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CN116606216A - Preparation method of gabapentin - Google Patents

Preparation method of gabapentin Download PDF

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CN116606216A
CN116606216A CN202310370916.5A CN202310370916A CN116606216A CN 116606216 A CN116606216 A CN 116606216A CN 202310370916 A CN202310370916 A CN 202310370916A CN 116606216 A CN116606216 A CN 116606216A
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CN116606216B (en
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彭家荣
何匡
朱银龙
袁晓虎
吴依阳
黄凯
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Zhejiang Shouxin Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a preparation method of a compound shown in a formula I, and relates to the field of drug synthesis. The preparation method takes cyclohexyl chloride as a raw material, and products are produced through cyanidation, substitution and hydrogenation reactions. The preparation method for preparing the gabapentin has the advantages of simple raw materials, relatively simplified steps, no need of intermediate process of the gabapentin hydrochloride, direct synthesis of the gabapentin with high purity, shortened production period, remarkably improved product yield and solving the problem that the traditional process is not easy to industrializeThe production has the disadvantage. The structure of the formula I is as follows:

Description

Preparation method of gabapentin
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of barpentadine.
Background
Gabapentin, chemical name 1- (aminomethyl) cyclohexane acetic acid, also known as 1- (methylamino) cyclohexane acetic acid, has a formula of C 9 H 17 NO 2 Antiepileptics, first developed by the company Warner-Lanbert in the united states, were first marketed in the united kingdom in 1993.
The structural formula is shown as follows.
Gabapentin is a derivative of gamma-aminobutyric acid (GABA) with a pharmacological effect different from that of existing antiepileptic drugs, and recent studies have shown that the effect of gabapentin is produced by altering GABA metabolism. It has the advantages of good tolerance and slight side effect. Gabapentin showed an epileptic effect in various animal models, and in addition, also in animal spasticity, analgesia, and amyotrophic lateral sclerosis models. Gabapentin has a high affinity for novel binding sites of brain tissue, and it can cross some barriers in vivo via amino acid transfer bodies, with less behavioral and cardiovascular side effects than other anticonvulsants. Additional treatments for epileptic patients with localized seizures that are not satisfactorily controlled or tolerated by conventional antiepileptic drugs, and epileptic patients with localized seizures and subsequent generalization.
The existing preparation method of gabapentin comprises the following steps:
route one:
the method for synthesizing gabapentin disclosed in patent 2015107555. X comprises the steps of adding cyclohexanone and ethyl cyanoacetate into anhydrous isopropanol solution of liquid ammonia to form a ring reaction; performing hydrolysis reaction on 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt in high-temperature liquid water by taking H2SO4 as a catalyst; adding phosphorus pentoxide into 1, 1-cyclohexyl diacid to carry out dehydration reaction in dichloroethane solvent; carrying out ammonolysis reaction on 1, 1-cyclohexyl diacetic anhydride in ammonia water; 1, 1-cyclohexyl oxalic acid acetamide is subjected to hofmann degradation reaction. The intermediate of the cyclohexyl diacetic acid is needed to be synthesized firstly, then the cyclohexyl diacetic acid monoamide is synthesized by reaction, the steps are complicated, and the yield of the product obtained by the preparation method is only 48.2-51.1%.
Route two:
as disclosed in patent 20150105806.4, a method for synthesizing gabapentin comprises the steps of carrying out an addition elimination reaction of cyclohexanone and diethyl malonate in an aprotic solvent at-5 to 5 ℃ with zirconium tetrachloride as a catalyst; carrying out Michael addition on the product obtained in the first step in an alcohol solvent; carrying out hydrogenation reaction on the product obtained in the second step and hydrogen by taking Pd as a catalyst; carrying out hydrolysis reaction on the product obtained in the third step under the condition of hydrochloric acid; and (3) carrying out ion exchange on the product obtained in the fourth step. But the yield of the product is only 43.2% -46.3%.
There is therefore a great need in the industry to improve these problems in order to achieve the industrialization of gabapentin. The gabapentin provided by the invention has the advantages of simple and cheap preparation raw materials, simple method operation, high yield and high purity of the prepared product, and is suitable for large-scale popularization.
Disclosure of Invention
The invention aims at the problems and provides a high-yield and high-purity gabapentin preparation method.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the preparation method of the gabapentin is characterized in that cyclohexyl chloride is used as a raw material, and products are generated through cyanidation, substitution and hydrogenation reactions, wherein the synthetic route is as follows:
the preparation method comprises the following steps:
1) Adding a solvent into cyclohexyl chloride, mixing with tetrabutylammonium cyanide, adding a catalyst for cyanide reaction, extracting, and concentrating to obtain a compound 2;
2) Dissolving the compound 2 in a solvent, cooling, adding lithium diisopropylamide, reacting for a period of time, dropwise adding bromoacetic acid tert-butyl, extracting, concentrating, and purifying to obtain a compound 3;
3) Adding hydrochloric acid-dioxane into the compound 3 for dissolution, and reacting to obtain a compound 4;
4) And adding a catalyst and an auxiliary agent into the compound 4, introducing hydrogen, and reacting to obtain a product I.
Preferably, the solvent of step 1) is selected from any one of acetonitrile or dimethylsulfoxide; further preferably, the solvent of step 1) is acetonitrile.
Preferably, the catalyst of step 1) is selected from at least one of CuI, cuCl, cuBr, TBAI; further preferably, the catalysts described in step 1) are CuI and TBAI.
Preferably, the temperature of the cyanation reaction in the step 1) is 20-30 ℃ and the reaction time is 10-24 hours; further preferably, the cyanation reaction in step 1) is carried out at a temperature of 25℃for a reaction time of 18 hours.
Preferably, the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide described in step 1) is 1:1.5-2; further preferably, the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide is 1:1.8.
preferably, the mole ratio of TBAI to tetrabutylammonium cyanide is 1:15-40; further preferably, the molar ratio of TBAI to tetrabutylammonium cyanide is 1:20-25 parts of a base; most preferably, 1:22.5.
12. the preparation method according to claim 2, wherein the solvent in step 2) is selected from any one of tetrahydrofuran, dichloromethane, acetone, acetonitrile, and dimethylsulfoxide; most preferably, the solvent of step 2) is tetrahydrofuran.
Preferably, the molar ratio of lithium diisopropylamide, tert-butyl bromoacetate and compound 2 in step 2) is 1-2:1-1.5:1, a step of; further preferably, the molar ratio of lithium diisopropylamide, tert-butyl bromoacetate to compound 2 is 1.5:1.2:1.
preferably, the temperature of the step 2) is reduced to-80 to-75 ℃, and further preferably, is-78 ℃.
Preferably, the catalyst in the step 4) is at least one selected from palladium carbon, raney nickel or rhodium carbon; further preferably, the catalyst of step 4) is selected from palladium on carbon.
Preferably, the auxiliary agent in the step 4) is at least one of organic acid, inorganic acid, organic base or inorganic base; further preferably, the auxiliary agent in the step 4) is at least one selected from sodium hydroxide, formic acid, acetic acid and triethylamine.
Preferably, the mass percentage of the sodium hydroxide is 40-60%.
Preferably, the specific conditions for the reaction described in step 4) are: the pressure is 0.9-1.2Mpa, the time is 4-12h, and the temperature is 30-60 ℃; further preferably, the specific conditions of the reaction described in step 4) are: the pressure was 1Mpa, the time was 8 hours, and the temperature was 50 ℃.
Compared with the prior art, the invention has the beneficial technical effects that:
the preparation method for preparing the gabapentin has the advantages of simple raw materials, relatively simplified steps, no need of intermediate process of the gabapentin hydrochloride, direct synthesis of the gabapentin with high purity, shortened production period, remarkably improved product yield and capability of solving the defect that the traditional process is not easy for industrial production.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. It is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited. Technical and scientific terms used in the examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The technical terms and abbreviations involved in this patent are explained as follows:
TBAI: tetrabutylammonium iodide
TBACN: tetrabutylammonium cyanide
MeCN: acetonitrile
CuI: copper iodide
CuCl: copper chloride
CuBr: copper bromide
THF: tetrahydrofuran (THF)
DMSO: dimethyl sulfoxide
LDA: lithium diisopropylamide
LiHMDS: lithium bis (trimethylsilyl) amide
Example 1.
1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, and TBAI (2.95 g,0.08 eq) and CuI (1.5 g,0.08 eq) were then added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentrating to obtain compound 2, cyclohexanecarbonitrile (11 g,98% year);
2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (75 mL,1.5 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (23.4 g,1.2 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, and extracting the water phase by using DCM was washed 3 times with anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography to obtain compound 3 (19.1 g,85% yeild);
3) Adding HCl-dioxane (20 mL) into the compound 3 obtained in the step 2) to dissolve, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (14.2 g, 100%);
4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and 50% aqueous NaOH solution (3.7 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, and the reaction was carried out at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 (13.05 g,90.1% yeild, 99.2% HPLC purity).
1 HNMR(400MHz，CDCl 3 )δ9.03(s,1H),2.49(s,4H),1.54-1.43(m,10H)。
Example 2.
1) Cyclohexylchloride (11.8 g,1 eq) was taken in a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (53.7 g,2.0 eq) was added after complete dissolution, and then TBAI (1.84 g,0.05 eq) and CuI (1.5 g,0.08 eq) were added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentrating to obtain compound 2, cyclohexanecarbonitrile (10.6 g,95% yeild);
2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (9 mL,1.8 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (29.2 g,1.5 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing the water phase by using DCM for 3 times, and washing the organic phase by anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography to obtain compound 3 (19.1 g,85% yeild);
3) Adding HCl-dioxane (20 mL) into the compound 3 obtained in the step 2) to dissolve, reacting for 3h at room temperature, and concentrating to obtain a compound 4 (13.5 g, 99%);
4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and formic acid (5 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, reacted at 50℃for 18 hours, the catalyst was filtered, and then methanol and water 5:3 (12.7 g,88% yeild, 99.2% HPLC purity).
Example 3.
In comparison with example 1, only the catalyst in step 1) was changed from TBAI and CuI to CuI, the equivalent weight being unchanged.
1) Taking cyclohexyl chloride (11.8 g,1 eq) in a 500mL three-necked flask, adding 110mL acetonitrile, adding tetrabutylammonium cyanide (48.3 g,1.8 eq) after full dissolution, then adding CuI (1.5 g,0.08 eq), and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentrating to obtain compound 2, cyclohexanecarbonitrile (9.5 g,85% yeild);
2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (65 mL,1.5 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (16.6 g,1.2 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing the water phase by using DCM for 3 times, and washing the organic phase by using anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography to obtain compound 3 (16.23 g,72.2% year);
3) Adding HCl-dioxane (16 mL) into the compound 3 obtained in the step 2) to dissolve, reacting for 3h at room temperature, and concentrating to obtain a compound 4 (11.9 g, 100%);
4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and 50% aqueous NaOH solution (3.1 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, and the reaction was carried out at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 to give the product I (8.4 g,80.2% yeild, 99.1% HPLC purity).
Example 4.
1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, and TBAI (2.95 g,0.08 eq) and CuI (1.5 g,0.08 eq) were then added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentrating to obtain compound 2, cyclohexanecarbonitrile (10.8 g,97% yeild);
2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (90 mL,1.8 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, then cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (28.9 g,1.5 eq), removing the dry ice ethanol bath after the dropwise addition is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing the water phase by using DCM for 3 times, and washing the organic phase by anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography to obtain compound 3 (18.5 g,84% yeild);
3) Adding HCl-dioxane (20 mL) into the compound 3 obtained in the step 2) for dissolution, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (13.3 g, 98%);
4) The compound 4 obtained in the step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and triethylamine (8.8 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, reacted at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 (11.6 g,85% yeild, 99.5% HPLC purity).
Other examples the nuclear magnetism of the final product was essentially the same as in example 1.
Comparative example 1.
In contrast to example 1, step 1) does not use a catalyst.
1) Taking cyclohexyl chloride (11.8 g,1 eq) in a 500mL three-necked flask, adding 110mL acetonitrile, adding tetrabutylammonium cyanide (48.3 g,1.8 eq) after full dissolution, and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentration gave compound 2, cyclohexanecarbonitrile (7.15 g,65% year).
Comparative example 2.
1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (26.8 g,1.0 eq) was added after complete dissolution, and TBAI (7.4 g,0.2 eq) and CuI (3.75 g,0.2 eq) were added to carry out cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentrating to obtain compound 2, cyclohexanecarbonitrile (7.8 g,71% yeild);
2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (36 mL,1.0 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (25.3 g,1.8 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing the water phase by using DCM for 3 times, and washing the organic phase by anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography to obtain compound 3 (12.7 g,79% yeild);
3) Adding HCl-dioxane (13 mL) into the compound 3 obtained in the step 2) to dissolve, reacting for 3h at room temperature, and concentrating to obtain a compound 4 (9.35 g, 99%);
4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and 50% aqueous NaOH solution (2.1 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, and the reaction was carried out at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 (7.2 g,75% yeild, 99.2% HPLC purity).
Comparative example 3.
In comparison with example 1, the only difference is that step 1) is to change the catalyst to Cu 2 O(1.14g，0.08eq)
1) In a 500mL three-necked flask, 110mL of acetonitrile was added to the mixture, and tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, followed by Cu 2 O (1.14 g,0.08 eq), and performing cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentration gave compound 2 cyclohexanecarbonitrile (5.7 g,52% year).
Comparative example 4.
In comparison with example 1, the only difference is that step 1) is to replace the catalyst with CuCl 2 (1.1g，0.08eq)
1) In a 500mL three-necked flask, 110mL of acetonitrile was added to the mixture, and tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, followed by CuCl 2 (1.1 g,0.08 eq), and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentration gave the compound 2 cyclohexanecarbonitrile (5.9 g,54% year).
Comparative example 5.
Compared with example 1, the only difference is that step 2) changes LDA to LiHMDS (25.05 g,1.5 eq)
1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, and TBAI (2.95 g,0.08 eq) and CuI (1.5 g,0.08 eq) were then added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase with DCM 3 times, washing the organic phase with anhydrous Na 2 SO 4 Drying and concentrating to obtain compound 2, cyclohexanecarbonitrile (10.8 g,96% yeild);
2) Dissolving compound 2 obtained in step 1) in THF (110 mL), cooling to-78deg.C with ethanol dry ice bath, slowly adding 1M LiHMDS (150 mL,1.5 eq) at a temperature below 0deg.C, stirring for 15min, cooling again to-78deg.C, slowly dropwise adding bromoacetic acid tert-butyl (23.4 g,1.2 eq), removing dry ice ethanol bath after dropwise adding, reacting for 12h, quenching with water, extracting with DCM, washing water phase with DCM for 3 times, and washing organic phase with anhydrous Na 2 SO 4 Drying, concentrating, and purifying by column chromatography to give compound 3 (13.9 g,62% yeild).
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (22)

1. A preparation method of gabapentin is characterized in that cyclohexyl chloride is used as a raw material, and products are generated through cyanidation, substitution and hydrogenation reactions, and the synthetic route is shown as follows:
2. the method of manufacturing according to claim 1, comprising the steps of:
1) Adding a solvent into cyclohexyl chloride, mixing with tetrabutylammonium cyanide, adding a catalyst for cyanide reaction, extracting, and concentrating to obtain a compound 2;
2) Dissolving the compound 2 in a solvent, cooling, adding lithium diisopropylamide, reacting for a period of time, dropwise adding bromoacetic acid tert-butyl, extracting, concentrating, and purifying to obtain a compound 3;
3) Adding hydrochloric acid-dioxane into the compound 3 for dissolution, and reacting to obtain a compound 4;
4) And adding a catalyst and an auxiliary agent into the compound 4, introducing hydrogen, and reacting to obtain a product I.
3. The method according to claim 2, wherein the solvent of step 1) is selected from any one of acetonitrile or dimethylsulfoxide.
4. A process according to claim 3, wherein the solvent of step 1) is acetonitrile.
5. The method of claim 2, wherein the catalyst of step 1) is at least one selected from CuI, cuCl, cuBr, TBAI.
6. The method according to claim 5, wherein the catalyst in step 1) is CuI or TBAI.
7. The process according to claim 2, wherein the cyanation reaction in step 1) is carried out at a temperature of 20 to 30 ℃ for a period of 10 to 24 hours.
8. The process according to claim 2, wherein the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide in step 1) is 1:1.5-2.
9. The method according to claim 8, wherein the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide in step 1) is 1:1.8.
10. the method according to claim 6, wherein the molar ratio of TBAI to tetrabutylammonium cyanide in step 1) is 1:15-40.
11. The method according to claim 10, wherein the molar ratio of TBAI to tetrabutylammonium cyanide in step 1) is 1:20-25.
12. The method according to claim 2, wherein the solvent in step 2) is selected from any one of tetrahydrofuran, dichloromethane, acetone, acetonitrile, and dimethylsulfoxide.
13. The method of claim 12, wherein the solvent in step 2) is tetrahydrofuran.
14. The preparation method according to claim 2, wherein the molar ratio of the lithium diisopropylamide, the tert-butyl bromoacetate and the compound 2 in the step 2) is 1-2:1-1.5:1.
15. the method according to claim 14, wherein the molar ratio of lithium diisopropylamide, tert-butyl bromoacetate to compound 2 in step 2) is 1.5:1.2:1.
16. the method according to claim 2, wherein the temperature of step 2) is reduced to-80 to-75 ℃.
17. The method of claim 2, wherein the catalyst of step 4) is at least one selected from palladium on carbon, raney nickel and rhodium on carbon.
18. The method of claim 17, wherein the catalyst of step 4) is selected from palladium on carbon.
19. The method according to claim 2, wherein the auxiliary agent in step 4) is at least one of an organic acid, an inorganic acid, an organic base or an inorganic base.
20. The method according to claim 19, wherein the auxiliary agent in step 4) is at least one selected from the group consisting of sodium hydroxide, formic acid, acetic acid, and triethylamine.
21. The preparation method of claim 20, wherein the mass percentage of the sodium hydroxide is 40-60%.
22. The method according to claim 2, wherein the specific conditions of the reaction in step 4) are: the pressure is 0.9-1.2Mpa, the time is 4-12h, and the temperature is 30-60 ℃.
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