WO2016045586A1 - 苯并恶唑并恶嗪酮类化合物的制备方法及其中间体和晶型 - Google Patents

苯并恶唑并恶嗪酮类化合物的制备方法及其中间体和晶型 Download PDF

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WO2016045586A1
WO2016045586A1 PCT/CN2015/090334 CN2015090334W WO2016045586A1 WO 2016045586 A1 WO2016045586 A1 WO 2016045586A1 CN 2015090334 W CN2015090334 W CN 2015090334W WO 2016045586 A1 WO2016045586 A1 WO 2016045586A1
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compound
solvent
reaction
group
sodium
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PCT/CN2015/090334
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English (en)
French (fr)
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陈曙辉
丁照中
龚刚立
颜小兵
黄巍
郭峰
段宝玲
高任龙
周平凡
路新华
董桂敏
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华北制药集团新药研究开发有限责任公司
南京明德新药研发股份有限公司
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Priority to CA2962474A priority Critical patent/CA2962474C/en
Priority to EP15845449.6A priority patent/EP3199536B1/en
Priority to US15/514,326 priority patent/US10106557B2/en
Priority to KR1020177011042A priority patent/KR102485412B1/ko
Priority to AU2015320137A priority patent/AU2015320137B2/en
Priority to JP2017535952A priority patent/JP6568221B2/ja
Publication of WO2016045586A1 publication Critical patent/WO2016045586A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • 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 present invention relates to a process for preparing a high-purity benzoxazoleoxazinone compound and a crystal form thereof, and to an intermediate compound for preparing a compound of the formula (I) and a process for the preparation thereof.
  • CN21310456006.5 describes a new class of oral Xa inhibitors for the prevention of postoperative deep vein thrombosis (DVT) and pulmonary embolism (PE), prevention of stroke during atrial fibrillation, and treatment of acute coronary syndrome (ACS) ). Its structure is as shown in formula (B-1):
  • the present invention provides a process for the preparation of a compound of formula (I),
  • R is an amino protecting group
  • X is F, Cl, Br or I
  • the above R is selected from the group consisting of an alkoxycarbonyl-based amino protecting group.
  • R is selected from the group consisting of Cbz, Boc, Fmoc, Alloc, Teco, methoxycarbonyl or ethoxycarbonyl.
  • R 2 is selected from the group consisting of
  • the base is selected from the group consisting of an alkali metal base, an alkaline earth metal base, or an organometallic base.
  • the alkali metal base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, and/or potassium hydrogencarbonate.
  • the alkaline earth metal base is selected from the group consisting of sodium hydride, potassium hydride, and/or calcium hydride.
  • the organometallic base is selected from the group consisting of sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, and/or aluminum isopropoxide.
  • the molar ratio of the compound (IV) to the base is from 1:1 to 5, specifically from 1:2 to 3.
  • the molar ratio of the above compound (III) to the compound (IV) is 1:1 to 2.
  • the reaction temperature of the above reaction is from -10 to 50 °C.
  • the reaction temperature of the above reaction is from 0 to 30 °C.
  • the reaction time of the above reaction is from 5 to 200 hours.
  • the reaction time of the above reaction is from 10 to 100 hours.
  • the reaction time for the above reaction is from 16 to 48 hours.
  • the above reaction is carried out in a reaction solvent selected from the group consisting of an amide solvent, an ether solvent, or any mixture thereof.
  • the amount of the above reaction solvent is from 10 to 50 times the weight of the compound (IV).
  • the amount of the above reaction solvent is 15 to 20 times the weight of the compound (IV).
  • the amide solvent is selected from the group consisting of DMF or DMAC.
  • the ether solvent is selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dioxane or methyl tert-butyl ether.
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the HA is selected from the group consisting of organic or inorganic acids.
  • the HA is selected from the group consisting of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, maleic acid or fumaric acid.
  • the above compound (i) can be prepared by reacting the compound (II) with a reducing agent, wherein:
  • the reducing agent is preferably an alkali metal hydride
  • the alkali metal hydride is preferably sodium borohydride, sodium triacetylborohydride, sodium cyanoborohydride, red aluminum and/or lithium aluminum hydride;
  • the molar ratio of the compound (II) to the reducing agent is preferably 1:1 to 5;
  • reaction is carried out in a reaction solvent, preferably a single organic solvent or a mixed organic solvent;
  • the organic solvent is preferably methanol, ethanol, tetrahydrofuran and/or dichloromethane;
  • the solvent is used in an amount of 5 to 20 times the weight of the compound (II);
  • the reaction temperature of the reaction is -10 to 50 ° C;
  • the reaction temperature of the reaction is 0 to 30 ° C;
  • the reaction time of the reaction is 2 to 30 hours;
  • the reaction time of the reaction is 8 to 16 hours.
  • the above compound (j) can be obtained by reacting the above compound (i) with methanesulfonyl chloride in the presence of a base, wherein:
  • the base is preferably an alkali metal base, an alkaline earth metal base, an organometallic base and/or an organic base;
  • the alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
  • the alkaline earth metal base is preferably sodium hydride, potassium hydride and/or calcium hydride;
  • the organometallic base is preferably sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide and/or aluminum isopropoxide;
  • the organic base is preferably diethylamine, triethylamine, DIEA, pyridine, DMAP and/or DBU;
  • the molar ratio of the compound (i) to the base is preferably 1:1 to 5;
  • the molar ratio of the compound (i) to the methanesulfonyl chloride is preferably 1:1 to 2;
  • reaction is carried out in a reaction solvent, preferably an aprotic organic solvent;
  • the organic solvent is preferably benzene, toluene, dioxane, dichloromethane, tetrahydrofuran and/or methyltetrahydrofuran;
  • the solvent is used in an amount of 5 to 20 times the weight of the compound (i);
  • the reaction temperature of the reaction is -20 to 50 ° C;
  • the reaction temperature of the reaction is preferably -5 to 15 ° C;
  • the reaction time of the reaction is 2 to 30 hours;
  • the reaction time of the reaction is 8 to 16 hours.
  • the above compound (k) can be obtained by reacting the above compound (j) with a potassium salt of phthalimide or by reacting the above compound (j) with phthalimide in a base.
  • a potassium salt of phthalimide or by reacting the above compound (j) with phthalimide in a base.
  • the base is preferably an alkali metal base, an alkaline earth metal base, an organometallic base, and an organic base;
  • the alkali metal base is lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
  • the alkaline earth metal base is sodium hydride, potassium hydride and/or calcium hydride;
  • the organometallic base is sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide and/or aluminum isopropoxide;
  • the molar ratio of the compound (j) to the base is preferably 1:1 to 5;
  • reaction is carried out in a reaction solvent, preferably an aprotic organic solvent;
  • the organic solvent is benzene, toluene, dioxane, tetrahydrofuran, DMF, DMSO and/or NMP;
  • the solvent is used in an amount of 5 to 20 times the weight of the above compound (i);
  • the reaction temperature of the reaction is 0 to 100 ° C;
  • the reaction temperature of the reaction is 20 to 80 ° C;
  • the reaction time of the reaction is 2 to 30 hours;
  • the reaction time of the reaction is 8 to 16 hours.
  • the above compound (II) can be used to prepare the compound (V),
  • the above compound (V) can be obtained by reacting the above compound (j) with a base, followed by addition of an acid salt;
  • the base is preferably an alkali metal base or an organic base
  • the alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
  • the organic base is preferably a hydrazine hydrate, an aqueous ammonia solution, an aqueous methylamine solution and/or a methylamine alcohol solution;
  • the acid is preferably a mineral acid or an organic acid
  • the inorganic acid is preferably hydrochloric acid or sulfuric acid
  • the organic acid is preferably oxalic acid, citric acid, maleic acid and/or fumaric acid;
  • the molar ratio of the compound (j) to the base is preferably 1:2 to 10;
  • the molar ratio of the compound (j) to the acid is preferably 1:2 to 10;
  • reaction is carried out in a reaction solvent, preferably a water or a protic organic solvent;
  • the organic solvent is preferably methanol, ethanol and/or isopropanol
  • the solvent is used in an amount of 5 to 20 times the weight of the above compound (i);
  • the reaction temperature of the reaction is 0 to 100 ° C;
  • the reaction temperature of the reaction is 20 to 80 ° C;
  • the reaction time of the reaction is 2 to 30 hours.
  • the above compound 1 can be obtained by reacting the above compound (V) with 5-chlorothiophene-2-carbonyl chloride in the presence of a base, wherein:
  • the molar ratio of the compound (V) to the base is preferably 1:1 to 3;
  • the molar ratio of the compound (V) to 5-chlorothiophene-2-carbonyl chloride is preferably 1:1 to 2;
  • reaction solvent which is preferably a mixed solvent of water and an organic solvent
  • the organic solvent is preferably an ether or aromatic solvent
  • the ether solvent is preferably tetrahydrofuran or methyltetrahydrofuran
  • the aromatic hydrocarbon solvent is preferably benzene, toluene, chlorobenzene or bromobenzene;
  • the volume ratio of the water to the organic solvent is 1:1 to 2;
  • the solvent is used in an amount of 5 to 20 times the weight of the above compound (V);
  • the reaction temperature of the reaction is 0 to 40 ° C, preferably 10 to 30 ° C;
  • the reaction time of the reaction is 5 to 30 hours.
  • 5-Chlorothiophene-2-carbonyl chloride can be prepared by the method disclosed in Example 1 of US Patent No. 2007149522, filed by Bayer Healthcare AG, in particular: 5-chlorothiophene-2- at 80 ° C Thionyl chloride is added to the toluene solution of formic acid, stirred for 2 to 3 hours, and concentrated to obtain the above 5-chlorothiophene-2-carbonyl chloride.
  • Compound (III') can be produced according to the following synthetic route
  • the compound (III') can also be produced from the above compound (g) by the method of Synthesis, (1), 178-183;
  • the compound (g) can be produced from the above compound (f) or the above compound (h) according to the method in Indian Patent Publication No. 2006MU00055, or the compound (g) can also be produced according to the following synthetic route.
  • Compound (f) can be prepared from the natural product isoascorbic acid according to the method in Organic Process Research & Development, 16(5), 1003-1012;
  • Compound (h) can be prepared from the natural product D-arabinose by the method of patent WO2001002020.
  • the present invention also provides an intermediate for preparing the compound (I), which has the following structure:
  • the R is an amino protecting group
  • the R is selected from an alkoxycarbonyl-based amino protecting group
  • the R is selected from the group consisting of Cbz, Boc, Fmoc, Alloc, Teco, methoxycarbonyl or ethoxycarbonyl;
  • the R 2 is selected from
  • the HA is selected from an organic or inorganic acid
  • the HA is selected from the group consisting of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, maleic acid or fumaric acid.
  • the invention also provides a preparation method of the intermediate (IV), which comprises the following reaction:
  • the preparation method of the above intermediate (IV) further comprises the following reaction:
  • the preparation method of the above intermediate (IV) further comprises the following reaction:
  • the preparation method of the above intermediate (IV) further comprises the following reaction:
  • the preparation method of the above intermediate (IV) further comprises the following reaction:
  • the compound (a) in the preparation method of the above intermediate (IV), can be obtained by reacting 2,4-difluoronitrobenzene with potassium t-butoxide, wherein:
  • the molar ratio of the 2,4-difluoronitrobenzene to potassium t-butoxide is preferably 1:1 to 3;
  • reaction is carried out in a reaction solvent, which is an organic solvent
  • the organic solvent is preferably an ether solvent or an aromatic hydrocarbon solvent
  • the ether solvent is preferably tetrahydrofuran or methyltetrahydrofuran
  • the aromatic hydrocarbon solvent is preferably benzene, toluene, chlorobenzene or bromobenzene;
  • the solvent is used in an amount of 5 to 20 times the weight of the above 2,4-difluoronitrobenzene;
  • the reaction temperature of the reaction is 0 to 40 ° C;
  • the reaction temperature of the reaction is 10 to 30 ° C;
  • the reaction time of the reaction is 1 to 30 hours;
  • the reaction time of the reaction is 3 to 8 hours.
  • the above compound (b) can be obtained by reacting the above compound (a) with R 2 -H in the presence of a base, wherein:
  • the base is selected from the group consisting of an alkali metal base, an alkaline earth metal base or an organometallic base;
  • the alkali metal base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
  • the alkaline earth metal base is selected from the group consisting of sodium hydride, potassium hydride and/or calcium hydride;
  • the organometallic base is selected from the group consisting of sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide and/or aluminum isopropoxide;
  • the molar ratio of the compound (a) to the base is 1:1 to 3;
  • the molar ratio of the compound (a) to R 2 -H is 1:1 to 2;
  • reaction is carried out in a reaction solvent selected from the group consisting of a mixed solvent of a nonpolar solvent and a polar solvent;
  • the non-polar solvent is selected from the group consisting of benzene, toluene, xylene chlorobenzene and/or bromobenzene;
  • the polar solvent is selected from the group consisting of DMF, DMSO or NMP;
  • the volume ratio of the non-polar solvent to the polar solvent is 1:0.5 to 2;
  • the solvent is used in an amount of from 5 to 20 times the weight of the compound (a).
  • the above compound (c) can be produced by reacting the above compound (b) with an acid, wherein:
  • the acid is preferably a mineral acid or an organic acid
  • the inorganic acid is preferably hydrochloric acid, sulfuric acid and/or nitric acid;
  • the organic acid is preferably trifluoroacetic acid, methanesulfonic acid and/or p-toluenesulfonic acid;
  • the molar ratio of the compound (b) to the acid is 1:5 to 30;
  • reaction is carried out in a reaction solvent, preferably water or an organic solvent;
  • the organic solvent is preferably ethyl acetate, methanol and/or dioxane;
  • the solvent is used in an amount of 5 to 20 times the weight of the compound (b);
  • the reaction temperature of the reaction is 0 to 50 ° C, preferably 10 to 30 ° C;
  • the reaction time of the reaction is 2 to 30 hours, preferably 2 to 8 hours.
  • the above compound (d) can be produced by reacting the above compound (c) with a hydrogenation reducing reagent/system, wherein:
  • the hydrogenated reducing agent/system is preferably a heavy metal catalytic hydrogenation system and a reducing metal;
  • the heavy metal catalytic hydrogenation system preferably uses dry palladium carbon, wet palladium carbon, Raney nickel or palladium hydroxide as a catalyst, and hydrogen as a reducing agent;
  • the reducing metal is preferably iron powder or zinc powder
  • the weight ratio of the compound (c) to the heavy metal is preferably 100: (2 to 30);
  • reaction is carried out in a reaction solvent, preferably a single organic solvent or a mixed organic solvent;
  • the organic solvent is preferably ethyl acetate, methanol, ethanol, tetrahydrofuran and/or DMF;
  • the solvent is used in an amount of 5 to 200 times the weight of the compound (d);
  • the reaction temperature of the reaction is 0 to 50 ° C, preferably 20 to 40 ° C;
  • the reaction time of the reaction is 2 to 30 hours, preferably 8 to 16 hours.
  • the compound (IV) can be prepared by reacting the compound (d) with a common amino protecting reagent in the presence of a base;
  • the amino protecting reagent is preferably selected from an alkoxycarbonyl amino protecting reagent
  • the amino protecting agent is selected from the group consisting of CbzCl, (Boc) 2 O, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, ethyl chloroformate, methyl chloroformate, fluorenylmethoxycarbonyl chloride, and armor.
  • the base is preferably an alkali metal base, an alkaline earth metal base, and an organometallic base;
  • the alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
  • the alkaline earth metal base is preferably sodium hydride, potassium hydride and/or calcium hydride;
  • the organometallic base is preferably sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide and/or aluminum isopropoxide.
  • the molar ratio of the compound (d) to the base is preferably 1:1 to 3;
  • the molar ratio of the compound (d) to the amino protecting agent is preferably 1:1 to 2;
  • reaction solvent which is preferably a mixed solvent of water and an organic solvent
  • the organic solvent is preferably benzene, toluene, dioxane, tetrahydrofuran and/or methyltetrahydrofuran;
  • the volume ratio of the water to the organic solvent is 1:0.5 to 2;
  • the solvent is used in an amount of 5 to 20 times the weight of the compound (d);
  • the reaction temperature of the reaction is -20 to 50 ° C, preferably -5 to 15 ° C;
  • the reaction time of the reaction is 2 to 30 hours.
  • compound (e) can be prepared by reacting compound (b) above with a hydrogenating reducing agent/system, wherein:
  • the hydrogenation reducing reagent/system is preferably a heavy metal catalytic hydrogenation system and/or a reducing metal;
  • the heavy metal catalytic hydrogenation system preferably uses dry palladium carbon, wet palladium carbon, Raney nickel and/or palladium hydroxide as a catalyst, and hydrogen as a reducing agent;
  • the reducing metal is preferably iron powder and/or zinc powder
  • the weight ratio of the compound (b) to the heavy metal is preferably from 100:2 to 30;
  • reaction is carried out in a reaction solvent, preferably a single organic solvent or a mixed organic solvent;
  • the organic solvent is preferably ethyl acetate, methanol, ethanol, tetrahydrofuran and/or DMF;
  • the solvent is used in an amount of 5 to 200 times the weight of the compound (b);
  • the reaction temperature of the reaction is 0 to 50 ° C, preferably 20 to 40 ° C;
  • the reaction time of the reaction is 2 to 30 hours, preferably 4 to 8 hours.
  • the method for producing the compound (IV) by reacting the compound (e) with an amino protecting agent can be referred to the method for producing the compound (IV) from the compound (d).
  • the present invention also provides two stable and promising crystalline forms of Compound 1, Form A and Form B, the structure of which is shown in Figures 1 and 2.
  • the present invention also provides a method for preparing Form A of Form 1 and Form B of Compound 1, comprising adding Compound 1 of any form to a solvent. Crystallize and produce different forms of crystal form, of which:
  • the solvent is preferably an organic solvent or a mixed solvent containing an alcohol solvent or water;
  • the organic solvent is preferably an alcohol or a ketone
  • the alcohol is preferably methanol, ethanol, isopropanol and/or n-butanol;
  • the ketone is preferably acetone and/or methyl ethyl ketone
  • the mixed solvent is preferably a mixed solvent of DMSO and ethanol or DMSO and water;
  • the volume ratio of the DMSO to ethanol or water is 1:0.5-5;
  • the solvent is used in an amount of from 3 to 50 times the weight of the compound 1.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • DCM dichloromethane
  • PE petroleum ether
  • EA ethyl acetate
  • Pd/C palladium carbon
  • DMF stands for N,N-dimethylformamide
  • DMAC stands for N, N - dimethylacetamide
  • DMSO dimethyl sulfoxide
  • EtOAc for ethyl acetate
  • EtOH for ethanol
  • MeOH for methanol
  • Cbz for benzyloxycarbonyl, an amine protecting group
  • Boc for tert-butylcarbonyl Amine protecting group
  • Fmoc represents fluorenylmethoxycarbonyl, an amine protecting group
  • Alloc represents an allyloxycarbonyl group, an amine protecting group
  • Teoc represents trimethylsilyloxycarbonyl, an amine Protecting group
  • HOAc stands for acetic acid
  • rt stands for room temperature
  • O/N stands for overnight
  • THF stands for tetrahydrofur
  • the invention provides the process for synthesizing the compound of the formula (I) and the intermediate thereof, and has the beneficial effects of overcoming the disadvantages of high cost of the starting materials in the prior art, large toxicity of the reagents used, harsh reaction conditions, difficulty in separation and purification, and difficulty in industrialization. .
  • the method for preparing the compound of the formula (I) of the present invention is a conventional or common reagent, which is readily available on the market and is inexpensive;
  • the intermediate compound (II) can be obtained by a one-step reaction between the new intermediate compound (IV) and the known intermediate compound (III), which effectively increases the reaction yield;
  • the reagents used in the reaction of each step are small molecules and easy to be purified.
  • the present invention has high industrial application value and economic value in the preparation of the compound of the formula (I) and its intermediate.
  • Form A is an XRPD spectrum of Form A crystal form Cu-K ⁇ radiation of Compound 1, wherein Form A is obtained by crystallizing a compound 1 in ethanol.
  • Figure 3 is a DSC chart of Form A of Compound 1.
  • PE: EA 1:1
  • Step 4 Synthesis of benzyl (2-hydroxy-4-(3-morphinolinone)phenyl)carbamate
  • Step 7 Synthesis of benzyl (2-hydroxy-4-(3-morphinolinone)phenyl)carbamate
  • Potassium hydroxide (1.12 kg, 19.98 mol) was slowly added to a mixed solvent of methanol (10 liters) and water (2.4 liters) under ice-water bath conditions, and the temperature was controlled to not exceed 45 °C.
  • oxygen is introduced into the reaction solution, and the reaction solution is lowered to 35 ° C, and an aqueous solution of D-(-)-arabinose (1 kg, 6.66 mol, dissolved in 2.4 liters of water) is added dropwise, and the mixture is added dropwise for more than 6 hours. (The entire process is kept open to oxygen) and the reaction temperature is maintained at 35 degrees.
  • the oxygen was continuously supplied for 2 hours, and then the air was introduced for 60 hours.
  • Isoascorbic acid (17.6 g, 0.1 mol) was dissolved in 250 ml of water and cooled to 0-6 °C.
  • Anhydrous sodium carbonate powder (21.2 g, 0.2 mol) was added portionwise to the reaction flask. After the end of the addition, stirring was continued while adding 30% hydrogen peroxide (22 mL), the internal temperature was raised from 6 ° C to 19 ° C, stirring was continued for 5 minutes in an ice bath, and the internal temperature was raised to 27 ° C.
  • the reaction solution was heated to 42 ° C and stirred for 30 minutes.
  • Zinc powder (1.0 g, 0.015 mol) was added to the reaction solution to quench excess hydrogen peroxide, and the starch iodide test paper showed negative.
  • the reaction solution was adjusted to pH 1.0 with 6N hydrochloric acid. At least a white solid was precipitated under reduced pressure at 50 °C. Extract with ethyl acetate (150 ml x 3). The organic phase was concentrated to 200 ml (10-15 vol); the temperature was lowered to 15-25 ° C, stirred for 5-8 hours; (a large amount of white solid precipitated) was filtered and dried to give 8.26 g (3R, 4R)-3, 4- Hydroxydihydrofuran-2(3H)-one, yield 70%.
  • Step 12 Synthesis of (2S,3R)-2,4-dibromo-3-hydroxybutanoic acid methyl ester
  • Step 13 (3R,3aS)-Methyl-1-keto-7-(3-ketomorpholine)-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d Synthesis of [1,4]oxazine-3-carboxylic acid to benzyl (2-hydroxy-4-(3-morphinolinone)phenyl)carbamate (68.5 g, 0.20 mol) with stirring at 0 °C (2S,3R)-2,4-dibromo-3-hydroxybutyric acid methyl ester (46.8 g, 0.24 mol), cesium carbonate (130.3 g, 0.40 mol) was added in one portion in a solution of DMF (700 mL).
  • reaction solution was stirred at 0 ° C for 10 hours. After the benzyl (2-hydroxy-4-(3-morphinolinone)phenyl)carbamate was completely removed, cesium carbonate (65.2 g, 0.20 mol) was continuously added at 0 °C. The reaction solution was gradually warmed to room temperature, and the reaction was stirred for 12 hours. The reaction mixture was cooled to 0 ° C, methanol (700 mL) was added and pH 1 was adjusted with 4N HCl / methanol. Thionyl chloride (58 mL, 0.80 mol) was slowly added dropwise at 0 ° C, and the addition was completed in about 1 hour.
  • reaction was further stirred at 0 ° C for 1 hour, and then gradually warmed to room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 40 ° C to remove methanol. After the remaining reaction mixture was cooled, it was added to a cold aqueous hydrochloric acid solution of pH 2.
  • Step 14 (3R,3aS)-3-(hydroxymethyl)-7-(3-ketomorpholine)-3a,4-dihydrobenzo[b]oxazole[3,4-d][1 , 4] Synthesis of oxazine-1(3H)-one to (3R,3aS)-methyl-1-keto-7-(3-ketomorpholine)-1,3,3a, stirring at 0 °C 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-3-carboxylic acid (38.3 g, 0.11 mol) in methanol/dichloromethane (660 mL, 2: 1) In a suspension, sodium borohydride (5.0 g, 0.13 mol) was added in portions and the addition was completed in about 40 minutes.
  • sodium borohydride 5.0 g, 0.13 mol
  • the reaction was stirred at 0 ° C for 20 minutes.
  • the reaction solution was warmed to room temperature, and the solvent was evaporated to dryness.
  • the crude product was slurried in water (40 mL) for 10 min, filtered, washed with water (20 mL) and dried in vacuo.
  • the aqueous phase was extracted with methanol / dichloromethane (1: 10), dried over anhydrous sodium sulfate and evaporated.
  • Step 15 ((3R,3aS)-1-one-7-(3-ketomorpholine)-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d][ Synthesis of 1,4]oxazin-3-yl)methanesulfonate
  • Step 16 2-(((3S,3aS)-1-one-7-(3-ketomorpholine)-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4- Synthesis of d][1,4]oxazin-3-yl)methyl)isoindole-1,3-dione
  • Step 17 (3S,3aS)-3-(aminomethyl)-7-(3-ketomorpholine))-3a,4-dihydrobenzo[b]oxazole[3,4-d][ 1,4] Synthesis of oxazine-1(3H)-one
  • MeOH 100 mL
  • 40% aqueous solution of methylamine (10.5mL, 135mmol)
  • reaction liquid was cooled to room temperature, and the reaction liquid was adjusted to pH 1 with a HCl-MeOH solution (12 mL, 12 M), and stirred for 1 hour to sufficiently form a salt.
  • the reaction solution was concentrated to remove a portion of methanol (about 50 mL) at 40 ° C to give a slurry.
  • methanol/dichloromethane 60 mL, 1:5 was added, and the mixture was beaten for 16 hours. After filtration, the filter cake was washed twice with MeOH (10 mL) and dried to give the desired hydrochloride salt (white solid, 7.0 g, yield 87%, purity 98%).
  • Step 18 5-Chloro-N-(((3S,3aS)-1-one-7-(3-ketomorpholine)-1,3,3a,4-tetrahydrobenzo[b]oxazole[ Synthesis of 3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide
  • Step 19 5-Chloro-N-(((3S,3aS)-1-one-7-(3-ketomorpholine)-1,3,3a,4-tetrahydrobenzo[b]oxazole[ Recrystallization of 3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (Form A)
  • step 18 2.8 g of the crude solid in step 18 was heated with 90 mL of ethanol to 70 ° C for 30 minutes, then cooled to room temperature and stirred for 16 hours.
  • the solid collected by filtration was 2.4 g, HPLC purity was 98.3%, yield 86%.
  • Step 20 5-Chloro-N-(((3S,3aS)-1-one-7-(3-ketomorpholine)-1,3,3a,4-tetrahydrobenzo[b]oxazole[ Recrystallization of 3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (Form B)
  • Example 7 For the preparation of Compound 7, reference is made to Example 1, in which the morpholin-3-one in Step 2 is replaced with a tetrahydropyrimidin-2(1H)-one.
  • Example 2 For the preparation of the compound 30, refer to Example 1, in which the morpholin-3-one in the step 2 was replaced with (R)-2-(methoxymethyl)pyrrolidine.
  • test compounds evaluated for their ability to inhibit human factor or other enzymes or Xa rats such as thrombin or trypsin, wherein the constant K i IC 50 values associated with inhibition.
  • Purified enzymes were used in the chromogenic assay. The initial rate of hydrolysis of the chromogenic substrate was measured using a FlexStation III (American Molecular Instruments Inc.) to determine the change in absorbance at 405 nm in the linear portion of the time course at 37 ° C (usually after 2 to 10 minutes of substrate addition).
  • the concentration of the inhibitor which caused a 50% decrease in the rate of substrate hydrolysis was determined by linear regression calculation by plotting the logarithmic curve of the relative speed of the hydrolysis (compared to the uninhibited control) to the concentration of the test compound.
  • IC 50 values of the test compound obtained by GraphPad Prism software. The curve was fitted using a "form dose effect (variable slope)".
  • the inhibition of coagulation factor Xa activity in human or rat was determined using Tris-HCl buffer (50 mM, pH 8.3, 150 mM NaCl). Add 50 ⁇ L of human coagulation factor Xa (Enzyme Research Laboratories, Inc; final concentration of 8.36 nM) or 50 ⁇ L of rat coagulation factor Xa (Enzyme Research Laboratories, Inc; final concentration of 57.5 nM) to Greiner 384 microtiter titration The IC50 was determined by the method in a suitable well of the plate .
  • the test compound having K i ⁇ 10 ⁇ M is considered to be positive, and a compound of K i ⁇ 1 ⁇ M is preferred in the present invention, more preferably a compound having a K i ⁇ 0.1 ⁇ M, more preferably a compound having a K i ⁇ 0.01 ⁇ M, further preferably K i ⁇ 0.001 ⁇ M compound.
  • K i ⁇ 0.1 ⁇ M thus compounds of the invention may be used as an effective inhibitor of factor Xa.
  • the inhibition of human thrombin activity was measured using a buffer (10 mM HEPES buffer, pH 7.4, 2 mM CaCl 2 ).
  • the appropriate wells in the Greiner 384 microtiter plate were selected for IC50 , buffer containing 50 ⁇ L of human thrombin (Sigma; T8885) at a final concentration of 0.05 NIH units/mL, assay buffer containing 2 ⁇ L of 2% (V/V) DMSO.
  • test compound Liquid (uninhibited control) or various concentrations of test compound diluted in assay buffer containing 2% (v/v) DMSO; added with 48 ⁇ L of substrate S-2238 (Chromogenix; chemical formula: HD-Phe -Pip-Arg-pNA ⁇ 2HCl) buffer at a final concentration of 30 ⁇ M.
  • substrate S-2238 Chromogenix; chemical formula: HD-Phe -Pip-Arg-pNA ⁇ 2HCl
  • the inhibition of human trypsin activity was measured using a buffer (50 mM Tris, pH 8.2, and 20 mM CaCl 2 ).
  • the appropriate wells in the Greiner 384 microtiter plate were assayed for IC50 , containing 50 ⁇ L of human trypsin (Sigma; T6424) buffer at a final concentration of 0.39 BAEE units/mL, containing 2 ⁇ L of 2% (V/V) DMSO.
  • the test compound was preincubated with the enzyme for 10 minutes, and then 48 ⁇ L of the substrate was added to obtain a final volume of 100 ⁇ L to start the test.
  • the activity of the test compound against prothrombinase is measured by the production of thrombin. Briefly, 12.5 ⁇ L of human factor Xa was incubated in 10 mM HEPES buffer and pH 7.4, 2 mM CaCl 2 to a final concentration of 0.5 nM, and 12.5 ⁇ L of human platelets (1 ⁇ 10 7 mL -1 ) was added at 37 ° C. minute. 25 ⁇ L of prothrombin was added to start the reaction at a final concentration of 0.5 ⁇ M, assay buffer containing 2 ⁇ L of 2% (V/V) DMSO (uninhibited control) or various concentrations of the test compound diluted to 2%. (V/V) DMSO in assay buffer. After 20 minutes, 48 ⁇ L of substrate S-2238 (Chromogenix) was added to a final concentration of 50 ⁇ M to determine thrombin activity.
  • substrate S-2238 Chromogenix
  • the compounds of the present invention exhibit potent anticoagulant activity through their specific anticoagulant factor Xa activity.

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Abstract

一种高纯度苯并恶唑并恶嗪酮类化合物的制备方法、晶型，以及制备式(Ⅰ)化合物的中间体化合物及其制备方法。

Description

苯并恶唑并恶嗪酮类化合物的制备方法及其中间体和晶型 技术领域
本发明涉及一种高纯度苯并恶唑并恶嗪酮类化合物的制备方法及晶型，本发明还涉及制备式(Ⅰ)化合物的中间体化合物及其制备方法。
背景技术
CN21310456006.5记载了一类全新的口服Xa因子抑制剂，用于预防术后深静脉血栓形成(DVT)和肺栓塞(PE)，预防在心房颤动时的中风，治疗急性冠脉综合征(ACS)。其结构如式(B-1)所示：
Figure PCTCN2015090334-appb-000001
发明内容
本发明提供了式(Ⅰ)化合物的制备方法，
Figure PCTCN2015090334-appb-000002
其包含如下步骤：
Figure PCTCN2015090334-appb-000003
其中，R为氨基保护基；
X为F、Cl、Br或I；
R2选自任选被取代的5或6元环氨基或杂环氨基，“杂”代表O、N、C(＝O)、C(＝O)NH，取代基独立地选自C1-4烷基或杂烷基。
本发明的一些方案中，上述R选自烷氧羰基类氨基保护基。
本发明的一些方案中，上述R选自Cbz、Boc、Fmoc、Alloc、Teco、甲氧羰基或乙氧羰基。
本发明的一些方案中，上述R2选自：
Figure PCTCN2015090334-appb-000004
Figure PCTCN2015090334-appb-000005
本发明的一些方案中，上述碱选自碱金属碱、碱土金属碱或有机金属碱。
本发明的一些方案中，上述碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾。
本发明的一些方案中，上述碱土金属碱选自氢化钠、氢化钾和/或氢化钙。
本发明的一些方案中，上述有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝。
本发明的一些方案中，上述化合物(Ⅳ)与上述碱的摩尔用量比为1:1～5,具体为1:2～3。
本发明的一些方案中，上述化合物(Ⅲ)和化合物(Ⅳ)的摩尔用量比为1:1～2。
本发明的一些方案中，上述反应的反应温度为-10～50℃。
本发明的一些方案中，上述反应的反应温度为0～30℃。
本发明的一些方案中，上述反应的反应时间为5～200小时。
本发明的一些方案中，上述反应的反应时间为10～100小时。
本发明的一些方案中，上述反应的反应时间为16～48小时。
本发明的一些方案中，上述反应在反应溶剂中进行，上述反应溶剂选自酰胺类溶剂、醚类溶剂或其任意混合物。
本发明的一些方案中，上述反应溶剂用量为化合物(Ⅳ)重量的10～50倍。
本发明的一些方案中，上述反应溶剂用量为化合物(Ⅳ)重量的15～20倍。
本发明的一些方案中，上述酰胺类溶剂选自DMF或DMAC。
本发明的一些方案中，上述醚类溶剂选自四氢呋喃、甲基四氢呋喃、二氧六环或甲基叔丁基醚。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000007
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000008
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000009
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000010
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000011
本发明的一些方案中，上述HA选自选自有机或无机酸。
本发明的一些方案中，上述HA选自盐酸、硫酸、草酸、柠檬酸、马来酸或富马酸。
本发明的一些方案中，上述化合物(i)可由化合物(Ⅱ)与还原剂反应制得，其中：
所述还原剂优选为碱金属氢化物；
所述碱金属氢化物优选为硼氢化钠、三乙酰基硼氢化钠、氰基硼氢化钠、红铝和/或四氢锂铝；
所述化合物(Ⅱ)与还原剂的摩尔用量比优选为1:1～5；
所述反应在反应溶剂中进行，所述溶剂优选为单一有机溶剂或混合有机溶剂；
所述有机溶剂优选为甲醇、乙醇、四氢呋喃和/或二氯甲烷；
所述溶剂用量为所述化合物(Ⅱ)重量的5～20倍；
所述反应的反应温度为-10～50℃；
所述反应的反应温度为0～30℃；
所述反应的反应时间为2～30小时；
所述反应的反应时间为8～16小时。
本发明的一些方案中，上述化合物(j)可由上述化合物(i)在碱存在下与甲磺酰氯反应制得，其中：
所述碱优选为碱金属碱、碱土金属碱、有机金属碱和/或有机碱；
所述碱金属碱优选为氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
所述碱土金属碱优选为氢化钠、氢化钾和/或氢化钙；
所述有机金属碱优选为甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝；
所述有机碱优选为二乙胺、三乙胺、DIEA、吡啶、DMAP和/或DBU；
所述化合物(i)与所述碱的摩尔用量比优选为1:1～5；
所述化合物(i)与所述甲磺酰氯的摩尔用量比优选为1:1～2；
所述反应在反应溶剂中进行，所述溶剂优选为非质子性有机溶剂；
所述有机溶剂优选为苯、甲苯、二氧六环、二氯甲烷、四氢呋喃和/或甲基四氢呋喃；
所述溶剂用量为所述化合物(i)重量的5～20倍；
所述反应的反应温度为-20～50℃；
所述反应的反应温度优选为-5～15℃；
所述反应的反应时间为2～30小时；
所述反应的反应时间为8～16小时。
本发明的一些方案中，上述化合物(k)可由上述化合物(j)与邻苯二甲酰亚胺钾盐反应制得，或由上述化合物(j)与邻苯二甲酰亚胺在碱作用下制得，其中：
所述碱优选为碱金属碱、碱土金属碱、有机金属碱及有机碱；
所述碱金属碱为氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
所述碱土金属碱为氢化钠、氢化钾和/或氢化钙；
所述有机金属碱为甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝；
所述化合物(j)与所述碱的摩尔用量比优选为1:1～5；
所述反应在反应溶剂中进行，所述溶剂优选为非质子性有机溶剂；
所述有机溶剂为苯、甲苯、二氧六环、四氢呋喃、DMF、DMSO和/或NMP；
所述溶剂用量为上述化合物(i)重量的5～20倍；
所述反应的反应温度为0～100℃；
所述反应的反应温度为20～80℃；
所述反应的反应时间为2～30小时；
所述反应的反应时间为8～16小时。
本发明的一些方案中，上述化合物(Ⅱ)可用于制备化合物(Ⅴ)，
Figure PCTCN2015090334-appb-000012
其中：
上述化合物(Ⅴ)可由上述化合物(j)与碱作用，然后加入酸成盐析出制得；
所述碱优选为碱金属碱或有机碱；
所述碱金属碱优选为氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
所述有机碱优选为水合肼、氨水、甲胺水溶液和/或甲胺醇溶液；
所述酸优选为无机酸或有机酸；
所述无机酸优选为盐酸或硫酸；
所述有机酸优选为草酸、柠檬酸、马来酸和/或富马酸；
所述化合物(j)与所述碱的摩尔用量比优选为1:2～10；
所述化合物(j)与所述酸的摩尔用量比优选为1:2～10；
所述反应在反应溶剂中进行，所述溶剂优选为水或质子性有机溶剂；
所述有机溶剂优选为甲醇、乙醇和/或异丙醇；
所述溶剂用量为上述化合物(i)重量的5～20倍；
所述反应的反应温度为0～100℃；
所述反应的反应温度为20～80℃；
所述反应的反应时间为2～30小时。
本发明的一些方案中，上述化合物1可由上述化合物(Ⅴ)在碱存在下与5-氯噻吩-2-甲酰氯反应制得，其中：
所述化合物(Ⅴ)与碱的摩尔用量比优选为1:1～3；
所述化合物(Ⅴ)与5-氯噻吩-2-甲酰氯的摩尔用量比优选为1:1～2；
所述反应在反应溶剂中进行，所述溶剂优选为水与有机溶剂的混合溶剂；
所述有机溶剂优选为醚类或芳烃类溶剂；
所述醚类溶剂优选为四氢呋喃或甲基四氢呋喃；
所述芳烃类溶剂优选为苯、甲苯、氯苯或溴苯；
所述水与有机溶剂的体积比为1:1～2；
所述溶剂用量为上述化合物(Ⅴ)的重量5～20倍；
所述反应的反应温度为0～40℃,优选为10～30℃；
所述反应的反应时间为5～30小时。
5-氯噻吩-2-甲酰氯可参考印度拜耳医药保健公司(Bayer Healthcare AG)申请的美国专利US2007149522实施例1中公布的方法制备，具体为：80℃条件下向5-氯噻吩-2-甲酸的甲苯溶液中加入氯化亚砜，搅拌2～3小时，浓缩即得到上述的5-氯噻吩-2-甲酰氯。
化合物(Ⅲ’)可以按照如下的合成路线制备
Figure PCTCN2015090334-appb-000013
化合物(Ⅲ’)也可按Synthesis,(1),178-183；1999文章上的方法由上述化合物(g)制备得到。
化合物(g)可按印度专利文献2006MU00055中的方法由上述化合物(f)或上述化合物(h)制备得到，或者，化合物(g)也可以按照如下合成路线制备。
Figure PCTCN2015090334-appb-000014
化合物(f)可按Organic Process Research&Development,16(5),1003-1012；2012文章中的方法由天然产物异抗坏血酸制备得到。
化合物(h)可按专利WO2001002020中的方法由天然产物D-阿拉伯糖制备。
本发明还提供了制备化合物(Ⅰ)的中间体，其结构如下：
Figure PCTCN2015090334-appb-000015
其中，
所述R为氨基保护基；
所述R选自烷氧羰基类氨基保护基；
所述R选自Cbz、Boc、Fmoc、Alloc、Teco、甲氧羰基或乙氧羰基；
所述R2选自任选被取代的5或6元环氨基或杂环氨基，“杂”代表O、N、C(＝O)或C(＝O)NH，取代基独立地选自C1-4烷基或杂烷基；
所述R2选自
Figure PCTCN2015090334-appb-000016
所述HA选自有机或无机酸；
所述HA选自盐酸、硫酸、草酸、柠檬酸、马来酸或富马酸。本发明还提供了中间体(Ⅳ)的制备方法，其包含如下反应：
Figure PCTCN2015090334-appb-000017
本发明的一些方案中，上述中间体(Ⅳ)的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000018
本发明的一些方案中，上述中间体(Ⅳ)的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000019
本发明的一些方案中，上述中间体(Ⅳ)的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000020
本发明的一些方案中，上述中间体(Ⅳ)的制备方法还包含如下反应：
Figure PCTCN2015090334-appb-000021
本发明的一些方案中，上述中间体(Ⅳ)的制备方法中，化合物(a)可由2,4-二氟硝基苯与叔丁醇钾反应制得，其中：
所述2,4-二氟硝基苯与叔丁醇钾的摩尔用量比优选为1:1～3；
所述反应在反应溶剂中进行，所述溶剂为有机溶剂；
所述有机溶剂优选为醚类溶剂或芳烃类溶剂；
所述醚类溶剂优选为四氢呋喃或甲基四氢呋喃；
所述芳烃类溶剂优选为苯、甲苯、氯苯或溴苯；
所述溶剂用量为上述2,4-二氟硝基苯重量的5～20倍；
所述反应的反应温度为0～40℃；
所述反应的反应温度为10～30℃；
所述反应的反应时间为1～30小时；
所述反应的反应时间为3～8小时。
本发明的一些方案中，上述化合物(b)可由上述化合物(a)在碱存在下与R2-H反应制得，其中：
所述碱选自碱金属碱、碱土金属碱或有机金属碱；
所述碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
所述碱土金属碱选自氢化钠、氢化钾和/或氢化钙；
所述有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝；
所述化合物(a)与所述碱的摩尔比为1:1～3；
所述化合物(a)与R2-H的摩尔比为1:1～2；
所述反应在反应溶剂中进行，反应溶剂选自非极性溶剂和极性溶剂的混合溶剂；
所述非极性溶剂选自苯、甲苯、二甲苯氯苯和/或溴苯；
所述极性溶剂选自DMF、DMSO或NMP；
所述非极性溶剂与极性溶剂的体积比为1:0.5～2；
所述溶剂用量为化合物(a)重量的5～20倍。
在本发明的一些技术方案中，上述化合物(c)可由上述化合物(b)与酸反应制得，其中：
所述酸优选为无机酸或有机酸；
所述无机酸优选为盐酸、硫酸和/或硝酸；
所述有机酸优选为三氟乙酸、甲磺酸和/或对甲苯磺酸；
所述化合物(b)与酸的摩尔用量比为1:5～30；
所述反应在反应溶剂中进行，所述溶剂优选为水或有机溶剂；
所述有机溶剂优选为乙酸乙酯、甲醇和/或二氧六环；
所述溶剂用量为化合物(b)的重量5～20倍；
所述反应的反应温度为0～50℃，优选为10～30℃；
所述反应的反应时间为2～30小时，优选为2～8小时。
在本发明的一些技术方案中，上述化合物(d)可由上述化合物(c)与氢化还原试剂/体系反应制得，其中：
所述氢化还原体试剂/体系优选为重金属催化氢化体系及还原性金属；
所述重金属催化氢化体系优选为以干钯碳、湿钯碳、雷尼镍或氢氧化钯为催化剂，氢气为还原剂；
所述还原性金属优选为铁粉或锌粉；
所述化合物(c)与所述重金属的重量用量比优选为100:(2～30)；
所述反应在反应溶剂中进行，所述溶剂优选为单一有机溶剂或混合有机溶剂；
所述有机溶剂优选为乙酸乙酯、甲醇、乙醇、四氢呋喃和/或DMF；
所述溶剂用量为化合物(d)重量的5～200倍；
所述反应的反应温度为0～50℃，优选为20～40℃；
所述反应的反应时间为2～30小时，优选为8～16小时。
本发明的一些技术方案中，化合物(Ⅳ)可由化合物(d)在碱存在下与常见氨基保护试剂反应制备；
所述氨基保护试剂优选自烷氧羰基类氨基保护试剂；
所述氨基保护试剂选自CbzCl、(Boc)2O、2-(叔丁氧羰基氧亚氨基)-2-苯乙腈、氯甲酸乙酯、氯甲酸甲酯、芴甲氧羰酰氯、芴甲氧羰酰琥珀酰亚胺、氯甲酸烯丙酯、N-[2-(三甲基硅基)乙氧羰氧基]琥珀酰亚胺等。
所述碱优选为碱金属碱、碱土金属碱及有机金属碱；
所述碱金属碱优选为氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
所述碱土金属碱优选为氢化钠、氢化钾和/或氢化钙；
所述有机金属碱优选为甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝。
所述化合物(d)与碱的摩尔用量比优选为1:1～3；
所述化合物(d)与氨基保护试剂的摩尔用量比优选为1:1～2；
所述反应在反应溶剂中进行，所述溶剂优选为水与有机溶剂的混合溶剂；
所述有机溶剂优选为苯、甲苯、二氧六环、四氢呋喃和/或甲基四氢呋喃；
所述水与有机溶剂的体积比为1:0.5～2；
所述溶剂用量为化合物(d)重量的5～20倍；
所述反应的反应温度为-20～50℃，优选为-5～15℃；
所述反应的反应时间为2～30小时。
本发明的一些技术方案中还提供了化合物(Ⅳ)的另一制备方法，其包括如下路线：
Figure PCTCN2015090334-appb-000022
本发明的一些方案中，化合物(e)可由上述化合物(b)与氢化还原剂/体系反应制得，其中：
所述氢化还原试剂/体系优选为重金属催化氢化体系和/或还原性金属；
所述重金属催化氢化体系优选为以干钯碳、湿钯碳、雷尼镍和/或氢氧化钯为催化剂，氢气为还原剂；
所述还原性金属优选为铁粉和/或锌粉；
所述化合物(b)与重金属的重量用量比优选为100:2～30；
所述反应在反应溶剂中进行，所述溶剂优选为单一有机溶剂或混合有机溶剂；
所述有机溶剂优选为乙酸乙酯、甲醇、乙醇、四氢呋喃和/或DMF；
所述溶剂用量为化合物(b)重量的5～200倍；
所述反应的反应温度为0～50℃,优选为20～40℃；
所述反应的反应时间为2～30小时，优选为4～8小时。
本发明的一些技术方案中，由化合物(e)和氨基保护试剂反应制备化合物(Ⅳ)的方法可参照由化合物(d)制备化合物(Ⅳ)的方法。
本发明还提供了化合物1的两个稳定且具有良好药用前景的晶型，A晶型和B晶型，其结构如图1和图2所示。
本发明还提供了化合物1的A晶型和B晶型的制备方法，包括将任意一种形式的化合物1加入到溶剂 结晶，并制得不同形式的晶型，其中：
所述溶剂优选为有机溶剂或含有醇类溶剂或水的混合溶剂；
所述有机溶剂优选为醇类或酮类；
所述醇类优选为甲醇、乙醇、异丙醇和/或正丁醇；
所述酮类优选为丙酮和/或甲基乙基酮；
所述混合溶剂优选为DMSO与乙醇或DMSO与水的混合溶剂；
所述DMSO与乙醇或水的体积比为1:0.5～5；
所述溶剂用量为化合物1重量的3～50倍。
定义和说明：
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的(Protective Groups In Organic Synthesis,Wiley and Sons,1991)是这方面的权威。本发明引用的所有参考文献整体上并入本发明。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词：DCM代表二氯甲烷；PE代表石油醚；EA代表乙酸乙酯；Pd/C代表钯碳；DMF代表N,N-二甲基甲酰胺；DMAC代表N,N-二甲基乙酰胺；DMSO代表二甲亚砜；EtOAc代表乙 酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，是一种胺保护基团；Boc代表叔丁基羰基是一种胺保护基团；Fmoc代表笏甲氧羰基，是一种胺保护基团；Alloc代表烯丙氧羰基，是一种胺保护基团；Teoc代表三甲基硅乙氧羰基，是一种胺保护基团；HOAc代表乙酸；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；DIEA代表二异丙基乙基胺；DMAP代表4-二甲氨基吡啶；DBU代表1,8-二氮杂二环十一碳-7-烯；tol代表甲苯；NH4Cl代表氯化铵；THF代表四氢呋喃；i-PrOH代表2-丙醇；mp代表熔点；NMP代表N-甲基吡咯烷酮；t-BuOK代表叔丁醇钾；AcOH代表冰醋酸；rf代表回流；MeNH2代表甲胺；Et3N代表三乙胺；H2O2代表过氧化氢；Con.HCl(aq)代表浓盐酸水溶液。
化合物经手工或者
Figure PCTCN2015090334-appb-000023
软件命名，市售化合物采用供应商目录名称。
本发明给出的合成式(Ⅰ)化合物及其中间体的工艺，有益效果为：克服现有技术中起始原料价格昂贵，所用试剂毒害大，反应条件苛刻，分离纯化困难，不易工业化等缺点。
具体地：
1)本发明制备式(Ⅰ)化合物方法原料为常规或常见试剂，在市场上容易获得且价格低廉；
2)中间体化合物(Ⅱ)可由新中间体化合物(Ⅳ)与已知中间体化合物(Ⅲ)经一步反应即得到，有效的提高了反应收率；
3)采用手性天然产物为原料引入手性中心，得到的式(Ⅰ)化合物具有高的光学纯度；
4)各步骤反应中所使用试剂均为小分子，易于纯化。
因此，本发明在制备式(Ⅰ)化合物及其中间体方面，具有很高的工业应用价值和经济价值。
附图说明
图1为化合物1的A晶型Cu-Kα辐射的XRPD谱图，其中A晶型由化合物1在乙醇中结晶析出制得。
图2为化合物1的B晶型Cu-Kα辐射的XRPD谱图，其中B晶型由化合物1在DMSO/EtOH体系结晶析出制得。
图3为化合物1的A晶型的DSC谱图。
图4为化合物1的B晶型的DSC谱图。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1：化合物1的制备
流程1:
Figure PCTCN2015090334-appb-000024
步骤1：2-(叔丁氧基)-4-氟-1-硝基苯的合成
冰水浴条件下，叔丁醇钾(387克，3.46摩尔)分批缓慢加入到2,4-二氟硝基苯(500克，3.14摩尔)的甲苯(2升)溶液中，保持温度不超过20℃。加毕，将反应液降到0℃保持温度搅拌2小时。TLC(石油醚)板检测反应完全，把反应液倾倒入冷的饱和氯化铵溶液(3升)中，乙酸乙酯萃取(1升x 3)。合并有机相旋干得到2-(叔丁氧基)-4-氟-1-硝基苯(670克，粗品，深红色油状物，HPLC纯度90％)，未进一步纯化，直接用于下一步反应。1HNMR(CDCl3，400MHz)δ7.82(dd,J＝9.2,6.0Hz,1H),6.93(dd,J＝10.4,2.8Hz,1H),6.84(m,1H),1.48(s,9H).
步骤2：4-(3-(叔丁氧基)-4-硝基苯基)吗啡啉-3-酮的合成
冰水浴条件下，叔丁醇钾(315克，2.81摩尔)分批缓慢加入到2-(叔丁氧基)-4-氟-1-硝基苯(600克，2.81摩尔)与吗啉-3-酮(284克，2.81摩尔)的甲苯和二甲基亚砜(1：1，1升)混合溶剂中，同时保持温度不超过20℃。加毕，将反应液加热到90℃，在这个温度下搅拌2小时。TLC(PE)板检测反应完全，把反应液倾倒入冷的饱和氯化铵溶液(4升)中，乙酸乙酯萃取(1升x 2)。合并的有机相用水(2升)洗，有机相旋干得到4-(3-(叔丁氧基)-4-硝基苯基)吗啡啉-3-酮(828克，粗品，深红色油状物，HPLC纯度80％)，未进一步纯化，直接用于下一步反应。1HNMR(CDCl3，400MHz)δ7.79(d,J＝9.2Hz,1H),7.42(d,J＝2.0Hz,1H),7.10(dd,J＝8.8,2.4Hz,1H),4.36(s,2H),4.06(t,J＝2.0Hz,2H),3.82(t,J＝2.0Hz,2H),1.45(s,9H).
步骤3：4-(4-氨基-3-(叔丁氧基)苯基)吗啡啉-3-酮的合成
铁粉(106克，1.90摩尔)加入到剧烈搅拌的4-(3-(叔丁氧基)-4-硝基苯基)吗啡啉-3-酮(140克，0.475摩尔)与氯化铵(101克，1.90摩尔)的乙醇和水(3:1，1.2L)的混合溶液中。加毕，反应搅拌大约半小时后开始剧烈放热，冰水冷却至不在剧烈放热，升至室温过夜，TLC(PE：EA＝1:1)板检测反应完全，过滤，甲醇洗残渣，TLC(PE：EA＝1:1)板检测洗涤完全，合并滤液旋干，水(500毫升)洗，二氯 甲烷(300毫升x 3)萃取。合并有机相旋干得到4-(4-氨基-3-(叔丁氧基)苯基)吗啡啉-3-酮(125克，粗品，黑色油状物，HPLC纯度70％)，未进一步纯化，直接用于下一步反应。1HNMR(CDCl3，400MHz)δ6.84(d,J＝2.0Hz,1H),6.75(m,1H),6.65(m,1H),4.76(brs,2H),4.14(s,2H),3.91(t,J＝2.0Hz,2H),3.62(t,J＝2.0Hz,2H),1.33(s,9H).
步骤4：(2-羟基-4-(3-吗啡啉酮)苯基)氨基甲酸苄酯的合成
4-(4-氨基-3-(叔丁氧基)苯基)吗啡啉-3-酮(400克，1.51摩尔)用4N盐酸溶液(1升)溶解搅拌反应过夜。反应液用冰水冷却，用12N的氢氧化钠溶液将反应液PH调至7左右，然后加入碳酸氢钠固体(190克，2.23摩尔)和四氢呋喃(600毫升)。冷却至0℃，缓慢滴加氯甲酸苄酯(258克，1.51摩尔)的四氢呋喃(500毫升)溶液，保持温度低于10℃。加毕，TLC(PE：EA 1:3)板检测反应完全。将二氯甲烷(2升)和水(1升)加入到反应液中，静置分液，水相用二氯甲烷(1升x 2)萃取。合并有机相旋干后加入乙醇(1升)搅拌打浆过滤，滤饼用乙醇(200毫升)洗两次，然后取出滤饼干燥得到(2-羟基-4-(3-吗啡啉酮)苯基)氨基甲酸苄酯(225克，HPLC纯度98％)，褐色固体。1HNMR(DMSO-d6，400MHz)δ9.95(brs,1H),8.52(s,1H),7.56(d,J＝9.2Hz,1H),7.45～7.33(m,5H),6.91(d,J＝2.4Hz,1H),6.79(dd,J＝8.4,2.0Hz,1H),5.15(s,2H),4.18(s,2H),3.95(t,J＝4.8Hz,2H),3.66(t,J＝4.8Hz,2H),1.33(s,9H).
流程2:
Figure PCTCN2015090334-appb-000025
步骤5：4-(3-(羟基)-4-硝基苯基)吗啡啉-3-酮的合成
10毫升的Con.HCl(aq)缓慢加入到4-(3-(叔丁氧基)-4-硝基苯基)吗啡啉-3-酮(10.0克，34.0毫摩尔)的乙酸乙酯(30毫升)溶液中。室温搅拌过夜，加入水(50毫升)，乙酸乙酯(30毫升x 2)萃取。合并有机相旋干得到粗品，乙醇(100毫升)打浆过滤旋干得到4-(3-(羟基)-4-硝基苯基)吗啡啉-3-酮(4.12克，HPLC纯度98％，收率51％)。1HNMR(DMSO-d6,400MHz)δ11.1(brs,1H),7.96(d,J＝8.0Hz,1H),7.31(d,J＝2.4Hz,1H),7.11(dd,J＝8.8,2.4Hz,1H),4.25(s,2H),3.98(t,J＝4.8Hz,2H),3.79(t,J＝4.8Hz,2H),1.33(s,9H).
步骤6：4-(4-氨基-3-(羟基)苯基)吗啡啉-3-酮的合成
在250毫升的氢化瓶中，氮气保护下，干钯碳(200毫克)加入到4-(3-(羟基)-4-硝基苯基)吗啡啉-3-酮(3.5克，14.7毫摩尔)的甲醇(100毫升)溶液中。反应液在30psi的氢气压力下，30℃下搅拌反应16小时。TLC(PE:EA＝1:1)板检测反应完全,过滤，用热的甲醇(200毫升)洗涤滤饼。合并有机相旋干得4-(4-氨基-3-(羟基)苯基)吗啡啉-3-酮(2.7克，HPLC纯度91％，收率88％)。1HNMR(DMSO-d6,400MHz)δ9.22(brs,1H),6.63(s,1H),6.57(d,J＝8.4Hz,1H),6.51(d,J＝8.4Hz,1H),4.59(brs,2H),4.13(s,2H),3.91(t,J＝4.4Hz,2H),3.57(t,J＝4.4Hz,2H).
步骤7：(2-羟基-4-(3-吗啡啉酮)苯基)氨基甲酸苄酯的合成
冰水浴下，碳酸氢钠固体(1.63克，19.4毫摩尔)加入到4-(4-氨基-3-(羟基)苯基)吗啡啉-3-酮(2.7克，12.9毫摩尔)的四氢呋喃(10毫升)和水(15毫升)的混合溶液中。冷却至0℃，缓慢滴加氯甲酸苄酯(1.63克，19.4毫摩尔)的四氢呋喃(5毫升)溶液，保持温度不超过5℃。加毕，TLC(PE:EA＝1:3)板检测反应完全。水(30毫升)加入到反应液中搅拌五分钟过滤，滤饼水(10毫升)洗，收集滤饼旋干，乙醇打浆得到(2-羟基-4-(3-吗啡啉酮)苯基)氨基甲酸苄酯(3.66克，白色固体，HPLC纯度96％，收率82％)。1HNMR(DMSO-d6，400MHz)δ9.95(brs,1H),8.52(s,1H),7.56(d,J＝9.2Hz,1H),7.45～7.33(m,5H),6.91(d,J＝2.4Hz,1H),6.79(dd,J＝8.4,2.0Hz,1H),5.15(s,2H),4.18(s,2H),3.95(t,J＝4.8Hz,2H),3.66(t,J＝4.8Hz,2H),1.33(s,9H).
流程3:
Figure PCTCN2015090334-appb-000026
步骤8：(2R,3R)-2,3,4-三羟基丁酸钾的合成
冰水浴条件下，将氢氧化钾(1.12千克，19.98摩尔)缓慢加入到甲醇(10升)和水(2.4升)的混合溶剂中，控制温度不超过45℃。加毕，通入氧气到反应液中，待反应液降到35℃，滴加D-(-)-阿拉伯糖(1千克，6.66摩尔，溶在2.4升水中)的水溶液，滴加超过6小时(整个过程保持通入氧气)并保持反应温度在35度。滴完后继续通入氧气2小时，再通入空气60小时。将反应液减压浓缩至2.4升油状物，再把油状物慢慢滴入快速搅拌的甲醇(10升)中，有大量白色固体析出。滴完后，过滤，并真空干燥后得白色固体(560克，收率48％)。1HNMR(D2O，400MHz)δ4.09(d,J＝4.0Hz,1H),3.97～3.92 (m,1H),3.65(d,J＝5.6Hz,1H).
步骤9：(2S,3R)-2,4-二溴-3-羟基丁酸甲酯的合成
将溴化氢/乙酸溶液(33％，2升)加入到盛有(2R,3R)-2,3,4-三羟基丁酸钾(560克，3.21摩尔)的反应器中。室温搅拌24小时，将反应液倒入无水甲醇(14升)中，再室温搅拌18小时，之后反应液加热到65℃回流4小时。反应液减压浓缩，加入水(1升)和乙酸乙酯(1.5升)萃取，分离出有机相，硫酸钠干燥，浓缩，得到(2S,3R)-2,4-二溴-3-羟基丁酸和(2S,3R)-2,4-二溴-3-羟基丁酸甲酯的油状混合物706克。硫酸(60毫升)缓慢加入到该混合物(680克)的甲醇(3.5升)溶液中，加热回流6小时，TLC(PE:EA＝10:1)板检测反应完全，将反应液浓缩，残留物溶在乙酸乙酯(800毫升)中，用水(500毫升)洗涤，有机相用无水硫酸钠干燥，过滤后浓缩得产物为灰白色固体(650克，收率74％)。1HNMR(CDCl3，400MHz)δ4.71(d,J＝3.6Hz,1H),4.20～4.15(m,1H),3.83(s,3H),3.55～3.48(m,2H).
步骤10：(2R,3S)-3-溴甲基环氧乙烷-2-羧酸甲酯的合成
将碳酸钾(503克，3.65摩尔)加入到(2S,3R)-2,4-二溴-3-羟基丁酸甲酯(200克，0.729摩尔)的丙酮(2.5升)溶液中，室温反应4小时，TLC(PE:EA＝10:1)板检测原料消失，将反应液过滤，减压浓缩得产物为淡黄色油状物，再用减压蒸馏装置将产物蒸出为无色透明液体(126克，90％)。
1HNMR(CDCl3，400MHz)δ3.83(s,3H),3.67～3.62(m,2H),3.57～3.52(m,1H),3.46～3.43(m,1H).
流程4:
Figure PCTCN2015090334-appb-000027
步骤11：(3R,4R)-3,4-二羟基二氢呋喃-2(3H)-酮的合成
将异抗坏血酸(17.6g，0.1mol)溶于250ml水中，并降温至0～6℃。将无水碳酸钠粉末(21.2g，0.2mol)分批加入反应瓶中。加料结束后，继续搅拌同时加入30％双氧水(22mL)，内部温度从6℃升高至19℃，继续在冰浴下搅拌5分钟，内部温度升至27℃。反应液被加热到42℃搅拌30分钟。将锌粉(1.0g，0.015mol)加入到反应液中淬灭过量的双氧水，淀粉碘化钾试纸检测显示阴性。将反应液用6N的盐酸调节pH值至1.0。在50℃下减压浓缩至少量白色固体析出。用乙酸乙酯(150ml x3)萃取。将有机相浓缩至200ml(10～15vol)；降温至15～25℃，搅拌5～8小时；(大量白色固体析出)过滤，烘干，得到8.26g(3R,4R)-3,4-二羟基二氢呋喃-2(3H)-酮，收率70％。
1HNMR(DMSO-d6，400MHz)δ5.78(brs,1H),5.37(brs,1H),4.39(d,J＝4.4Hz,1H),4.30～4.22(m,2H), 4.05(d,J＝10.0Hz,1H).
步骤12：(2S,3R)-2,4-二溴-3-羟基丁酸甲酯的合成
1L烧瓶中加入(3R,4R)-3,4-二羟基二氢呋喃-2(3H)-酮(26.0g，221mmol)，和182.0mL 33％氢溴酸乙酸溶液。混合物在室温下搅拌24小时后，加入959.0mL甲醇，继续搅拌36小时。所得反应液加热到65～75℃，回流4小时。反应液减压浓缩后，加入水(70.0mL)和乙酸乙酯(105.0mL)萃取，分离出有机相，硫酸钠干燥，浓缩，得到的粗品油状混合物51g。硫酸(4.1mL)缓慢加入到该混合物(51.0g)的甲醇(239.0mL)溶液中，加热回流6小时(60～70℃)。将反应液浓缩，残留物溶在乙酸乙酯(60.0mL)中，用水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤后浓缩得产物为灰白色固体(51g，收率：83％)。1HNMR(D2O，400MHz)δ3.98(d,J＝4.0Hz,1H),3.86～3.81(m,2H),3.54～3.51(m,2H).
流程5
Figure PCTCN2015090334-appb-000028
步骤13：(3R,3aS)-甲基-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-羧酸的合成在0℃搅拌下，向(2-羟基-4-(3-吗啡啉酮)苯基)氨基甲酸苄酯(68.5g,0.20mol)的DMF(700mL)溶液中，依次一次性加入(2S,3R)-2,4-二溴-3-羟基丁酸甲酯(46.8g,0.24mol)，碳酸铯(130.3g,0.40mol)。该反应液在0℃下，搅拌反应10小时。待检测(2-羟基-4-(3-吗啡啉酮)苯基)氨基甲酸苄酯完全消失后，在0℃下，继续加入碳酸铯(65.2g,0.20mol)。反应液逐渐升温至室温，搅拌反应12小时。反应混合液降温到0℃，加入甲醇(700mL)，用4N HCl/甲醇溶液调节pH＝1。在0℃下，缓慢滴加二氯亚砜(58 mL,0.80mol),约1小时滴加完。在0℃下，继续搅拌反应1小时后，再逐渐升温至室温反应16小时。待检测反应完全后，反应液在40℃下，减压浓缩除去甲醇。剩下的反应混合物降温后，加入到pH为2的冷的盐酸水溶液中。过滤收集固体得到粗品，粗品用冷的盐酸水溶液(40mL,pH＝2)洗两次，甲醇(40mL)洗两次，真空干燥得到目标产物为白色固体(38g,收率:54％)。1HNMR(DMSO-d6，400MHz)δ7.81(d,J＝8.4Hz,1H),7.08～7.02(m,2H),5.15(d,J＝6.8Hz,1H),4.58(d,J＝9.2,3.2Hz,1H),4.40(m,1H),4.18(s,2H),4.15(m,1H),3.95(t,J＝4.4Hz,1H),3.80(s,2H),3.69(t,J＝4.4Hz,1H).
步骤14：(3R,3aS)-3-(羟甲基)-7-(3-酮吗啡啉)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮的合成在0℃搅拌下，向(3R,3aS)-甲基-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-羧酸(38.3g,0.11mol)的混合甲醇/二氯甲烷(660mL,2:1)悬浊液中，分批加入硼氢化钠(5.0g,0.13mol)，约40分钟加完。在0℃下，搅拌反应20分钟。反应液升温至室温，在40℃下，减压浓缩除去溶剂，得到粗品。该粗品在水(40mL)中打浆10分钟，过滤，水(20mL)洗一次，真空干燥得到目标产物28g。水相用甲醇/二氯甲烷(1:10)萃取，无水硫酸钠干燥，浓缩得到目标产物5g，总收率为90％。1HNMR(DMSO-d6，400MHz)δ7.84(d,J＝8.8Hz,1H),7.05～6.99(m,2H),5.34(brs,1H),4.54(d,J＝7.2Hz,1H),4.45(m,1H),4.18(s,2H),4.02(t,J＝4.4Hz,1H),3.95(s,2H),3.77～3.68(m,4H).
步骤15：((3R,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲磺酸甲酯的合成
在0℃搅拌下，向(3R,3aS)-3-(羟甲基)-7-(3-酮吗啡啉)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(19.2g,60mmol)的二氯甲烷(600mL)悬浊液中，一次性加入三乙胺(25mL,180mmol)，滴加甲烷磺酰氯(9mL,120mmol)，约20分钟加完。在0℃下，搅拌反应1小时，再逐渐升温至室温反应16小时。待检测反应基本完全后，加入饱和碳酸氢钠溶液(200mL)。混合液过滤，滤液分液，水相用二氯甲烷(100mL x 2)萃取。合并有机相，用饱和食盐水(200mL)洗两次，用无水硫酸钠干燥，浓缩后与固体合并得到目标产物(21g,收率:87％)。
1HNMR(DMSO-d6，400MHz)δ7.84(d,J＝8.4Hz,1H),7.07～7.01(m,2H),4.79(m,1H),4.64～4.58(m,3H),4.18(s,2H),4.07(d,J＝5.6Hz,2H),3.95(t,J＝4.8Hz,1H),3.69(t,J＝4.8Hz,1H),3.28(s,2H).
步骤16：2-(((3S,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)异吲哚-1,3-二酮的合成
将((3R,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲磺酸甲酯(5.4g, 13.5mmol)溶于DMF(55mL)中。在25℃搅拌下，一次性加入邻苯二甲酰亚胺钾盐(3.75g,20.3mmol)，搅拌10分钟后升温至70℃，反应16小时。待检测反应基本完全后，冷却至室温，加入到冰水(180mL)中。过滤收集固体得到粗品，粗品用冰水(20mL)洗两次，干燥得到目标产物为白色固体(5.4g,收率:90％)。1HNMR(DMSO-d6，400MHz)δ7.95～7.85(m,4H),7.80(d,J＝8.8Hz,1H),7.04(d,J＝2.4Hz,1H),7.00(dd,J＝8.8,2.4Hz,1H),4.73(m,1H),4.72(m,1H),4.18～4.03(m,6H),3.94(t,J＝4.8Hz,1H),3.68(t,J＝4.8Hz,1H).
步骤17：(3S,3aS)-3-(氨甲基)-7-(3-酮吗啡啉))-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮的合成向250毫升反应瓶中，加入MeOH(100mL)，随后加入化合物2-(((3S,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)异吲哚-1,3-二酮(10.11g,22.5mmol)，充分搅拌均匀后，一次性加入40％甲胺水溶液(10.5mL,135mmol)，搅拌10分钟后升温至65℃，继续搅拌4小时，检测原料反应完全。然后将反应液冷却至室温，用HCl-MeOH溶液(12mL,12M)调节反应液pH＝1，搅拌1小时，充分成盐。在40℃下，反应液浓缩除去部分甲醇(约50mL)得到浆状液。随后加入甲醇/二氯甲烷(60mL，1:5)，打浆16小时，过过滤，滤饼用MeOH(10mL)洗两次，干燥得到目标产的盐酸盐(白色固体，7.0g，收率为87％，纯度98％)。1HNMR(DMSO-d6，400MHz)δ7.85(d,J＝8.4Hz,1H),6.98～6.95(m,2H),4.82(m,1H),4.59(d,J＝10.4Hz,1H),4.29(s,2H),4.12～4.01(m,4H),3.71(t,J＝5.6Hz,1H),3.52～3.47(m,2H),3.28(s,1H).
步骤18：5-氯-N-(((3S,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺的合成
向250毫升反应瓶中，加入水(30mL)，丙酮(54mL)，随后加入碳酸钠(2.48g,23.4mmol)，充分搅拌完全溶解后，降温至0-5℃，加入(3S,3aS)-3-(氨甲基)-7-(3-酮吗啡啉))-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮盐酸盐(6.40g,18.0mmol)，约10分钟加完。在0-5℃下，搅拌至完全溶解(约30分钟)。随后，在0-5℃下，滴加5-氯噻吩-2-酰氯(3.90g,21.6mmol)的甲苯(11mL)溶液,大约20分钟滴加完。滴加完后，继续在0-5℃下搅拌反应0.5小时，再逐渐升温至20度反应1小时。反应过程中逐渐有固体析出。TLC(DCM：MeOH＝20:1)板检测反应至反应完全，向反应液中加入水(100mL)，搅拌20分钟。随后在45℃下浓缩除去有机溶剂，过滤，收集固体，固体用水(50ml)洗，干燥得到目标产物(白色固体，8.40g,收率99％，HPLC纯度94％，手性纯度99％)。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.71(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.05(d,J＝2.0Hz,1H),7.05(dd,J＝8.8,2.0Hz,1H),4.62-4.51(m,2H),4.18(s,2H),4.11-4.01(m,2H),3.95 (t,J＝5.2Hz,2H),3.73(t,J＝5.2Hz,2H),3.68(t,J＝5.2Hz,2H).
步骤19：5-氯-N-(((3S,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺的重结晶(A晶型)
将2.8g步骤18中粗品固体用90mL乙醇加热到70℃搅拌30分钟，然后降温至室温搅拌16小时，过滤收集固体为2.4g，HPLC纯度为98.3％，收率86％。
步骤20：5-氯-N-(((3S,3aS)-1-酮-7-(3-酮吗啡啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺的重结晶(B晶型)
从步骤18中粗品固体中取出500mg固体，加入0.65mL DMSO搅拌溶解，随后加入1.3mL EtOH加热到80℃全部溶解，随后自然降温至0-10℃，有大量固体析出，过滤收集固体得到400mg，HPLC纯度为99.3％，收率80％。
实施例2：化合物2的制备
Figure PCTCN2015090334-appb-000029
化合物2的制备方法参照实施例1，其中，将步骤2中的吗啉-3-酮替换为哌啶-2-酮。
1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),7.83(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),6.87-6.93(m,2H),4.50-4.64(m,2H),3.99-4.13(m,2H),3.73(t,J＝5.6Hz,2H),3.52-3.60(m,2H),2.37(t,J＝6.0Hz,2H),1.77-1.90(m,4H)；LCMS(ESI)m/z:462.1(M+1).
实施例3：化合物7的制备
Figure PCTCN2015090334-appb-000030
化合物7的制备方法参照实施例1，其中，将步骤2中的吗啉-3-酮替换为四氢嘧啶-2(1H)-酮。
1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.69-7.75(m,2H),7.20(d,J＝4.0Hz,1H),6.85-6.95(m,2H),6.55(s,1H),4.47-4.62(m,2H),3.94-4.10(m,2H),3.71(t,J＝5.6Hz,2H),3.56(t,J＝5.6Hz,2H),3.20(td,J＝5.2,2.0Hz,2H),1.91(t,J＝6.0Hz,2H)；LCMS(ESI)m/z:463.0(M+1).
实施例4：化合物8的制备
Figure PCTCN2015090334-appb-000031
化合物8的制备方法参照实施例1，其中，将步骤2中的吗啉-3-酮替换为吡啶-2(1H)-酮。
1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),7.95(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.59(dd,J＝6.8,1.6Hz,1H),7.49(ddd,J＝9.2,6.8,2.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.06(d,J＝2.4Hz,1H),7.01(dd,J＝8.8,2.4Hz,1H),6.45(d,J＝9.2Hz,1H),6.29(td,J＝6.8,1.2Hz,1H),4.56-4.69(m,2H),4.03-4.16(m,2H),3.75(t,J＝5.6Hz,2H)；LCMS(ESI)m/z:458.1(M+1).
实施例5：化合物30的制备
Figure PCTCN2015090334-appb-000032
化合物30的制备方法参照实施例1，其中，将步骤2中的吗啉-3-酮替换为(R)-2-(甲氧基甲基)吡咯烷。
1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.4Hz,1H),7.71(d,J＝4.0Hz,1H),7.57(d,J＝9.2Hz,1H),7.21(d,J＝4.0Hz,1H),6.27(dd,J＝9.2,2.8Hz,1H),6.16(d,J＝2.8Hz,1H),4.53-4.46(m,2H),3.97-3.95(m,2H),3.78-3.73(m,1H),3.70(t,J＝5.6Hz,2H),3.33-3.31(m,2H),3.27(s,3H),3.21-3.17(m,1H),3.01-2.95(m,1H),1.99-1.87(m,4H)；LCMS(ESI)m/z:478.1(M+1).
实施例6：化合物34的制备
Figure PCTCN2015090334-appb-000033
化合物34的制备方法参照实施例1，其中，将步骤2中的吗啉-3-酮替换为1H-1,2,4-三唑。
1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),9.05(t,J＝5.6Hz,1H),8.22(s,1H),8.02(d,J＝8.4Hz,1H),7.75(d,J＝4.0Hz,3H),7.52(m,2H),7.22(d,J＝4.0Hz,1H),4.64(m,2H),4.14(m,2H),3.75(t,J＝5.6Hz,2H)；LCMS(ESI)m/z:432(M+1).
体外活性评价
通过测定IC50值来评价受试化合物对人或大鼠的Ⅹa因子或其他酶如凝血酶或胰蛋白酶的抑制能力，其中IC50值与抑制常数Ki相关联。在显色测定中使用纯化的酶。使用FlexStation III(美国分子仪器公 司)测定37℃下时间进程中线性部分(通常是加入底物2～10分钟后)在405nm处的吸光度的变化来测量发色底物水解的初始速度。通过绘制水解的相对速度(与未受抑制的对照组相比)对受试化合物浓度的对数曲线后，通过线性回归计算，测定导致底物水解的速率降低50％的抑制剂的浓度。根据Cheng-Prusoff equation:Ki＝IC50/(1+[S]/Km)计算酶抑制常数(Ki)，其中[S]为底物浓度，Km为通过双倒数作图法确定的米-曼二氏常数。通过GraphPad Prism软件得到受试化合物的IC50值。使用“形剂量效应(可变斜率)”拟合曲线。
人/大鼠凝血因子Xa试验：
采用Tris-HCl缓冲液(50mM,pH 8.3,150mM NaCl)测定人或大鼠的凝血因子Xa活性抑制作用。通过将50μL人凝血因子Xa(Enzyme Research Laboratories,Inc；终浓度为8.36nM)或50μL大鼠凝血因子Xa(Enzyme Research Laboratories,Inc；终浓度为57.5nM)的缓冲液滴加到Greiner 384微量滴定板的合适孔中的方法测定IC50。含2μL 2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中，并添加48μL衬底S-2222(Chromogenix；化学式：Bz-IIe-Glu(γ-OR)-Gly-Arg-pNA·HCl R＝H(50％)，其中R＝CH3(50％))的测定缓冲液，终浓度为0.172mM。该试验中将受试化合物与酶预培养10分钟，然后加入底物S-2222得到100μL终体积以开始试验。
Ki<10μM的受试化合物被认为是积极的，本发明优选Ki<1μM的化合物，更优选Ki<0.1μM的化合物，更优选Ki<0.01μM的化合物，进一步优选Ki<0.001μM的化合物。经上述试验方法测定，本发明的一些化合物Ki<0.1μM，因此本发明的化合物可作为有效的Ⅹa因子抑制剂。
人凝血酶试验：
采用缓冲液(10mM的HEPES缓冲液，pH 7.4,2mM CaCl2)测定人凝血酶活性抑制作用。选择Greiner 384微量滴定板中合适的孔测定IC50，含有50μL人凝血酶(Sigma公司；T8885)的缓冲液，终浓度为0.05NIH单位/mL，含2μL2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中；加入含有48μL底物S-2238(Chromogenix；化学式：H-D-Phe-Pip-Arg-pNA·2HCl)的缓冲液，终浓度为30μM。该试验中将受试化合物与酶预培养10分钟，然后加入底物得到100μL终体积以开始试验。
人胰蛋白酶试验：
采用缓冲液(50mM Tris,pH 8.2,and 20mM CaCl2)测定人胰蛋白酶活性抑制作用。选择Greiner 384微量滴定板中合适的孔测定IC50，含有50μL人胰蛋白酶(Sigma公司；T6424)的缓冲液，终浓度为0.39BAEE单位/mL，含2μL 2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中；含有底物S-2222(Chromogenix)的缓冲液，终浓度 为30μM。该试验中将受试化合物与酶预培养10分钟，然后加入底物48μL，得到终体积100μL以开始试验。
凝血酶原试验：
通过凝血酶的生成测量受试化合物对凝血酶原酶的活性。简单地说，在10mM HEPES缓冲液和pH7.4,2mM CaCl2中温育12.5μL人因子Xa，终浓度为0.5nM，并在37℃加入12.5μL人血小板(1×107mL-1)10分钟。加入25μL凝血酶原以开始反应，终浓度为0.5μM，含2μL 2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中。20分钟后，加入48μL底物S-2238(Chromogenix)至终浓度为50μM以测定凝血酶活性。
表1：本发明化合物体外筛选试验结果
Figure PCTCN2015090334-appb-000034
结论：本发明化合物通过其特定的抗凝血因子Xa活性表现出很强的抗凝血活性。

Claims (11)

  1. 式(Ⅰ)化合物的制备方法，
    Figure PCTCN2015090334-appb-100001
    其包含如下步骤：
    Figure PCTCN2015090334-appb-100002
    其中，
    R为氨基保护基，优选自烷氧羰基类氨基保护基，更优选自Cbz、Boc、Fmoc、Alloc、Teco、甲氧羰基或乙氧羰基；
    X为F、Cl、Br或I；
    R2选自任选被取代的5或6元环氨基或杂环氨基，“杂”代表O、N、C(＝O)或C(＝O)NH，取代基独立地选自C1-4烷基或杂烷基；
    优选地，R2选自
    Figure PCTCN2015090334-appb-100003
  2. 根据权利要求1所述制备方法，其中，所述碱选自碱金属碱、碱土金属碱或有机金属碱；
    优选地，所述碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
    优选地，碱土金属碱选自氢化钠、氢化钾和/或氢化钙；
    优选地，有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝。
  3. 根据权利要求1所述制备方法，其中，化合物(Ⅳ)与所述碱的摩尔用量比为1:1～5,具体为1:2～3；化合物(Ⅲ)和化合物(Ⅳ)的摩尔用量比为1:1～2；
    反应温度为-10～50℃，具体为0～30℃；和/或
    反应时间为5～200小时，具体为10～100小时，更具体为16～48小时。
  4. 根据权利要求1所述制备方法，该反应在反应溶剂中进行，所述反应溶剂选自酰胺类溶剂、醚类溶剂或其任意混合物；
    优选地，所述反应溶剂用量为化合物(Ⅳ)重量的10～50倍，更优选为15～20倍；
    优选地，酰胺类溶剂选自DMF或DMAC；和/或
    优选地，醚类溶剂选自四氢呋喃、甲基四氢呋喃、二氧六环或甲基叔丁基醚。
  5. 根据权利要求1～4任意一项所述的制备方法，其包含如下反应路线：
    Figure PCTCN2015090334-appb-100004
    Figure PCTCN2015090334-appb-100005
    其中，HA选自有机或无机酸，优选地，HA选自盐酸、硫酸、草酸、柠檬酸、马来酸或富马酸。
  6. 作为制备式(Ⅰ)化合物中间体的下式化合物：
    Figure PCTCN2015090334-appb-100006
    其中，
    R为氨基保护基，优选自烷氧羰基类氨基保护基，更优选自Cbz、Boc、Fmoc、Alloc、Teco、甲氧羰基或乙氧羰基；
    R2选自任选被取代的5或6元环氨基或杂环氨基，“杂”代表O、N、C(＝O)或C(＝O)NH，取代基独立地选自C1-4烷基或杂烷基；
    优选地，R2选自
    Figure PCTCN2015090334-appb-100007
    HA选自有机或无机酸，优选地，HA选自盐酸、硫酸、草酸、柠檬酸、马来酸或富马酸。
  7. 根据权利要求6所述化合物(Ⅳ)的制备方法，包含如下步骤：
    Figure PCTCN2015090334-appb-100008
  8. 根据权利要求7所述制备方法，其中，所述碱选自碱金属碱、碱土金属碱或有机金属碱；
    优选地，化合物(a)与碱的摩尔比为1:1～3；
    优选地，化合物(a)与R2-H的摩尔比为1:1～2；
    优选地，所述碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾；
    优选地，碱土金属碱选自氢化钠、氢化钾和/或氢化钙；
    优选地，有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝；
    优选地，该反应在反应溶剂中进行，所述反应溶剂选自非极性溶剂和极性溶剂的混合溶剂；
    优选地，非极性溶剂选自苯、甲苯、二甲苯、氯苯或溴苯；
    优选地，极性溶剂选自DMF、DMSO或NMP；
    优选地，非极性溶剂与极性溶剂的体积比为1:0.5～2；和/或
    优选地，溶剂用量为化合物(a)重量的5～20倍。
  9. 根据权利要求7或8所述的制备方法，其包含如下反应路线：
    Figure PCTCN2015090334-appb-100009
    Figure PCTCN2015090334-appb-100010
  10. 下式化合物1的晶型，其结构如图1或图2所示。
    Figure PCTCN2015090334-appb-100011
  11. 根据权利要求10所述晶型的制备方法，包括将任意一种形式的化合物1加入到溶剂中结晶制得，其中，
    优选地，溶剂用量为化合物1重量的3～50倍；
    优选地，所述溶剂选自醇类溶剂或者含有醇类溶剂或水的混合溶剂；
    优选地，所述醇类溶剂选自甲醇、乙醇、异丙醇和/或正丁醇；
    优选地，所述混合溶剂选自DMSO与乙醇或水的混合溶剂；或
    优选地，所述DMSO与乙醇或水的体积比为1:0.5～5。
PCT/CN2015/090334 2014-09-26 2015-09-23 苯并恶唑并恶嗪酮类化合物的制备方法及其中间体和晶型 WO2016045586A1 (zh)

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