to obtain the trans-3-amino cyclobutanol.

8. The method for synthesizing trans-3-aminobutanol according to claim 7, wherein the catalyst in the step 3) is palladium on carbon and/or palladium hydroxide.

9. The method for synthesizing trans-3-aminobutanol according to claim 7, wherein the alcoholic solvent in the step 3) is one or more of methanol, ethanol, n-propanol and isopropanol, preferably methanol.

10. Trans-3-aminobutanol produced by the process according to any one of claims 1 to 9.

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a novel synthesis method of trans-3-aminobutanol.

Background

Trans-3-aminocyclobutanol is a key intermediate of Tyk2 inhibitors and some new cannabinoid compounds.

Currently, there are mainly 1 synthetic route for this intermediate, as shown below. In the method, expensive 3-oxocyclobutanecarboxylic acid is used as a starting material, and under the action of diphenyl phosphorazidate, curtius rearrangement occurs; 3-tert-butoxycarbonylaminocyclobutanone; then cis-3-tert-butoxycarbonylamino cyclobutanol is generated under the action of a reducing agent, then a Mitsunobu reaction is carried out, the configuration inversion is carried out, and the trans-3-amino cyclobutanol hydrochloride is obtained by hydrolysis and tert-butoxycarbonylation removal.

In addition to the expensive starting materials, explosive diphenyl azide phosphate is used in the first step of Curtius rearrangement reaction, so that the potential safety hazard is high; meanwhile, due to the instability of the four-membered ring, ring opening is easy to occur in the rearrangement process, more byproducts are generated, and the yield is greatly influenced; in addition, the trans-isomer which can be avoided in the reduction stage can obtain cis-products in the subsequent Mitsunobu reaction, and the cis-products are difficult to purify to obtain high-purity final products; finally, the last step of the route can only obtain hydrochloride of trans-3-aminocyclobutanol under the acidic condition of tert-butyloxycarbonyl, and further rectification and purification are difficult.

In conclusion, the development of the pharmaceutical industry needs trans-3-aminocyclobutanol, which is a kind of medical intermediate, but the current synthetic method has a larger space for improvement.

Disclosure of Invention

The invention provides a novel method for synthesizing trans-3-aminocyclobutanol, aiming at the problems of low safety, low yield, difficulty in obtaining high-purity products and the like of the existing route for synthesizing the trans-3-aminocyclobutanol.

The method specifically comprises the following reaction steps:

1) carrying out mitsunobu reaction on a compound (cis-3-dibenzyl cyclobutanol) in a formula II and a carboxylic acid substance under the action of a condensing agent, and carrying out salt formation and purification to generate a compound (trans-3-dibenzyl cyclobutyl carboxylate hydrochloride) in a formula III;

2) hydrolyzing the compound of formula III under alkaline conditions to obtain a compound of formula IV (trans-3-dibenzyl cyclobutanol);

3) and removing benzyl from the compound shown in the formula IV under the action of a catalyst to obtain the compound shown in the formula I (trans-3-amino cyclobutanol).

The three steps are as follows:

the specific technical scheme is as follows:

1) adding tetrahydrofuran (5-12 volume), a compound of a formula II (cis-3-dibenzyl cyclobutanol), triphenylphosphine (1.6-2.3 equivalent) and carboxylic acid substances (1.01-1.3 equivalent) into a reaction kettle, cooling to 0-10 ℃ under the protection of nitrogen, keeping the temperature, dropwise adding a condensing agent (1.6-2.3 equivalent), reacting for 30-60 min, and then distilling under reduced pressure to remove tetrahydrofuran;

then adding ethyl acetate, filtering, washing a filter cake with ethyl acetate, and adjusting the pH of the filtrate to 2-3 by using a hydrogen chloride methanol solution to form a salt;

filtering, pulping the filter cake with a small amount of ethyl acetate, and drying to obtain the compound shown in the formula III.

2) Adding a compound shown in the formula III, tetrahydrofuran, water and alkali (sodium hydroxide or potassium hydroxide) into a reaction kettle, and heating and refluxing to react until complete hydrolysis;

distilling to remove tetrahydrofuran, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating, crystallizing with small amount of isopropanol, and drying to obtain compound of formula IV.

3) Adding a compound of formula IV, an alcohol solvent, palladium carbon or palladium hydroxide into a hydrogenation kettle, vacuumizing, replacing with nitrogen for 3 times, then replacing with hydrogen for 3 times, pressurizing the hydrogen to 0.5-1.5MPa, and heating to 30-45 ℃ for reaction until benzyl is completely removed.

Filtering, concentrating the filtrate to obtain crude product, and further rectifying to obtain the compound of formula I.

Further, the condensation reagent required in the step (1) may be selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, etc., preferably diisopropyl azodicarboxylate; the desired carboxylic acid can be selected from benzoic acid, p-nitrobenzoic acid, and the like, with p-nitrobenzoic acid being preferred.

Further, the required alkali in the step (2) is sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide.

Further, the required catalyst in step (3) is palladium carbon, palladium hydroxide and the like, preferably palladium hydroxide; the alcohol solvent is methanol, ethanol, isopropanol, n-propanol, etc., preferably methanol.

The invention has the beneficial effects that: the synthesis method for synthesizing the trans-3-aminocyclobutanol has the characteristics of novel process route, total molar yield of more than 70 percent, short route, high chemical purity and easy production method.

Detailed Description

Example 1

S1: inversion of Mitsunobu configuration

470mL of tetrahydrofuran, 47g of compound II, 101g of triphenylphosphine and 32g of p-nitrobenzoic acid are added into a reaction kettle, the temperature is reduced to 10 ℃ under the protection of nitrogen, and diisopropyl azodicarboxylate is dropwise added under the condition of heat preservation. After the dropwise addition, the reaction was carried out for 30min and the tetrahydrofuran was distilled off under reduced pressure. Adding ethyl acetate, filtering, washing a filter cake with ethyl acetate, and adjusting the pH of the filtrate to 2-3 by using a hydrogen chloride methanol solution; filtering, pulping the filter cake with a small amount of ethyl acetate, and drying to obtain 71.66g of hydrochloride of the p-nitrobenzoic acid trans-3-dibenzyl cyclobutyl ester, with the yield of 90%.

S2: hydrolysis

Adding 30g of hydrochloride of trans-3-dibenzyl cyclobutyl p-nitrobenzoate, 150mL of tetrahydrofuran, 150mL of water and 8.0g of sodium hydroxide into a reaction kettle, heating and refluxing for 3 hours, distilling to remove tetrahydrofuran, extracting with dichloromethane, drying anhydrous sodium sulfate and concentrating to obtain a product; a small amount of isopropanol is crystallized and dried to obtain 16.3g of trans-3-dibenzyl cyclobutanol with the yield of 92 percent.

S3: hydrodebenzylation

Adding 100g of trans-3-dibenzyl cyclobutanol, 1000mL of methanol and 10g of 10% palladium hydroxide into a hydrogenation kettle, vacuumizing, replacing for 3 times by nitrogen, and then replacing for 3 times by hydrogen; pressurizing hydrogen to 1.0-1.2MPa, heating to 30-45 ℃ and reacting for 24 hours; after the reaction, the reaction solution is filtered, the filtrate is concentrated to obtain a crude product, and the crude product is further rectified to obtain 29.3g of trans-3-aminocyclobutanol, wherein the yield is 90 percent, and the GC purity is 99.5 percent.

Example 2

S1: inversion of Mitsunobu configuration

470mL of tetrahydrofuran, 47g of the compound II, 101g of triphenylphosphine, and 32g of p-nitrobenzoic acid were added to the reaction vessel. Cooling to 10 ℃ under the protection of nitrogen, and dropwise adding azodicarbonic acid diethyl ester while keeping the temperature. After the dropwise addition, the reaction was carried out for 30min and the tetrahydrofuran was distilled off under reduced pressure. Ethyl acetate was added, filtration was carried out, the filter cake was washed with ethyl acetate, and the filtrate was adjusted to pH 2-3 with a methanolic solution of hydrogen chloride. Filtering, pulping the filter cake with a small amount of ethyl acetate, and drying to obtain 67.69g of hydrochloride of the p-nitrobenzoic acid trans-3-dibenzyl cyclobutyl ester, with the yield of 85%.

S2: hydrolysis

Adding 30g of hydrochloride of trans-3-dibenzyl cyclobutyl p-nitrobenzoate, 150mL of tetrahydrofuran, 150mL of water and 11.1g of potassium hydroxide into a reaction kettle, heating and refluxing for 3 hours, distilling to remove tetrahydrofuran, extracting with dichloromethane, drying with anhydrous sodium sulfate, and concentrating to obtain the product. A small amount of isopropanol is crystallized and dried to obtain 15.9g of trans-3-dibenzyl cyclobutanol with the yield of 90 percent.

S3: hydrodebenzylation

100g of trans-3-dibenzylcyclobutanol, 1000mL of isopropanol, and 10g of 10% palladium on carbon were added to a hydrogenation reactor, followed by vacuum evacuation, 3-fold nitrogen substitution, and 3-fold hydrogen substitution. Pressurizing hydrogen to 1.0-1.2MPa, heating to 30-45 deg.c and reacting for 24 hr. Filtering, and concentrating the filtrate to obtain crude product. Further rectification was carried out to obtain 28.7g of trans-3-aminocyclobutanol with a yield of 88% and a GC purity of 99.6%.