WO2021018085A1 - 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 - Google Patents

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 Download PDF

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WO2021018085A1
WO2021018085A1 PCT/CN2020/104791 CN2020104791W WO2021018085A1 WO 2021018085 A1 WO2021018085 A1 WO 2021018085A1 CN 2020104791 W CN2020104791 W CN 2020104791W WO 2021018085 A1 WO2021018085 A1 WO 2021018085A1
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formula
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刘声民
林荆鑫
郑辉
叶美其
高照波
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浙江九洲药业股份有限公司
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    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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 medical synthesis, in particular to a preparation method of hexahydrofurofuranol derivatives, its intermediates and a preparation method thereof.
  • R 1 is alkyl or arylalkyl and R 2 is alkyl or arylalkyl;
  • the present invention prepares (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol and hexahydrofuro[2,3-b]- through condensation, deprotection and cyclization reaction.
  • the report of the preparation method of 3-alcohol is basically in a blank state. The method is simple to operate, has relatively high output, and has strong applicability for industrial scale-up production. This method has brought tremendous help to both the economic benefits of drug synthesis and the operation process.
  • the method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol and -hexahydrofuro[2,3-b]-3-ol of the present invention is based on methoxy
  • the base alcohol reaction was started, and a method for preparing key intermediates for darunavir, which was different from the starting materials in the existing patent applications, was researched and developed.
  • the preparation method of the invention has low cost and mild reaction conditions, and 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 present invention provides an intermediate compound for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, the structural formula is as follows:
  • R 1 and R 2 are hydrogen or hydroxy protecting groups
  • R 3 is alkyl, acyl, ether, ester or aryl
  • X is oxygen, sulfur or nitrogen.
  • the hydroxy protecting group is alkyl, silyl, C 2-11 acyl, C 4-9 cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl, C 2-11 Ether group, C 2-11 ester group
  • the silyl group is a tetramethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a tri-n-butylsilyl group, and a tert-butyldimethylsilyl group
  • the alkyl group is a C 1 -C 8 alkyl group
  • the aryl group is a phenyl group, a furyl group, a thienyl group or an indolyl group
  • the second aspect of the present invention provides a method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol formula IV, which consists of a compound of formula II' in the presence of an acid through a ring Synthesis reaction preparation,
  • R 2 , R 3 , and X are the same as above;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid.
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the third aspect of the present invention provides a method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol formula IV.
  • the compound of the above formula II is used in acid, alkali or metal catalyst
  • the compound of formula II' is prepared by deprotection in the presence of conditions, and then prepared by cyclization of the compound of formula II' in the presence of acid,
  • R 1 , R 2 , R 3 , and X are the same as above;
  • the base in the deprotection step is an organic base or an inorganic base
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the fourth aspect of the present invention provides a method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol formula IV, which consists of a compound of formula I undergoing condensation reaction in the presence of an acid
  • the compound of formula II is prepared, and the compound of formula II is prepared by deprotection in the presence of acid or base to obtain the compound of formula II', which is then prepared by cyclization of the compound of formula II' in the presence of acid,
  • R 1 , R 2 , R 3 , and X are the same as above.
  • the organic acid in the condensation reaction step is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid, and the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, and sulfuric acid , Phosphoric acid, aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, preferably p-toluenesulfonic acid;
  • the reaction temperature of the condensation reaction step is 10-50°C, preferably 15-35°C;
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzene
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid
  • the Lewis acid is selected from Aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the fifth aspect of the present invention provides an intermediate compound of formula V of hexahydrofuro[2,3-b]-3-ol, the structural formula is as follows:
  • R 1 and R 2 are hydrogen or hydroxy protecting groups
  • R 3 is alkyl, acyl, ether, ester or aryl
  • X is oxygen, sulfur or nitrogen.
  • the hydroxy protecting group is alkyl, silyl, C 2-11 acyl, C 4-9 cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl, C 2-11 Ether group, C 2-11 ester group
  • the silyl group is a tetramethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a tri-n-butylsilyl group, and a tert-butyldimethylsilyl group
  • the alkyl group is a C 1 -C 8 alkyl group
  • the aryl group is a phenyl group, a furyl group, a thienyl group or an indolyl group
  • the sixth aspect of the present invention provides a preparation method of hexahydrofuro[2,3-b]-3-ol formula VI, which is prepared by cyclization reaction of an intermediate compound of formula V'in the presence of an acid,
  • R 2 , R 3 , and X are the same as above;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid.
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the seventh aspect of the present invention provides a method for preparing hexahydrofuro[2,3-b]-3-ol formula VI, which is prepared by deprotecting an intermediate compound of formula V under acid, alkali or metal catalyst conditions.
  • the V'compound is prepared from the compound of formula V'through a cyclization reaction in the presence of an acid,
  • R 1 , R 2 , R 3 , and X are the same as above;
  • the base in the deprotection step is an organic base or an inorganic base
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the eighth aspect of the present invention provides a method for preparing hexahydrofuro[2,3-b]-3-ol formula VI.
  • a compound of formula V is prepared by condensation reaction of a compound of formula I in the presence of an acid.
  • the compound is prepared by deprotection in the presence of acid, base or metal catalyst to obtain the compound of formula V', and then prepared from the compound of formula V'by cyclization reaction in the presence of acid,
  • R 1 , R 2 , R 3 , and X are the same as above.
  • the organic acid in the condensation reaction step is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid, and the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, and sulfuric acid , Phosphoric acid, aluminum chloride, iron chloride, boron trifluoride, niobium pentachloride, preferably p-toluenesulfonic acid;
  • the reaction temperature of the condensation reaction step is 10-50°C, preferably 15-35°C;
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzene
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid
  • the Lewis acid is selected from Aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • hexahydrofuro[2,3-b]-3-ol is prepared according to the above method, with low cost and mild reaction conditions, which provides another route suitable for industrialization for the preparation of the key intermediate of darunavir
  • the compound 30 aqueous solution was cooled by -2 to 5°C, concentrated hydrochloric acid (0.85 g, 8.5 mmol) was added, and the mixture was incubated at 0 to 5°C for about 5 to 8 hours, and sampled for GC detection. After the reaction, the pH was adjusted to 7-8 with sodium carbonate, and concentrated to dryness under reduced pressure at 50-70°C to obtain an oily substance. Add ethyl acetate and stir, filter, rinse the filter cake with ethyl acetate, and collect the filtrate. Concentrate under reduced pressure until no liquid flows out to obtain 0.95 g of oily compound 40 with a yield of 90.4% and a GC purity of 87.5%.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

本发明涉及医药合成领域，具体涉及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。该制备方法包括缩合反应、脱保护、环合反应，如式（A）所示：其中，R 1和R 2为氢或羟基保护基，R 3为烷基、酰基、醚基、酯基或芳基,X为氧、硫或氮。在六氢呋喃并呋喃醇衍生物的制备过程中，式I化合物通过缩合反应，采用这样的途径能够非常高光学纯度制备得到产物。该制备方法能商业化生产制备达芦那韦关键中间体(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇，是一条非常经济，适合于工业化生产的路线。

Description

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
本申请要求于2019年8月1日提交中国专利局、申请号为201910706770.0、发明名称为“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”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药合成领域，具体涉及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。
背景技术
具有下列式IV结构的化合物为化学名称为(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇：
Figure PCTCN2020104791-appb-000001
属于六氢呋喃并呋喃醇衍生物的一种，是抗艾滋病药物达芦那韦的中间体。
其消旋结构也属于抗艾滋病药物达芦那韦的中间体。
中国专利申请CN101541775公开了在式Ti(Hal) n(OR) 4-n的钛盐存在使用式(II)的2,3-二氢呋喃与式(III)的乙醛酸酯衍生物反应，其中n是0、1、2或3和R是烷基或芳基烷基，和随后使所得的反应产物与式(IV)的醇反应而形成式(V)的化合物：
Figure PCTCN2020104791-appb-000002
其中R 1是烷基或芳基烷基和R 2是烷基或芳基烷基；
将所得的式(V)的化合物还原而形成式(VI)的化合物；
Figure PCTCN2020104791-appb-000003
将式(VI)的化合物环化而形成式(I)的化合物；
Figure PCTCN2020104791-appb-000004
再经过手性分离得到(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇。
本发明通过缩合，再经过脱保护和环合反应制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇以及六氢呋喃并[2,3-b]-3-醇的制备方法的报道基本处于空白状态，该方法操作简单，产量相对较高，工业化放大生产适用性强。该方法无论是对于药物合成的经济效益还是操作流程都带来了的巨大的帮助。
发明内容
本发明的制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇以及-六氢呋喃并[2,3-b]-3-醇的方法从与甲氧基醇反应着手，研究开发出了不同于已有专利申请中的起始原料制备达芦那韦关键中间体的制备方法。本发明的制备方法成本低，反应条件温和，为该达芦那韦关键中间体的制备提供了另一条适合产业化的路线。
为实现本发明的技术目的，本发明提供了如下的技术方案：
本发明的第一方面提供了制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇的中间体化合物，结构式如下：
Figure PCTCN2020104791-appb-000005
其中，R 1和R 2为氢或羟基保护基，R 3为烷基、酰基、醚基、酯基或芳基；X为氧、硫或氮。所述羟基保护基为烷基，硅烷基，C 2-11的酰基，C 4-9的环烯基，芳基，芳烷基，芳酰基，苯基，取代苯基，C 2-11的醚基，C 2-11的酯基；所述硅烷基为四甲基硅烷基，三甲基硅烷基，三乙基硅烷基，三正丁基硅烷基，叔丁基二甲基硅烷基；所述烷基为C 1-C 8的烷基；所述芳基为苯基，呋喃基，噻吩基或吲哚基；所述取代苯基为烷基取代的苯基，烷氧基烷基取代的苯基，硝基烷基取代的苯基或卤素取代的苯基；所述烷基取代的苯基为苄基，二苯甲基，三苯甲基；所述烷氧基烷基取代的苯基为对甲氧基苄基；所述硝基烷基取代的苯基为对硝基苄 基；所述卤素取代的苯基为对氯苯基，所述醚基为氧醚或硫醚；所述酯基为羰基酯，硫酸酯或磷酸酯。
本发明第二方面提供了一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇式IV的制备方法，由式II’化合物在酸存在条件下经环合反应制备，
Figure PCTCN2020104791-appb-000006
其中，R 2、R 3、X的定义与上述相同；
所述环合反应步骤酸为有机酸、无机酸或路易斯酸。
所述环合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸，间硝基苯甲酸，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌，优选为盐酸；
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
本发明第三方面提供了一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇式IV的制备方法，由上述式II化合物在酸、碱或金属催化剂存在条件下脱保护制备得到式II’化合物，再由式II’化合物在酸存在条件下经环合制备得到，
Figure PCTCN2020104791-appb-000007
其中，R 1，R 2、R 3、X的定义与上述相同；
所述脱保护步骤碱为有机碱或无机碱；
所述脱保护步骤有机碱选自三乙胺、三甲胺、二异丙基乙胺、二氮杂二环、吡啶、咪唑，无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、氢氧化锂，硼氢化钠，四氢铝锂，红铝，金属催化剂选自钯试剂，镍试剂，优选为碳酸钠；
所述脱保护步骤的反应温度为10-50℃，优选为15-35℃；
所述环合反应步骤酸为有机酸、无机酸或路易斯酸；
所述环合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸、间硝基苯甲酸，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌，优选为盐酸；
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
本发明第四方面提供了一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇式IV的制备方法，由式I化合物在酸存在条件下经缩合反应制备得到式II化合物，式II化合物在酸或碱存在条件下经脱保护制备得到式II’化合物，再由式II’化合物在酸存在条件下经环合制备得到，
Figure PCTCN2020104791-appb-000008
其中，R 1，R 2、R 3、X的定义与上述相同。
所述缩合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸、间硝基苯甲酸，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，氯化铝、氯化铁、三氟化硼、五氯化铌，优选为对苯甲磺酸；
所述缩合反应步骤的反应温度为10-50℃，优选为15-35℃；
所述脱保护步骤有机碱选自三乙胺、三甲胺、二异丙基乙胺、二氮杂二环、吡啶、咪唑，无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、氢氧化锂，硼氢化钠，四氢铝锂，红铝，金属催化剂选自钯试剂，镍试剂，优选为碳酸钠；
所述脱保护步骤的反应温度为10-50℃，优选为15-35℃；
所述环合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌，优选为盐酸；
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
按照上述方法制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇，成本低，反应条件温和，为该达芦那韦关键中间体的制备提供了另一条适合产业化的路线。
本发明的第五方面提供了六氢呋喃并[2,3-b]-3-醇的中间体式V化合物，结构式如下：
Figure PCTCN2020104791-appb-000009
或其异构体。
其中，R 1和R 2为氢或羟基保护基，R 3为烷基、酰基、醚基、酯基或芳基；X为氧、硫或氮。所述羟基保护基为烷基，硅烷基，C 2-11的酰基，C 4-9的环烯基，芳基，芳烷基，芳酰基，苯基，取代苯基，C 2-11的醚基，C 2-11的酯基；所述硅烷基为四甲基硅烷基，三甲基硅烷基，三乙基硅烷基，三正丁基硅烷基，叔丁基二甲基硅烷基；所述烷基为C 1-C 8的烷基；所述芳基为苯基，呋喃基，噻吩基或吲哚基；所述取代苯基为烷基取代的苯基，烷氧基烷基取代的苯基，硝基烷基取代的苯基或卤素取代的苯基；所述烷基取代的苯基为苄基，二苯甲基，三苯甲基；所述烷氧基烷基取代的苯基为对甲氧基苄基；所述硝基烷基取代的苯基为对硝基苄基；所述卤素取代的苯基为对氯苯基，所述醚基为氧醚或硫醚；所述酯基为羰基酯，硫酸酯或磷酸酯。
本发明第六方面提供了一种六氢呋喃并[2,3-b]-3-醇式VI的制备方法，由中间体式V’化合物在酸存在条件下经环合反应制备得到，
Figure PCTCN2020104791-appb-000010
其中，R 2、R 3、X的定义与上述相同；
所述环合反应步骤酸为有机酸、无机酸或路易斯酸。
所述环合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸，间硝基苯甲酸，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌，优选为盐酸；
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
本发明第七方面提供了一种六氢呋喃并[2,3-b]-3-醇式VI的制备方法，由 中间体式V化合物在酸、碱或金属催化剂条件下经脱保护制备得到式V’化合物，再由式V’化合物在酸存在条件下经环合反应制备得到，
Figure PCTCN2020104791-appb-000011
其中，R 1，R 2、R 3、X的定义与上述相同；
所述脱保护步骤碱为有机碱或无机碱；
所述脱保护步骤有机碱选自三乙胺、三甲胺、二异丙基乙胺、二氮杂二环、吡啶、咪唑，无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、氢氧化锂，硼氢化钠，四氢铝锂，红铝，金属催化剂选自钯试剂，镍试剂，优选为碳酸钠；
所述脱保护步骤的反应温度为10-50℃，优选为15-35℃；
所述环合反应步骤酸为有机酸、无机酸或路易斯酸；
所述环合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸、间硝基苯甲酸，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌，优选为盐酸；
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
本发明第八方面提供了一种六氢呋喃并[2,3-b]-3-醇式VI的制备方法，由式I化合物在酸存在条件下经缩合反应制备得到式V化合物，式V化合物在酸、碱或金属催化剂存在条件下经脱保护制备得到式V’化合物，再由式V’化合物在酸存在条件下经环合反应制备得到，
Figure PCTCN2020104791-appb-000012
其中，R 1，R 2、R 3、X的定义与上述相同。
所述缩合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸、间硝基苯甲酸，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，氯化铝、 氯化铁、三氟化硼、五氯化铌，优选为对苯甲磺酸；
所述缩合反应步骤的反应温度为10-50℃，优选为15-35℃；
所述脱保护步骤有机碱选自三乙胺、三甲胺、二异丙基乙胺、二氮杂二环、吡啶、咪唑，无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、氢氧化锂，硼氢化钠，四氢铝锂，红铝，金属催化剂选自钯试剂，镍试剂，优选为碳酸钠；
所述脱保护步骤的反应温度为10-50℃，优选为15-35℃；
所述环合反应步骤有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯，无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌，优选为盐酸；
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
所述环合反应步骤反应温度为-10-20℃，优选为-5-15℃。
按照上述方法制备六氢呋喃并[2,3-b]-3-醇，成本低，反应条件温和，为该达芦那韦关键中间体的制备提供了另一条适合产业化的路线
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明提供的方法制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇以及-六氢呋喃并[2,3-b]-3-醇进行详细说明。需要理解的是，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。
实施例1：
Figure PCTCN2020104791-appb-000013
向干燥的四口烧瓶加入化合物I(1.0g，3.96mmol)，乙二醇甲醚4g和一水对甲苯磺酸(0.038g，0.22mmol)，于20～25℃保温搅拌，反应约1h后，取样检测，反应结束后，碳酸钠调至中性，于60-70℃减压浓缩至干，得到油状化合物II。
化合物II中加入4g甲醇和碳酸钠(0.21g，1.98mmol)，20～25℃保温反应，5～8h取样检测。反应结束后，过滤、用适量甲醇淋洗滤饼，滤液40-50℃减压、 浓缩至干，得粘稠状物。加入3ml水和甲苯1ml搅拌，静置分层，收集水层，水层为化合物III水溶液。
化合物III水溶液降温0～5℃，加入浓盐酸(0.45g，4.38mmol)，于0～5℃保温约8h，取样GC检测。反应结束后用碳酸钠调至弱碱性pH＝7-8，并于60-70℃减压浓缩干，得粘稠状物。加入乙酸乙酯搅拌、过滤、滤饼用乙酸乙酯淋洗，收集滤液。减压浓缩至无液体流出，得0.54g油状化合物IV，收率89.4％，GC纯度86.3％。
实施例2：
Figure PCTCN2020104791-appb-000014
向干燥的四口烧瓶加入化合物I’(1.3g，5.15mmol)，乙二醇甲醚5g和一水对甲苯磺酸(0.049g，0.26mmol)，25～30℃保温搅拌，反应1h后，取样检测，反应结束后，碳酸钠调至中性，开始60-70℃减压浓缩至干，得到油状化合物II’。
化合物II’中加入5g甲醇和碳酸钠(0.27g，2.55mmol)，22～28℃保温反应，10h取样检测。原料消失，停止反应，过滤、甲醇淋洗滤饼，滤液45-50℃减压、浓缩干，得粘稠油状物。加入3ml水和甲苯1ml搅拌，静置分层，收集水层，水层为化合物III’水溶液。
化合物III’水溶液降温-2～3℃，加入浓盐酸(0.58g，5.66mmol)，并于-2～3℃保温约6～9h，取样GC检测。反应结束后用碳酸钠调至弱碱性pH＝7-8，55-70℃减压浓缩干，得粘稠状物。加入乙酸乙酯搅拌、过滤、滤饼用乙酸乙酯淋洗，收集滤液。减压浓缩至无液体流出，得0.68g油状化合物IV’，收率85.6％，GC纯度88.1％。
实施例3：
Figure PCTCN2020104791-appb-000015
向干燥的四口烧瓶加入化合物10(1.8g，7.13mmol)，乙二醇甲醚7.2g和一水对甲苯磺酸(0.068g，0.36mmol)，于22～26℃保温搅拌，反应约0.5～1h，取样检测，反应结束后，碳酸钠调至中性，于60-70℃减压浓缩干，得到油状化合物20。
化合物20中加入7g甲醇和碳酸钠(0.38g，3.56mmol)，22～26℃保温反应，6～10h取样检测。反应结束后，过滤、适量甲醇淋洗，滤液40-50℃减压、浓缩至干，得粘稠状物。加入5ml和甲苯2ml搅拌，静置分层，收集水层，水层为化合物30水溶液。
化合物30水溶液降温-2～5℃，加入浓盐酸(0.85g，8.5mmol)，于0～5℃保温约5～8h，取样GC检测。反应结束后用碳酸钠调pH＝7-8，并于50-70℃减压浓缩干，得油状物。加入乙酸乙酯搅拌、过滤、滤饼用乙酸乙酯淋洗，收集滤液。减压浓缩至无液体流出，得0.95g油状化合物40，收率90.4％，GC纯度87.5％。
实施例4：
Figure PCTCN2020104791-appb-000016
向干燥的四口烧瓶加入化合物10’(1.5g，5.95mmol)，乙二醇甲醚6g和一水对甲苯磺酸(0.057g，0.3mmol)，于20～25℃保温搅拌，反应约1h后，取样检测，反应结束后，碳酸钠调至中性，开始60-70℃减压浓缩干，得到油状化合物20’。
化合物20’中加入6g甲醇和碳酸钠(0.32g，2.98mmol)，并于25～30℃保温反应，8～10h取样检测。反应结束后，过滤、甲醇淋洗，滤液40-50℃减压、浓缩至干，得油状物。加入5ml和甲苯2ml搅拌，静置分层，收集水层，水层为化 合物30’水溶液。
化合物30’水溶液降温-1～5℃，加入浓盐酸(0.67g，6.54mmol)，于0～5℃保温约8～10h。反应结束，用碳酸钠调pH＝7-8后，50-70℃减压浓缩干，得粘稠状物。加入乙酸乙酯搅拌、过滤、滤饼用乙酸乙酯淋洗，收集滤液。减压浓缩至无液体流出，得0.8g油状化合物40’，收率85.0％，GC纯度80.2％。
实施例5：
Figure PCTCN2020104791-appb-000017
向干燥的四口烧瓶加入化合物10’(1.5g，5.95mmol)，乙二醇甲醚6g和一水对甲苯磺酸(0.057g，0.3mmol)，于20～25℃保温搅拌，反应约1h后，取样检测，反应结束后，碳酸钠调至中性，开始60-70℃减压浓缩干，得到油状化合物20’。
化合物20’中加入6g甲醇和碳酸钠(0.32g，2.98mmol)，并于25～30℃保温反应，8～10h取样检测。反应结束后，过滤、甲醇淋洗，滤液40-50℃减压、浓缩至干，得油状物。加入5ml和甲苯2ml搅拌，静置分层，收集水层，水层为化合物30’水溶液。
化合物30’水溶液降温-1～5℃，加入浓盐酸(0.67g，6.54mmol)，于0～5℃保温约8～10h。反应结束，用碳酸钠调pH＝7-8后，50-70℃减压浓缩干，得粘稠状物。加入乙酸乙酯搅拌、过滤、滤饼用乙酸乙酯淋洗，收集滤液。减压浓缩至无液体流出，得0.8g油状化合物40’，收率84.0％，GC纯度80％。

Claims (14)

  1. 一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇中间体式II化合物，其特征在于，结构式如下：
    Figure PCTCN2020104791-appb-100001
    其中，R 1和R 2为氢或羟基保护基，R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫或氮。
  2. 一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇式IV的制备方法，其特征在于，由中间体式II’化合物在酸存在条件下经环合反应制备得到，
    Figure PCTCN2020104791-appb-100002
    其中，R 2为氢或羟基保护基,R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫氮，所述酸为有机酸、无机酸或路易斯酸。
  3. 一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇式IV的制备方法，其特征在于，由中间体式II化合物在酸、碱或金属催化剂条件下经脱保护制备得到式II’化合物，再由式II’化合物在酸存在条件下经环合反应制备得到，
    Figure PCTCN2020104791-appb-100003
    其中，R 1和R 2为氢或羟基保护基,R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫或氮，所述酸为有机酸、无机酸或路易斯酸，所述碱为有机碱或无机碱，所述金属催化剂为钯试剂、镍试剂。
  4. 一种(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇式IV的制备方法，其特征在于，由式I化合物在酸存在条件下经缩合反应制备得到式II化合物，式II化合物在酸、碱或金属催化剂存在条件下经脱保护制备得到式II’化合物，再由式II’化合物在酸存在条件下经环合反应制备得到，
    Figure PCTCN2020104791-appb-100004
    其中，R 1和R 2为氢或羟基保护基,R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫或氮，所述酸为有机酸、无机酸或路易斯酸，所述碱为有机碱或无机碱，所述金属催化剂为钯试剂、镍试剂。
  5. 一种六氢呋喃并[2,3-b]-3-醇中间体式V化合物，其特征在于，结构式如下：
    Figure PCTCN2020104791-appb-100005
    或其异构体。
  6. 一种六氢呋喃并[2,3-b]-3-醇式VI的制备方法，其特征在于，由中间体式V’化合物在酸存在条件下经环合反应制备得到，
    Figure PCTCN2020104791-appb-100006
    其中，R 2为氢或羟基保护基,R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫氮，所述酸为有机酸、无机酸或路易斯酸。
  7. 一种六氢呋喃并[2,3-b]-3-醇式VI的制备方法，其特征在于，由中间体式V化合物在酸、碱或金属催化剂条件下经脱保护制备得到式V’化合物，再由式V’化合物在酸存在条件下经环合反应制备得到，
    Figure PCTCN2020104791-appb-100007
    其中，R 1和R 2为氢或羟基保护基,R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫或氮，所述酸为有机酸、无机酸或路易斯酸，所述碱为有机碱或无机碱，所述金属催化剂为钯试剂、镍试剂。
  8. 一种六氢呋喃并[2,3-b]-3-醇式VI的制备方法，其特征在于，由式I化合物在酸存在条件下经缩合反应制备得到式V化合物，式V化合物在酸、碱或金属催化剂存在条件下经脱保护制备得到式V’化合物，再由式V’化合物在酸存在条件下经环合反应制备得到，
    Figure PCTCN2020104791-appb-100008
    其中，R 1和R 2为氢或羟基保护基,R 3为烷基、酰基、醚基、酯基或芳基，X为氧、硫或氮，所述酸为有机酸、无机酸或路易斯酸，所述碱为有机碱或无机碱，所述金属催化剂为钯试剂、镍试剂。
  9. 根据权利要求1-8所述的化合物，其特征在于，所述羟基保护基为烷基，硅烷基，C 2-11的酰基，C 4-9的环烯基，芳基，芳烷基，芳酰基，苯基，取代苯基，C 2-11的醚基，C 2-11的酯基；所述硅烷基为四甲基硅烷基，三甲基硅烷基，三乙基硅烷基，三正丁基硅烷基，叔丁基二甲基硅烷基；所述烷基为C 1-C 8的烷基；所述芳基为苯基，呋喃基，噻吩基或吲哚基；所述取代苯基为烷基取代的苯基，烷氧基烷基取代的苯基，硝基烷基取代的苯基或卤素取代的苯基；所述烷基取代的苯基为苄基，二苯甲基，三苯甲基；所述烷氧基烷基取代的苯基为对甲氧基苄基；所述硝基烷基取代的苯基为对硝基苄基；所述卤素取代的苯基为对氯苯基；所述醚基为氧醚或硫醚；所述酯基为羰基酯，硫酸酯或磷酸酯。
  10. 根据权利要求2、3、4、6、7、8所述的方法，其特征在于，所述有机酸选自对苯甲磺酸、二氯乙酸、二溴乙酸、间硝基苯磺酸，间硝基苯甲酸，所述无机酸选自亚硝酸、氢氟酸、盐酸、硫酸、磷酸，路易斯酸选自氯化铝、氯化铁、三氟化硼、五氯化铌。
  11. 根据权利要求3、4、7、8所述的方法，其特征在于，所述无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠、氢氧化锂，硼氢化钠，四氢铝锂，红铝，所述有机碱选自三乙胺、三甲胺、二异丙基乙胺、二氮杂二环、吡啶、咪唑，所述金属试剂选自钯试剂、镍试剂。
  12. 根据权利要求2、3、4、6、7、8、所述的方法，其特征在于，环合反应步骤反应温度为-10-20℃。
  13. 根据权利要求3、4、7、8、9所述的方法，其特征在于，脱保护步骤反应温度为10-50℃。
  14. 根据权利要求4、8所述的方法，其特征在于，缩合反应步骤反应温度为10-50℃。
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