WO2017041228A1 - Procédé de préparation d'un dérivé d'hexahydrofurofuranol, intermédiaire correspondant et procédé de préparation correspondant - Google Patents

Procédé de préparation d'un dérivé d'hexahydrofurofuranol, intermédiaire correspondant et procédé de préparation correspondant Download PDF

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WO2017041228A1
WO2017041228A1 PCT/CN2015/089162 CN2015089162W WO2017041228A1 WO 2017041228 A1 WO2017041228 A1 WO 2017041228A1 CN 2015089162 W CN2015089162 W CN 2015089162W WO 2017041228 A1 WO2017041228 A1 WO 2017041228A1
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formula
group
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prepared
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朱国良
张斌
陈小华
李杰平
钱灵锋
徐立
杜小华
何大伟
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浙江九洲药业股份有限公司
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Priority to PCT/CN2015/089162 priority Critical patent/WO2017041228A1/fr
Priority to CN202010282019.5A priority patent/CN111410607B/zh
Priority to CN201610726487.0A priority patent/CN106496263B/zh
Publication of WO2017041228A1 publication Critical patent/WO2017041228A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • 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
    • C07C69/675—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 of saturated hydroxy-carboxylic 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
    • C07C69/67—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
    • C07C69/708—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • 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
    • C07D407/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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 System
    • 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
    • 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 System
    • 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 the field of pharmaceutical synthesis, in particular to a preparation method of a hexahydrofuranfuranol derivative, an intermediate thereof and a preparation method thereof.
  • a compound having the structure of the following formula Z is a chemical name of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol:
  • One of the derivatives of hexahydrofuranfuranol is an intermediate of the anti-AIDS drug darunavir.
  • the method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol of the present invention starts from the selection of starting materials, and the research and development are different from the above-mentioned existing patent applications.
  • the starting material is used to prepare a key intermediate of darunavir.
  • the preparation method of the present invention provides another route suitable for industrialization for the preparation of the key intermediate of darunavir.
  • the present invention provides the following technical solutions:
  • the first aspect of the invention provides the following compound of formula B,
  • R 1 , R 2 are hydrogen, the same or different are carboxy protecting groups such as alkyl, substituted phenyl such as alkyl substituted phenyl, alkoxyalkyl substituted phenyl, nitroalkyl substituted Phenyl or silane group;
  • PG is hydrogen or a hydroxy protecting group such as an alkyl group, an alkylsilyl group, an aryl group or the like.
  • the alkyl group is a C 1 -C 8 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl;
  • the alkyl-substituted phenyl group is a benzyl group, a benzyl group, a trityl group;
  • the alkoxyalkyl-substituted phenyl group is a p-methoxybenzyl group;
  • the nitroalkyl-substituted phenyl group is a p-nitrobenzyl group, etc., preferably, Methyl, isopropyl, tert-butyl, benzyl;
  • the alkyl silicon group is trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl;
  • the aryl group is pheny
  • a second aspect of the invention provides the following compound of formula C,
  • R 2 has the same definition as defined in the compound of formula B above.
  • a third aspect of the invention provides the following compound of formula D,
  • the fourth aspect of the present invention provides a method for preparing a compound of the formula B and the formula B-1, wherein The compound of the formula B-1 is prepared by reacting a compound of the formula A1 with a compound of the formula A2, and the compound of the formula B is the same, and the compound of the formula A1 is adjusted to its racemate,
  • R 1 , R 2 , PG are the same as defined above, and X is a leaving group.
  • X may be a halogen atom, preferably an iodine atom, a bromine atom; a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a benzenesulfonyloxy group.
  • R 1 , R 2 and X are the same as defined above.
  • R 1 , R 2 and X are the same as defined above.
  • R 1 , R 2 and X are the same as defined above.
  • R 1 , R 2 and X are the same as defined above.
  • the compound of the formula B-1 wherein the protecting group is hydrogen can be prepared by deprotecting the protecting group to an alkyl group, a benzyl group or an alkylsilyl group.
  • the alkyl group is subjected to acid hydrolysis to a hydroxyl group, and the benzyl group and the diphenylmethyl group are deprotected to a hydroxyl group by palladium carbon, and the alkyl silicon group is deprotected to a hydroxyl group by an acid such as trifluoroacetic acid.
  • the reaction for preparing the compound of the formula B-1 is carried out in the presence of a base.
  • the base is an alkyl lithium or a compound of the following structure,
  • L 1, L 2 is alkyl, cycloalkyl, alkylsilyl, M being a metal atom such as lithium, potassium and sodium.
  • the base is lithium diisopropylamide, lithium cyclohexylamide, hexamethyl Lithium silicon nitride, sodium hexamethyldisilazide, potassium hexamethyldisilazide or n-butyllithium.
  • the base is lithium diisopropylamide.
  • the base is usually used in an amount of from 2.0 to 3.5 mol, preferably from 2.2 mol to 3.0 mol, per mol of the compound of the formula A1.
  • the reaction solvent is an ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran or the like.
  • the reaction temperature is -78 ° C to 70 ° C, preferably -78 ° C to 0 ° C.
  • the compound of the formula B-1 obtained by the reaction of the compound of the formula A1 with the compound of the formula A2 is mostly present in a compound of the following configuration
  • a person skilled in the art can purify the compound of the formula B-1 by column chromatography or the like.
  • the completion of the reaction may first pass through three processes of deprotection, post-cyclization, and hydrolysis, or may be hydrolysis first, then deprotection, re-cyclization, and It may be a process of first deprotecting, post-hydrolysis, and re-cyclization. That is, these three processes in any order.
  • the deprotecting reagent is acid or palladium carbon, and the cyclizing reagent may be an acid, wherein the acid is an inorganic acid or an organic acid; and the hydrolysis reagent is an inorganic base.
  • the inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is trifluoroacetic acid, and the inorganic base is sodium hydroxide, sodium carbonate or the like.
  • the preparation of the compound of the formula C of the present invention can also be carried out by reacting the compound of the formula A1 with the compound of the formula A2, and then subjecting it to a one-pot reaction of deprotection, cyclization and hydrolysis in any order.
  • the fifth aspect of the present invention provides a method for preparing a compound of the formula C1, an organic amine salt, wherein the organic amine reagent may be an amine having an active hydrogen such as a primary amine on nitrogen, or an amine having no active hydrogen on the nitrogen such as a tertiary amine. Amines, etc.
  • the organic amine reagent may be dibenzylamine, benzylamine, dicyclohexylamine, cyclohexylamine, aniline, diethylamine, diisopropylamine, (S)-phenethylamine, diisopropylethylamine.
  • Triethylamine preferably dibenzylamine.
  • the organic amine is usually used in an amount of from 0.5 to 1.5 mol, preferably from 0.8 to 1.3 mol, per mol of the compound of the formula C1.
  • the solvent is an alcohol solvent, a ketone solvent, an ether solvent, or an ester solvent.
  • It is an alcohol solvent, an ether solvent or a ketone solvent.
  • the alcohol solvent is methanol, ethanol, 2-propanol, 1-propanol, tert-butanol;
  • the ketone solvent is methyl isobutyl ketone or acetone;
  • the ether solvent is methyl t-butyl Ether or diisopropyl ether;
  • the ester solvent is ethyl acetate.
  • the formation of the organic amine salt can be carried out by heating to a temperature of usually 20 ° C to 100 ° C, preferably 50 ° C to 80 ° C, followed by cooling to a temperature of usually -20 ° C to 40 ° C, preferably -10 ° C to 25 ° C.
  • the recrystallization solvent is the same as the above reaction solvent, and is preferably a ketone solvent such as acetone.
  • the compound of the formula C1 can be further obtained by a free step. However, it can also be used in the next reaction without being liberated.
  • the acid used in the free step is a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.
  • a process for the preparation of a compound of the formula D-1 which is prepared from the above-mentioned compound of the formula C1 and an organic amine salt.
  • the acid binding agent is a tertiary amine such as triethylamine or diisopropylethylamine, and may also be pyridine.
  • the solvent is an ether solvent such as tetrahydrofuran or a halogenated alkane solvent such as dichloromethane.
  • the reaction temperature is from 0 ° C to 50 ° C.
  • a catalyst may optionally be added to the reaction, and the catalyst is 4-dimethylaminopyridine.
  • a seventh aspect of the invention provides a process for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol from a compound of formula D-1. It is prepared from the compound of the formula D-1 by reduction and cyclization in two steps.
  • the reducing agent is an aluminum reagent such as lithium aluminum hydride, diisobutylaluminum hydride or sodium dihydrobis(2-methoxyethoxy)aluminate (red aluminum), tri-tert-butoxy aluminum hydride lithium.
  • aluminum reagent such as lithium aluminum hydride, diisobutylaluminum hydride or sodium dihydrobis(2-methoxyethoxy)aluminate (red aluminum), tri-tert-butoxy aluminum hydride lithium.
  • the solvent for the reduction reaction is an ether solvent, a single solvent or a mixed solvent of a halogenated hydrocarbon or a hydrocarbon solvent.
  • the ether solvent is tetrahydrofuran; the halogenated hydrocarbon solvent is dichloromethane, chlorobenzene.
  • the cyclizing reagent is a mineral acid, an organic acid or an aqueous solution.
  • the inorganic acid is hydrochloric acid, sulfuric acid; the organic acid is methanesulfonic acid, p-toluenesulfonic acid.
  • the solvent for the cyclization reaction is an ether solvent and an alcohol solvent.
  • a more preferred embodiment is the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol by a one-pot reaction of the compound of formula C1 and the organic amine salt.
  • reaction solvent is preferably an ether solvent.
  • Another preferred embodiment is the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol by a one-pot reaction of a compound of formula C1.
  • reaction solvent is preferably an ether solvent.
  • the invention prepares the key intermediate of darunavir (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, starting from the compound of formula A1,
  • R 1 and R 2 are the same as defined above. This is different from the starting materials reported in the prior patent documents. The specific preparation method is also different from the prior patent documents, but the preparation method can industrially produce the key intermediate of darunavir.
  • control temperature does not exceed -60 ° C, drop, maintain internal temperature Stir for 30 min, slowly warm to -20 ° C, use for half an hour, then cool to -60 ° C ⁇ -70 ° C, add 2-iodoethyl tert-butyl ether (27.4 g, 2.0 eq) dropwise, stir and keep stirring for half an hour After that, the temperature was raised to -20 ° C and stirred overnight.
  • the reaction system was added with 90 ml of water and 40 ml of ethyl acetate, and the mixture was stirred for 5 min, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (40 ml ⁇ 3). Part of the column was separated and identified as the target compound in a yield of 80%.
  • Product spectrum data is as follows:
  • control temperature does not exceed -60 ° C, drip, maintain internal temperature for 30min, slowly warm to -20 ° C, use half an hour, then cool to -60 ° C ⁇ -70 ° C, add 2-iodoethyl tert-Butyl ether (9.58 g, 2.0 eq) was added and stirred for half an hour, then warmed to -20 ° C and stirred overnight.
  • the reaction system was added with 90 ml of water and 40 ml of ethyl acetate, and the mixture was stirred for 5 min, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (40 ml ⁇ 3). Partial separation of the column, determined as the target Compound, yield 60%.
  • Product spectrum data is as follows:
  • the compound of the formula B-1 whose protecting group is a trimethylsilyl group can be prepared according to the embodiment 1 or 2.
  • a compound of formula B-1 wherein the protecting group is benzyl can be prepared as in Example 1 or 2.
  • the compound of formula B-1 having a protecting group of hydrogen can be prepared by deprotection, and the product spectrum data is as follows:
  • Example 8 Preparation of a compound of formula C1 ⁇ dibenzylamine salt A one-pot reaction of (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol

Abstract

La présente invention concerne le domaine de la synthèse pharmaceutique, en particulier un procédé de préparation d'un dérivé d'hexahydrofurofuranol, un intermédiaire correspondant et un procédé de préparation correspondant. Le procédé de préparation utilise un composé de formule A1 en tant que matériau initial, R1 et R2 représentant des alkyles identiques ou différents, qui est différent du matériau initial rapporté par les documents de brevets actuels, et le procédé de préparation spécifique est différent de celui des documents de brevets de l'état antérieur de la technique ; cependant, le procédé de préparation permet d'obtenir la production industrielle d'un intermédiaire clé du Darunavir, le (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-alcool.
PCT/CN2015/089162 2015-09-08 2015-09-08 Procédé de préparation d'un dérivé d'hexahydrofurofuranol, intermédiaire correspondant et procédé de préparation correspondant WO2017041228A1 (fr)

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PCT/CN2015/089162 WO2017041228A1 (fr) 2015-09-08 2015-09-08 Procédé de préparation d'un dérivé d'hexahydrofurofuranol, intermédiaire correspondant et procédé de préparation correspondant
CN202010282019.5A CN111410607B (zh) 2015-09-08 2016-08-24 六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法
CN201610726487.0A CN106496263B (zh) 2015-09-08 2016-08-24 六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法

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PCT/CN2015/089162 WO2017041228A1 (fr) 2015-09-08 2015-09-08 Procédé de préparation d'un dérivé d'hexahydrofurofuranol, intermédiaire correspondant et procédé de préparation correspondant

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CN107043385B (zh) * 2016-02-05 2019-07-09 成都博腾药业有限公司 一种制备地瑞那韦中间体的方法

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