CN114426497A - Preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride - Google Patents
Preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride Download PDFInfo
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- CN114426497A CN114426497A CN202210103862.1A CN202210103862A CN114426497A CN 114426497 A CN114426497 A CN 114426497A CN 202210103862 A CN202210103862 A CN 202210103862A CN 114426497 A CN114426497 A CN 114426497A
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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Abstract
The invention discloses a preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride, belonging to the technical field of organic synthesis. The method comprises the steps of taking 4-keto cyclohexane carboxylic ester and chiral ligand reagent tert-butyl sulfinamide as raw materials, carrying out reductive amination under catalysis of Lewis acid to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester, then saponifying under alkaline conditions to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid, finally introducing hydrogen chloride for deprotection, and purifying to obtain trans-4-aminocyclohexanecarboxylic acid hydrochloride. The invention adopts an intermediate obtained by condensing a chiral ligand reagent, namely tertiary butyl sulfinyl amine and 4-oxocyclohexane carboxylic ester, so that the reduction reaction has high stereoselectivity, the proportion of trans-products is more than 95 percent, and meanwhile, the tertiary butyl sulfinyl group is stable under the alkaline condition and is easy to leave under the acidic condition, the reaction condition is mild, the operation is simple and convenient, the yield is high, and the industrial production is easy.
Description
Technical Field
The invention relates to a preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride, belonging to the technical field of organic synthesis.
Background
Trans-4-aminocyclohexanecarboxylic acid hydrochloride, CAS: 27960-59-4, English name: trans-4-Aminocyclohexane-1-carboxylic acid hydrochloride, trans-4-Aminocyclohexane carboxylic acid (ACCA) and derivatives thereof are one of important medical intermediates, and are mainly used for synthesizing short peptides, polypeptides, isoquinuclidinone and other medicaments. Is one of the important building blocks for constructing active medicine. At present, the development of derivatives thereof reaches hundreds of products which are commercialized or under development.
The European Journal of Medicinal Chemistry, 2001, 36, 265-286 reports the use of 4-aminobenzoic acid as starting material and catalytic hydrogenation of Pto2 to give a cis-trans product ratio of 4-cyclohexylcarboxylic acid of 16: 49. US2018148424 reports that condensation of a mixture of ethyl 4-aminocyclohexanecarboxylate with acetaldehyde is performed to obtain a cis-trans product ratio of the 4-cyclohexylcarboxylic acid derivative of 10/1. US201240984 reports that the cis-trans product ratio of 4-cyclohexylcarboxylic acid derivatives obtained by the reduction of 4-oxocyclohexanecarboxylic acid ethyl ester with sodium triacetoxyborohydride is 5/2.
Therefore, there is a need to develop a suitable synthetic method to solve the problems of efficiently producing more trans-products or how to separate cis-trans isomers, and a preparation method which is easy to purify, safe to operate and suitable for industrial scale-up production.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride. The method comprises the steps of taking 4-keto cyclohexane carboxylic ester and chiral ligand reagent tert-butyl sulfinamide as raw materials, carrying out reductive amination under catalysis of Lewis acid to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester, then saponifying under alkaline conditions to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid, finally introducing hydrogen chloride for deprotection, and purifying to obtain trans-4-aminocyclohexanecarboxylic acid hydrochloride. The invention adopts an intermediate obtained by condensing a chiral ligand reagent, namely tertiary butyl sulfinyl amine and 4-oxocyclohexane carboxylic ester, so that the reduction reaction has high stereoselectivity, the proportion of trans-products is more than 95 percent, and meanwhile, the tertiary butyl sulfinyl group is stable under the alkaline condition and is easy to leave under the acidic condition, the reaction condition is mild, the operation is simple and convenient, the yield is high, and the industrial production is easy.
The invention relates to a preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride, which comprises the following reaction equation:
the method comprises the following steps:
reductive amination: mixing 4-keto cyclohexane carboxylate, chiral ligand reagent tert-butyl sulfinamide and anhydrous Lewis acid in an organic solvent, and then adding a reduction reagent to react to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylate;
saponification reaction: dissolving trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester in an organic solvent, adding an aqueous solution of inorganic base for hydrolysis, and then acidifying to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid;
deprotection reaction: dissolving trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid in dichloromethane, introducing hydrogen chloride at-10-0 ℃, and then concentrating and recrystallizing isopropyl ether to obtain trans-4-aminocyclohexanecarboxylic acid hydrochloride;
further, in the above technical solution, the reductive amination is performed, the organic solvent is selected from dichloromethane or toluene, the anhydrous lewis acid is selected from anhydrous magnesium sulfate or tetraethyl titanate, and the reducing agent is selected from sodium triacetoxyborohydride or sodium borohydride.
Further, in the technical scheme, the 4-ketocyclohexane carboxylic ester is 4-ketocyclohexane carboxylic methyl ester, 4-ketocyclohexane carboxylic ethyl ester and 4-ketocyclohexane carboxylic isopropyl ester through reductive amination.
Further, in the above technical scheme, in the reductive amination, the molar ratio of 4-ketocyclohexane carboxylate, chiral ligand reagent tert-butyl sulfinamide, anhydrous lewis acid and reducing reagent is 1: 1.1-1.2: 1.5-1.8: 1.2-1.3.
Further, in the above technical solution, in the saponification reaction, the organic solvent is selected from tetrahydrofuran or corresponding alcohol (methanol, ethanol or isopropanol).
Further, in the above technical solution, in the saponification reaction, the alkali agent is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
Further, in the technical scheme, the crude trans-4-aminocyclohexanecarboxylic acid hydrochloride is recrystallized in isopropyl ether through deprotection reaction, so that not only can the purity be improved, but also the stereoisomerism of the crude trans-4-aminocyclohexanecarboxylic acid hydrochloride can be improved.
Advantageous effects of the invention
The invention adopts an intermediate obtained by condensing a chiral ligand reagent, namely tert-butyl sulfinamide and 4-oxocyclohexanecarboxylic acid tert-butyl ester, so that the reduction reaction has high stereoselectivity, the proportion of trans-products is more than 95%, a very small amount of cis-products are removed through a post-treatment step, and meanwhile, the tert-butyl sulfinyl group is stable under an alkaline condition and is easy to leave under an acidic condition, the reaction is easy to control, the reaction condition is mild, the operation is simple and convenient, the yield is high, and the industrial production is easy to realize.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of trans-4-aminocyclohexanecarboxylic acid hydrochloride
Example 1
To 150ml of a toluene solution containing 17g of ethyl 4-ketocyclohexanecarboxylate was added 14.5g (1.2eq) of (R) -tert-butylsulfinamide and 44ml (1.2eq) of ethyl titanate in a reaction flask, and the mixture was stirred at 70 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding 6.4g (1.5eq) of sodium borohydride in batches, stirring for 2 hours, adding 50ml (quenching) of methanol after the reaction is finished, continuing stirring for 30 minutes, adding saturated salt water for washing, filtering insoluble substances from an organic phase, and concentrating under reduced pressure to obtain 22g of a target substance with yield of 80 percent. And LC/MS 275.
Example 2
To the reaction flask were added 27.5g of ethyl trans 4-tert-butylsulfinylcyclohexanecarboxylate and 100mL of methanol, and 50mL (1eq) of 2M aqueous sodium hydroxide solution was added dropwise with stirring at 0 ℃ and stirred overnight for 4 hours. After completion of the TLC monitoring, 5ml of water was added and the pH was adjusted to 4-4.5 with 1M HCI solution. The mother liquor solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 21.76g of the target 4-tert-butylsulfinylcyclohexanecarboxylic acid in 88% yield. HPLC: 99.4%, LC/MS: 247.
Example 3
Adding 24.8g of trans-4-tert-butylsulfinylcyclohexanecarboxylic acid and 150ml of dichloromethane into a reaction bottle, stirring and dissolving, slowly introducing hydrogen chloride at the temperature of-5 ℃, stirring for 1 hour at room temperature, repeating the reaction for 2 times, then after the reaction is finished, concentrating the solvent under reduced pressure, replacing by isopropyl ether, adding isopropyl ether, heating to 55 ℃, then cooling to 0 ℃, and filtering to obtain 16.2g of trans-4-aminocyclohexanecarboxylic acid hydrochloride with the yield of 90%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (6)
1. The preparation method of trans-4-aminocyclohexanecarboxylic acid hydrochloride is characterized by comprising the following steps:
R＝Me,Et,i-Pr
reductive amination: mixing 4-keto cyclohexane carboxylate, chiral ligand reagent tert-butyl sulfinamide and anhydrous Lewis acid in an organic solvent, and then adding a reduction reagent to react to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylate;
saponification reaction: dissolving trans-4-tert-butyl sulfinamide cyclohexane carboxylic ester in an organic solvent, adding an aqueous solution of inorganic base for hydrolysis, and then acidifying to obtain trans-4-tert-butyl sulfinamide cyclohexane carboxylic acid;
deprotection reaction: dissolving trans-4-tert-butylsulfinamide cyclohexanecarboxylic acid in dichloromethane, introducing hydrogen chloride at-10 to 0 ℃, and then, concentrating and recrystallizing isopropyl ether to obtain trans-4-aminocyclohexanecarboxylic acid hydrochloride.
2. The process for preparing trans-4-aminocyclohexanecarboxylic acid hydrochloride according to claim 1, characterized in that: reductive amination, wherein the organic solvent is selected from dichloromethane or toluene, the anhydrous Lewis acid is selected from anhydrous magnesium sulfate or tetraethyl titanate, and the reducing agent is selected from sodium triacetoxyborohydride or sodium borohydride.
3. The process for the preparation of trans-4-aminocyclohexanecarboxylic acid hydrochloride according to claim 1, wherein: reductive amination, wherein the 4-ketocyclohexane carboxylic acid ester is 4-ketocyclohexane carboxylic acid methyl ester, 4-ketocyclohexane carboxylic acid ethyl ester and 4-ketocyclohexane carboxylic acid isopropyl ester.
4. The process for the preparation of trans-4-aminocyclohexanecarboxylic acid hydrochloride according to claim 1, wherein: in reductive amination, the molar ratio of 4-oxocyclohexane carboxylate, chiral ligand reagent tert-butyl sulfenamide, anhydrous lewis acid and reducing reagent is 1: 1.1-1.2: 1.5-1.8: 1.2-1.3.
5. The process for the preparation of trans-4-aminocyclohexanecarboxylic acid hydrochloride according to claim 1, wherein: in the saponification reaction, the organic solvent is selected from tetrahydrofuran or corresponding alcohol (methanol, ethanol or isopropanol).
6. The process for the preparation of trans-4-aminocyclohexanecarboxylic acid hydrochloride according to claim 1, wherein: and (3) carrying out deprotection reaction, and recrystallizing the trans-4-aminocyclohexanecarboxylic acid hydrochloride crude product in isopropyl ether, so that not only can the purity be improved, but also the stereoisomerism of the crude product can be improved.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115433102A (en) * | 2022-10-16 | 2022-12-06 | 大连双硼医药化工有限公司 | Preparation method of trans- (1R, 2R) -2-aminocyclohexanecarboxylic acid ethyl ester hydrochloride |
| CN117285459A (en) * | 2023-11-24 | 2023-12-26 | 上海美迪西生物医药股份有限公司 | Preparation method of small molecule kinase inhibitor compound |
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2022
- 2022-01-27 CN CN202210103862.1A patent/CN114426497A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115433102A (en) * | 2022-10-16 | 2022-12-06 | 大连双硼医药化工有限公司 | Preparation method of trans- (1R, 2R) -2-aminocyclohexanecarboxylic acid ethyl ester hydrochloride |
| CN115433102B (en) * | 2022-10-16 | 2024-02-27 | 大连双硼医药化工有限公司 | Preparation method of trans- (1R, 2R) -2-aminocyclohexane ethyl carboxylate hydrochloride |
| CN117285459A (en) * | 2023-11-24 | 2023-12-26 | 上海美迪西生物医药股份有限公司 | Preparation method of small molecule kinase inhibitor compound |
| CN117285459B (en) * | 2023-11-24 | 2024-02-27 | 上海美迪西生物医药股份有限公司 | Preparation method of small molecule kinase inhibitor compound |
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