WO2020078204A1 - Method for preparing 3-hydroxy-6-oxohexanoate - Google Patents

Method for preparing 3-hydroxy-6-oxohexanoate Download PDF

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WO2020078204A1
WO2020078204A1 PCT/CN2019/108982 CN2019108982W WO2020078204A1 WO 2020078204 A1 WO2020078204 A1 WO 2020078204A1 CN 2019108982 W CN2019108982 W CN 2019108982W WO 2020078204 A1 WO2020078204 A1 WO 2020078204A1
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compound
formula
reaction
hydroxy
solvent
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王保林
戚聿新
刘月盛
张伟
张明峰
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新发药业有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C47/263—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups acyclic
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
    • C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a preparation method of 3-hydroxy-6-oxohexanoic acid ester, which belongs to the field of medicine, biochemical industry.
  • 3-Hydroxy-6-oxohexanoic acid ester (I) is an important intermediate for organic synthesis, containing aldehyde groups, hydroxyl groups and ester groups. It can be used as a synth to prepare compounds for different purposes. Its 3-position carbon atom is Chiral carbon has two configurations of R / S, among which S-3-hydroxy-6-oxohexanoic acid ester (I S ) can be used to prepare Vaborbactam.
  • Vaborbactam is a new class of ⁇ -lactamase inhibitors, used in combination with meropenem, for the treatment of complex urinary tract infection (cUTI) and acute pyelonephritis (AP) in adult patients.
  • R-3-hydroxy-6-oxohexanoate (I R ) can be used to prepare the isomer of Vaborbactam.
  • the relevant structural formula is as follows:
  • the raw materials used in this reaction route are special and difficult to obtain, and the oxidant used is also difficult to purchase.
  • the reaction selectivity of this route is poor, the yield is less than 30%, and the content of by-products such as epoxy, o-diol and ⁇ , ⁇ -unsaturated alcohol will be equivalent to the main product.
  • the practical application value of this reaction method is not high.
  • the invention provides a convenient preparation method of 3-hydroxy-6-oxohexanoate compounds suitable for industrial applications.
  • the technical objective of the present invention is to reduce the cost of raw materials, increase the yield, and make the preparation process simple and easy.
  • the invention uses halogenated acetaldehyde acetal as the starting material, which is cheap and easy to obtain, the process is simple, does not require excessively harsh reaction conditions, the cost is low, and the reaction process is green and environmentally friendly.
  • the compound name in this specification is based on the structural formula, and the compound name, compound number and structural formula have the same referential relationship.
  • Step A1 reacting the compound of formula III and carbon monoxide in an alcohol solvent under the action of a catalyst to obtain the compound of formula IV;
  • Step A2 In an acidic solution, the compound of formula IV is deacetalized to obtain the compound of formula I;
  • Step B1 In the solvent B, react the compound of formula III with cyanide to obtain an epoxy ring-opening intermediate, and continue to react with a hydroxyl protecting reagent to obtain the compound of formula V;
  • Step B2 in an alkaline solution, hydrolyze the compound of formula V to a carboxylate by cyano, and then remove the acetal protecting group in an acidic solution to obtain the compound of formula VI;
  • Step B3 In the solvent C, the compound of formula VI is subjected to esterification and deprotection reaction to obtain the compound of formula I.
  • n 0, 1 or 2;
  • R 1 and R 2 are each independently one of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and benzyl; when n is When 1 or 2, R 1 and R 2 are each independently -CH 2- , -RCH-, and R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or Phenyl.
  • PG stands for trimethylsilyl (TMS), dimethyl tert-butylsilyl (TBDMS), benzyl (Bn), methanesulfonyl (Ms), p-toluenesulfonyl (Ts).
  • the solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methoxycyclopentane, hexane , One of heptane or toluene, or a combination thereof; the mass ratio of the solvent A to the compound of formula II is (2-10): 1.
  • the molar ratio of the magnesium powder to the compound of formula II is (1.0-1.5): 1, further preferably the molar ratio of the magnesium powder to the compound of formula II is (1.02-1.3): 1.
  • the Grignard reaction temperature is 25-55 ° C; further preferably, the Grignard reaction temperature is 30-40 ° C.
  • the Grignard reaction time is 0.5-5 hours; further preferably, the Grignard reaction time is 1-3 hours.
  • the Grignard reaction temperature is an important factor. High temperature will cause side reactions and affect the content of Grignard reagent products.
  • the halogen in the epihalohydrin is chlorine or bromine.
  • the epihalohydrin is selected from (R, S) -epichlorohydrin, S-epichlorohydrin, R-epichlorohydrin, (R, S) -epibromopropane, S-ring Oxybromopropane or R-epoxybromopropane.
  • the chirality of the epihalohydrin used in this step (1) determines the chiral configuration of the final compound of formula I.
  • step (1) the molar ratio of the epihalohydrin to the compound of formula IV is (0.9-1.2): 1.
  • the reaction temperature of the Grignard reagent and the epihalohydrin is 0-40 ° C, further preferably the reaction temperature is 5-20 ° C, and most preferably the reaction temperature is 10-15 °C.
  • the reaction time of the Grignard reagent and the epihalohydrin is 0.5-5 hours, preferably 1-3 hours. The control of the reaction temperature is very important, and high temperature will cause side reactions.
  • the reaction of the pathway A includes one or more of the following conditions:
  • the alcohol solvent is one or a combination of methanol, ethanol, isopropanol, butanol, t-butanol, isobutanol or benzyl alcohol; the mass ratio of the alcohol solvent to the compound of formula III is (4- 20): 1.
  • the catalyst is palladium carbon, palladium chloride, palladium hydroxide, tris (triphenylphosphine) rhodium chloride, Grubbs catalyst, iridium / alumina, (1,5-cyclooctadiene) ( Pyrimidine) (tricyclohexylphosphine) iridium (I) hexafluorophosphate or dicobalt octacarbonyl; the amount of the catalyst accounts for 1.0-20.0% of the mass of the compound of formula III.
  • the catalytic reaction temperature is 10-80 ° C, further preferably the catalytic reaction temperature is 30-50 ° C.
  • the catalytic reaction time is 2-20 hours; further preferably, the catalytic reaction time is 5-12 hours.
  • the acidic solution is sulfuric acid, hydrochloric acid or phosphoric acid, and the hydrogen ion concentration is 3-8 mol / L; the mass ratio of the acidic solution to the compound of formula IV is 8-20: 1.
  • the deacetal protection reaction temperature is 10-80 ° C, further preferably the deacetal protection reaction temperature is 35-60 ° C.
  • the deacetal protection reaction time is 0.5-5 hours; further preferably, the reaction time is 1-3 hours.
  • the reaction of the pathway B includes one or more of the following conditions:
  • the solvent B is ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, dichloromethane, One or a combination of two or more of chloroform, 1,2-dichloroethane, benzene, toluene, chlorobenzene, xylene, and dichlorobenzene; the mass ratio of the solvent B to the compound of formula III is 4- 20: 1.
  • step B1 the cyanide is sodium cyanide or potassium cyanide; the molar ratio of the cyanide to the compound of formula V is 1-2: 1.
  • step B1 the reaction temperature of the compound of formula III with cyanide is 10 ° C to 60 ° C; the reaction time is 1-8 hours.
  • the hydroxyl protection reagent is trimethylchlorosilane, trimethyliodosilane, dimethyl tert-butylchlorosilane, dimethyl tert-butyliodosilane, methanesulfonyl chloride, p-toluenesulfonyl chloride , Benzyl chloride, benzyl bromide, trifluoroacetic acid or acetic anhydride, the molar ratio of the hydroxyl protecting group to the compound of formula III is 1-2: 1.
  • Step B1 the hydroxyl protection reaction temperature is 0 ° C-120 ° C.
  • the hydroxyl protection reaction time is 1-10 hours.
  • the further preferred reaction temperature and time are determined according to different hydroxyl protecting group reagents.
  • the alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, or potassium carbonate.
  • concentration of the alkaline solution is 10-40% by mass.
  • the mass ratio of the alkaline solution to the compound of formula V is 2-20: 1; further preferably the mass ratio of the alkaline solution to the compound of formula V is 3-10: 1.
  • step B2 the temperature of the hydrolysis reaction is from 20 ° C to 100 ° C; the hydrolysis reaction time is from 1 to 8 hours.
  • step B2 the acidic solution is 5-20% dilute sulfuric acid, 10-30% hydrochloric acid or 30-50% phosphoric acid solution; the mass ratio of the acidic solution to the compound of formula V is 3-30: 1. It is further preferred that the mass ratio of the acidic solution to the compound of formula V is 4-10: 1.
  • step B2 the temperature of the acidification reaction is 10 ° C-50 ° C, further preferably 30-40 ° C, and the reaction time is 1-8 hours.
  • the solvent C is ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether and dichloromethane, One or a combination of chloroform, 1,2-dichloroethane, benzene, toluene, chlorobenzene, xylene, and dichlorobenzene; the mass ratio of the solvent C to the compound of formula VI is 4-20 :1.
  • step B3 the esterification reagent is carbonate, sulfate, p-toluenesulfonate; the molar ratio of the esterification reagent to the compound of formula VI is 1-5: 1.
  • step B3 the esterification reaction temperature is 0 ° C-100 ° C; the reaction time is 1-8 hours.
  • the further preferred reaction temperature and time are determined according to different esterification reagents.
  • the deprotection reaction in step B3 can be performed according to the prior art. Particularly preferably, the deprotection reaction is carried out under the action of a catalyst and hydrogen.
  • the catalyst is palladium-carbon or Raney nickel, the mass ratio of palladium-carbon addition to compound VI is 1.0% -5.0%, the mass ratio of raney nickel addition to compound VI is 5.0% -20.0%, preferably palladium-carbon catalyst ;
  • Deprotection reaction temperature is 20-80 °C, reaction time is 1-6 hours, preferably deprotection reaction temperature is 40-60 °C, reaction time is 2-4 hours, hydrogen pressure during deprotection process is 0.2-1.0MPa.
  • the halogenated acetaldehyde acetal (II) is used as a raw material, the corresponding format reagent is prepared by first acting with magnesium powder, and the reaction with the halogenated propylene oxide is continued to obtain the intermediate III, and then the compound III is passed through two types One way to prepare the target compound I.
  • Route A is the reaction of III with carbon monoxide in an alcohol solvent under the action of a metal catalyst to obtain intermediate IV, which is then hydrolyzed to obtain the compound of formula I.
  • Route B is to use cyanide and intermediate III to obtain epoxy ring-opening intermediate V, then hydrolyze the cyano group to obtain intermediate VI, and finally obtain the product formula I by esterification and deprotection.
  • reaction route 2 The reaction process is described as the following reaction route 2:
  • X is chlorine, bromine
  • n 0, 1 , 2; when n is 0, R 1 and R 2 are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl Groups; when n is 1 or 2, R 1 and R 2 are each independently -CH 2- , -RCH-, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl Group, tert-butyl, phenyl;
  • R 3 OH is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, benzyl alcohol, ethylene glycol, propylene glycol or 1,3-butanediol;
  • PG is trimethylsilyl (TMS), dimethyl tert-butylsilyl (TBDMS), benzyl (Bn), methanesulfonyl (Ms), p-toluenesulfonyl (Ts).
  • the post-processing of the intermediate product in each step can be performed with reference to the prior art in the art.
  • the preferred post-processing method of the intermediate product of the present invention is as follows:
  • step (1) After the reaction in step (1) is completed, the resulting reaction mixture is added to a mixed solution of water and dichloromethane, stirred, and allowed to stand for liquid separation.
  • the aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride 1-2 times, and then the solvent was distilled off under reduced pressure, and then distilled under reduced pressure (85-95 ° C / 2 -3mmHg) to give the compound of formula III.
  • step A1 in step (2) After the reaction of step A1 in step (2) is completed, cool to room temperature, replace carbon monoxide with nitrogen, and then open the reactor. The catalyst was filtered off, and the filtrate was distilled to remove the solvent, and then the compound of formula VI was obtained by distillation under reduced pressure (110-125 ° C / 2-3 mmHg).
  • step A2 in step (2) After the reaction of step A2 in step (2) is completed, after cooling to room temperature, ethyl acetate is added, the liquid is separated, the aqueous phase is extracted with ethyl acetate 2-3 times, the organic phases are combined, the solvent is distilled off, and then the vacuum distillation 120-140 ° C / 2-3mmHg) to obtain compound I.
  • step B1 in step (2) After the reaction of step B1 in step (2) is completed, it is cooled to room temperature, water and dichloromethane are added, stirred and allowed to stand for separation. The aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, the organic phase was washed with a saturated sodium chloride aqueous solution, and then the solvent was distilled off, and the compound V was obtained by distillation under reduced pressure (105-120 ° C / 2-3 mmHg).
  • step B2 dichloromethane was added, stirred and allowed to stand for separation.
  • the aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain compound VI.
  • step B3 of step (2) After the reaction of step B3 of step (2), water and ethyl acetate are added, stirred and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate 2-3 times, the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain compound I.
  • the present invention uses halogenated acetaldehyde acetal as the starting material, which is cheap and easy to obtain; the reaction type involved is classic, the reaction conditions are easy to control, the operation is safe and convenient, the process is green and environmentally friendly, the cost is low, and industrialization is easy to achieve.
  • the reaction of each step of the method of the present invention has good reaction selectivity, and the total yield of 3-hydroxy-6-oxohexanoic acid ester is 72.5% -78.7%, which is significantly higher than the 30% yield reported in the existing literature. improve.
  • Conditions such as the reaction temperature of the Grignard reagent, the reaction temperature of the Grignard reagent and epichlorohydrin, and the temperature of the acid action in the method of the present invention are important factors that affect the reaction yield and the ease of separation and purification. Conditions such as the ratio of each reactant are more conducive to further reducing costs and improving yield under the preferred scheme.
  • the 3-hydroxy-6-oxohexanoic acid ester prepared by the invention has high purity and can be used as a novel non- ⁇ -lactam ⁇ -lactamase inhibitor Vaborbactam or its The starting material of the structure.
  • Example 2 Replace 23.5 g (0.25 mol) (R, S) -epichlorohydrin in Example 1 with 23.5 g (0.25 mol) S-epichlorohydrin, the rest is the same as in Example 1 to obtain 33.2 g 4S-4,5 -Epoxy n-pentyl glycol acetal (III 2 ), gas phase purity 99.2%, ee value 99.0%, yield 92.3%.
  • Example 3 Replace 23.5 g (0.25 mol) (R, S) -epichlorohydrin in Example 3 with 23.5 g (0.25 mol) S-epichlorohydrin, and the rest is the same as in Example 3 to obtain 33.3 g 4S-4,5 -Epoxy n-pentyl dimethyl acetal (III 4 ), gas phase purity 99.3%, ee value 99.1%, yield 91.2%.
  • III4 36.5 g (0.25 mol) of III4 obtained in Example 4 was used to replace 36.0 g (0.25 mol) of 2S- (3,4-epoxy) butyl-1,3-dioxolane (III 2 ) used in Example 7
  • the rest is the same as that in Example 7.
  • vacuum distillation 100-115 ° C / 2-3mmHg
  • 59.2 g of the product compound V 2 was obtained , with a gas phase purity of 99.7%, an ee value of 99.3%, and a yield of 89.9%.
  • Comparative Example 1 shows that the temperature is an important factor in the preparation of Grignard reagents. When the temperature is high, there are many coupling reactions of Grignard reagents, and the by-product 1,4-butanedialdehyde diacetal is more, because its boiling point is close to the product. Difficult to separate and purify.
  • Comparative Example 2 shows that when the resulting Grignard reagent reacts with S-epichlorohydrin, if the temperature is high, the reaction between the Grignard reagent and S-epichlorohydrin (target reaction) through the ring-opening-closing mechanism will decrease and increase. Side reaction between Grignard reagent and S-epichlorohydrin via SN2 mechanism (product is enantiomer: 2R- (3,4-epoxy) butyl-1,3-dioxolane) , Product ee value is low.
  • Comparative Example 3 shows that after the addition of acid, if the temperature is high, it will cause the configuration conversion of the 3-position hydroxyl group, which is not conducive to maintaining the product configuration.

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Abstract

A method for preparing 3-hydroxy-6-oxohexanoate. In the method, haloacetaldehyde acetal is used as the starting material, and is subjected to Grignardation and nucleophilic substitution reaction to obtain key epoxide intermediates; then a target product is obtained by metal-catalyzed carburization reaction in carbon monoxide, or a target product is obtained by means of a carburization reaction carried out using a cyanide, hydrolysis of the cyano group and an acetal, and esterification. The obtained target product is used in preparation of Vaborbactam and isomers thereof. The method uses raw materials which are cheap and easy to obtain, has reaction conditions which are mild and easy to control and a simple and safe process, is environment-friendly and low in costs, and can implement green industrial production.

Description

一种3-羟基-6-氧代己酸酯的制备方法Method for preparing 3-hydroxy-6-oxohexanoic acid ester 技术领域Technical field
本发明涉及一种3-羟基-6-氧代己酸酯的制备方法，属于医药生物化工领域。The invention relates to a preparation method of 3-hydroxy-6-oxohexanoic acid ester, which belongs to the field of medicine, biochemical industry.
背景技术Background technique
3-羟基-6-氧代己酸酯(I)是一种重要的有机合成中间体，含有醛基、羟基和酯基，可以作为合成子制备不同用途的化合物，其3-位碳原子为手性碳，有R/S两种构型，其中S-3-羟基-6-氧代己酸酯(I S)可以用来制备Vaborbactam。Vaborbactam是一类新的β内酰胺酶抑制剂,与美罗培南合用,用于成人患者复杂性尿路感染(cUTI)和急性肾盂肾炎(AP)的治疗。R-3-羟基-6-氧代己酸酯(I R)则可用来制备Vaborbactam的异构体。相关结构式如下： 3-Hydroxy-6-oxohexanoic acid ester (I) is an important intermediate for organic synthesis, containing aldehyde groups, hydroxyl groups and ester groups. It can be used as a synth to prepare compounds for different purposes. Its 3-position carbon atom is Chiral carbon has two configurations of R / S, among which S-3-hydroxy-6-oxohexanoic acid ester (I S ) can be used to prepare Vaborbactam. Vaborbactam is a new class of β-lactamase inhibitors, used in combination with meropenem, for the treatment of complex urinary tract infection (cUTI) and acute pyelonephritis (AP) in adult patients. R-3-hydroxy-6-oxohexanoate (I R ) can be used to prepare the isomer of Vaborbactam. The relevant structural formula is as follows:
Figure PCTCN2019108982-appb-000001
Figure PCTCN2019108982-appb-000001
文献J.Org.Chem.,1986,51,3913-3915报道了在碱性条件下，利用特殊的氧化剂Na 2Fe(CN) 5NO氧化3,6-二羟基-5-氨基己酸叔丁酯的底物制得3-羟基-6-氧代己酸酯。反应路线1如下： Document J. Org. Chem., 1986, 51, 3913-3915 reported the oxidation of tert-butyl 3,6-dihydroxy-5-aminocaproate using alkaline oxidant Na 2 Fe (CN) 5 NO under alkaline conditions The substrate of the ester produces 3-hydroxy-6-oxohexanoate. Reaction route 1 is as follows:
Figure PCTCN2019108982-appb-000002
Figure PCTCN2019108982-appb-000002
反应路线1Reaction route 1
该反应路线所用原料特殊，不易获得，所使用氧化剂也较难购买。该路线反应选择性较差，收率不足30％，且会产生环氧、邻二醇以及α,β-不饱和醇等副产物含量与主产物相当。该反应方法实际应用价值不高。The raw materials used in this reaction route are special and difficult to obtain, and the oxidant used is also difficult to purchase. The reaction selectivity of this route is poor, the yield is less than 30%, and the content of by-products such as epoxy, o-diol and α, β-unsaturated alcohol will be equivalent to the main product. The practical application value of this reaction method is not high.
发明内容Summary of the invention
本发明提供一种适于工业应用的3-羟基-6-氧代己酸酯化合物的简便制备方法。本发明技术目标在于降低原料成本，提高收率，使制备过程简便易行。The invention provides a convenient preparation method of 3-hydroxy-6-oxohexanoate compounds suitable for industrial applications. The technical objective of the present invention is to reduce the cost of raw materials, increase the yield, and make the preparation process simple and easy.
本发明以卤代乙醛缩醛为起始原料，价廉易得，工艺过程简便，不需要过于苛刻的反应条件，成本低，反应过程绿色环保。The invention uses halogenated acetaldehyde acetal as the starting material, which is cheap and easy to obtain, the process is simple, does not require excessively harsh reaction conditions, the cost is low, and the reaction process is green and environmentally friendly.
术语说明：Explanation of terms:
式II化合物：卤代乙醛缩醛；Compound of formula II: halogenated acetaldehyde acetal;
式III化合物：4,5-环氧正戊基缩醛；Compound of formula III: 4,5-epoxy n-pentyl acetal;
式IV化合物：6-缩醛基-3-羟基-己酸酯；Compound of formula IV: 6-acetal-3-hydroxy-hexanoate;
式V化合物：3-保护基氧基-6-缩醛基己酸；Compound of formula V: 3-protecting group oxy-6-acetal hexanoic acid;
式VI化合物：3-保护基氧基-6-氧代己酸；Compound of formula VI: 3-protecting group oxy-6-oxohexanoic acid;
式I化合物：3-羟基-6-氧代己酸酯。Compound of formula I: 3-hydroxy-6-oxohexanoate.
本说明书中的化合物名称以结构式为依据，化合物名称、化合物编号与结构式具有相同的指代关系。The compound name in this specification is based on the structural formula, and the compound name, compound number and structural formula have the same referential relationship.
本发明的技术方案如下：The technical solution of the present invention is as follows:
一种式I所示化合物3-羟基-6-氧代己酸酯的制备方法，A method for preparing the compound 3-hydroxy-6-oxohexanoate of formula I,
Figure PCTCN2019108982-appb-000003
Figure PCTCN2019108982-appb-000003
包括步骤：Including steps:
(1)于溶剂A中，式II化合物和镁粉经格氏反应制备格氏试剂，将所得格氏试剂滴加至环氧卤丙烷中，反应制备式III化合物；(1) In the solvent A, the compound of formula II and magnesium powder are subjected to the Grignard reaction to prepare the Grignard reagent, and the obtained Grignard reagent is added dropwise to the epihalohydrin to prepare the compound of formula III;
(2)由式III化合物制备3-羟基-6-氧代己酸酯(I)，采用以下途径A或途径B：(2) To prepare 3-hydroxy-6-oxohexanoate (I) from the compound of formula III, use the following route A or route B:
途径A：Route A:
步骤A1：在催化剂作用下，于醇溶剂中使式III化合物和一氧化碳反应，得到式IV化合物；Step A1: reacting the compound of formula III and carbon monoxide in an alcohol solvent under the action of a catalyst to obtain the compound of formula IV;
步骤A2：于酸性溶液中，使式IV化合物经脱缩醛保护基得到式I化合物；Step A2: In an acidic solution, the compound of formula IV is deacetalized to obtain the compound of formula I;
或者，途径B：Or, Path B:
步骤B1：于溶剂B中，使式III化合物与氰化物反应得到环氧开环的中间体，继续与羟基保护试剂反应得到式V化合物；Step B1: In the solvent B, react the compound of formula III with cyanide to obtain an epoxy ring-opening intermediate, and continue to react with a hydroxyl protecting reagent to obtain the compound of formula V;
步骤B2：于碱溶液中，使式V化合物经氰基水解为羧酸盐，再于酸性溶液中脱缩醛保护基得到式VI化合物；Step B2: in an alkaline solution, hydrolyze the compound of formula V to a carboxylate by cyano, and then remove the acetal protecting group in an acidic solution to obtain the compound of formula VI;
步骤B3：于溶剂C中，使式VI化合物通过酯化、脱保护反应，得到式I化合物。Step B3: In the solvent C, the compound of formula VI is subjected to esterification and deprotection reaction to obtain the compound of formula I.
Figure PCTCN2019108982-appb-000004
Figure PCTCN2019108982-appb-000004
其中，n＝0、1或2；Among them, n = 0, 1 or 2;
当n为0时，R 1、R 2分别各自独立地为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、苄基中的一种；当n为1或2时，R 1、R 2分别各自独立地为-CH 2-、-RCH-，R为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基或苯基。 When n is 0, R 1 and R 2 are each independently one of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and benzyl; when n is When 1 or 2, R 1 and R 2 are each independently -CH 2- , -RCH-, and R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or Phenyl.
PG代表三甲基硅基(TMS)、二甲基叔丁基硅基(TBDMS)、苄基(Bn)、甲磺酰基 (Ms)、对甲基苯磺酰基(Ts)。PG stands for trimethylsilyl (TMS), dimethyl tert-butylsilyl (TBDMS), benzyl (Bn), methanesulfonyl (Ms), p-toluenesulfonyl (Ts).
根据本发明优选的，步骤(1)中，所述溶剂A为四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚、甲氧基环戊烷、己烷、庚烷或甲苯之一或组合；所述溶剂A与式Ⅱ化合物的质量比为(2-10):1。According to a preferred embodiment of the present invention, in step (1), the solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methoxycyclopentane, hexane , One of heptane or toluene, or a combination thereof; the mass ratio of the solvent A to the compound of formula II is (2-10): 1.
根据本发明优选的，步骤(1)中，所述镁粉与式II化合物的摩尔比为(1.0-1.5):1，进一步优选镁粉与式II化合物的摩尔比为(1.02-1.3):1。According to a preferred embodiment of the present invention, in step (1), the molar ratio of the magnesium powder to the compound of formula II is (1.0-1.5): 1, further preferably the molar ratio of the magnesium powder to the compound of formula II is (1.02-1.3): 1.
根据本发明优选的，步骤(1)中，所述格氏反应温度为25-55℃；进一步优选所述格氏反应温度为30-40℃。所述格氏反应时间为0.5-5小时；进一步优选，所述格氏反应时间为1-3小时。格氏反应温度为重要因素，温度高会导致副反应而影响格氏试剂产物含量。According to a preferred embodiment of the present invention, in step (1), the Grignard reaction temperature is 25-55 ° C; further preferably, the Grignard reaction temperature is 30-40 ° C. The Grignard reaction time is 0.5-5 hours; further preferably, the Grignard reaction time is 1-3 hours. The Grignard reaction temperature is an important factor. High temperature will cause side reactions and affect the content of Grignard reagent products.
根据本发明优选的，步骤(1)中，所述环氧卤丙烷中的卤素为氯或溴。进一步优选，所述环氧卤丙烷选自(R,S)-环氧氯丙烷、S-环氧氯丙烷、R-环氧氯丙烷、(R,S)-环氧溴丙烷、S-环氧溴丙烷或R-环氧溴丙烷。该步骤(1)中所用环氧卤丙烷的手性决定终产物式I化合物的手性构型。According to a preferred embodiment of the present invention, in step (1), the halogen in the epihalohydrin is chlorine or bromine. Further preferably, the epihalohydrin is selected from (R, S) -epichlorohydrin, S-epichlorohydrin, R-epichlorohydrin, (R, S) -epibromopropane, S-ring Oxybromopropane or R-epoxybromopropane. The chirality of the epihalohydrin used in this step (1) determines the chiral configuration of the final compound of formula I.
根据本发明优选的，步骤(1)中，所述环氧卤丙烷与式IV化合物的摩尔比为(0.9-1.2):1。According to a preferred embodiment of the present invention, in step (1), the molar ratio of the epihalohydrin to the compound of formula IV is (0.9-1.2): 1.
根据本发明优选的，步骤(1)中，所述格氏试剂和环氧卤丙烷的反应温度为0～40℃，进一步优选反应温度为5～20℃，最优选该反应温度为10-15℃。所述格氏试剂和环氧卤丙烷的反应时间为0.5-5小时，优选为1-3小时。该反应温度的控制十分重要，温度高会有副反应发生。According to a preferred embodiment of the present invention, in step (1), the reaction temperature of the Grignard reagent and the epihalohydrin is 0-40 ° C, further preferably the reaction temperature is 5-20 ° C, and most preferably the reaction temperature is 10-15 ℃. The reaction time of the Grignard reagent and the epihalohydrin is 0.5-5 hours, preferably 1-3 hours. The control of the reaction temperature is very important, and high temperature will cause side reactions.
根据本发明优选的，步骤(2)中，所述途径A的反应包括下列条件之一种或多种：According to a preferred embodiment of the present invention, in step (2), the reaction of the pathway A includes one or more of the following conditions:
步骤A1中，所述醇溶剂为甲醇、乙醇、异丙醇、丁醇、叔丁醇、异丁醇或苄醇之一或组合；所述醇溶剂与式III化合物的质量比为(4-20):1。In step A1, the alcohol solvent is one or a combination of methanol, ethanol, isopropanol, butanol, t-butanol, isobutanol or benzyl alcohol; the mass ratio of the alcohol solvent to the compound of formula III is (4- 20): 1.
步骤A1中，所述催化剂为钯碳、氯化钯、氢氧化钯、三(三苯基膦)氯化铑、格拉布催化剂、铱/氧化铝、(1,5-环辛二烯)(嘧啶)(三环己基膦)铱(I)六氟磷酸盐或八羰基二钴；所述催化剂用量占式III化合物质量的的1.0-20.0％。In step A1, the catalyst is palladium carbon, palladium chloride, palladium hydroxide, tris (triphenylphosphine) rhodium chloride, Grubbs catalyst, iridium / alumina, (1,5-cyclooctadiene) ( Pyrimidine) (tricyclohexylphosphine) iridium (I) hexafluorophosphate or dicobalt octacarbonyl; the amount of the catalyst accounts for 1.0-20.0% of the mass of the compound of formula III.
步骤A1中，所述催化反应温度为10-80℃，进一步优选所述催化反应温度为30-50℃。所述催化反应时间为2-20小时；进一步优选所述催化反应时间为5-12小时。In step A1, the catalytic reaction temperature is 10-80 ° C, further preferably the catalytic reaction temperature is 30-50 ° C. The catalytic reaction time is 2-20 hours; further preferably, the catalytic reaction time is 5-12 hours.
步骤A2中，所述酸性溶液为硫酸、盐酸或磷酸，氢离子浓度为3-8mol/L；所述酸性溶液与式IV化合物的质量比为8-20:1。In step A2, the acidic solution is sulfuric acid, hydrochloric acid or phosphoric acid, and the hydrogen ion concentration is 3-8 mol / L; the mass ratio of the acidic solution to the compound of formula IV is 8-20: 1.
步骤A2中，所述脱缩醛保护反应温度为10-80℃，进一步优选所述脱缩醛保护反应温度为35-60℃。所述脱缩醛保护反应时间为0.5-5小时；进一步优选该反应时间为1-3小时。In step A2, the deacetal protection reaction temperature is 10-80 ° C, further preferably the deacetal protection reaction temperature is 35-60 ° C. The deacetal protection reaction time is 0.5-5 hours; further preferably, the reaction time is 1-3 hours.
根据本发明优选的，步骤(2)中，所述途径B的反应包括下列条件之一种或多种：According to a preferred embodiment of the present invention, in step (2), the reaction of the pathway B includes one or more of the following conditions:
步骤B1中，所述溶剂B为乙酸乙酯、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲氧基环戊烷、甲基叔丁基醚，二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、氯苯、二 甲苯、二氯苯溶剂中的一种或两种以上的组合；所述溶剂B与式III化合物的质量比为4-20:1。In step B1, the solvent B is ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, dichloromethane, One or a combination of two or more of chloroform, 1,2-dichloroethane, benzene, toluene, chlorobenzene, xylene, and dichlorobenzene; the mass ratio of the solvent B to the compound of formula III is 4- 20: 1.
步骤B1中，所述氰化物为氰化钠或氰化钾；所述氰化物与式V化合物的摩尔比为1-2:1。In step B1, the cyanide is sodium cyanide or potassium cyanide; the molar ratio of the cyanide to the compound of formula V is 1-2: 1.
步骤B1中，所述式III化合物与氰化物反应的温度为10℃～60℃；所述反应时间为1-8小时。In step B1, the reaction temperature of the compound of formula III with cyanide is 10 ° C to 60 ° C; the reaction time is 1-8 hours.
步骤B1中，所述羟基保护试剂为三甲基氯硅烷、三甲基碘硅烷、二甲基叔丁基氯硅烷、二甲基叔丁基碘硅烷、甲磺酰氯、对甲基苯磺酰氯、苄氯、苄溴、三氟乙酸或乙酸酐，所述羟基保护基与式III化合物的摩尔比为1-2:1。In step B1, the hydroxyl protection reagent is trimethylchlorosilane, trimethyliodosilane, dimethyl tert-butylchlorosilane, dimethyl tert-butyliodosilane, methanesulfonyl chloride, p-toluenesulfonyl chloride , Benzyl chloride, benzyl bromide, trifluoroacetic acid or acetic anhydride, the molar ratio of the hydroxyl protecting group to the compound of formula III is 1-2: 1.
步骤B1，所述羟基保护反应温度为0℃-120℃。所述羟基保护反应时间为1-10小时。根据不同的羟基保护基试剂确定进一步优选的反应温度和时间。Step B1, the hydroxyl protection reaction temperature is 0 ° C-120 ° C. The hydroxyl protection reaction time is 1-10 hours. The further preferred reaction temperature and time are determined according to different hydroxyl protecting group reagents.
步骤B2中，所述碱溶液为氢氧化钠、氢氧化钾、氢氧化钙、氢氧化钡、碳酸钠或碳酸钾的水溶液。优选碱溶液浓度为10-40％质量百分比。所述碱溶液与式V化合物的质量比为2-20:1；进一步优选碱溶液与式V化合物的质量比为3-10:1。In step B2, the alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, or potassium carbonate. Preferably, the concentration of the alkaline solution is 10-40% by mass. The mass ratio of the alkaline solution to the compound of formula V is 2-20: 1; further preferably the mass ratio of the alkaline solution to the compound of formula V is 3-10: 1.
步骤B2中，所述水解反应的温度为20℃-100℃；所述水解反应时间为1-8小时。In step B2, the temperature of the hydrolysis reaction is from 20 ° C to 100 ° C; the hydrolysis reaction time is from 1 to 8 hours.
步骤B2中，所述酸性溶液为质量分数5-20％的稀硫酸、10-30％的盐酸或30-50％的磷酸溶液；所述酸性溶液与式V化合物的质量比为3-30:1。进一步优选酸性溶液与式V化合物的质量比为4-10:1。In step B2, the acidic solution is 5-20% dilute sulfuric acid, 10-30% hydrochloric acid or 30-50% phosphoric acid solution; the mass ratio of the acidic solution to the compound of formula V is 3-30: 1. It is further preferred that the mass ratio of the acidic solution to the compound of formula V is 4-10: 1.
步骤B2中，所述酸化反应的温度为10℃-50℃，进一步优选30-40℃，反应时间为1-8小时。In step B2, the temperature of the acidification reaction is 10 ° C-50 ° C, further preferably 30-40 ° C, and the reaction time is 1-8 hours.
步骤B3中，所述溶剂C为乙酸乙酯、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲氧基环戊烷、甲基叔丁基醚以及二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、氯苯、二甲苯、二氯苯中的一种或两种以上的组合；所述溶剂C与式VI化合物的质量比为4-20:1。In step B3, the solvent C is ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether and dichloromethane, One or a combination of chloroform, 1,2-dichloroethane, benzene, toluene, chlorobenzene, xylene, and dichlorobenzene; the mass ratio of the solvent C to the compound of formula VI is 4-20 :1.
步骤B3中，所述酯化试剂为碳酸酯、硫酸酯、对甲苯磺酸酯；所述酯化试剂与式VI化合物的摩尔比为1-5:1。In step B3, the esterification reagent is carbonate, sulfate, p-toluenesulfonate; the molar ratio of the esterification reagent to the compound of formula VI is 1-5: 1.
步骤B3中，所述酯化反应温度为0℃-100℃；反应时间为1-8小时。根据不同的酯化试剂确定进一步优选的反应温度和时间。In step B3, the esterification reaction temperature is 0 ° C-100 ° C; the reaction time is 1-8 hours. The further preferred reaction temperature and time are determined according to different esterification reagents.
步骤B3中的脱保护反应按现有技术即可。特别优选的，所述脱保护反应于催化剂和氢气作用下进行。所述催化剂为钯碳或兰尼镍，钯碳加入量和化合物Ⅵ的质量比为1.0％-5.0％，兰尼镍加入量和化合物Ⅵ的质量比为5.0％-20.0％，优选钯碳催化剂；脱保护反应温度为20-80℃，反应时间为1-6小时，优选脱保护反应温度为40-60℃，反应时间为2-4小时，脱保护过程中氢气压力为0.2-1.0MPa。The deprotection reaction in step B3 can be performed according to the prior art. Particularly preferably, the deprotection reaction is carried out under the action of a catalyst and hydrogen. The catalyst is palladium-carbon or Raney nickel, the mass ratio of palladium-carbon addition to compound VI is 1.0% -5.0%, the mass ratio of raney nickel addition to compound VI is 5.0% -20.0%, preferably palladium-carbon catalyst ; Deprotection reaction temperature is 20-80 ℃, reaction time is 1-6 hours, preferably deprotection reaction temperature is 40-60 ℃, reaction time is 2-4 hours, hydrogen pressure during deprotection process is 0.2-1.0MPa.
本发明的方法中，以卤代乙醛缩醛(II)为原料，先与镁粉作用制得相应格式试剂，继续与卤代环氧丙烷反应得到中间体III，然后由化合物III经两种途径之一制备目标化合物I。In the method of the present invention, the halogenated acetaldehyde acetal (II) is used as a raw material, the corresponding format reagent is prepared by first acting with magnesium powder, and the reaction with the halogenated propylene oxide is continued to obtain the intermediate III, and then the compound III is passed through two types One way to prepare the target compound I.
途径A是在醇溶剂中、金属催化剂作用下，III与一氧化碳反应得到中间体IV，继续水解缩醛即得产品式I化合物。Route A is the reaction of III with carbon monoxide in an alcohol solvent under the action of a metal catalyst to obtain intermediate IV, which is then hydrolyzed to obtain the compound of formula I.
途径B是利用氰化物与中间体III作用得到环氧开环的中间体V，再水解氰基得到中间 体VI，最后经酯化、脱保护得到产品式I化合物。Route B is to use cyanide and intermediate III to obtain epoxy ring-opening intermediate V, then hydrolyze the cyano group to obtain intermediate VI, and finally obtain the product formula I by esterification and deprotection.
反应过程描述为以下反应路线2：The reaction process is described as the following reaction route 2:
Figure PCTCN2019108982-appb-000005
Figure PCTCN2019108982-appb-000005
方案A：Option A:
Figure PCTCN2019108982-appb-000006
Figure PCTCN2019108982-appb-000006
方案B：Option B:
Figure PCTCN2019108982-appb-000007
Figure PCTCN2019108982-appb-000007
其中，X为氯、溴；Among them, X is chlorine, bromine;
n＝0,1,2；其中当n为0时，R 1、R 2分别各自独立地为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、苄基等；当n为1或2时，R 1、R 2分别各自独立地为-CH 2-、-RCH-，R为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、苯基； n = 0, 1 , 2; when n is 0, R 1 and R 2 are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl Groups; when n is 1 or 2, R 1 and R 2 are each independently -CH 2- , -RCH-, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl Group, tert-butyl, phenyl;
R 3OH为甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、叔丁醇、苄醇、乙二醇、丙二醇或1,3-丁二醇； R 3 OH is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, benzyl alcohol, ethylene glycol, propylene glycol or 1,3-butanediol;
PG为三甲基硅基(TMS)、二甲基叔丁基硅基(TBDMS)、苄基(Bn)、甲磺酰基(Ms)、对甲基苯磺酰基(Ts)。PG is trimethylsilyl (TMS), dimethyl tert-butylsilyl (TBDMS), benzyl (Bn), methanesulfonyl (Ms), p-toluenesulfonyl (Ts).
反应路线2Reaction Route 2
根据本发明的方法，各步骤中的中间产物的后处理，可以参考本领域现有技术进行。本发明优选的中间产物的后处理方法如下：According to the method of the present invention, the post-processing of the intermediate product in each step can be performed with reference to the prior art in the art. The preferred post-processing method of the intermediate product of the present invention is as follows:
步骤(1)的反应结束后，将所得反应混合物加至水和二氯甲烷混合液中，搅拌后静置分液。水相以二氯甲烷萃取2-3次，合并有机相，将有机相以饱和氯化钠水溶液洗涤1-2次，然后减压蒸馏除溶剂后，再减压蒸馏(85-95℃/2-3mmHg)得到式III化合物。After the reaction in step (1) is completed, the resulting reaction mixture is added to a mixed solution of water and dichloromethane, stirred, and allowed to stand for liquid separation. The aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride 1-2 times, and then the solvent was distilled off under reduced pressure, and then distilled under reduced pressure (85-95 ° C / 2 -3mmHg) to give the compound of formula III.
步骤(2)之步骤A1的反应结束后，冷却至室温，用氮气置换一氧化碳后打开反应釜。滤除催化剂，滤液经蒸馏除去溶剂后，再通过减压蒸馏(110-125℃/2-3mmHg)得到式VI化合物。After the reaction of step A1 in step (2) is completed, cool to room temperature, replace carbon monoxide with nitrogen, and then open the reactor. The catalyst was filtered off, and the filtrate was distilled to remove the solvent, and then the compound of formula VI was obtained by distillation under reduced pressure (110-125 ° C / 2-3 mmHg).
步骤(2)之步骤A2的反应结束后，冷却至室温后，加入乙酸乙酯，分液，以乙酸乙酯萃取水相2-3次，合并有机相，蒸馏除去溶剂，然后减压蒸馏(120-140℃/2-3mmHg)后得到化合物I。After the reaction of step A2 in step (2) is completed, after cooling to room temperature, ethyl acetate is added, the liquid is separated, the aqueous phase is extracted with ethyl acetate 2-3 times, the organic phases are combined, the solvent is distilled off, and then the vacuum distillation 120-140 ° C / 2-3mmHg) to obtain compound I.
步骤(2)之步骤B1的反应结束后,冷却至室温，加入水和二氯甲烷，搅拌后静置分层。水相以二氯甲烷萃取2-3次，合并有机相，以饱和氯化钠水溶液洗涤有机相，然后蒸馏除去溶剂后，减压蒸馏(105-120℃/2-3mmHg)得到化合物V。After the reaction of step B1 in step (2) is completed, it is cooled to room temperature, water and dichloromethane are added, stirred and allowed to stand for separation. The aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, the organic phase was washed with a saturated sodium chloride aqueous solution, and then the solvent was distilled off, and the compound V was obtained by distillation under reduced pressure (105-120 ° C / 2-3 mmHg).
步骤(2)之步骤B2的反应结束后,加入二氯甲烷，搅拌后静置分层。以二氯甲烷萃取水相2-3次，合并有机相，减压蒸馏除去溶剂后得化合物VI。After the reaction of step B2 in step (2), dichloromethane was added, stirred and allowed to stand for separation. The aqueous phase was extracted with dichloromethane 2-3 times, the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain compound VI.
步骤(2)之步骤B3的反应结束后,加入水和乙酸乙酯，搅拌后静置分层。以乙酸乙酯萃取水相2-3次，合并有机相，减压蒸馏除去溶剂后，得到化合物I。After the reaction of step B3 of step (2), water and ethyl acetate are added, stirred and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate 2-3 times, the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain compound I.
本发明的有益效果：The beneficial effects of the invention:
1、本发明以卤代乙醛缩醛为起始原料，价廉易得；所涉及反应类型经典，反应条件易于控制，操作安全简便，过程绿色环保，成本低，易于实现工业化。1. The present invention uses halogenated acetaldehyde acetal as the starting material, which is cheap and easy to obtain; the reaction type involved is classic, the reaction conditions are easy to control, the operation is safe and convenient, the process is green and environmentally friendly, the cost is low, and industrialization is easy to achieve.
2、本发明的方法各步骤的反应选择性好，制备3-羟基-6-氧代己酸酯的总收率在72.5％-78.7％，比现有文献报道的30％左右收率有显著提高。本发明方法中格氏试剂的反应温度、格氏试剂和环氧氯丙烷的反应温度、酸作用的温度等条件是影响反应收率及分离纯化简易性的重要因素。各反应物比例等条件在优选方案下更有利于进一步地降低成本、提高收率。2. The reaction of each step of the method of the present invention has good reaction selectivity, and the total yield of 3-hydroxy-6-oxohexanoic acid ester is 72.5% -78.7%, which is significantly higher than the 30% yield reported in the existing literature. improve. Conditions such as the reaction temperature of the Grignard reagent, the reaction temperature of the Grignard reagent and epichlorohydrin, and the temperature of the acid action in the method of the present invention are important factors that affect the reaction yield and the ease of separation and purification. Conditions such as the ratio of each reactant are more conducive to further reducing costs and improving yield under the preferred scheme.
3、本发明制备的3-羟基-6-氧代己酸酯纯度高，可以作为以环状硼酸为药效基团的新型非β-内酰胺类β-内酰胺酶抑制剂Vaborbactam或其异构体的起始原料。3. The 3-hydroxy-6-oxohexanoic acid ester prepared by the invention has high purity and can be used as a novel non-β-lactam β-lactamase inhibitor Vaborbactam or its The starting material of the structure.
具体实施方式detailed description
以下所述的实施例对本发明的技术方案进行了详细完整的说明，但是本发明不仅限于以下实施例。基于本发明的实施例，任何本领域技术人员结合本技术方案衍生出的任何不具备创造性的方案或实施例，或基于本发明方案的任何不具备创造性的实施顺序的变化，均属于本发明的保护范围。The following embodiments describe the technical solutions of the present invention in detail and completely, but the present invention is not limited to the following embodiments. Based on the embodiments of the present invention, any non-inventive solutions or embodiments derived from those skilled in the art combined with the technical solutions, or any changes in the implementation order of the non-inventive solutions based on the solutions of the present invention belong to the present invention. protected range.
实施例中的％均为质量百分比，有特别说明的除外。The% in the examples are all mass percentages, unless otherwise specified.
利用气相或液相色谱仪监控反应过程和产品纯度，利用配有手性柱(ES-OVS，150mm×4.6mm，安捷伦)的液相色谱仪检测光学纯度(面积比％)，并计算收率和ee值。Use gas or liquid chromatograph to monitor the reaction process and product purity, use liquid chromatograph equipped with chiral column (ES-OVS, 150mm × 4.6mm, Agilent) to detect optical purity (area ratio%), and calculate the yield And ee value.
实施例1：(4R,4S)-4,5-环氧正戊基乙二醇缩醛(III  1)的制备 Example 1: Preparation of (4R, 4S) -4,5-epoxy n-pentyl glycol acetal (III 1 )
氮气保护下，向装有搅拌、温度计的500毫升四口烧瓶中加入100克四氢呋喃，6.7克(0.28摩尔)镁粉，1.8克溴乙醛缩乙二醇(II 1)，0.02克碘，反应引发后，于30-35℃之间滴加40.0克(共0.25摩尔)溴乙醛缩乙二醇(II 1)在120克四氢呋喃中的溶液，1小时滴毕，此后35-40℃搅拌反应2小时。冷却至20-25℃，转移至恒压滴液漏斗中待用。 Under the protection of nitrogen, add 500 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 1.8 g of bromoacetaldehyde ethylene glycol (II 1 ), 0.02 g of iodine to a 500 ml four-necked flask equipped with a stirring and a reaction. After initiation, a solution of 40.0 g (total 0.25 mol) of bromoacetaldehyde ethylene glycol (II 1 ) in 120 g of tetrahydrofuran was added dropwise at 30-35 ° C. After 1 hour, the solution was stirred at 35-40 ° C. 2 hours. Cool to 20-25 ° C and transfer to a constant pressure dropping funnel for use.
在另一个装有搅拌、温度计的500毫升四口烧瓶中加入50克四氢呋喃，23.5克(0.25 摩尔)(R,S)-环氧氯丙烷。控制温度在0-5℃，滴加所得格氏试剂，2小时滴加完毕，10-15℃搅拌反应2小时。将所得反应混合物加至60克水和100克二氯甲烷混合物中，搅拌15分钟后静置分液。水相以二氯甲烷萃取两次，每次50克。合并有机相后，以30克饱和氯化钠水溶液洗涤一次。有机相减压蒸馏除去溶剂后，减压蒸馏(85-95℃/2-3mmHg)得到32.6克(4R,4S)-4,5-环氧正戊基乙二醇缩醛(III 1)，气相纯度98.6％,收率为90.6％。 In another 500 ml four-necked flask equipped with a stirring and thermometer, 50 g of tetrahydrofuran and 23.5 g (0.25 mol) of (R, S) -epichlorohydrin were added. The temperature is controlled at 0-5 ° C, the resulting Grignard reagent is added dropwise, the addition is completed after 2 hours, and the reaction is stirred at 10-15 ° C for 2 hours. The resulting reaction mixture was added to a mixture of 60 g of water and 100 g of dichloromethane, stirred for 15 minutes, and allowed to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane, 50 g each time. After combining the organic phases, it was washed once with 30 g of saturated aqueous sodium chloride solution. After the organic phase was distilled off under reduced pressure, the solvent was distilled under reduced pressure (85-95 ° C / 2-3mmHg) to obtain 32.6 g (4R, 4S) -4,5-epoxy n-pentyl glycol acetal (III 1 ), The gas phase purity was 98.6%, and the yield was 90.6%.
以上产物(4R,4S)-4,5-环氧正戊基乙二醇缩醛也称(2R,2S)-(3,4-环氧)丁基-1,3-二氧环戊烷。The above product (4R, 4S) -4,5-epoxy n-pentyl glycol acetal is also called (2R, 2S)-(3,4-epoxy) butyl-1,3-dioxolane .
实施例2：4S-4,5-环氧正戊基乙二醇缩醛(III 2)的制备 Example 2: Preparation of 4S-4,5-epoxy n-pentyl glycol acetal (III 2 )
以23.5克(0.25摩尔)S-环氧氯丙烷替代实施例1中的23.5克(0.25摩尔)(R,S)-环氧氯丙烷，其余同实施例1，得到33.2克4S-4,5-环氧正戊基乙二醇缩醛(III 2)，气相纯度99.2％,ee值为99.0％，收率为92.3％。 Replace 23.5 g (0.25 mol) (R, S) -epichlorohydrin in Example 1 with 23.5 g (0.25 mol) S-epichlorohydrin, the rest is the same as in Example 1 to obtain 33.2 g 4S-4,5 -Epoxy n-pentyl glycol acetal (III 2 ), gas phase purity 99.2%, ee value 99.0%, yield 92.3%.
以上产物4S-4,5-环氧正戊基乙二醇缩醛也称2S-(3,4-环氧)丁基-1,3-二氧环戊烷。The above product 4S-4,5-epoxy n-pentyl glycol acetal is also called 2S- (3,4-epoxy) butyl-1,3-dioxolane.
实施例3：(4R,4S)-4,5-环氧正戊基二甲缩醛(III 3)的制备 Example 3: Preparation of (4R, 4S) -4,5-epoxy n-pentyl dimethyl acetal (III 3 )
氮气保护下，向装有搅拌、温度计的500毫升四口烧瓶中加入100克四氢呋喃，6.7克(0.28摩尔)镁粉，2.3克溴乙醛缩二甲醇(II 2)，0.02克碘，反应引发后，于30-35℃之间滴加40.0克(共0.25摩尔)溴乙醛缩二甲醇(II 2)和120克四氢呋喃的溶液，1小时滴毕，此后35-40℃搅拌反应2小时。冷却至20-25℃，转移至恒压滴液漏斗中待用。 Under the protection of nitrogen, add 100 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 2.3 g of bromoacetaldehyde dimethyl acetal (II 2 ), 0.02 g of iodine to a 500 ml four-necked flask equipped with a stirring and thermometer, the reaction is initiated After that, a solution of 40.0 g (total 0.25 mol) of bromoacetaldehyde dimethyl acetal (II 2 ) and 120 g of tetrahydrofuran was added dropwise at 30-35 ° C, and the solution was dropped in 1 hour, after which the reaction was stirred at 35-40 ° C for 2 hours. Cool to 20-25 ° C and transfer to a constant pressure dropping funnel for use.
在另一个装有搅拌、温度计的500毫升四口烧瓶中加入50克四氢呋喃，23.5克(0.25摩尔)(R,S)-环氧氯丙烷。控制温度在0-5℃，滴加所得格氏试剂,2小时滴加完毕，10-15℃搅拌反应2小时。将所得反应混合物加至60克水和100克二氯甲烷混合物中，搅拌15分钟后静置分液。水相以二氯甲烷萃取两次，每次50克。合并有机相后，以30克饱和氯化钠水洗涤一次。有机相减压蒸馏除去溶剂，减压蒸馏(80-90℃/2-3mmHg)得到33.5克(4R,4S)-4,5-环氧正戊基二甲缩醛(III 3)，气相纯度98.6％,收率为91.8％。 In another 500 ml four-necked flask equipped with a stirring and thermometer, 50 g of tetrahydrofuran and 23.5 g (0.25 mol) of (R, S) -epichlorohydrin were added. Control the temperature at 0-5 ° C, add the obtained Grignard reagent dropwise, the addition is completed after 2 hours, and the reaction is stirred at 10-15 ° C for 2 hours. The resulting reaction mixture was added to a mixture of 60 g of water and 100 g of dichloromethane, stirred for 15 minutes, and allowed to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane, 50 g each time. After the organic phases were combined, they were washed once with 30 g of saturated sodium chloride water. The organic phase was distilled under reduced pressure to remove the solvent, and the reduced pressure distillation (80-90 ° C / 2-3mmHg) gave 33.5 g (4R, 4S) -4,5-epoxy n-pentyl dimethyl acetal (III 3 ), gas phase purity 98.6%, the yield was 91.8%.
实施例4：4S-4,5-环氧正戊基二甲缩醛(III 4)的制备 Example 4: Preparation of 4S-4,5-epoxy n-pentyl dimethyl acetal (III 4 )
以23.5克(0.25摩尔)S-环氧氯丙烷替代实施例3中的23.5克(0.25摩尔)(R,S)-环氧氯丙烷，其余同实施例3，得到33.3克4S-4,5-环氧正戊基二甲缩醛(III 4)，气相纯度99.3％,ee值为99.1％，收率为91.2％。 Replace 23.5 g (0.25 mol) (R, S) -epichlorohydrin in Example 3 with 23.5 g (0.25 mol) S-epichlorohydrin, and the rest is the same as in Example 3 to obtain 33.3 g 4S-4,5 -Epoxy n-pentyl dimethyl acetal (III 4 ), gas phase purity 99.3%, ee value 99.1%, yield 91.2%.
实施例5：3S-羟基-6-乙二醇缩醛基己酸叔丁酯(IV 1)的制备(途径A之步骤A1) Example 5: Preparation of tert-butyl 3S-hydroxy-6-ethylene glycol acetal hexanoate (IV 1 ) (Step A1 of Route A)
向高压釜中，加入50克无水四氢呋喃，37克(0.5摩尔)叔丁醇，36.0克(0.25摩尔)实施例2所得2S-(3,4-环氧)丁基-1,3-二氧环戊烷(III 2)，8.5克(0.025摩尔)Co 2(CO) 8。合釜，以氮气置换三次后，再以一氧化碳置换三次，然后保持一氧化碳压力为0.9-1.1MPa，40-45℃下搅拌反应10小时。反应结束后，冷却至室温。氮气置换一氧化碳后开釜。将反应液转移后过滤，滤除催化剂。滤液经蒸馏除去溶剂后，再通过减压蒸馏(110-125℃/2-3mmHg)得到55.9克产品化合物IV 1，气相纯度99.6％，ee值为99.2％，收率为90.8％。 To the autoclave, add 50 g of anhydrous tetrahydrofuran, 37 g (0.5 mol) of tert-butanol, and 36.0 g (0.25 mol) of the 2S- (3,4-epoxy) butyl-1,3-dioxide obtained in Example 2. Oxycyclopentane (III 2 ), 8.5 g (0.025 mol) Co 2 (CO) 8 . Combine the kettle and replace it with nitrogen three times, then replace it with carbon monoxide three times, and then maintain the carbon monoxide pressure at 0.9-1.1MPa, and stir the reaction at 40-45 ° C for 10 hours. After the reaction was completed, it was cooled to room temperature. After replacing the carbon monoxide with nitrogen, the kettle was opened. After transferring the reaction solution and filtering, the catalyst was filtered off. After the filtrate was distilled to remove the solvent, it was distilled under reduced pressure (110-125 ° C / 2-3 mmHg) to obtain 55.9 g of product compound IV 1 with a gas phase purity of 99.6%, an ee value of 99.2%, and a yield of 90.8%.
实施例6：3S-羟基-6-二甲醇缩醛基己酸叔丁酯(IV 2)的制备(途径A之步骤A1) Example 6: Preparation of tert-butyl 3S-hydroxy-6-dimethanol acetalhexanoate (IV 2 ) (Step A1 of Route A)
向高压釜中，加入50克无水四氢呋喃，37克(0.5摩尔)叔丁醇，36.5克(0.25摩尔)实施例4所得化合物III 4，8.5克(0.025摩尔)Co 2(CO) 8。合釜，以氮气置换三次后，再以一氧化碳置换三次，然后保持一氧化碳压力为1.0-1.2MPa，40-45℃下搅拌反应8小时。反应结束后，冷却至室温。氮气置换一氧化碳后开釜。将滤液转移后过滤，滤除催化剂。滤液经蒸馏除去溶剂后，再通过减压蒸馏(110-125℃/2-3mmHg)得到56.6克产品化合物IV 2，气相纯度99.5％，ee值为99.0％，收率为91.2％。 To the autoclave, 50 g of anhydrous tetrahydrofuran, 37 g (0.5 mol) of tert-butanol, 36.5 g (0.25 mol) of the compound III 4 obtained in Example 4 , and 8.5 g (0.025 mol) of Co 2 (CO) 8 were added . Combine the kettle and replace it with nitrogen three times, then replace it with carbon monoxide three times, and then maintain the carbon monoxide pressure at 1.0-1.2MPa, and stir the reaction at 40-45 ° C for 8 hours. After the reaction was completed, it was cooled to room temperature. After replacing the carbon monoxide with nitrogen, the kettle was opened. After transferring the filtrate and filtering, the catalyst was filtered off. After removing the solvent by distillation, the filtrate was distilled under reduced pressure (110-125 ° C / 2-3 mmHg) to obtain 56.6 g of product compound IV 2 with a gas phase purity of 99.5%, an ee value of 99.0%, and a yield of 91.2%.
实施例7：3S-苄氧基-6-乙二醇缩醛基己腈(V 1)的制备(途径B之步骤B1) Example 7: Preparation of 3S-benzyloxy-6-ethylene glycol acetal nitrile (V 1 ) (Step B1 of Route B)
氮气保护下，向装有搅拌、温度计和回流冷凝管的250毫升四口烧瓶中加入100克四氢呋喃，36.0克(0.25摩尔)实施例2方法所得2S-(3,4-环氧)丁基-1,3-二氧环戊烷(III 2)。滴加入31.8克(0.26摩尔)40％氰化钠水溶液。1小时加毕，此后30-35℃搅拌反应4小时。然后，滴加38.0克苄氯和60克四氢呋喃的溶液。2小时滴加完毕，此后升温至50-55℃搅拌反应4小时。冷却至室温，加入80克水，100克二氯甲烷，搅拌15分钟后静置分液。水相以二氯甲烷萃取两次，每次30克。合并有机相后，以30克饱和氯化钠水溶液洗涤。有机相蒸馏除去溶剂后，减压蒸馏(105-120℃/2-3mmHg)得到59.4克产品化合物V 1，气相纯度99.3％,ee值为99.0％，收率为90.9％。 Under a nitrogen atmosphere, 100 g of tetrahydrofuran and 36.0 g (0.25 mol) of 2S- (3,4-epoxy) butyl-obtained in the method of Example 2 were added to a 250 ml four-necked flask equipped with a stirring, thermometer and reflux condenser 1,3-dioxolane (III 2 ). 31.8 g (0.26 mol) of 40% aqueous sodium cyanide solution was added dropwise. After 1 hour, the reaction was stirred at 30-35 ° C for 4 hours. Then, a solution of 38.0 g of benzyl chloride and 60 g of tetrahydrofuran was added dropwise. After 2 hours of dropping, the temperature was raised to 50-55 ° C and the reaction was stirred for 4 hours. After cooling to room temperature, 80 g of water and 100 g of dichloromethane were added, and after stirring for 15 minutes, the solution was allowed to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane, 30 g each time. After the organic phases were combined, they were washed with 30 g of saturated aqueous sodium chloride solution. After the organic phase was distilled to remove the solvent, vacuum distillation (105-120 ° C / 2-3 mmHg) gave 59.4 g of product compound V 1 with a gas phase purity of 99.3%, an ee value of 99.0%, and a yield of 90.9%.
实施例8：3S-苄氧基-6-氧代己酸(VI 1)的制备(途径B之步骤B2) Example 8: Preparation of 3S-benzyloxy-6-oxohexanoic acid (VI 1 ) (Step B2 of Route B)
向装有搅拌、温度计和回流冷凝管的500毫升四口烧瓶中加入200克16％氢氧化钠溶液，65.3克(0.25摩尔)实施例7方法所得产品化合物V 1，升温至80-85℃，搅拌反应4小时。冷却至室温后，加入300克18％的盐酸，30-35℃搅拌反应1小时。加入100克二氯甲烷，静置分层。以二氯甲烷萃取水相两次，每次30克。合并有机相，减压蒸馏除去溶剂后得到57.0克产品化合物VI 1，液相纯度99.5％,ee值为99.4％，收率为96.6％。 Into a 500 ml four-necked flask equipped with a stirrer, thermometer and reflux condenser, 200 g of 16% sodium hydroxide solution, 65.3 g (0.25 mol) of the product compound V 1 obtained in the method of Example 7 was heated to 80-85 ° C, The reaction was stirred for 4 hours. After cooling to room temperature, 300 g of 18% hydrochloric acid was added, and the reaction was stirred at 30-35 ° C for 1 hour. Add 100 grams of dichloromethane and leave to separate. The aqueous phase was extracted twice with dichloromethane, 30 g each time. The organic phases were combined and the solvent was distilled off under reduced pressure to obtain 57.0 g of product compound VI 1 with a liquid phase purity of 99.5%, an ee value of 99.4%, and a yield of 96.6%.
实施例9：3S-羟基-6-氧代己酸乙酯(I S1)的制备(途径B之步骤B3) Example 9: Preparation of 3S-hydroxy-6-oxohexanoic acid ethyl ester (I S1 ) (Step B3 of Route B)
向装有搅拌、温度计和回流冷凝管的500毫升四口烧瓶中加入200克无水四氢呋喃，59.1克(0.25摩尔)实施例8方法所得化合物VI 1，53.0克(0.5摩尔)碳酸钠，46.3克(0.3摩尔)硫酸二乙酯。升温至50-55℃，搅拌反应4小时。冷却至室温后，过滤，将所得滤液转移至高压釜中，加入1.0克5％钯碳，密闭压力釜，氮气置换三次，再以氢气置换三次后，维持压力为0.2-0.3MPa，30-35℃搅拌反应3小时，脱除苄基，氮气置换三次，滤除钯碳催化剂，向滤液中加入100克水，100克乙酸乙酯，分液。以乙酸乙酯萃取水相两次，每次40克。合并有机相，蒸馏除去溶剂后，减压蒸馏(105-120℃/2-3mmHg)得到46.0克产品化合物I S1，气相纯度99.7％，ee值99.3％，收率为91.0％。 Into a 500 ml four-necked flask equipped with a stirrer, thermometer and reflux condenser, 200 g of anhydrous tetrahydrofuran, 59.1 g (0.25 mol) of compound VI 1 obtained in the method of Example 8, 53.0 g (0.5 mol) of sodium carbonate, 46.3 g (0.3 mol) diethyl sulfate. The temperature was raised to 50-55 ° C, and the reaction was stirred for 4 hours. After cooling to room temperature, filtering, transferring the resulting filtrate to an autoclave, adding 1.0 g of 5% palladium carbon, sealing the autoclave, replacing with nitrogen three times, and replacing with hydrogen three times, maintaining the pressure at 0.2-0.3MPa, 30-35 The reaction was stirred at ℃ for 3 hours, the benzyl group was removed, the nitrogen was replaced three times, the palladium-carbon catalyst was filtered off, 100 g of water and 100 g of ethyl acetate were added to the filtrate, and the liquid was separated. The aqueous phase was extracted twice with ethyl acetate, 40 g each time. After combining the organic phases and distilling off the solvent, distillation under reduced pressure (105-120 ° C / 2-3 mmHg) gave 46.0 g of product compound I S1 with a gas phase purity of 99.7%, an ee value of 99.3%, and a yield of 91.0%.
核磁数据： 1H NMR(400MHz,CDCl 3)ppm：δ9.91(t,1H),4.02(q,2H),3.96(m,1H),3.12(d,1H),2.65(m,2H),2.52(m,1H),2.44(m,1H),1.76(m,1H),1.70(m,1H),1.06(t,3H) Nuclear magnetic data: 1 H NMR (400 MHz, CDCl 3 ) ppm: δ 9.91 (t, 1H), 4.02 (q, 2H), 3.96 (m, 1H), 3.12 (d, 1H), 2.65 (m, 2H) , 2.52 (m, 1H), 2.44 (m, 1H), 1.76 (m, 1H), 1.70 (m, 1H), 1.06 (t, 3H)
实施例10：3S-苄氧基-6-二甲醇缩醛基己腈(V 2)的制备(途径B之步骤B1) Example 10: Preparation of 3S-benzyloxy-6-dimethanol acetal hexanonitrile (V 2 ) (Step B1 of Route B)
以36.5克(0.25摩尔)实施例4方法所得III4代替实施例7所用36.0克(0.25摩尔)2S-(3,4-环氧)丁基-1,3-二氧环戊烷(III 2)，其余同实施例7，经减压蒸馏(100-115℃/2-3mmHg)得到59.2克产品化合物V 2，气相纯度99.7％,ee值为99.3％，收率为89.9％。 36.5 g (0.25 mol) of III4 obtained in Example 4 was used to replace 36.0 g (0.25 mol) of 2S- (3,4-epoxy) butyl-1,3-dioxolane (III 2 ) used in Example 7 The rest is the same as that in Example 7. After vacuum distillation (100-115 ° C / 2-3mmHg), 59.2 g of the product compound V 2 was obtained , with a gas phase purity of 99.7%, an ee value of 99.3%, and a yield of 89.9%.
实施例11：3S-苄氧基-6-氧代己酸(VI 1)的制备(途径B之步骤B2) Example 11: Preparation of 3S-benzyloxy-6-oxohexanoic acid (VI 1 ) (Step B2 of Route B)
以65.8克(0.25摩尔)实施例10方法所得产品V 2代替实施例8所用65.3克(0.25摩尔)V 1，其余同实施例8，减压蒸馏除去溶剂后得到57.1克产品化合物VI 1，液相纯度99.5％,ee值为99.2％，收率为96.7％。 65.8 g (0.25 mol) of the product V 2 obtained in the method of Example 10 was used to replace 65.3 g (0.25 mol) of V 1 used in Example 8, and the rest was the same as in Example 8. After the solvent was distilled off under reduced pressure, 57.1 g of the product compound VI 1 was obtained. The phase purity was 99.5%, the ee value was 99.2%, and the yield was 96.7%.
实施例12：3S-羟基-6-氧代己酸乙酯(I S1)的制备(途径B之步骤B3) Example 12: Preparation of ethyl 3S-hydroxy-6-oxohexanoate (I S1 ) (Step B3 of Route B)
利用59.1克(0.25摩尔)实施例11方法所得VI 1化合物代替同样质量的由实施例8方法所得化合物VI 1，其余操作同实施例9，减压蒸馏(105-120℃/2-3mmHg)得到46.2克产品化合物I S1，气相纯度99.5％，ee值99.2％，收率为91.4％。 Using 59.1 g (0.25 mol) of the VI 1 compound obtained in the method of Example 11 instead of the same quality of the compound VI 1 obtained in the method of Example 8, the rest of the operation is the same as in Example 9 and reduced pressure distillation (105-120 ° C / 2-3 mmHg) 46.2 g of product compound I S1 has a gas phase purity of 99.5%, an ee value of 99.2%, and a yield of 91.4%.
实施例13：3S-羟基-6-氧代己酸叔丁酯(I S2)的制备(途径A之步骤A2) Example 13: Preparation of tert-butyl 3S-hydroxy-6-oxohexanoate (I S2 ) (Step A2 of Route A)
向装有搅拌、温度计的500毫升四口烧瓶中加入300克5％的稀盐酸，24.6克(0.1摩尔)实施例5方法所得产品化合物IV 1，升温至35-40℃反应2小时。冷却至室温后，加入50克乙酸乙酯，分液。以乙酸乙酯萃取水相两次，每次50克。合并有机相，蒸馏除去溶剂，然后减压蒸馏(120-140℃/2-3mmHg)后得到18.9克产品化合物I S2，气相纯度99.5％，光学纯度99.2％，收率为93.9％。 Into a 500 ml four-necked flask equipped with a stirring and thermometer, 300 g of 5% dilute hydrochloric acid and 24.6 g (0.1 mol) of the product compound IV 1 obtained in the method of Example 5 were heated to 35-40 ° C for 2 hours. After cooling to room temperature, 50 g of ethyl acetate was added and the liquid was separated. The aqueous phase was extracted twice with ethyl acetate, 50 g each time. The organic phases were combined, the solvent was distilled off, and then distillation under reduced pressure (120-140 ° C / 2-3 mmHg) gave 18.9 g of product compound I S2 with a gas phase purity of 99.5%, optical purity of 99.2%, and a yield of 93.9%.
核磁数据： 1H NMR(400MHz,CDCl 3)ppm：δ9.88(t,1H),3.94(m,1H),3.12(d,1H),2.65(m,2H),2.52(m,1H),2.44(m,1H),1.76(m,1H),1.70(m,1H),1.42(s,9H) Nuclear magnetic data: 1 H NMR (400 MHz, CDCl 3 ) ppm: δ 9.88 (t, 1H), 3.94 (m, 1H), 3.12 (d, 1H), 2.65 (m, 2H), 2.52 (m, 1H) , 2.44 (m, 1H), 1.76 (m, 1H), 1.70 (m, 1H), 1.42 (s, 9H)
实施例14：3S-羟基-6-氧代己酸叔丁酯(I S2)的制备(途径A之步骤A2) Example 14: Preparation of tert-butyl 3S-hydroxy-6-oxohexanoate (I S2 ) (Step A2 of Route A)
向装有搅拌、温度计的500毫升四口烧瓶中加入300克5％的稀盐酸，24.8克(0.1摩尔)实施例6方法所得产品化合物IV 2，升温至50-55℃反应2小时。冷却至室温后，加入50克乙酸乙酯，分液。以乙酸乙酯萃取水相两次，每次50克。合并有机相，蒸馏除去溶剂，然后减压蒸馏(120-140℃/2-3mmHg)后得到18.7克产品化合物I S2，气相纯度99.7％，光学纯度99.4％，收率为92.5％。 Into a 500 ml four-necked flask equipped with a stirring and thermometer, 300 g of 5% dilute hydrochloric acid and 24.8 g (0.1 mol) of the product compound IV 2 obtained in the method of Example 6 were heated to 50-55 ° C for 2 hours. After cooling to room temperature, 50 g of ethyl acetate was added and the liquid was separated. The aqueous phase was extracted twice with ethyl acetate, 50 g each time. The organic phases were combined, the solvent was distilled off, and then distilled under reduced pressure (120-140 ° C / 2-3 mmHg) to obtain 18.7 g of product compound I S2 with a gas phase purity of 99.7%, an optical purity of 99.4%, and a yield of 92.5%.
对比例1：4S-4,5-环氧正戊基乙二醇缩醛或2S-(3,4-环氧)丁基-1,3-二氧环戊烷(III 2)的制备 Comparative Example 1: Preparation of 4S-4,5-epoxy n-pentyl glycol acetal or 2S- (3,4-epoxy) butyl-1,3-dioxolane (III 2 )
氮气保护下，向装有搅拌、温度计的500毫升四口烧瓶中加入100克四氢呋喃，6.7克(0.28摩尔)镁粉，1.8克溴乙醛缩乙二醇(II 1)，0.02克碘，反应引发后，于30-35℃之间滴加40.0克(共0.25摩尔)溴乙醛缩乙二醇(II 1)在120克四氢呋喃中的溶液，1小时滴毕，此后57-60℃搅拌反应2小时。冷却至20-25℃，转移至恒压滴液漏斗中待用。 Under the protection of nitrogen, add 500 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 1.8 g of bromoacetaldehyde ethylene glycol (II 1 ), 0.02 g of iodine to a 500 ml four-necked flask equipped with a stirring and a reaction. After initiation, a solution of 40.0 g (total 0.25 mol) of bromoacetaldehyde ethylene glycol (II 1 ) in 120 g of tetrahydrofuran was added dropwise at 30-35 ° C. After 1 hour, the solution was stirred at 57-60 ° C. 2 hours. Cool to 20-25 ° C and transfer to a constant pressure dropping funnel for use.
在另一个装有搅拌、温度计的500毫升四口烧瓶中加入50克四氢呋喃，23.5克(0.25摩尔)S-环氧氯丙烷，保持温度于0-5℃之间，滴加所得格氏试剂，2小时滴加完毕，10-15℃搅拌反应2小时。将所得反应混合物加至60克水和100克二氯甲烷混合物中，搅拌15分钟 后静置分液。水相以二氯甲烷萃取两次，每次50克。合并有机相后，以30克饱和氯化钠水溶液洗涤一次。有机相减压蒸馏除去溶剂后，减压蒸馏(85-95℃/2-3mmHg)得到30.2克2S-(3,4-环氧)丁基-1,3-二氧环戊烷(III 2)和1,4-丁二醛二缩乙二醇混合物，外标法分析化合物III 2含量为83.2％,计算化合物III 2收率为70.0％。 Add 50 grams of tetrahydrofuran, 23.5 grams (0.25 moles) of S-epichlorohydrin to another 500-mL four-necked flask equipped with a stirring and thermometer, keep the temperature between 0-5 ° C, and add the resulting Grignard reagent, After 2 hours of dropping, the reaction was stirred at 10-15 ° C for 2 hours. The resulting reaction mixture was added to a mixture of 60 g of water and 100 g of dichloromethane, stirred for 15 minutes, and allowed to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane, 50 g each time. After combining the organic phases, it was washed once with 30 g of saturated aqueous sodium chloride solution. After the organic phase was distilled off under reduced pressure, the solvent was distilled under reduced pressure (85-95 ° C / 2-3mmHg) to obtain 30.2 g of 2S- (3,4-epoxy) butyl-1,3-dioxolane (III 2 ) And 1,4-butanedialdehyde diethylene glycol mixture, the content of compound III 2 was 83.2% by external standard analysis, and the yield of compound III 2 was calculated to be 70.0%.
对比例1表明制备格氏试剂时，温度为重要因素，温度高时，格氏试剂偶合副反应多，副产物1,4-丁二醛二缩乙二醇多，因其沸点和产品接近，难于分离纯化。Comparative Example 1 shows that the temperature is an important factor in the preparation of Grignard reagents. When the temperature is high, there are many coupling reactions of Grignard reagents, and the by-product 1,4-butanedialdehyde diacetal is more, because its boiling point is close to the product. Difficult to separate and purify.
对比例2：4S-4,5-环氧正戊基乙二醇缩醛或2S-(3,4-环氧)丁基-1,3-二氧环戊烷(III 2)的制备 Comparative Example 2: Preparation of 4S-4,5-epoxy n-pentyl glycol acetal or 2S- (3,4-epoxy) butyl-1,3-dioxolane (III 2 )
氮气保护下，向装有搅拌、温度计的500毫升四口烧瓶中加入100克四氢呋喃，6.7克(0.28摩尔)镁粉，1.8克溴乙醛缩乙二醇(II 1)，0.02克碘，反应引发后，于30-35℃之间滴加40.0克(共0.25摩尔)溴乙醛缩乙二醇(II 1)在120克四氢呋喃中的溶液，1小时滴毕，此后35-40℃搅拌反应2小时。冷却至20-25℃，转移至恒压滴液漏斗中待用。 Under the protection of nitrogen, add 500 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 1.8 g of bromoacetaldehyde ethylene glycol (II 1 ), 0.02 g of iodine to a 500 ml four-necked flask equipped with a stirring and a reaction. After initiation, a solution of 40.0 g (total 0.25 mol) of bromoacetaldehyde ethylene glycol (II 1 ) in 120 g of tetrahydrofuran was added dropwise at 30-35 ° C. After 1 hour, the solution was stirred at 35-40 ° C. 2 hours. Cool to 20-25 ° C and transfer to a constant pressure dropping funnel for use.
在另一个装有搅拌、温度计的500毫升四口烧瓶中加入50克四氢呋喃，23.5克(0.25摩尔)S-环氧氯丙烷，保持温度于0-5℃之间，滴加所得格氏试剂，2小时滴加完毕，40-45℃搅拌反应2小时。将所得反应混合物加至60克水和100克二氯甲烷混合物中，搅拌15分钟后静置分液。水相以二氯甲烷萃取两次，每次50克。合并有机相后，以30克饱和氯化钠水溶液洗涤一次。有机相减压蒸馏除去溶剂后，减压蒸馏(85-95℃/2-3mmHg)得到32.1克产物，其中2S-(3,4-环氧)丁基-1,3-二氧环戊烷的气相纯度为75.7％,2R-(3,4-环氧)丁基-1,3-二氧环戊烷的气相纯度为23.9％，ee％值为52.0％，收率为89.3％。Add 50 grams of tetrahydrofuran, 23.5 grams (0.25 moles) of S-epichlorohydrin to another 500-mL four-necked flask equipped with a stirring and thermometer, keep the temperature between 0-5 ° C, and add the resulting Grignard reagent, After 2 hours of dropping, the reaction was stirred at 40-45 ° C for 2 hours. The resulting reaction mixture was added to a mixture of 60 g of water and 100 g of dichloromethane, stirred for 15 minutes, and allowed to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane, 50 g each time. After combining the organic phases, it was washed once with 30 g of saturated aqueous sodium chloride solution. After the organic phase was distilled under reduced pressure to remove the solvent, reduced pressure distillation (85-95 ° C / 2-3mmHg) gave 32.1 g of product, of which 2S- (3,4-epoxy) butyl-1,3-dioxolane The gas-phase purity of is 75.7%, the gas-phase purity of 2R- (3,4-epoxy) butyl-1,3-dioxolane is 23.9%, the ee% value is 52.0%, and the yield is 89.3%.
对比例2表明所得格氏试剂和S-环氧氯丙烷反应时，如果温度高，会降低经由开环-关环机制进行的格氏试剂和S-环氧氯丙烷反应(目标反应)，增加格氏试剂和S-环氧氯丙烷经由SN2机制进行的副反应(生成产物为对映异构体：2R-(3,4-环氧)丁基-1,3-二氧环戊烷)，产品ee值低。Comparative Example 2 shows that when the resulting Grignard reagent reacts with S-epichlorohydrin, if the temperature is high, the reaction between the Grignard reagent and S-epichlorohydrin (target reaction) through the ring-opening-closing mechanism will decrease and increase. Side reaction between Grignard reagent and S-epichlorohydrin via SN2 mechanism (product is enantiomer: 2R- (3,4-epoxy) butyl-1,3-dioxolane) , Product ee value is low.
对比例3：3S-苄氧基-6-氧代己酸(VI 1)的制备 Comparative Example 3: Preparation of 3S-benzyloxy-6-oxohexanoic acid (VI 1 )
向装有搅拌、温度计和回流冷凝管的500毫升四口烧瓶中加入200克16％氢氧化钠溶液，65.3克(0.25摩尔)实施例7方法所得产品化合物V 1，升温至80-85℃，搅拌反应4小时。冷却至室温后，加入300克18％的盐酸，55-60℃搅拌反应1小时。加入100克二氯甲烷，分液。以二氯甲烷萃取水相两次，每次30克。合并有机相，减压蒸馏除去溶剂后得到55.3克3S-苄氧基-6-氧代己酸和3R-苄氧基-6-氧代己酸混合物，液相纯度分别为72.6％和26.3％，ee值为46.9％，收率为93.7％。 Into a 500 ml four-necked flask equipped with a stirrer, thermometer and reflux condenser, 200 g of 16% sodium hydroxide solution, 65.3 g (0.25 mol) of the product compound V 1 obtained in the method of Example 7 was heated to 80-85 ° C, The reaction was stirred for 4 hours. After cooling to room temperature, 300 g of 18% hydrochloric acid was added, and the reaction was stirred at 55-60 ° C for 1 hour. Add 100 grams of dichloromethane and separate. The aqueous phase was extracted twice with dichloromethane, 30 g each time. The organic phases were combined and the solvent was distilled off under reduced pressure to obtain 55.3 g of a mixture of 3S-benzyloxy-6-oxohexanoic acid and 3R-benzyloxy-6-oxohexanoic acid. The liquid phase purity was 72.6% and 26.3%, respectively. The ee value is 46.9%, and the yield is 93.7%.
对比例3表明加入酸后，如果温度高，会导致3-位羟基的构型转化，不利于产品构型保持。Comparative Example 3 shows that after the addition of acid, if the temperature is high, it will cause the configuration conversion of the 3-position hydroxyl group, which is not conducive to maintaining the product configuration.

Claims (10)

  1. 一种式I所示化合物3-羟基-6-氧代己酸酯的制备方法，A method for preparing the compound 3-hydroxy-6-oxohexanoate of formula I,
    Figure PCTCN2019108982-appb-100001
    Figure PCTCN2019108982-appb-100001
    包括步骤：Including steps:
    (1)于溶剂A中，式II化合物和镁粉经格氏反应制备格氏试剂，将所得格氏试剂滴加至环氧卤丙烷中，反应制备式III化合物；(1) In the solvent A, the compound of formula II and magnesium powder are subjected to the Grignard reaction to prepare the Grignard reagent, and the obtained Grignard reagent is added dropwise to the epoxyhalopropane to react to prepare the compound of formula III;
    (2)由式III化合物制备3-羟基-6-氧代己酸酯(I)，采用以下途径A或途径B：(2) To prepare 3-hydroxy-6-oxohexanoate (I) from the compound of formula III, use the following route A or route B:
    途径A：Route A:
    步骤A1：在催化剂作用下，于醇溶剂中使式III化合物和一氧化碳反应，得到式IV化合物；Step A1: Under the action of the catalyst, the compound of formula III and carbon monoxide are reacted in an alcohol solvent to obtain the compound of formula IV;
    步骤A2：于酸性溶液中，使式IV化合物经脱缩醛保护基得到式I化合物；Step A2: In an acidic solution, the compound of formula IV is deacetalized to obtain the compound of formula I;
    或者，or,
    途径B：Route B:
    步骤B1：于溶剂B中，使式III化合物与氰化物反应得到环氧开环的中间体，继续与羟基保护试剂反应得到式V化合物；Step B1: In the solvent B, react the compound of formula III with cyanide to obtain an epoxy ring-opening intermediate, and continue to react with a hydroxyl protecting reagent to obtain the compound of formula V;
    步骤B2：于碱溶液中，使式V化合物经氰基水解为羧酸盐，再于酸性溶液中脱缩醛保护基得到式VI化合物；Step B2: in an alkaline solution, hydrolyze the compound of formula V to a carboxylate by cyano, and then remove the acetal protecting group in an acidic solution to obtain the compound of formula VI;
    步骤B3：于溶剂C中，使式VI化合物通过酯化、脱保护反应，得到式I化合物；Step B3: In the solvent C, the compound of formula VI is subjected to esterification and deprotection reaction to obtain the compound of formula I;
    Figure PCTCN2019108982-appb-100002
    Figure PCTCN2019108982-appb-100002
    其中，n＝0、1或2；Among them, n = 0, 1 or 2;
    当n为0时，R 1、R 2分别各自独立地为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、苄基中的一种；当n为1或2时，R 1、R 2分别各自独立地为-CH 2-、-RCH-，R为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基或苯基； When n is 0, R 1 and R 2 are each independently one of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and benzyl; when n is When 1 or 2, R 1 and R 2 are each independently -CH 2- , -RCH-, and R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or Phenyl
    PG代表三甲基硅基(TMS)、二甲基叔丁基硅基(TBDMS)、苄基(Bn)、甲磺酰基(Ms)、对甲基苯磺酰基(Ts)。PG stands for trimethylsilyl (TMS), dimethyl tert-butylsilyl (TBDMS), benzyl (Bn), methanesulfonyl (Ms), p-toluenesulfonyl (Ts).
  2. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(1)中，所述溶剂A为四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲基叔丁基醚、甲氧基环戊烷、己 烷、庚烷或甲苯之一或组合；所述溶剂A与式Ⅱ化合物的质量比为(2-10):1。The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, wherein in step (1), the solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di One or a combination of oxane, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane or toluene; the mass ratio of the solvent A to the compound of formula II is (2-10): 1.
  3. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(1)中，所述镁粉与式II化合物的摩尔比为(1.0-1.5):1，优选镁粉与式II化合物的摩尔比为(1.02-1.3):1。The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, wherein in step (1), the molar ratio of the magnesium powder to the compound of formula II is (1.0-1.5): 1. Preferably, the molar ratio of magnesium powder to the compound of formula II is (1.02-1.3): 1.
  4. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(1)中，所述格氏反应温度为25-55℃；优选所述格氏反应温度为30-40℃。The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that, in step (1), the Grignard reaction temperature is 25-55 ° C; preferably the Grignard reaction The temperature is 30-40 ° C.
  5. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(1)中，所述环氧卤丙烷中的卤素为氯或溴；优选的，所述环氧卤丙烷选自(R,S)-环氧氯丙烷、S-环氧氯丙烷、R-环氧氯丙烷、(R,S)-环氧溴丙烷、S-环氧溴丙烷或R-环氧溴丙烷；进一步优选，所述环氧卤丙烷与式IV化合物的摩尔比为(0.9-1.2):1。The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that, in step (1), the halogen in the epihalohydrin is chlorine or bromine; preferably, The epichlorohydrin is selected from (R, S) -epichlorohydrin, S-epichlorohydrin, R-epichlorohydrin, (R, S) -epibromopropane, S-epibromopropane or R-epoxybromopropane; further preferably, the molar ratio of the epihalohydrin to the compound of formula IV is (0.9-1.2): 1.
  6. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(1)中，所述格氏试剂和环氧卤丙烷的反应温度为0～40℃，优选反应温度为5～20℃。The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that in step (1), the reaction temperature of the Grignard reagent and the epihalohydrin is 0-40 ° C The reaction temperature is preferably 5-20 ° C.
  7. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(2)中，所述途径A的反应包括下列条件之一种或多种：The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that, in step (2), the reaction of the pathway A includes one or more of the following conditions:
    a.步骤A1中，所述醇溶剂为甲醇、乙醇、异丙醇、丁醇、叔丁醇、异丁醇或苄醇之一或组合；a. In step A1, the alcohol solvent is one or a combination of methanol, ethanol, isopropanol, butanol, tert-butanol, isobutanol or benzyl alcohol;
    b.步骤A1中，所述醇溶剂与式III化合物的质量比为(4-20):1；b. In step A1, the mass ratio of the alcohol solvent to the compound of formula III is (4-20): 1;
    c.步骤A1中，所述催化剂为钯碳、氯化钯、氢氧化钯、三(三苯基膦)氯化铑、格拉布催化剂、铱/氧化铝、(1,5-环辛二烯)(嘧啶)(三环己基膦)铱(I)六氟磷酸盐或八羰基二钴；c. In step A1, the catalyst is palladium carbon, palladium chloride, palladium hydroxide, tris (triphenylphosphine) rhodium chloride, Grubbs catalyst, iridium / alumina, (1,5-cyclooctadiene ) (Pyrimidine) (tricyclohexylphosphine) iridium (I) hexafluorophosphate or octacarbonyl dicobalt;
    d.步骤A1中，所述催化剂用量占式III化合物质量的的1.0-20.0％；d. In step A1, the amount of the catalyst accounts for 1.0-20.0% of the mass of the compound of formula III;
    e.步骤A1中，所述催化反应温度为10-80℃；优选所述催化反应温度为30-50℃；e step A1, the catalytic reaction temperature is 10-80 ℃; preferably the catalytic reaction temperature is 30-50 ℃;
    f.步骤A2中，所述酸性溶液为硫酸、盐酸或磷酸，氢离子浓度为3-8mol/L；f. In step A2, the acidic solution is sulfuric acid, hydrochloric acid or phosphoric acid, and the hydrogen ion concentration is 3-8 mol / L;
    g.步骤A2中，所述酸性溶液与式IV化合物的质量比为8-20:1；g. In step A2, the mass ratio of the acidic solution to the compound of formula IV is 8-20: 1;
    h.步骤A2中，所述脱缩醛保护反应温度为10-80℃；优选所述脱缩醛保护反应温度为35-60℃。h. In step A2, the deacetal protection reaction temperature is 10-80 ° C; preferably, the deacetal protection reaction temperature is 35-60 ° C.
  8. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(2)中，所述途径B的步骤B1的反应包括下列条件之一种或多种：The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that, in step (2), the reaction of step B1 of the route B includes one or more of the following conditions :
    a.步骤B1中，所述溶剂B为乙酸乙酯、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲氧基环戊烷、甲基叔丁基醚，二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、氯苯、二甲苯、二氯苯溶剂中的一种或两种以上的组合；a. In step B1, the solvent B is ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether, dichloro One or a combination of two or more of methane, chloroform, 1,2-dichloroethane, benzene, toluene, chlorobenzene, xylene, and dichlorobenzene;
    b.所述溶剂B与式III化合物的质量比为4-20:1；b. The mass ratio of the solvent B to the compound of formula III is 4-20: 1;
    c.步骤B1中，所述氰化物为氰化钠或氰化钾；c. In step B1, the cyanide is sodium cyanide or potassium cyanide;
    d.所述氰化物与式V化合物的摩尔比为1-2:1；d. The molar ratio of the cyanide to the compound of formula V is 1-2: 1;
    e.步骤B1中，所述式III化合物与氰化物反应的温度为10℃～60℃；e. In step B1, the reaction temperature of the compound of formula III with cyanide is 10 ° C to 60 ° C;
    f.步骤B1中，所述羟基保护试剂为三甲基氯硅烷、三甲基碘硅烷、二甲基叔丁基氯硅烷、二甲基叔丁基碘硅烷、甲磺酰氯、对甲基苯磺酰氯、苄氯、苄溴、三氟乙酸或乙酸酐；f. In step B1, the hydroxyl protecting reagent is trimethylchlorosilane, trimethyliodosilane, dimethyl tert-butylchlorosilane, dimethyl tert-butyliodosilane, methanesulfonyl chloride, p-methylbenzene Sulfonyl chloride, benzyl chloride, benzyl bromide, trifluoroacetic acid or acetic anhydride;
    g.步骤B1中，所述羟基保护基与式III化合物的摩尔比为1-2:1；g. In step B1, the molar ratio of the hydroxy protecting group to the compound of formula III is 1-2: 1;
    h.步骤B1中，所述羟基保护反应温度为0℃-120℃。h. In step B1, the hydroxyl protection reaction temperature is 0 ° C-120 ° C.
  9. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(2)中，所述途径B的步骤B2的反应包括下列条件之一种或多种：The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that, in step (2), the reaction of step B2 of the route B includes one or more of the following conditions :
    a.步骤B2中，所述碱溶液为氢氧化钠、氢氧化钾、氢氧化钙、氢氧化钡、碳酸钠或碳酸钾的水溶液；a. In step B2, the alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, or potassium carbonate;
    b.步骤B2中，所述碱溶液浓度为10-40％质量百分比；b. In step B2, the concentration of the alkaline solution is 10-40% by mass;
    c.所述碱溶液与式V化合物的质量比为2-20:1；优选碱溶液与式V化合物的质量比为3-10:1；c. The mass ratio of the alkaline solution to the compound of formula V is 2-20: 1; preferably the mass ratio of the alkaline solution to the compound of formula V is 3-10: 1;
    d.步骤B2中，所述水解反应的温度为20℃-100℃，反应时间为1-8小时；d. In step B2, the temperature of the hydrolysis reaction is 20 ° C-100 ° C, and the reaction time is 1-8 hours;
    e.步骤B2中，所述酸性溶液为质量分数5-20％的稀硫酸、10-30％的盐酸或30-50％的磷酸溶液；e step B2, the acidic solution is 5-20% dilute sulfuric acid, 10-30% hydrochloric acid or 30-50% phosphoric acid solution;
    f.所述酸性溶液与式V化合物的质量比为3-30:1；f. The mass ratio of the acidic solution to the compound of formula V is 3-30: 1;
    g.步骤B2中，所述酸化反应的温度为10℃-50℃；优选30-40℃。g. In step B2, the temperature of the acidification reaction is 10 ° C-50 ° C; preferably 30-40 ° C.
  10. 根据权利要求1所述的3-羟基-6-氧代己酸酯的制备方法，其特征在于，步骤(2)中，所述途径B的步骤B3的反应包括下列条件之一种或多种：The method for preparing 3-hydroxy-6-oxohexanoic acid ester according to claim 1, characterized in that, in step (2), the reaction of step B3 of the route B includes one or more of the following conditions :
    a.步骤B3中，所述溶剂C为乙酸乙酯、乙腈、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、甲氧基环戊烷、甲基叔丁基醚以及二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、氯苯、二甲苯、二氯苯中的一种或两种以上的组合；a. In step B3, the solvent C is ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methoxycyclopentane, methyl tert-butyl ether and dichloro One or a combination of two or more of methane, chloroform, 1,2-dichloroethane, benzene, toluene, chlorobenzene, xylene, and dichlorobenzene;
    b.所述溶剂C与式VI化合物的质量比为4-20:1；b. The mass ratio of the solvent C to the compound of formula VI is 4-20: 1;
    c.步骤B3中，所述酯化试剂为碳酸酯、硫酸酯、对甲苯磺酸酯；c. In step B3, the esterification reagent is carbonate, sulfate, p-toluenesulfonate;
    d.所述酯化试剂与式VI化合物的摩尔比为1-5:1；d. The molar ratio of the esterification reagent to the compound of formula VI is 1-5: 1;
    e.步骤B3，所述酯化反应温度为0℃-100℃。e. Step B3, the esterification reaction temperature is 0 ° C-100 ° C.
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