CN117800875B - Preparation method of trans- (N-Boc-4-aminocyclohexyl) acetic acid - Google Patents
Preparation method of trans- (N-Boc-4-aminocyclohexyl) acetic acid Download PDFInfo
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- CN117800875B CN117800875B CN202311775337.5A CN202311775337A CN117800875B CN 117800875 B CN117800875 B CN 117800875B CN 202311775337 A CN202311775337 A CN 202311775337A CN 117800875 B CN117800875 B CN 117800875B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention provides a preparation method of trans- (N-Boc-4-aminocyclohexyl) acetic acid, which comprises the following specific steps: the first step, 4-isoxazoleboronic acid pinacol ester and N-Boc-4-bromoaniline undergo a coupling reaction to obtain N-Boc-4-isoxazoloaniline; secondly, adding and purifying under ruthenium/carbon catalytic hydrogenation to obtain trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester; and thirdly, carrying out ring opening hydrolysis on potassium fluoride and potassium hydroxide to obtain trans- (N-Boc-4-aminocyclohexyl) acetic acid. Compared with the existing literature, the preparation method provided by the invention has the advantages of high enantioselectivity, high total yield, simple operation and wide substrate applicability.
Description
Technical Field
The invention relates to a preparation method of trans- (N-Boc-4-aminocyclohexyl) acetic acid, belonging to the technical field of medical intermediates.
Background
Trans- (N-Boc-4-aminocyclohexyl) acetic acid is a central pharmaceutical intermediate, which is a key intermediate of calicheat (Cariprazine). The kallizin (commodity Vraylar) capsule is an atypical antipsychotic, belongs to a dopamine D2 and D3 receptor partial agonist, and is mainly used for treating adult schizophrenia and bipolar mania.
There are two main types of trans- (N-Boc-4-aminocyclohexyl) acetic acid preparation in the prior art:
The first (patent US5977110,1999, a and WO 2019/16848, 2019, a 1) discloses the route: the preparation method comprises the steps of adding benzene ring by catalytic hydrogenation of Raney nickel or palladium carbon of p-nitrophenylacetic acid and reducing nitro, and then carrying out Boc protection on amino by di-tert-butyl dicarbonate under alkaline conditions. The trans isomer obtained in this way is relatively small and the yield is low.
The reaction scheme is expressed as follows by using the equation:
The second (also patent WO 2019/16848, 2019, a 1) provides another route: nucleophilic substitution of acetamido cyclohexanone with ethoxy-2- (diethoxyphosphoryl) acetate, then Pd/C catalytic hydrogenation of double bond, subsequent hydrolysis of ester with sodium hydroxide, purification, then deacetylation protection, and finally Boc protection. The method has the advantages of more steps, complex operation and low yield.
The reaction scheme is expressed as follows by using the equation:
In order to make up for the defects of the existing synthesis method, the preparation method of the trans- (N-Boc-4-aminocyclohexyl) acetic acid needs to be improved, and a synthesis route with high enantioselectivity, high total yield and simple operation is developed.
Disclosure of Invention
In order to better solve the problems, the present discovery provides a preparation method of trans- (N-Boc-4-aminocyclohexyl) acetic acid, which comprises the following specific steps: coupling reaction of 4-isoxazoleboronic acid pinacol ester and N-Boc-4-bromoaniline to obtain N-Boc-4-isoxazoloaniline; adding and purifying under ruthenium/carbon catalytic hydrogenation to obtain trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester; the potassium fluoride and potassium hydroxide are subjected to ring opening hydrolysis to obtain trans- (N-Boc-4-aminocyclohexyl) acetic acid. Compared with the existing literature, the preparation method provided by the invention has the advantages of high enantioselectivity, high total yield, simple operation and wide substrate applicability.
To achieve the above object, the process of trans- (N-Boc-4-aminocyclohexyl) acetic acid according to the present invention comprises the steps of:
First, coupling reaction: dissolving 4-isoxazoleboronic acid pinacol ester, N-Boc-4-bromoaniline, a palladium catalyst and potassium acetate in an organic solvent, and heating and coupling under the protection of inert gas to obtain N-Boc-4-isoxazoleboronic acid;
second, catalytic hydrogenation: mixing N-Boc-4-isoxazolidine, ruthenium/carbon and an organic solvent, hydrogenating to 1.0-1.5Mpa, heating to catalyze the hydrogenation to obtain a trans/cis-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester mixture, and recrystallizing to obtain trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester;
Thirdly, hydrolysis reaction: and (3) heating up the trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester, potassium fluoride and DMSO, then cooling, adding potassium hydroxide aqueous solution, and hydrolyzing to obtain trans- (N-Boc-4-aminocyclohexyl) acetic acid.
The reaction scheme is shown below:
Further, the catalyst in the first step is selected from PdCl 2dppf、Pd(PPh3)4.
Further, the organic solvent in the first step is selected from 1, 4-dioxane or ethylene glycol dimethyl ether.
Further, in the first step, the mole ratio of the 4-isoxazoleboronic acid pinacol ester, the N-Boc-4-bromoaniline and the catalyst to the potassium acetate is 1:1.05-1.08:0.008-0.010:3.5-4.0.
Further, in the second step, the ruthenium/carbon is selected from 5% ruthenium/carbon, the addition amount is 1-2% of the weight of the raw material, and the organic solvent is selected from ethanol/water=70:30 or isopropanol/water=80:20.
Further, in the second step, the molar ratio of the 3-pyridine-2-borate carboxylic acid to the thionyl chloride is 1:1.3-1.4.
Further, in the third step, the mol ratio of the trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester to potassium fluoride to potassium hydroxide is 1:2.5-3.0:2.5:3.0.
Advantageous effects of the invention
Compared with the prior art, the preparation method of the trans- (N-Boc-4-aminocyclohexyl) acetic acid has the advantages of high enantioselectivity in the second step, high trans proportion up to 90%, easy purification, simple integral operation and high total yield.
Drawings
FIG. 1 is a HNMR spectrum (11.63 ppm peak not labeled) of trans- (N-Boc-4-aminocyclohexyl) acetic acid as a product in example 5.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
Example 1
97.5G (0.5 mol) of 4-isoxazoleboronic acid pinacol ester, 142.9g (0.525 mol) of N-Boc-4-bromoaniline, 3g (0.004 mol) of PdCl 2 (dppf) and 176.7g (1.8 mol) of potassium acetate are dissolved in 900mL of 1, 4-dioxane and reacted for 4 hours under the protection of nitrogen, the temperature is raised to 85-90 ℃, sampling 4-isoxazoleboronic acid pinacol ester is obtained after the reaction, the hot filtration is carried out, the filtrate is concentrated under reduced pressure until no liquid flows out, 600mL of dichloromethane and 200mL of petroleum ether are added for hot pulping to obtain 116 gN-Boc-4-isoxazoloaniline, the yield is obtained 89.1％,HPLC 98.9％.1HNMR(400MHz,CDCl3)δ:9.36(s,1H),8.68(d,1H),8.05(d,1H),7.78-7.74(m,2H),7.61-7.57(m,2H),1.39(s,9H).
Example 2
97.5G (0.5 mol) of 4-isoxazoleboronic acid pinacol ester, 142.9g (0.525 mol) of N-Boc-4-bromoaniline, 3.7g (0.005 mol) of PdCl 2 (dppf) and 196.3g (2.0 mol) of potassium acetate are dissolved in 1000mL of ethylene glycol dimethyl ether, the mixture is heated to 85-90 ℃ under the protection of nitrogen gas for reaction for 21 hours, the residual 1.3% of 4-isoxazoleboronic acid pinacol ester is sampled, the mixture is filtered while the mixture is hot, the filtrate is concentrated under reduced pressure until no liquid flows out, 600mL of dichloromethane and 200mL of petroleum ether are added, and the mixture is thermally beaten to obtain 110g N-Boc-4-isoxazoloaniline with the yield of 84.5% and the HPLC of 98.7%.
Example 3
26G (0.1 mol) of N-Boc-4-isoxazolidine and 0.52g of 5% Ru/C are dissolved in 210mL and 50mL of water, a high-pressure stainless steel reaction kettle is pressurized to 0.2Mpa by nitrogen and replaced three times, pressurized to 1Mpa by hydrogen and replaced three times, heated to 70-75 ℃ by hydrogen, the pressure is kept at 1.0-1.5Mpa, the reaction is carried out for 24 hours, the proportion of the tert-butyl ester of the trans/cis-4- (isoxazol-4-yl) cyclohexane carbamate is 86%/12%, the pressure is relieved, the temperature is reduced to room temperature, the mixture is filtered by diatomite, the filter cake is leached by isopropanol, the filtrate is concentrated under reduced pressure until no liquid flows out, 120mL of MTBE is added for heating and dissolution, then the temperature is reduced to 35 ℃, 60mL of N-heptane is added dropwise, the temperature is reduced to 5-10 ℃, the filtration is carried out, the filter cake is leached by a mixed solvent of cold MTBE and N-heptane, and the reaction is dried to obtain 19.3g of trans-4- (isoxazol-4-yl) cyclohexane carbamate in a yield 72.6％,HPLC 99.6％.1HNMR(400MHz,DMSO-d6)δ:8.19(d,1H),7.96(d,1H),7.61(s,1H),3.57-3.52(m,1H),2.68-2.63(m,1H),1.85-1.74(m,4H),1.60-1.49(m,4H),1.41(s,9H).
Example 4
26G (0.1 mol) of N-Boc-4-isoxazolidine and 0.3g of 5% Ru/C are dissolved in 185mL and 75mL of water, a high-pressure stainless steel reaction kettle is pressurized to 0.2Mpa by nitrogen and replaced three times, pressurized to 1Mpa by hydrogen and replaced three times, the temperature is raised to 70-75 ℃ and the pressure is kept at 1.0-1.5Mpa by the hydrogen, the reaction is carried out for 16 hours, the proportion of the tert-butyl ester of the trans/cis-4- (isoxazol-4-yl) cyclohexane carbamate is 90%/10%, the pressure is relieved, the temperature is reduced to room temperature, the diatomite is used for filtering, the filter cake is leached by ethanol, the filtrate is concentrated to be free of liquid outflow, 120mL of MTBE is added for heating and dissolution, then the temperature is reduced to 35 ℃, 60mL of N-heptane is added dropwise, the temperature is reduced to 5-10 ℃, the filter cake is leached by a mixed solvent of cold MTBE and N-heptane, and 20.7g of trans-4- (isoxazol-4-yl) cyclohexane carbamate is obtained by HPLC, the yield is 77.8%, and 99.6% is obtained by drying.
Example 5
26.6G (0.1 mol) of trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester, 17.4g (0.3 mol) of potassium fluoride are dissolved in 100mL of dimethyl sulfoxide, the mixture is heated to 110 to 115 ℃ for reaction for 3 hours under the protection of nitrogen gas, cooled to room temperature, 42.1g (0.3 mol) of 40 percent potassium hydroxide is added, the mixture is heated to 85 to 90 ℃ for reaction for 11 hours, 100mL of toluene and 60mL of water are added, layering is carried out while the mixture is hot, the water phase is reserved, the water phase is cooled to 10 to 15 ℃,1 percent sulfuric acid solution is dropwise added to pH=3.5 to 4.0, then the mixture is heated to 40 ℃ for stirring for 2 hours, the mixture is cooled to room temperature, filtered, and a filter cake deionized water and N-heptane are leached to obtain 23.5g of trans- (N-Boc-4-aminocyclohexyl) acetic acid, the yield 91.3％,HPLC 99.8％.1HNMR(400MHz,CDCl3)δ:11.63(s,1H),4.41(m,1H),3.99(m,1H),2.23-2.27(m,2H),2.02(m,2H),1.83-1.86(m,2H),1.74-1.78(m,1H),1.46(s,9H),1.06-1.20(m,4H).
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (5)
1. A method for preparing trans- (N-Boc-4-aminocyclohexyl) acetic acid, which is characterized by comprising the following steps:
First, coupling reaction: dissolving 4-isoxazoleboronic acid pinacol ester, N-Boc-4-bromoaniline, a palladium catalyst and potassium acetate in an organic solvent, and heating and coupling under the protection of inert gas to obtain N-Boc-4-isoxazoleboronic acid; the palladium catalyst is selected from PdCl 2 (dppf) or Pd (PPh 3)4;
Second, catalytic hydrogenation: mixing N-Boc-4-isoxazolidine, ruthenium/carbon and an organic solvent, hydrogenating to 1.0-1.5Mpa, heating to catalyze the hydrogenation to obtain a trans/cis-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester mixture, and recrystallizing to obtain trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester; the organic solvent is selected from ethanol/water=70:30 or isopropanol/water=80:20;
Thirdly, hydrolysis reaction: and (3) heating up the trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester, potassium fluoride and DMSO for reaction, then cooling, adding potassium hydroxide aqueous solution for hydrolysis reaction, and finally adding hydrochloric acid aqueous solution for treatment to obtain trans- (N-Boc-4-aminocyclohexyl) acetic acid.
2. The process for producing trans- (N-Boc-4-aminocyclohexyl) acetic acid according to claim 1, wherein: in the first step, the organic solvent is selected from 1, 4-dioxane or ethylene glycol dimethyl ether.
3. The process for producing trans- (N-Boc-4-aminocyclohexyl) acetic acid according to claim 1, wherein: in the first step, the mole ratio of the 4-isoxazoleboronic acid pinacol ester, the N-Boc-4-bromoaniline and the palladium catalyst to the potassium acetate is 1:1.05-1.08:0.008-0.010:3.5-4.0.
4. The process for producing trans- (N-Boc-4-aminocyclohexyl) acetic acid according to claim 1, wherein: in the second step, the ruthenium/carbon is selected from 5% ruthenium/carbon, and the addition amount is 1-2% of the weight of the raw material.
5. The process for producing trans- (N-Boc-4-aminocyclohexyl) acetic acid according to claim 1, wherein: in the third step, the mol ratio of the trans-4- (isoxazol-4-yl) cyclohexane carbamic acid tert-butyl ester to potassium fluoride to potassium hydroxide is 1:2.5-3.0:2.5:3.0.
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| CN115819417A (en) * | 2016-09-09 | 2023-03-21 | 因赛特公司 | Pyrazolopyridine derivatives as HPK1 modulators and their use for the treatment of cancer |
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| JP2013010750A (en) * | 2011-06-02 | 2013-01-17 | Taisho Pharmaceutical Co Ltd | Medicine containing two-pyridone compound |
| GB201216017D0 (en) * | 2012-09-07 | 2012-10-24 | Cancer Rec Tech Ltd | Inhibitor compounds |
| ES2661437T3 (en) * | 2013-06-21 | 2018-04-02 | Zenith Epigenetics Corp. | New substituted bicyclic compounds as bromodomain inhibitors |
| CN104151183B (en) * | 2014-07-29 | 2016-04-13 | 浙江工业大学 | A kind of preparation method of 4-acetyl aminomethyl methyl cyclohexanecarboxylaand |
| CN106316886A (en) * | 2016-08-24 | 2017-01-11 | 泰州精英化成医药科技有限公司 | Cis form-3- (tert butoxycarbonylamino) naphthenic acid preparing method |
| CN107011216A (en) * | 2017-03-31 | 2017-08-04 | 泰州新威生物科技有限公司 | A kind of preparation method of trans 4 Boc aminocyclohexane acetic acid |
| WO2019016828A1 (en) * | 2017-07-15 | 2019-01-24 | Msn Laboratories Private Limited, R&D Center | Novel processes for the preparation of trans-n-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl] cyclohexyl}-n',n'-dimethylurea hydrochloride and polymorphs thereof |
| CN116410082A (en) * | 2023-03-13 | 2023-07-11 | 苏州敬业医药化工有限公司 | Preparation method of trans-p-methylcyclohexyl formic acid |
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| CN115819417A (en) * | 2016-09-09 | 2023-03-21 | 因赛特公司 | Pyrazolopyridine derivatives as HPK1 modulators and their use for the treatment of cancer |
| CN109824516A (en) * | 2019-03-14 | 2019-05-31 | 泰州精英化成医药科技有限公司 | A kind of preparation method of trans- -4- hydroxyl thiacyclohexane t-butyl formate |
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