Intermediate of 2, 3-dimethyl cyclopropyl formic acid and synthesis method thereof

Abstract

The invention provides a synthesis method of an intermediate for synthesizing 2, 3-dimethyl cyclopropyl formic acid, and the structural formula is as follows: # imgabs0 #. The synthesis method comprises the following steps: (1) reacting diazoacetate G with cis-2-butene to obtain a mixture H; (2) hydrolyzing the mixture H to obtain a cis-trans carboxylic acid mixture I; (3) reacting the mixture I with a chlorination reagent to obtain an acyl chloride intermediate J; (4) reacting the acyl chloride intermediate J with benzyl alcohol to obtain a mixture B; and (5) carrying out column chromatography separation on the mixture B to obtain (1 alpha, 2 beta, 3 beta)-2, 3-dimethyl cyclopropyl benzyl formate C and (1 alpha, 2 alpha, 3 alpha)-2, 3-dimethyl cyclopropyl benzyl formate D. The other synthetic method comprises the following steps: reacting benzyl diazoacetate with cis-2-butene to obtain a mixture B, and then separating through column chromatography to obtain a pure compound C and a pure compound D. The preparation method has the advantages of few reaction steps, simple and easily available raw materials, and easy industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to an intermediate of 2,3-dimethylcyclopropylcarboxylic acid and a synthesis method thereof. Background Art

[0002] Cyclopropane compounds are widely present in natural products and drug molecules, especially in plant hormones and pesticides. As a highly strained three-membered ring structure, cyclopropane is also of great significance for optimizing the drugability of drug molecules. It can replace straight-chain alkanes to increase oral availability, replace cycloalkanes to improve lipophilicity, replace double bonds to improve drugability, replace benzene rings to reduce hydrophobicity, and replace olefins with polycyclic skeletons to reduce toxicity. Therefore, a series of methods have been developed to synthesize three-membered rings. The most common one is the metal-catalyzed addition reaction of diazo compounds to olefins. In addition, there are Simmons-Smith reaction, Corey-Chaykovsky reaction, Kulinkovich reaction, Wadsworth-Emmons reaction, etc. There are few previous reports on the preparation of pure (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid. Moreover, the existing methods cannot be applied on a large scale. For example, expensive rhodium catalysts are used to synthesize ethyl 2,3-dimethylcyclopropylcarboxylate (WO 2018 / 222101A1, Hopkins, Brian, T; Ma Bin et.al.), or preparative gas chromatography is used to separate the two isomers of ethyl 2,3-dimethylcyclopropylcarboxylate (J.Am.Chem.Soc., 1977, 99, 3, 816–821). The use of preparative gas chromatography is firstly expensive; secondly, the sample loading capacity is small, and the amount of sample obtained each time is small, which makes it difficult to achieve industrial application. As an important synthetic building block, a large-scale and low-cost method for preparing (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid has not been reported. In view of its important significance in drug synthesis, it is urgent to develop a method for large-scale production of pure (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid. Summary of the invention

[0003] In view of the defects in the prior art, the object of the present invention is to provide an intermediate of 2,3-dimethylcyclopropylcarboxylic acid and a synthesis method thereof.

[0004] The object of the present invention is achieved through the following solutions:

[0005] The first aspect of the present invention provides an intermediate of 2,3-dimethylcyclopropylcarboxylic acid, the intermediate structural formula of which is shown below:

[0006]

[0007] The second aspect of the present invention provides a method for synthesizing the intermediate of the above-mentioned 2,3-dimethylcyclopropylcarboxylic acid, comprising the following steps:

[0008] Step (1), diazoacetate G Cyclopropanation reaction with cis-2-butene catalyzed by copper salts gave a mixture of cis and trans Wherein, R=Me or Et; wherein the diazoacetate G is prepared by diazotization reaction of glycine ester hydrochloride and sodium nitrite. The solvents include dichloromethane, chloroform, 1,2-dichloroethane, preferably dichloromethane; the acid can be selected from sulfuric acid, hydrochloric acid, acetic acid, preferably sulfuric acid; sodium nitrite / glycine ester=1-1.5 (molar ratio), preferably 1.05-1.1.

[0009] Step (2), the mixture H undergoes a hydrolysis reaction under the action of a base to obtain a mixture I of the corresponding cis-trans carboxylic acids. Directly used for the next reaction;

[0010] Step (3), the mixture of cis-trans carboxylic acids I is converted into an acyl chloride intermediate J under the action of a chlorinating agent.

[0011] Step (4), the acyl chloride intermediate J reacts with benzyl alcohol under alkaline conditions to obtain a mixture B of (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester and (1α, 2α, 3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester

[0012] Step (5), mixture B was separated by column chromatography to obtain pure (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D Wherein, the mixture B is separated by normal phase column chromatography, and the stationary phase includes silica gel, aluminum oxide, preferably silica gel. The amount of silica gel / crude product = 100-40 (weight ratio): 1, preferably 50-80: 1. The eluent includes: ethyl acetate, acetone, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, n-heptane, cyclohexane, and one of them or a mixed solvent composed of two of them can be selected, preferably a mixed solvent composed of ethyl acetate and petroleum ether.

[0013] Preferably, the organic solvent selected in step (1) is dichloromethane, chloroform or 1,2-dichloroethane, preferably dichloromethane; the copper salt catalyst is selected from one of tetrafluoroborate tetraacetonitrile copper (I), trifluoromethanesulfonate tetraacetonitrile copper (I), hexafluorophosphate tetraacetonitrile copper (I), cuprous chloride and cuprous iodide, preferably tetrafluoroborate tetraacetonitrile copper (I), trifluoromethanesulfonate tetraacetonitrile copper (I), hexafluorophosphate tetraacetonitrile copper (I); the copper salt catalyst and diazoacetate G are reacted to form a diazoacetate. The molar ratio is (0.1-1):100, preferably (0.5-1):100; the molar ratio of cis-2-butene to diazoacetate G is (6-4):1, preferably (5-4):1; diazoacetate G is slowly added dropwise to the organic solution of cis-2-butene at low temperature, and the addition time is 4-12 hours, preferably 6-8 hours (slow addition is one of the key factors to improve the yield of the reaction), and the reaction temperature ranges from -10°C to 25°C, preferably from -5°C to 5°C.

[0014] Preferably, in step (2), the solvent is methanol, ethanol or tetrahydrofuran, preferably methanol, and the base is NaOH or KOH; in step (3), the chlorination reagent is oxalyl chloride or dichlorothionyl, and the solvent is dichloromethane, chloroform, 1,2-dichloroethane or toluene, preferably dichloromethane.

[0015] Preferably, in step (4), the solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane or toluene, preferably dichloromethane; the base is selected from triethylamine, diisopropylethylamine or pyridine, preferably triethylamine.

[0016] Preferably, the (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D obtained in step (5) are reacted with hydrogen in the presence of a metal catalyst to generate the corresponding (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid E. and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid F In this step, the solvent selection includes methanol, ethanol, propanol, isopropanol, tetrahydrofuran, ethyl acetate or DMF, preferably methanol, ethanol, ethyl acetate; the catalyst selection includes Pd / C, Pt / C or Raney Ni. Preferably 5% Pd / C (wet product containing water, safer), the reaction result using Pt / C is also very good, the price of Pt / C is lower than that of Pd / C (with the same precious metal content), and the reaction speed is much slower. Taking 5% Pd / C as an example, the catalyst dosage, catalyst / substrate = 0.1% to 1% (weight ratio), preferably 0.5% to 1%, hydrogen pressure, normal pressure to 4atm., preferably normal pressure to 2atm.

[0017] The specific synthetic route is as follows:

[0018]

[0019] The third aspect of the present invention provides a method for synthesizing the intermediate of the above-mentioned 2,3-dimethylcyclopropylcarboxylic acid, comprising the following steps:

[0020] Step (1), benzyl diazoacetate A Cyclopropanation reaction with cis-2-butene in the presence of a copper salt catalyst gave a mixture of (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester B.

[0021] Step (2), mixture B was separated by column chromatography to obtain pure (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D

[0022] Compounds C and D react with hydrogen in the presence of a metal catalyst to generate the corresponding (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid E. and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid F In this step, the solvent selection includes methanol, ethanol, propanol, isopropanol, tetrahydrofuran, ethyl acetate or DMF, preferably methanol, ethanol, ethyl acetate; the catalyst selection includes Pd / C, Pt / C or Raney Ni. Preferably 5% Pd / C (wet product containing water, safer), the reaction result using Pt / C is also very good, the price of Pt / C is lower than that of Pd / C (with the same precious metal content), and the reaction speed is much slower. Taking 5% Pd / C as an example, the catalyst dosage, catalyst / substrate = 0.1% to 1% (weight ratio), preferably 0.5% to 1%, hydrogen pressure, normal pressure to 4atm., preferably normal pressure to 2atm.

[0023] Preferably, the benzyl diazoacetate A is prepared by diazotization reaction of glycine benzyl hydrochloride and sodium nitrite. The solvent selected includes dichloromethane, chloroform, 1,2-dichloroethane, preferably dichloromethane; the acid can be selected from sulfuric acid, hydrochloric acid, acetic acid, preferably sulfuric acid; sodium nitrite / glycine ester = 1 to 1.5 (molar ratio), preferably 1.05 to 1.1.

[0024] Preferably, in step (1), the organic solvent is selected from dichloromethane, chloroform or 1,2-dichloroethane, preferably dichloromethane; the copper salt catalyst is selected from one of tetrafluoroborate tetraacetonitrile copper (I), trifluoromethanesulfonate tetraacetonitrile copper (I), hexafluorophosphate tetraacetonitrile copper (I), cuprous chloride and cuprous iodide, preferably tetrafluoroborate tetraacetonitrile copper (I), trifluoromethanesulfonate tetraacetonitrile copper (I), hexafluorophosphate tetraacetonitrile copper (I); the molar ratio of the copper salt catalyst to benzyl diazoacetate A is (0.1-1):100, preferably (0.5-1):100; the molar ratio of cis-2-butene to benzyl diazoacetate A is (6-4):1, preferably (5-4):1.

[0025] Preferably, in step (1), cis-2-butene is dissolved in an organic solvent, and then benzyl diazoacetate A is slowly added dropwise thereto for 4 to 12 hours, preferably 6 to 8 hours (slow addition is one of the key factors for improving the yield of the reaction), and the reaction temperature ranges from -10°C to 25°C, preferably from -5°C to 5°C.

[0026] Preferably, in step (2), the separation of cis-trans isomers is carried out by normal phase column chromatography, and the stationary phase comprises silica gel, aluminum oxide, preferably silica gel. The amount of silica gel / crude product = 100-40 (weight ratio): 1, preferably 50-80: 1. The eluent comprises: ethyl acetate, acetone, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, n-heptane, cyclohexane, one of which can be selected, or a mixed solvent composed of two of them, preferably a mixed solvent composed of ethyl acetate and petroleum ether.

[0027] The specific synthetic route is as follows:

[0028]

[0029] Compared with the prior art, the present invention has the following beneficial effects: the preparation method of the present invention has fewer reaction steps, simple and easily available raw materials, low cost, and easy industrial production. For the target compound, compared with separation by preparing the gas phase, the method of the present invention solves the long-standing problem of difficulty in industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0031] Figure 1 is the hydrogen spectrum of compound E;

[0032] Figure 2 is the hydrogen spectrum of compound F. DETAILED DESCRIPTION

[0033] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several changes and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0034] The invention develops a method for preparing pure (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid and (1α, 2α, 3α)-2,3-dimethylcyclopropylcarboxylic acid which can be used for large-scale production.

[0035] Route 1:

[0036]

[0037] Glycine benzyl hydrochloride is used as the starting material, and a diazotization reaction is carried out with sodium nitrite to obtain benzyl diazoacetate (A). Under the catalysis of cuprous salt, benzyl diazoacetate and cis-2-butene undergo a cyclopropanation reaction of a carbene insertion reaction mechanism to obtain a mixture B of (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester, with a molar ratio of about 2 / 1. The mixture B is separated by silica gel column chromatography or medium pressure preparative silica gel column chromatography to obtain pure (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D, respectively. Then, through catalytic hydrogenation with a metal catalyst such as Pd / C and removal of the benzyl group, the target products (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid E and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid F were obtained respectively.

[0038] Route 2:

[0039]

[0040] Using cheap and readily available glycine ester hydrochloride as the starting material, such as glycine ethyl ester hydrochloride, glycine methyl ester hydrochloride, etc., the corresponding diazoacetic acid ester G is prepared by diazotization reaction, and cyclopropanation reaction with cis-2-butene is carried out under the catalysis of cuprous salt to obtain a cis-trans mixture H, and the molar ratio of trans / cis is about 2 / 1. The ester is hydrolyzed under the action of NaOH or KOH to obtain the corresponding cis-trans carboxylic acid mixture I, and the molar ratio of trans / cis is about 2.5 / 1 (because under the action of alkali, part of the cis compound is converted into the thermodynamically more stable trans compound during the hydrolysis process). The obtained cis-trans carboxylic acid mixture I is converted into the acid chloride intermediate J under the action of oxalyl chloride or SOCl2, and then reacted with benzyl alcohol to obtain (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester mixture B. The cis / trans ester mixture B is separated by column chromatography to obtain (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D, respectively. Then C and D are reacted with hydrogen under the catalysis of a metal catalyst, such as Pd / C or Pt / C, to generate the corresponding cis and trans carboxylic acids, to obtain the target products (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid E and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid F, respectively.

[0041] Comparison between route 1 and route 2:

[0042] 1. Route 1 contains 3 steps of reaction, and Route 2 contains 5 steps of reaction. Route 1 is shorter.

[0043] 2. The starting materials of route 2, glycine ethyl ester hydrochloride or glycine methyl ester hydrochloride, are very cheap and readily available, much cheaper than the starting materials of route 1, glycine benzyl ester hydrochloride. Because the steric hindrance of the ethyl group (or methyl group) is smaller than that of the benzyl group, the carbene complex formed by ethyl diazoacetate (or methyl ester) and the cuprous salt catalyst has a higher reaction activity than that of benzyl diazoacetate, a faster reaction speed, a higher utilization rate of the diazo ester, and a slightly higher yield of the reaction based on the diazo ester.

[0044] 3. The cis-trans ratios in the copper salt-catalyzed cyclopropanation reaction of diazo esters with olefins in both routes are close. In the subsequent ester hydrolysis reaction in route 2, part of the cis product is converted into a thermodynamically more stable trans product, which improves the selectivity for the trans product and is beneficial to the formation of the trans product.

[0045] Therefore, according to actual production needs, Route 1 or Route 2 can be selected for large-scale production.

[0046] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0047] Example 1

[0048] (1) Preparation of benzyl diazoacetate (A)

[0049] Take 20.00g of glycine benzyl ester hydrochloride (99.2mmol) and dissolve it in 100mL H2O, add 100mL of dichloromethane, and then cool the mixture to 0-5℃. Dissolve 7.52g (109.1mmol) of sodium nitrite in 20mL H2O to form an aqueous solution in advance, and then slowly drip the aqueous solution into the mixture, and control the internal temperature ≤5℃ during the dripping process. After the dripping is completed, add a 10% sulfuric acid aqueous solution to the reaction system, adjust the pH value of the aqueous phase to 3.5-4.0, and control the internal temperature ≤5℃ during the dripping process. After the dripping is completed, continue to stir at 0-5℃ for 2 hours. After the reaction is completed, slowly add a saturated sodium carbonate aqueous solution to the reaction solution, and adjust the pH value of the aqueous phase to 6.0-6.5. Let it stand for stratification and separate the lower organic phase. The organic phase is washed with 50mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate is directly used for the next step reaction.

[0050] (2) Preparation of Compound B

[0051] Under nitrogen protection, add 50 mL of dichloromethane and 0.31 g (0.99 mmol) of tetrafluoroborate tetraacetonitrile copper (I) to a 500 mL reaction bottle equipped with an efficient reflux condenser (coolant temperature is -20 to -15 ° C), and cool the dichloromethane to -10 to -5 ° C while stirring. Under rapid stirring, slowly pass cis-2-butene (boiling point 3.7 ° C, gaseous at room temperature and pressure) stored in a steel bottle into dichloromethane to dissolve cis-2-butene in dichloromethane. Pass 22.20 g of cis-2-butene (396 mmol, cis-2-butene / benzyl diazoacetate = 4 / 1 (molar ratio) into the reaction bottle, and determine the amount of olefin passed by weighing the reaction bottle). Adjust the temperature of the reaction solution to 0±3°C, and then slowly add the solution of benzyl diazoacetate obtained in the first step to the reaction bottle. During the addition, the reaction temperature is maintained within the range of 0±3°C, and the total addition time is controlled to be 6-8 hours. During the addition, gas can be observed to be continuously generated through the bubbler. After the addition is completed, continue to stir at 0±3°C for 2 to 3 hours until no gas is generated. Remove the reflux condenser, connect the reaction bottle to a dry ice cold trap, and slowly warm the reaction solution to room temperature. In this process, unreacted cis-2-butene is recovered by a dry ice cold trap. The residue is desolventized on a rotary evaporator to dryness to obtain a crude product B.

[0052] (3) Preparation of Compounds C and D

[0053] The crude product B obtained in the previous step was separated and purified by silica gel column chromatography. Column chromatography conditions: the stationary phase is 300-400 mesh silica gel, silica gel / crude product (weight ratio) = 60-70 / 1, eluent: ethyl acetate / petroleum ether = 1 / 100-1 / 50. The compound D has a larger Rf value, and the compound C has a smaller Rf value. Purification by silica gel column chromatography gave 9.31 g of compound C (46% yield relative to glycine benzyl hydrochloride) and 4.43 g of compound D (22% yield relative to glycine benzyl hydrochloride), respectively. The main by-products in the reaction are dibenzyl maleate and dibenzyl fumarate. Compound C is a colorless transparent oil, and the hydrogen spectrum data are: 1 H NMR (400M Hz, CDCl3): 7.40-7.29 (m, 5H), 5.10 (s, 2H), 1.58-1.47 (m, 2H), 1.11 (m, 6H), 1.06 (t, J = 4.4Hz, 1H).

[0054] Compound D is a colorless transparent oil, and its hydrogen spectrum data are: 1 H NMR (400M Hz, CDCl3): 7.40-7.28 (m, 5H), 5.10 (s, 2H), 1.68 (t, J = 8.8Hz, 1H), 1.48-1.35 (m, 2H), 1.21 (m, 6H).

[0055] (4) Preparation of Compound E

[0056] 9.31g of compound C was dissolved in 93mL of methanol, and 91mg of 10% Pd / C (containing 50% water) was added. The air was replaced with nitrogen 3 times, and then replaced with hydrogen 3 times. Then, the mixture was stirred at room temperature for 3 hours under 1atm of hydrogen. TLC showed that the raw material disappeared. The reaction solution was filtered to remove the catalyst, and the filtrate was evaporated to dryness on a rotary evaporator to obtain 5.06g of white solid E, with a yield of 96%. The hydrogen spectrum is as follows Figure 1 As shown, the spectrum data is: 1 H NMR (400 MHz, CDCl3): 1.56-1.52 (m, 2H), 1.12-1.10 (m, 6H), 1.00 (t, J = 4.4 Hz, 1H), melting point: 70.0-71.7°C.

[0057] (5) Preparation of Compound F

[0058] 4.43 g of compound D was dissolved in 44 mL of methanol, 44 mg of 10% Pd / C (50% water content) was added, the air was replaced with nitrogen 3 times, and then the nitrogen was replaced with hydrogen 3 times, and then stirred at room temperature for 3 hours under 1 atm of hydrogen. TLC showed that the raw material disappeared. The reaction solution was filtered to remove the catalyst, and the filtrate was evaporated to dryness on a rotary evaporator to obtain 2.32 g of white solid F, with a yield of 95%. The hydrogen spectrum is as follows Figure 2 As shown, the spectrum data is: 1 H NMR (400 MHz, CDCl3): 1.63 (t, J = 8.8 Hz, 1H), 1.51-1.44 (m, 2H), 1.20-1.18 (m, 6H). Melting point: 75.7-77.6°C.

[0059] Example 2

[0060] The difference from Example 1 is that cis-2-butene / benzyl diazoacetate = 5 / 1 (molar ratio), and the rest of the operations are the same as Example 1. Finally, 9.54 g of compound C (yield relative to glycine benzyl ester hydrochloride, 47%) and 4.60 g of compound D (yield relative to glycine benzyl ester hydrochloride, 23%) were obtained.

[0061] Example 3

[0062] (1) Synthesis of ethyl diazoacetate G (R = Et)

[0063] Take 14.00g (100mmol) of glycine ethyl ester hydrochloride and dissolve it in 30mL H2O, add 100mL of dichloromethane, and then cool the mixture to 0-5℃. Dissolve 7.61g (110mmol) of sodium nitrite in 20mL H2O to form an aqueous solution in advance, and then slowly drop the aqueous solution into the mixture, and control the internal temperature ≤5℃ during the dropwise addition. After the dropwise addition is completed, add 10% sulfuric acid aqueous solution to the reaction system, adjust the pH value of the aqueous phase to 3.5-4.0, and control the internal temperature ≤5℃ during the dropwise addition. After the dropwise addition is completed, continue to stir at 0-5℃ for 2 hours. After the reaction is completed, slowly add saturated sodium carbonate aqueous solution to the reaction solution, and adjust the pH value of the aqueous phase to 6.0-6.5. Let it stand for stratification and separate the lower organic phase. The organic phase is washed with 50mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate is directly used for the next step reaction.

[0064] (2) Synthesis of Compound H

[0065] Under nitrogen protection, add 50 mL of dichloromethane and 0.37 g (1 mmol) of tetraacetonitrile copper (I) trifluoromethanesulfonate to a 500 mL reaction bottle equipped with an efficient reflux condenser (coolant temperature is -20 to -15 ° C), and cool the dichloromethane to -10 to -5 ° C while stirring. Under rapid stirring, slowly pass cis-2-butene (boiling point 3.7 ° C, gaseous at room temperature and pressure) stored in a steel bottle into dichloromethane to dissolve cis-2-butene in dichloromethane. Pass 22.46 g of cis-2-butene (400 mmol, cis-2-butene / ethyl diazoacetate = 4 / 1 (molar ratio), and determine the amount of olefin passed by weighing the reaction bottle) into the reaction bottle. Adjust the temperature of the reaction solution to 0±3°C, and then slowly add the solution of ethyl diazoacetate obtained in the first step to the reaction bottle. During the addition, the reaction temperature is kept within the range of 0±3°C, and the total addition time is controlled to be 6-8 hours. During the addition, gas can be observed to be continuously generated through the bubbler. After the addition is completed, continue to stir at 0±3°C for 1 to 2 hours until no gas is generated. Remove the reflux condenser, connect the reaction bottle to a dry ice cold trap, and slowly warm the reaction solution to room temperature. In this process, unreacted cis-2-butene is recovered by the ice cold trap. Add 50mL of dichloromethane to the residue, then add 100mL of 4% ammonia water, stir at room temperature for 1 hour, stand for stratification, and separate the lower organic phase. The organic phase is washed with 50mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure on a rotary evaporator to remove the organic solvent to obtain a light brown oily crude product H. The crude product H is subjected to reduced pressure distillation using a circulating water pump to obtain a colorless oil H12.25g with a yield of 86%. GC analysis showed that the cis / trans is 1 / 2 (molar ratio), and the main impurities are diethyl maleate and diethyl fumarate. Column chromatography was performed on compound H, but it was unsuccessful. Rectification under reduced pressure and atmospheric pressure was also attempted, but the separation of cis and trans isomers was also unsuccessful.

[0066] (3) Synthesis of Compound I

[0067] In a 250mL flask, 11.95g of compound H (84.0mmol, 1.0eq.) was dissolved in 72mL of methanol, and a solution of 16.47g of KOH (294.1mmol, 3.5eq.) dissolved in 36mL of water was added. After the reaction solution was stirred at room temperature for 2 hours, it was concentrated under reduced pressure on a rotary evaporator to remove methanol. The remaining solution was adjusted to pH = 2-3 with a 3M HCl aqueous solution, and then extracted with 36mL of dichloromethane three times. After the organic phases were combined, they were washed once with 40mL of water and 40mL of 5% sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 9.33g of white solid I with a yield of 97.3%. This crude product was directly used in the next step. GC analysis showed that the cis acid / trans acid in this crude product was 1 / 2.5 (molar ratio).

[0068] (4) Synthesis of Compound J

[0069] In a dry 250 mL flask, 12.04 g of oxalyl chloride (94.8 mmol, 1.2 eq.) was dissolved in 90 mL of dichloromethane, 9.02 g (79.0 mmol, 1.0 eq.) of crude compound I was added in batches, and one drop of N,N-dimethylformamide was added as a catalyst. After stirring at room temperature for 2 hours, the reaction solution was evaporated to dryness under reduced pressure to obtain crude product J.

[0070] (5) Synthesis of Compound B

[0071] The crude product J was dissolved in 90 mL of dichloromethane and cooled to 0-5°C, then 12.82 g of benzyl alcohol (118.6 mmol, 1.5 eq.) was slowly added, and then 23.99 g of triethylamine (237.1 mmol, 3.0 eq.) was slowly added dropwise. After stirring at room temperature for 4 hours, the reaction solution was diluted with 90 mL of dichloromethane, and then washed with 50 mL of water, 50 mL of 0.1 M HCl aqueous solution, 50 mL of saturated NaHCO3 solution and 50 mL of 5% brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound B.

[0072] (6) Preparation of Compounds C and D

[0073] The obtained crude product B was separated and purified by silica gel column chromatography. Column chromatography conditions: the stationary phase is 300-400 mesh silica gel, silica gel / crude product (weight ratio) = 60-70 / 1, eluent: ethyl acetate / petroleum ether = 1 / 100-1 / 50. The compound with a larger Rf value is compound D, and the compound with a smaller Rf is compound C. Purification by silica gel column chromatography gave 10.73 g of colorless oil C (based on glycine ethyl ester hydrochloride, yield 52%) and 4.29 g of colorless oil D (based on glycine ethyl ester hydrochloride, yield 21%).

[0074] (7) Preparation of Compounds E and F

[0075] The steps are the same as those in Example 1.

[0076] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various changes or modifications within the scope of the claims, which does not affect the essence of the present invention. In the absence of conflict, the embodiments of the present application and the features in the embodiments can be combined with each other arbitrarily.

[0077] Example 4

[0078] The difference from Example 3 is that cis-2-butene / ethyl diazoacetate = 5 / 1 (molar ratio), and the rest of the operations are the same as Example 1. Finally, 10.93 g of compound C (yield based on glycine ethyl ester hydrochloride 53%) and 4.09 g of compound D (yield based on glycine ethyl ester hydrochloride 20%) were obtained.

[0079] Comparative Example 1

[0080] The difference from Example 1 is that cis-2-butene / benzyl diazoacetate = 2 / 1 (molar ratio), and the rest of the operations are the same as in Example 1. Finally, 5.7 g of compound C (28% yield relative to glycine benzyl hydrochloride) and 2.7 g of compound D (13% yield relative to glycine benzyl hydrochloride) were obtained. Reducing the amount of olefins results in a decrease in yield and a significant increase in the dimerization side reaction of diazoacetate.

[0081] Comparative Example 2

[0082] The difference from Example 1 is that cis-2-butene / benzyl diazoacetate = 1 / 1 (molar ratio), and the rest of the operations are the same as in Example 1. Finally, 3.05 g of compound C (15% yield relative to glycine benzyl hydrochloride) and 1.45 g of compound D (7% yield relative to glycine benzyl hydrochloride) were obtained. Reducing the amount of olefin used will increase the side reaction of diazo coupling itself to dibenzyl maleate or dibenzyl fumarate, resulting in a decrease in yield.

[0083] Comparative Example 3

[0084] The difference from Example 3 is that cis-2-butene / ethyl diazoacetate=2 / 1 (molar ratio), and the remaining operations are the same as in Example 3. Finally, 6.19g of compound C (yield based on glycine ethyl ester hydrochloride 30%) and 2.86g of compound D (yield based on glycine ethyl ester hydrochloride 14%) were obtained respectively. Reducing the amount of olefins results in a decrease in yield and an obvious increase in the dimerization side reaction of diazoacetate.

[0085] Comparative Example 4

[0086] The difference from Example 3 is that cis-2-butene / ethyl diazoacetate = 1 / 1 (molar ratio), and the rest of the operations are the same as in Example 3. Finally, 3.5 g of compound C (yield based on glycine ethyl ester hydrochloride 17%) and 1.63 g of compound D (yield based on glycine ethyl ester hydrochloride 8%) were obtained respectively. Reducing the amount of olefins used will increase the side reaction of diazo coupling itself to diethyl maleate or diethyl fumarate, resulting in a decrease in yield.

Claims

1. An intermediate for synthesizing 2,3-dimethylcyclopropylcarboxylic acid, characterized in that: The intermediate structural formula is shown below:

2. A method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 1, characterized in that: The steps include: Step (1), diazoacetate G Cyclopropanation reaction with cis-2-butene catalyzed by copper salts gave a mixture of cis and trans Wherein, R=Me or Et; Step (2), the mixture H undergoes a hydrolysis reaction under the action of a base to obtain a mixture I of the corresponding cis-trans carboxylic acids. Used directly in the next reaction; Step (3), the mixture of cis-trans carboxylic acids I is converted into an acyl chloride intermediate J under the action of a chlorinating agent. Step (4), the acyl chloride intermediate J reacts with benzyl alcohol under alkaline conditions to obtain a mixture B of (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester and (1α, 2α, 3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester Step (5), mixture B was separated by column chromatography to obtain pure (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D 3. The method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 2, characterized in that: In step (1), the organic solvent is selected from dichloromethane, chloroform or 1,2-dichloroethane; the copper salt catalyst is selected from one of tetrafluoroborate tetraacetonitrile copper (I), trifluoromethanesulfonate tetraacetonitrile copper (I), hexafluorophosphate tetraacetonitrile copper (I), cuprous chloride and cuprous iodide; the molar ratio of the copper salt catalyst to the diazoacetate G is (0.1-1):100; the molar ratio of cis-2-butene to the diazoacetate G is (6-4):1; and the diazoacetate G is slowly added dropwise to the organic solution of cis-2-butene at low temperature.

4. The method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 2, characterized in that: In step (2), the solvent is methanol, ethanol or tetrahydrofuran, and the base is NaOH or KOH; in step (3), the chlorination reagent is oxalyl chloride or dichlorothionyl, and the solvent is dichloromethane, chloroform, 1,2-dichloroethane or toluene.

5. The method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 2, characterized in that: In step (4), the solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane or toluene; the base is selected from triethylamine, diisopropylethylamine or pyridine.

6. A method for synthesizing 2,3-dimethylcyclopropylcarboxylic acid, characterized in that: The method comprises the following steps: using the synthesis method of the intermediate of 2,3-dimethylcyclopropylcarboxylic acid as claimed in claim 2 to prepare compound (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and compound (1α, 2α, 3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D; and then reacting compound C and compound D with hydrogen under the action of a metal catalyst to generate corresponding (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid E. and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid F 7. A method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 1, characterized in that: The steps include: Step (1), benzyl diazoacetate A Cyclopropanation reaction with cis-2-butene in the presence of a copper salt catalyst gave a mixture of (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester B. Step (2), mixture B was separated by column chromatography to obtain pure (1α, 2β, 3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D 8. The method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 7, characterized in that: The benzyl diazoacetate A is prepared by diazotization reaction of glycine benzyl hydrochloride and sodium nitrite.

9. The method for synthesizing an intermediate of 2,3-dimethylcyclopropylcarboxylic acid according to claim 7, characterized in that: In step (1), the organic solvent is selected from dichloromethane, chloroform or 1,2-dichloroethane; the copper salt catalyst is selected from one of tetrafluoroborate tetraacetonitrile copper (I), trifluoromethanesulfonate tetraacetonitrile copper (I), hexafluorophosphate tetraacetonitrile copper (I), cuprous chloride and cuprous iodide; the molar ratio of the copper salt catalyst to benzyl diazoacetate A is (0.1-1):100; the molar ratio of cis-2-butene to benzyl diazoacetate A is (6-4) : 1, dissolving cis-2-butene in an organic solvent, and then slowly adding benzyl diazoacetate A thereto, the adding time is 4 to 12 hours, and the reaction temperature ranges from -10°C to 25°C; in step (2), the weight ratio of the amount of silica gel used for column chromatography separation to the crude product is (100 to 40): 1; the eluent is selected from one or two of ethyl acetate, acetone, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, n-heptane, and cyclohexane.

10. A method for synthesizing 2,3-dimethylcyclopropylcarboxylic acid, characterized in that: The method comprises the following steps: using the synthesis method of the intermediate of 2,3-dimethylcyclopropylcarboxylic acid as claimed in claim 7 to prepare compound (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester C and compound (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid benzyl ester D; and then reacting compound C and compound D with hydrogen under the action of a metal catalyst to generate corresponding (1α,2β,3β)-2,3-dimethylcyclopropylcarboxylic acid E. and (1α,2α,3α)-2,3-dimethylcyclopropylcarboxylic acid F

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