Preparation method of (1S, 2R)-2-methyl ester cyclopropane-1-carboxylic acid
By using alkali monohydrolysis and salt separation methods in the preparation of (1S,2R)-2-methyl cyclopropane-1-carboxylic acid, the problem of not being easy to buy and not being able to produce large-scale products is solved. , realizes an efficient and low-cost preparation method, suitable for industrial production.
Patent Information
- Application Number
- CN202411585389.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-08
- Publication Date
- 2025-02-18
AI Technical Summary
In the prior art, the raw materials for preparing (1S,2R)-2-methyl cyclopropane-1-carboxylic acid are not easy to buy and cannot be produced in large quantities, resulting in a complex preparation process and high cost.
Cis-2-methyl cyclopropane-1-carboxylic acid was prepared by dimethyl cis-1,2-cyclomalonate and alkali monohydrolysis, and was then used to salt-forming separation method with (1R,2R)-N, N-dimethyl-1,2-diaminocyclohexane was dissolved and dissociated to prepare (1S,2R)-2-methyl ester cyclopropane-1-carboxylic acid with high optical purity.
It realizes a preparation method with simple operation, mild conditions and low cost, suitable for industrial scale production, and the splitter can be recycled and reused, improving production efficiency and product purity.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing (1S, 2R)-2-(carbomethoxy)cyclopropane-1-carboxylic acid, belonging to the technical field of pharmaceutical intermediate synthesis. Background Art
[0002] (1S,2R)-2-Carbomethoxycyclopropane-1-carboxylic acid is a chiral molecule with biological activity. It has a rigid structure of cyclopropane. Cyclopropane analogs can be used as potential candidate drugs for biological evaluation of antiviral and antitumor activities. (1S,2R)-2-Carbomethoxycyclopropane-1-carboxylic acid has a wide range of applications in drug synthesis, photoelectrochemistry, and pesticides. Patent US2019 / 100500, 2019, A1 discloses that (1S,2R)-2-carbomethoxycyclopropane-1-carboxylic acid can be used to synthesize c-Abl kinase inhibitors, which can be used for tumor inhibition and nervous system treatment. Patent WO 2022 / 76975, 2022, A1 discloses that (1S,2R)-2-(Carbomethoxy)cyclopropane-1-carboxylic acid can also be synthesized to inhibit Bcr-Abl tyrosine kinase, and is used to treat blood diseases or cancer.
[0003] There are few reports on the synthesis of (1S,2R)-2-methyl cyclopropane-1-carboxylic acid. The literature [Helvetica ChimicaActa, 1991, 74, 1941-1952] reported the synthesis of (1S,2R)-2-(methyl cyclopropane-1-carboxylic acid) using cis-1,2-cyclopropanedicarboxylic acid dimethyl ester and sodium hydroxide pH 7.5-8.0 (phosphate buffer) under the action of pig liver esterase; the yield was 92%. However, the pig liver esterase is not easy to purchase. The reaction route is shown as follows:
[0004]
[0005] The literature [Journal of Organic Chemistry, 2000, 65, 6984-6991] reported that 3-oxabicyclo[3.1.0]hexane-2,4-dione was reacted with quinidine in tetrahydrofuran and toluene to obtain (1S,2R)-2-(methyl ester)cyclopropane-1-carboxylic acid, and the final product was not separated and purified. This method failed to effectively separate. It belongs to the cis-mesogenic product, and the reaction route is shown as follows:
[0006]
[0007] In order to solve the defects in the prior art that the raw materials for preparing (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid are not easy to purchase and cannot be mass-produced, the present invention provides a preparation method of (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid. The preparation method has simple operation, mild conditions, low cost, and the resolving agent and another configuration can be recycled and reused, so as to be suitable for industrial-scale production. Summary of the invention
[0008] In order to overcome the defects of the above-mentioned technology, the present invention discloses a method for preparing (1S, 2R)-2-methoxycyclopropane-1-carboxylic acid. Cis-1,2-cyclopropanedicarboxylic acid dimethyl ester is used as a raw material, and firstly, it is monohydrolyzed with a base to prepare cis-2-methoxycyclopropane-1-carboxylic acid, and then (1R, 2R)-N,N-dimethyl-1,2-diaminocyclohexane is used as a resolving agent, and it is split with cis-2-methoxycyclopropane-1-carboxylic acid by a salt splitting method, and (1S, 2R)-2-methoxycyclopropane-1-carboxylic acid is prepared by dissociation, and finally (1S, 2R)-2-methoxycyclopropane-1-carboxylic acid with high optical purity is obtained. The present invention is simple to operate, the splitting reagent can be recycled, the conditions are mild and it is suitable for industrial production.
[0009] The preparation method of chiral (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid of the present invention has a reaction scheme as follows:
[0010]
[0011] The preparation method of chiral (1S, 2R)-2-(methyl ester) cyclopropane-1-carboxylic acid comprises the following steps: the first step: mixing cis-1,2-cyclopropanedicarboxylic acid dimethyl ester with an organic solvent, adding a base to react to obtain a monohydrolysis product cis-2-methyl ester cyclopropane-1-carboxylic acid.
[0012] Step 2: Mix cis-2-methoxycyclopropane-1-carboxylic acid with a mixed solvent, add a resolving agent, heat to dissolve, cool, and filter to obtain (1S, 2R)-2-methoxycyclopropane-1-carboxylic acid / (1R, 2R)-N,N-dimethyl-1,2-diaminocyclohexane salt (the mother liquor is used for another configuration and recovery of the resolving agent); add acid to dissociate the salt to obtain (1S, 2R)-2-methoxycyclopropane-1-carboxylic acid.
[0013] Furthermore, in the above technical solution, the organic solvent in the first step is selected from a single solvent or a mixed solvent of methanol or tetrahydrofuran.
[0014] Furthermore, in the above technical solution, the base in the first step is selected from barium hydroxide octahydrate or sodium methoxide.
[0015] Furthermore, in the above technical solution, the reaction temperature in the first step is selected from 0-25°C.
[0016] Furthermore, in the above technical solution, the molar ratio of dimethyl cis-1,2-cyclopropanedicarboxylate to the base in the first step is 1:0.6-1.1.
[0017] Furthermore, in the above technical solution, the mixed solvent in the first step is selected from a mixed solvent consisting of ethanol / isopropyl acetate or isopropyl alcohol / ethyl acetate.
[0018] Furthermore, in the above technical solution, the molar ratio of cis-2-(methyl ester)cyclopropane-1-carboxylic acid to (1R,2R)-N,N-dimethyl-1,2-diaminocyclohexane in the second step is 1:0.48-0.52.
[0019] Furthermore, in the above technical scheme, the salt in the second step is added to dichloromethane and dissociated with dilute hydrochloric acid to obtain (1S, 2R)-2-methylcarbocyclopropane-1-carboxylic acid in the organic phase; sodium hydroxide is added to the aqueous phase to adjust it to alkalinity, and (1R, 2R)-N,N-dimethyl-1,2-diaminocyclohexane is extracted and recovered.
[0020] Advantageous Effects of the Invention
[0021] The chiral resolving agent (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine is stable in nature, easy to recycle and reuse, and has good industrial application value. In the resolving of the compound, the crystallization and filtration effects are good, and the ee value can be obtained at one time to reach more than 99.0%.
[0022] According to the experimental results, when the splitting agent and cis-2-methoxycyclopropane-1-carboxylic acid are salted, the molar ratio of the two is 1:2, that is, 1eq of the splitting agent is salted with 2eq of cis-2-methoxycyclopropane-1-carboxylic acid, corresponding to a 1 / 1 complexation salt between the amino group and the carboxyl group. DETAILED DESCRIPTION
[0023] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.
[0024] Based on the above work, the researchers in this research group conducted a lot of hard creative exploration and experiments to further explore the solvent environment and specific process conditions, in order to find a base with good monohydrolysis effect and a method with good splitting ability that can directly split (1S,2R)-2-(methyl)cyclopropane-1-carboxylic acid.
[0025]
[0026] For the first step, single hydrolysis, various bases were tried for hydrolysis, and it was found that sodium methoxide and barium hydroxide octahydrate were more effective, among which barium hydroxide octahydrate was preferred.
[0027] The following table shows the screening of used bases and solvents, including the ratio of double hydrolysis:
[0028]
[0029]
[0030] Of the above tables, two are particularly preferred as embodiments.
[0031] Example 1
[0032]
[0033] 158.2 g (1.0 mol) of cis-1,2-cyclopropanedicarboxylic acid dimethyl ester and 1200 mL of tetrahydrofuran were added into a 2L four-necked bottle, cooled to 0-5°C, 198.1 g (1.1 mol, 1.1 eq) of 30% sodium methoxide methanol solution was added dropwise, the temperature was slowly raised to room temperature for reaction for 16 hours, and the remaining 1.2% of the raw material was sampled for HPLC. 1 M hydrochloric acid was added to adjust the pH to 2.5-3.0, and the tetrahydrofuran was distilled out by concentration under reduced pressure. 500 mL*3 of dichloromethane was added for extraction, the organic phases were combined, washed with water and saturated sodium chloride aqueous solution, respectively, the organic phases were concentrated under reduced pressure, replaced with n-heptane, 1000 mL of n-heptane was added, heated to 50-60°C, 0.1 g of seed crystals was added, the temperature was slowly lowered to 10-15°C, filtered, the filter cake was rinsed with cold n-heptane, and dried to obtain 119.2 g of cis-2-methyl ester cyclopropane-1-carboxylic acid, with a yield of 82.7%, HPLC 99.4%.
[0034] Example 2
[0035]
[0036] 158.2 g (1.0 mol) of dimethyl cis-1,2-cyclopropanedicarboxylate, 800 mL of methanol and 400 mL of tetrahydrofuran were added into a 2L four-necked bottle, and 189.3 g (0.6 mol, 0.6 eq) of barium hydroxide octahydrate was added at a temperature of 20-25°C, and the mixture was reacted at room temperature for 24 hours. The remaining 0.2% of the raw material was sampled for HPLC, and the filter cake was rinsed with a small amount of tetrahydrofuran, and the filter cake was put back into a 2L four-necked bottle, and 200 mL of water and 1000 mL of dichloromethane were added. 5M The pH value was adjusted to 2.5-3.0 with hydrochloric acid. After the system was clarified, it was allowed to stand for stratification. 500 mL of dichloromethane was added to the aqueous phase for extraction. The organic phases were combined and washed with water and a saturated aqueous sodium chloride solution, respectively. The organic phase was concentrated under reduced pressure and replaced with n-heptane. 1000 mL of n-heptane was added, heated to 50-60°C, 0.1 g of seed crystals was added, the temperature was slowly lowered to 10-15°C, filtered, the filter cake was rinsed with cold n-heptane, and dried to obtain 130.7 g of cis-2-methyl ester cyclopropane-1-carboxylic acid with a yield of 90.7% and an HPLC yield of 99.2%.
[0037]
[0038] For the second step of salt separation, we tried a variety of chiral amine alkaline separation agents for separation, and found that (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine was the best and had a good filtration effect. The following table shows the screening of chiral separation agents used and their Ee values for one separation:
[0039]
[0040] Example 3
[0041]
[0042] Add 28.8 g (0.2 mol, 1 eq) of cis-2-carbomethoxycyclopropane-1-carboxylic acid, 90 mL of ethanol and 225 mL of isopropyl acetate into a 1 L four-necked bottle, add 14.2 g (0.1 mol, 0.5 eq) of (1R, 2R)-N, N-dimethyl-1, 2-diaminocyclohexane at a temperature of 20-25 ° C, then heat to 75-78 ° C and stir for 6-9 hours, slowly cool to room temperature, stir for 2 hours, then slowly cool to 0 ° C, stir for 4 hours, filter, and wash the filter cake with a cold ethanol / ethyl acetate mixed solvent (the mother liquor is retained and can be recovered). The obtained filter cake was put into a 1L four-necked bottle, 225mL of dichloromethane and 50mL of water were added, and 2M hydrochloric acid was added dropwise to adjust the pH to 2.5-3.0. After the system was clarified, it was allowed to stand for stratification. The aqueous phase was extracted with 100mL*2 of dichloromethane, the organic phases were combined, washed with 80mL of water, the aqueous phase was retained (to be recovered chiral resolving agent), the organic phase was concentrated under reduced pressure, replaced with n-heptane, and solids were gradually precipitated by adding n-heptane. The mixture was stirred at 0°C for 6 hours, filtered, the filter cake was rinsed with cold n-heptane, and dried to obtain 11.56g of cis-2-(methyl ester)cyclopropane-1-carboxylic acid, with a yield of 40.1%, HPLC 99.7%, and 99.3% ee. 1 H NMR (400MHz, DMSO-d6): 12.33(s,1H),3.55(s,3H),2.16-2.10(m,1H),2.03-1.99(m,1H),1.36-1.31(m,1H),1.20-1.16(m,1H).
[0043] Example 4
[0044]
[0045] 28.8 g (0.2 mol, 1 eq) of cis-2-carbomethoxycyclopropane-1-carboxylic acid, 150 mL of isopropyl alcohol and 185 mL of isopropyl acetate were added into a 1 L four-necked bottle, and the temperature was controlled at 20-25 ° C. 14.2 g (0.1 mol, 0.5 eq) of (1R, 2R)-N, N-dimethyl-1, 2-diaminocyclohexane was added, and then the temperature was raised to 77-80 ° C. and stirred for 10 hours, and then the temperature was slowly lowered to room temperature and stirred for 3 hours, and then the temperature was slowly lowered to 0 ° C. and stirred for 2 hours, and filtered. The filter cake was rinsed with a cold isopropanol / ethyl acetate mixed solvent (the mother liquor was retained and recovered), and the obtained filter cake was then The mixture was put into a 1L four-necked bottle, 225mL of dichloromethane and 50mL of water were added, and 2M hydrochloric acid was added dropwise to adjust the pH to 2.5-3.0. After the system was clarified, the mixture was allowed to stand for stratification. 100mL*2 of dichloromethane was added to the aqueous phase for extraction. The organic phases were combined and washed with 80mL of water. The aqueous phase was retained (to be recovered as the chiral resolving agent). The organic phase was concentrated under reduced pressure and replaced with n-heptane. Solids gradually precipitated when n-heptane was added. The mixture was stirred at 10°C for 6 hours, filtered, and the filter cake was rinsed with cold n-heptane. The mixture was dried to obtain 10.32g of cis-2-methyl ester cyclopropane-1-carboxylic acid with a yield of 35.8%, HPLC 99.6%, and 99.1% ee.
[0046] The above-described embodiments are only preferred embodiments of the present invention, and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious changes made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.
Claims
1. A method for preparing (1S, 2R)-2-(carbomethoxy)cyclopropane-1-carboxylic acid, characterized in that: The steps include: The first step: mixing cis-1,2-cyclopropanedicarboxylic acid dimethyl ester with an organic solvent, adding a base to react to obtain a monohydrolysis product cis-2-(methyl ester)cyclopropane-1-carboxylic acid; Step 2: Mix cis-2-(methyl ester)cyclopropane-1-carboxylic acid with a mixed solvent, add a resolving agent, heat to dissolve, cool, and filter to obtain (1S, 2R)-2-methyl ester cyclopropane-1-carboxylic acid / (1R, 2R)-N,N-dimethyl-1,2-diaminocyclohexane salt, and add acid to dissociate the salt to obtain (1S, 2R)-2-methyl ester cyclopropane-1-carboxylic acid.
2. The method for preparing (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the first step, the organic solvent is selected from at least one of methanol and tetrahydrofuran.
3. The method for preparing (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the first step, the base is selected from barium hydroxide octahydrate or sodium methoxide.
4. The method for preparing (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the first step, the reaction temperature is selected from 0-25°C.
5. The method for preparing (1S, 2R)-2-(carbomethoxy)cyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the first step, the molar ratio of dimethyl cis-1,2-cyclopropanedicarboxylate to the base is 1:0.6-1.
1.
6. The method for preparing (1S, 2R)-2-(carbomethoxy)cyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the second step, the mixed solvent is selected from a mixed solvent consisting of ethanol / isopropyl acetate or isopropyl alcohol / isopropyl acetate.
7. The method for preparing (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the second step, the molar ratio of cis-2-(carbomethoxy)cyclopropane-1-carboxylic acid to (1R,2R)-N,N-dimethyl-1,2-diaminocyclohexane is 1:0.48-0.
52.
8. The method for preparing (1S, 2R)-2-carbomethoxycyclopropane-1-carboxylic acid according to claim 1, characterized in that: In the second step, dichloromethane is added to the salt, and dilute hydrochloric acid is used for dissociation, and (1S, 2R)-2-methylcarbocyclopropane-1-carboxylic acid is obtained in the organic phase; sodium hydroxide is added to the aqueous phase to adjust it to alkalinity, and (1R, 2R)-N,N-dimethyl-1,2-diaminocyclohexane is extracted and recovered.