CN114057627A - Preparation method of hepatitis C and neocorolla drug intermediate and salt thereof - Google Patents
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Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of a hepatitis C and neocorolla drug intermediate and a salt thereof, which comprises the following steps: the method comprises the following steps: dissolving a compound shown in a formula IV in a solvent, carrying out addition reaction with 2-diazopropane or reaction with 2, 2-dihalogenopropane under the action of a metal reagent, and carrying out subsequent treatment and purification to obtain a compound shown in a formula V; step two: dispersing the compound of the formula V prepared in the step one in a solvent, and deprotecting to obtain a compound of the formula I, namely (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate; compared with the prior reports, the synthesis method disclosed by the invention has the advantages of short reaction steps, easily available raw materials, simple reaction conditions, short production time and lower production cost.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of an intermediate of hepatitis C and neocorolla drugs and salts thereof, wherein the intermediate is (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate.
Background
(1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylate (a compound shown in a formula (I)) and corresponding salts thereof are important medical intermediates and are applied as key intermediates in the synthesis of various antiviral drugs. Boceprevir (a compound shown in formula (II)) which is developed by piolin america and marketed in 2011 for treating chronic hepatitis c in certain adult patients can be efficiently synthesized via the compound of formula (I) (WO 2005/107745). The Covid-19 therapeutic drug Paxlovid (PF-07321332, a compound represented by formula (III)) disclosed by Peucedanum USA can also be synthesized by (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylate (Science, 2021, 374(6575), 1586-1593.):
1. at present, (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylates and their corresponding salts have mainly the following synthesis scheme:
WO2004/113295 discloses a (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]The specific route of the synthesis method of hexyl-2-carboxylate is shown as follows:
the synthesis method starts from the caronic anhydride, has complicated synthesis steps, uses an expensive palladium catalyst in the reaction process, and seriously influences the production cost and the productivity of the product.
2. The synthesis method disclosed in patent WO2007/075790 starts from caronic anhydride and synthesizes the compound shown in formula (I) through multiple steps:
the synthetic method has complex steps, needs highly toxic cyanide in the reaction, has poor reaction selectivity, and can obtain a finished product meeting the requirements only by additional crystallization, resolution and purification.
3. Patent CN103435532B discloses a process for the multi-step synthesis of compounds of formula (I) from 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride salt:
the raw material of the synthesis method still needs to be synthesized by the caronic anhydride, and meanwhile, the reaction selectivity of the second step is poor, the yield is low, and the production cost is high because the second step needs to be separated and purified by crystallization.
Disclosure of Invention
The purpose of the invention is: overcomes the defects in the prior art, provides a step section, has low production cost, does not relate to the conventional intermediates of the prior industry, namely the caronic anhydride and the 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane, and preparation method of intermediate and salt thereof suitable for industrial production of hepatitis C and neocarzino medicine, wherein the intermediate is (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a process for preparing the intermediate (1) of hepatitis C and neocoronating medicine or its saltR,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate, the preparation method comprisingThe method comprises the following steps:
wherein R1 is one of hydrogen, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl and p-methoxybenzyl;
r2 is one of hydrogen, methyl, ethyl, n-propyl and isopropyl;
the method comprises the following steps: dissolving a compound shown in a formula IV in a solvent, carrying out addition reaction with 2-diazopropane or reaction with 2, 2-dihalogenopropane under the action of a metal reagent, and carrying out subsequent treatment and purification to obtain a compound shown in a formula V;
step two: dispersing the compound of the formula V prepared in the step one in a solvent, and deprotecting to obtain a compound of the formula I, namely (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate.
A process for preparing the intermediate (1) of hepatitis C and neocoronating medicine or its saltR,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate, the preparation method comprising the steps of:
wherein R1 is one of hydrogen, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl and p-methoxybenzyl;
r2 is one of hydrogen, methyl, ethyl, n-propyl, isopropyl and tert-butyl;
the method comprises the following steps: dissolving a compound shown in a formula IV in a solvent, carrying out addition reaction with 2-diazopropane or reaction with 2, 2-dihalogenopropane under the action of a metal reagent, and carrying out subsequent treatment and purification to obtain a compound shown in a formula V;
step two: dispersing the compound of the formula V prepared in the step one in a solvent, and deprotecting to obtain a compound of the formula I, namely (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate;
step three: and (3) reacting the compound I prepared in the second step with acid to form a salt.
Further, the solvent in the first step is one or more selected from diethyl ether, tetrahydrofuran, petroleum ether, n-hexane, n-pentane, n-heptane and dichloromethane.
Further, in the first step, the dihalogenated propane is selected from one of 2, 2-dichloropropane, 2, 2-dibromopropane and 2, 2-diiodopropane.
Further, in the first step, the metal reagent is selected from one or more of alkyl lithium reagent, zinc copper reagent and cobalt reagent.
Further, in the first step, when the compound of formula IV is subjected to addition reaction with 2-diazopropane, the subsequent treatment comprises heating, light irradiation or ultrasonic method.
Further, in the first step, when the compound of formula IV and 2-diazopropane are subjected to addition reaction, the reaction temperature is-40 to 40 ℃, and a single-wavelength or continuous spectrum light source with the wavelength ranging from 190 to 450 nm can be adopted for illumination.
Further, when the compound of formula IV is reacted with 2, 2-dihalopropane in the first step, the molar ratio of the compound of formula IV to 2, 2-dihalopropane is 1: (1-5), the reaction temperature can be-20 to 80 ℃.
Further, the molar ratio of the compound of formula IV to any one of the metal reagents in step one is 1: (0.1-5).
Further, the organic solvent in the second step is selected from one of methanol, ethanol, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether and isopropyl ether.
The technical scheme adopted by the invention has the beneficial effects that:
compared with the prior reports, the synthesis method disclosed by the invention has the advantages of short reaction steps, easily available raw materials, simple reaction conditions, short production time and lower production cost.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. If the temperature is not particularly emphasized, the reaction is usually carried out at room temperature, and the room temperature in the present invention is 10 to 30 ℃.
The raw material reagents in the present invention are all commercially available without specific description.
Example 1 (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of methyl hexyl-2-carboxylate
(S)-N-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterHMethyl-pyrrole-2-carboxylate can be conveniently prepared in high yield by a published method (document US 2008/0027262).
Under the protection of nitrogen, adding (S)N-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterH-pyrrole-2-carboxylic acid methyl ester (1.00 eq, 34.2 g) was dissolved in 800 mL of dry dichloromethane, cooled to-78 ℃ in a dry ice acetone bath, followed by dropwise addition of a 2-diazopropane in ether solution (prepared according to the document org. synth., 1970, 50, 27.) until TLC monitoring of the completion of the conversion of the starting material. Heating the system to 20-25 ℃, continuing to react for 2 h, concentrating the replacement solvent into methyl tert-butyl ether, and then cooling in an ice-water bath. Maintained at 0-5 ℃, irradiated with 300-. After the reaction is completed, the solvent is removed by concentration to obtain the objective compound (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester (29.3 g) in 72.3% yield with 97.2% d.e. selectivity ESI-MS: M/z 170.3 [ M-Boc + H]+。
Example 2 (1)R,2S,5S)-NBenzyloxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]]Synthesis of methyl hexyl-2-carboxylate
(2S,4R)-N-benzyloxycarbonyl-4-hydroxyprolineThe methyl ester can be conveniently prepared in high yield by a known method (document CN 112930350A).
Under nitrogen protection, 48.1 g of an ethyl acetate solution of 1-propylcyclic phosphoric anhydride (50% w/w, 1.32 eq.) was added to the reactor, and after cooling to 0 ℃ with stirring, 15.9 g (2 g) of the resulting mixture was added dropwiseS,4R)-NA solution of benzyloxycarbonyl-4-hydroxyproline methyl ester (1.00 eq.) in 50 mL of ethyl acetate. After the completion of the dropwise addition, the reaction was maintained until completion of the raw material reaction by TLC, and the reaction solution was washed with 50 mL of water. Drying the organic phase with anhydrous sodium sulfate and concentrating to obtain the compound (S) -NBenzyloxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester.
Under the protection of nitrogen, adding (S)NBenzyloxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester was dissolved in 100 mL dry dichloromethane and the dry ice acetone bath was cooled to-78 ℃ followed by dropwise addition of 2-diazopropane in ether until TLC monitoring of the completion of the conversion of starting material. Heating the system to 20-25 ℃, continuing to react for 0.5 h, concentrating the replacement solvent into methyl tert-butyl ether, and then cooling in an ice-water bath. Maintained at 0-5 ℃, irradiated with 300-. After the reaction is completed, the solvent is removed by concentration to obtain the objective compound (1)R,2S,5S)-NBenzyloxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]]Hexyl-2-carboxylic acid methyl ester (11.1 g) in 64.3% yield with 91.4% d.e. selectivity ESI-MS: M/z 304.2 [ M + H ]]+。
Example 3 (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of methyl hexyl-2-carboxylate
Under the protection of nitrogen, (S) -doped organic silicon is added into 200 mL of diethyl ether-n-hexane (1: 4) mixed solutionN-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterH-pyrrole-2-carboxylic acid methyl ester (1.00 eq, 11.5 g) and 2, 2-dibromopropane (3.00 eq, 30.6 g), dry ice acetone bath cooled to-78 ℃. A solution of n-butyllithium in n-hexane (2.00 eq.) was then slowly added dropwise.After the dropwise addition is finished, the temperature is raised to 20-25 ℃, the reaction is continued for 12 hours, then saturated ammonium chloride solution is added, the organic phase is washed by water and dried by anhydrous sodium sulfate, the solvent is removed by concentration, and the micro-butter-shaped compound (1) is obtained by purifying by column chromatography (petroleum ether/ethyl acetate)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester (6.42 g), 47.1% yield, with 91.4% d.e. selectivity.
Example 4 (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of methyl hexyl-2-carboxylate
Under nitrogen protection, a three-necked flask was charged with zinc-copper reagent (copper 1-3%, 3.00 eq. 26.7 g), 50 mL of methyl tert-butyl ether and 300 mL of dichloromethane. A small amount of solid iodine was added and the reaction was stirred until the purple color turned brown. Followed by dropwise addition of (S) -N-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterHPyrrole-2-carboxylic acid methyl ester (1.00 eq, 30.0 g) and slowly warmed to slight reflux followed by the slow dropwise addition of 2, 2-diiodopropane (3.0 eq, 117 g). After completion of the dropwise addition, reflux reaction was carried out for 24 hours, insoluble matter was removed by filtration, the filtrate was washed with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate) to give the objective compound (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester (24.2 g), yield 68.1%, with 94.6% d.e. selectivity.
Example 5 (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of methyl hexyl-2-carboxylate
Adding the compound (S) -plus material into the three-mouth bottle under the protection of nitrogenN-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterH-pyrrole-2-carboxylic acid methyl ester (1.00 eq., 980 mg), 2, 6-bis [1- (2-tert-butylphenyl imino) ethyl]Pyridine (0.10 eq., 184 mg), cobalt (II) bromide (0.10 eq., 94 mg), zinc powder (2.00 eq., 564 mg), zinc bromide (1.00 eq., 626 mg) and tetrahydrofuran (25 mL), and after stirring at room temperature for 1 hour, 2-dichloropropane (2.00 eq., 974 mg) was added and the reaction was maintained for 24 hours. Concentrating to remove solvent after reaction, extracting with ethyl acetate and water, filtering to remove insoluble substances, washing organic phase with water, drying with saturated sodium chloride, and purifying the crude product with column chromatography (petroleum ether/ethyl acetate) to obtain micro-butter-like compound (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester (1.03 g), yield 88.7%, with 98.8% d.e. selectivity.
Example 6 (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of methyl hexyl-2-carboxylate hydrochloride (Tetrahedron, 2017, 73, 4285-
90 g of the compound (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester was dissolved in 360 mL of ethyl acetate and cooled to 0 ℃ and 450 mL of an ethyl acetate solution of hydrogen chloride (2)N) After stirring at constant temperature for 4 hours, the reaction mixture was concentrated and 720 mL of methyl t-butyl ether was added. The resulting solid was slurried with 180 mL of methyl tert-butyl ether, filtered and dried to give a white-like solid compound (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester hydrochloride (64.2 g), yield 93.4%.1H (400 MHz, DMSO-d 6): 4.13 (d, J =2 Hz, 1H), 3.79 (s, 3H), 3.61-3.57 (m, 1H), 3.03 (dd, J =10 Hz, J =2 Hz, 1H), 1.90-1.87 (m, 1H), 1.78-1.74 (m, 1H), 1.07(s, 3H), 1.04 (s, 3H)，ESI-MS: m/z 170.2 [M+H]+。
Example 7 (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3 ],1,0]Synthesis of methyl hexyl-2-carboxylate hydrochloride
In a pressure-resistant reactor, 2.0 g of Compound (1)R,2S,5S)-NBenzyloxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]]Hexyl-2-carboxylic acid methyl ester (1.00 eq.) was dissolved in 50 mL of methanol, 5% palladium on carbon catalyst (0.10 w/w) was added, and after replacing nitrogen twice, hydrogen was replaced and pressurized to 1.0 MPa, followed by heating to 40-45 ℃ for 6 hours. After completion of the reaction, the nitrogen gas was replaced and filtered, and the filtrate was concentrated and replaced with 1, 4-dioxane. Subsequently, 25 mL of a dioxane solution of hydrogen chloride (4 mol/L) was added dropwise at 0-5 ℃ and stirred for 2 h. After the reaction was completed, the solid was filtered and washed with 20 mL of methyl t-butyl ether, and dried to obtain a white-like solid compound (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid methyl ester hydrochloride (1.18 g), yield 87.0%.
Example 8 (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of ethyl hexyl-2-carboxylate
(S)-N-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterHEthyl-pyrrole-2-carboxylate can be prepared by a known method (Tetrahedron, 2003, 59, 3307-propanone 3314).
Under the protection of nitrogen, adding (S)N-tert-butoxycarbonyl-2, 5-dihydro-1-carboxylic acid esterH-pyrrole-2-carboxylic acid ethyl ester (1.00 eq, 1.45 g) was dissolved in 30 mL of dry dichloromethane and the dry ice acetone bath was cooled to-78 ℃ followed by dropwise addition of 2-diazopropane in ether until TLC monitoring of the completion of the conversion of the starting material. Heating the system to 20-25 ℃, continuing to react for 0.5 h, concentrating the replacement solvent into methyl tert-butyl ether, and then cooling in an ice-water bath. Maintained at 0-5 ℃, irradiated with 300-. After the reaction is completed, the solvent column layer is removed by concentrationThe target compound (1) is obtained by separationR,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Ethyl hexyl-2-carboxylate (1.30 g) in 76.3% yield with 93.6% d.e., ESI-MS: M/z 184.3 [ M-Boc + H ]]+。
Example 9 (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Synthesis of ethyl hexyl-2-carboxylate hydrochloride
0.50 g of Compound (1)R,2S,5S)-N-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid ethyl ester was dissolved in 10 mL of ethyl acetate and the temperature was reduced to 0 ℃ and 5 mL of a solution of hydrogen chloride in ethyl acetate (2)N) After stirring at constant temperature for 4 hours, the reaction mixture was concentrated and 5 mL of methyl t-butyl ether was added. The resulting solid was slurried with 5 mL of methyl tert-butyl ether, filtered and dried to give a white-like solid compound (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylic acid ethyl ester hydrochloride (326 mg), yield 84.1%.1H (400 MHz, DMSO-d 6): 4.14-4.07(m, 3H), 3.67-3.62 (m, 1H), 3.03-2.97 (m, 1H), 1.94-1.89 (m, 1H), 1.76-1.72 (m, 1H), 1.21(s, 3H), 1.08(s, 3H), 1.04 (s, 3H)，ESI-MS: m/z 184.3 [M+H]+，206.3 [M+Na]+。
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.
Claims (10)
1. A process for preparing the intermediate (1) of hepatitis C and neocoronating medicine or its saltR,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylates characterized by: the preparation method of the intermediate comprises the following steps:
wherein R1 is one of hydrogen, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl and p-methoxybenzyl;
r2 is one of hydrogen, methyl, ethyl, n-propyl, isopropyl and tert-butyl;
the method comprises the following steps: dissolving a compound shown in a formula IV in a solvent, carrying out addition reaction with 2-diazopropane or reaction with 2, 2-dihalogenopropane under the action of a metal reagent, and carrying out subsequent treatment and purification to obtain a compound shown in a formula V;
step two: dispersing the compound of the formula V prepared in the step one in a solvent, and deprotecting to obtain a compound of the formula I, namely (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate.
2. A process for preparing the intermediate (1) of hepatitis C and neocoronating medicine or its saltR,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylates characterized by: the preparation method of the intermediate salt comprises the following steps:
wherein R1 is one of hydrogen, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl and p-methoxybenzyl;
r2 is one of hydrogen, methyl, ethyl, n-propyl, isopropyl and tert-butyl;
the method comprises the following steps: dissolving a compound shown in a formula IV in a solvent, carrying out addition reaction with 2-diazopropane or reaction with 2, 2-dihalogenopropane under the action of a metal reagent, and carrying out subsequent treatment and purification to obtain a compound shown in a formula V;
step two: step (ii) ofDispersing the prepared compound of formula V in a solvent, and deprotecting to obtain the compound of formula I, i.e. (1)R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0]Hexyl-2-carboxylate;
step three: and (3) reacting the compound I prepared in the second step with acid to form a salt.
3. The production method according to any one of claims 1 or 2, characterized in that: the solvent in the first step is one or more selected from diethyl ether, tetrahydrofuran, petroleum ether, n-hexane, n-pentane, n-heptane and dichloromethane.
4. The production method according to any one of claims 1 or 2, characterized in that: in the first step, the 2, 2-dihalogenopropane is selected from one of 2, 2-dichloropropane, 2, 2-dibromopropane and 2, 2-diiodopropane.
5. The production method according to any one of claims 1 or 2, characterized in that: the metal reagent in the step one is selected from one or more of alkyl lithium reagent, zinc copper reagent and cobalt reagent.
6. The production method according to any one of claims 1 or 2, characterized in that: in the first step, when the compound shown in the formula IV and 2-diazopropane are subjected to addition reaction, the subsequent treatment comprises a heating, illumination or ultrasonic initiation method.
7. The method of claim 6, wherein: in the first step, when the compound shown in the formula IV and 2-diazopropane are subjected to addition reaction, the reaction temperature is-40 ℃, and a single wavelength or continuous spectrum light source with the wavelength ranging from 190-450 nm is adopted for illumination.
8. The production method according to any one of claims 1 or 2, characterized in that: in the step one, when the compound of the formula IV is reacted with the 2, 2-dihalogenopropane, the molar ratio of the compound of the formula IV to the dihalogenopropane is 1: (1-5) the reaction temperature is-20 to 80 ℃.
9. The production method according to any one of claims 1 or 2, characterized in that: the molar ratio of the compound of formula IV to any one of the metal reagents in step one is 1: (0.1-5).
10. The production method according to any one of claims 1 or 2, characterized in that: the organic solvent in the second step is selected from one of methanol, ethanol, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether and isopropyl ether.
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