WO2020078204A1 - Procédé de préparation de 3-hydroxy-6-oxohexanoate - Google Patents

Procédé de préparation de 3-hydroxy-6-oxohexanoate Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
reaction
hydroxy
solvent
Prior art date
Application number
PCT/CN2019/108982
Other languages
English (en)
Chinese (zh)
Inventor
王保林
戚聿新
刘月盛
张伟
张明峰
Original Assignee
新发药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 新发药业有限公司 filed Critical 新发药业有限公司
Publication of WO2020078204A1 publication Critical patent/WO2020078204A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • C07C69/67—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de 3-hydroxy-6-oxohexanoate. Le procédé selon l'invention consiste à utiliser un acétal d'haloacétaldéhyde comme matériau de départ, et le soumettre à une addition de Grignard et à une réaction de substitution nucléophile pour obtenir des intermédiaires d'époxyde clés ; puis obtenir un produit cible par réaction de carburation catalysée par un métal dans du monoxyde de carbone, ou obtenir un produit cible par réaction de carburation réalisée à l'aide d'un cyanure, d'une hydrolyse du groupe cyano et d'un acétal, et d'une estérification. Le produit cible obtenu est utilisé dans la préparation de Vaborbactam et d'isomères de celui-ci. Le procédé utilise des matières premières bon marché et faciles à obtenir, présente des conditions de réaction modérées et faciles à contrôler et un processus simple et sans danger ; ledit procédé est respectueux de l'environnement et est à faible coût, et peut servir dans une production industrielle écologique.
PCT/CN2019/108982 2018-10-16 2019-09-29 Procédé de préparation de 3-hydroxy-6-oxohexanoate WO2020078204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811202269.2 2018-10-16
CN201811202269.2A CN111056942B (zh) 2018-10-16 2018-10-16 一种3-羟基-6-氧代己酸酯的制备方法

Publications (1)

Publication Number Publication Date
WO2020078204A1 true WO2020078204A1 (fr) 2020-04-23

Family

ID=70284391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/108982 WO2020078204A1 (fr) 2018-10-16 2019-09-29 Procédé de préparation de 3-hydroxy-6-oxohexanoate

Country Status (2)

Country Link
CN (1) CN111056942B (fr)
WO (1) WO2020078204A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102838511A (zh) * 2011-06-24 2012-12-26 浙江海翔药业股份有限公司 一种西他列汀的中间体及其制备方法和应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102838511A (zh) * 2011-06-24 2012-12-26 浙江海翔药业股份有限公司 一种西他列汀的中间体及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DENMARK , SCOTT E. ET AL.: "Carbonylative Ring Opening of Terminal Epoxides at Atmospheric Pressure", J. ORG. CHEM., vol. 72, no. 25, December 2007 (2007-12-01), pages 9630 - 9634, XP055702281 *
KUBIZNA, PETER ET AL.: "Synthesis of 2, 6-disubstituted Piperidine Alkaloids from Ladybird Beetles Calvia 10-guttata and Calvia 14-guttata", TETRAHEDRON, vol. 66, 2 February 2010 (2010-02-02), pages 2351 - 2355, XP026932584, DOI: 10.1016/j.tet.2010.01.106 *
MCGARVEY, GLENN J. ET AL.: "Sodium Nitroprusside Mediated Substitution of Oxygen for Nitrogen at Saturated Carbon Centers", J. ORG. CHEM., vol. 51, no. 20, October 1986 (1986-10-01), pages 3913 - 3915, XP055702293 *

Also Published As

Publication number Publication date
CN111056942B (zh) 2021-08-17
CN111056942A (zh) 2020-04-24

Similar Documents

Publication Publication Date Title
WO2017076293A1 (fr) Procédé pour préparer un intermédiaire d'oxazolidinone
US20200385355A1 (en) Method for synthesis of roxadustat and intermediate compounds thereof
WO2009149797A1 (fr) Procédé de préparation de dérivés d’acide 1-(2-halobiphényl-4-yl)-cyclopropane carboxylique
WO2023051768A1 (fr) Procédés de préparation de chlorhydrate d'acide (s)-4-chloro-2-aminobutyrique et de (s)-4-chloro-2-aminobutyrate
CN100564339C (zh) 2,3-二氟-5-溴苯酚的制备方法
WO2006080555A1 (fr) Procede de production du (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phtalimidomethylcyclopropane
CN111995522B (zh) 一种抗蚜威中间体2-甲基乙酰乙酸甲酯的合成方法
WO2020078204A1 (fr) Procédé de préparation de 3-hydroxy-6-oxohexanoate
CN109956941A (zh) 一种阿维巴坦的简便制备方法
CN110734368B (zh) 一种布帕伐醌的制备方法
CA2568800A1 (fr) Procede de production d'un derive de 3-aminomethyltetrahydrofurane
CN101709034B (zh) 双环[2.2.2]辛烷‑1，4‑二羧酸单甲酯的合成方法
CN111100042B (zh) 一种2-甲氧基-5-磺酰胺基苯甲酸的制备方法
WO2021238965A1 (fr) Procédé de préparation de méthyl (s)-2-amino-3-(4-(2,3-diméthylpyridin-4-yl)phénylpropionate et son sel
CN106496055A (zh) 一种抗心衰新药的关键组分沙库比曲的新合成方法
JP5448572B2 (ja) アセチル化合物、該アセチル化合物の製造方法、および該アセチル化合物を使用したナフトール化合物の製造方法
CN110240561A (zh) 一种低成本的3-羟基吡啶的制备方法
CN111217709A (zh) 一种（1-氟环丙基）甲胺盐酸盐的制备方法
CN115784922B (zh) 一种(2s)-2-氨基-4-(环丙基/环丁基)丁酸的制备方法
CN111662233B (zh) 一种一步法合成4-氯-1h-咪唑-2-羧酸乙酯的方法
CN110386891A (zh) 一种艾瑞昔布的制备方法
CN111763198B (zh) 一种5-取代环丙基甲酰氨基吲哚衍生物的制备方法
CN108329332A (zh) 一种制备Glecaprevir的方法
CN115286559B (zh) 抗新冠药物帕罗韦德关键中间体的制备方法
CN111484417B (zh) 一种卤泛曲林盐酸盐的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19872539

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19872539

Country of ref document: EP

Kind code of ref document: A1