WO2019223764A1 - 一种用于制备炔基吡啶类脯氨酰羟化酶抑制剂的方法 - Google Patents

一种用于制备炔基吡啶类脯氨酰羟化酶抑制剂的方法 Download PDF

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WO2019223764A1
WO2019223764A1 PCT/CN2019/088150 CN2019088150W WO2019223764A1 WO 2019223764 A1 WO2019223764 A1 WO 2019223764A1 CN 2019088150 W CN2019088150 W CN 2019088150W WO 2019223764 A1 WO2019223764 A1 WO 2019223764A1
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formula
compound represented
group
preparing
reaction
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PCT/CN2019/088150
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English (en)
French (fr)
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卢刚
黄建
胡逸民
祝令建
邹洋
崔华
尤启冬
张晓进
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苏州盛迪亚生物医药有限公司
上海盛迪医药有限公司
江苏恒瑞医药股份有限公司
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Priority to JP2020564452A priority Critical patent/JP2021523921A/ja
Priority to CA3098564A priority patent/CA3098564A1/en
Priority to CN201980004497.5A priority patent/CN111094246B/zh
Priority to EP19807109.4A priority patent/EP3805204A4/en
Priority to AU2019272405A priority patent/AU2019272405A1/en
Priority to KR1020207036200A priority patent/KR20210013095A/ko
Priority to BR112020023325-0A priority patent/BR112020023325A2/pt
Priority to US17/056,045 priority patent/US20210206720A1/en
Priority to MX2020012083A priority patent/MX2020012083A/es
Publication of WO2019223764A1 publication Critical patent/WO2019223764A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/10—Chlorides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/122—Halides of copper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
    • B01J31/30—Halides
    • 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 method for preparing an alkynylpyridine-type prolyl hydroxylase inhibitor.
  • Prolyl hydroxylase (PHD) inhibitors are a class of drugs used to treat and prevent anemia and ischemic diseases (such as chronic kidney disease anemia, myocardial ischemia, cerebral ischemia, stroke, etc.) Potential therapy. Its mechanism of action is to increase the content of the hypoxia-inducible factor (HIF) alpha subunit by inhibiting PHD, thereby increasing the production and secretion of erythropoietin (EPO), promoting the maturation of red blood cells, and increasing the oxygen transport from the blood. The ability to improve symptoms of anemia or ischemia.
  • HIF hypoxia-inducible factor
  • EPO erythropoietin
  • CN105130888A discloses a method for preparing such compounds, examples are as follows:
  • 3-hydroxy-5-bromopyridine-2-carboxylic acid was used as a starting material to form an amide with glycine methyl ester hydrochloride.
  • the obtained amide and substituted propyne were used in cuprous iodide and dichloro (ditriphenylphosphine) palladium. Under the action, the coupling product is obtained through microwave reaction, and the ester group is deprotected to obtain the final product.
  • this process has the following problems: 1) In the method for preparing starting material 3-hydroxy-5-bromopyridine-2-carboxylic acid, from 5-bromo-3-nitro-2-cyanopyridine to 5-bromo-3 -The step of hydroxy-2-cyanopyridine is intensely exothermic and generates a large amount of impurities, which is not suitable for industrial production, and the use of phenolic hydroxyl unprotected compounds is prone to the esterification reaction of the raw material itself in the next step; 2) the step of forming an amide 1-Hydroxybenzotriazole (HOBT) is used as the condensing agent.
  • HOBT 1-Hydroxybenzotriazole
  • the present invention provides a method for preparing a compound represented by the formula (III), which is characterized in that the compound represented by the formula (IV) is obtained after reacting with a compound represented by the formula (VI) in the presence of a palladium catalyst, a copper catalyst and a base,
  • R 1 is a hydroxyl protecting group
  • R 2 is a carboxy protecting group
  • R 3 is a C 1 -C 4 alkyl group, a phenyl group, a substituted phenyl group, a 5- to 6-membered aromatic heterocyclic ring containing oxygen or nitrogen, a substituted 5- to 6-membered aromatic heterocyclic ring containing oxygen or nitrogen, the substituent Is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, halogen, cyano, Phenyl or oxygen- or nitrogen-containing 5- to 6-membered aromatic heterocyclic ring, wherein R 4 is C 1 -C 4 alkyl; R 5 and R 6 are each independently selected from hydrogen or C 1 -C 4 alkyl, or R 5. R 6 is connected to form a 3-7 membered nitrogen-containing heterocyclic ring;
  • L is -CH 2- , -CH 2 O- or R 7 is selected from hydrogen, C 1 -C 4 alkyl or phenyl;
  • n is selected from 0 or 1;
  • X is iodine, bromine, chlorine or triflate.
  • the method for preparing a compound represented by formula (III) provided by the present invention is characterized in that the palladium catalyst is selected from the group consisting of Pd 2 (dba) 3 , Pd (dba) 2 , Pd (OAc) 2 , Pd (tfa) 2 , Pd (Piv) 2 , Pd (OTf) 2 , Pd (PPh 3 ) 4 , PdCl 2 , Pd (PPh 3 ) 2 Cl 2 , Pd (dppf) Cl 2 , preferably at least one of Pd (PPh 3 ) 2 Cl 2
  • the copper catalyst is selected from at least one of CuI, CuBr, CuCl, CuF, preferably CuI;
  • the base is selected from at least one of triethylamine, trimethylamine, and diisopropylethylamine, preferably three Ethylamine.
  • the method for preparing a compound represented by formula (III) provided by the present invention is characterized in that the amount ratio of the palladium catalyst to the substance of the compound represented by formula (IV) is 0.001: 1-1: 1, preferably 0.01: 1- 0.05: 1; the amount ratio of the substance of the copper catalyst to the palladium catalyst is 10: 1-1: 10, preferably 2: 1-1: 2.
  • the invention provides a method for preparing a compound represented by formula (III), characterized in that the reaction solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and N, N-dimethylformamide. At least one of N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, hexamethylphosphoryltriamine, 1,3-dimethyl-2-imidazolinone, Tetrahydrofuran is preferred.
  • the present invention provides a method for preparing a compound represented by formula (I), which is characterized by comprising a method for preparing a compound represented by formula (III), further comprising a step of removing R 1 and R 2 ,
  • R 1 , R 2 , R 3 , L, n are as described above.
  • R 1 , R 2 , R 3 , L, n are as described above.
  • the method for preparing a compound represented by formula (II) provided by the present invention is characterized in that the reaction assistant is selected from the group consisting of lithium chloride, tin dichloride, tin tetrachloride, cerium trichloride, antimony pentachloride, and chlorine.
  • the method for preparing a compound represented by formula (II) provided by the present invention is characterized in that the amount ratio of the reaction assistant to the substance of the compound represented by formula (III) is 10: 1-1: 1, preferably 7: 1 -3: 1.
  • the method for preparing a compound represented by the formula (I) provided by the present invention further comprises the step of preparing the compound represented by the formula (II).
  • the method for preparing a compound represented by formula (I), a compound represented by formula (II), and a compound represented by formula (III) provided by the present invention further comprises hydrolyzing the compound represented by formula (II) under basic conditions to obtain formula (I) The steps of the compounding shown,
  • R 2 , R 3 , L, n are as described above.
  • the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide At least one of these is preferably sodium hydroxide.
  • the reaction solvent is selected from the group consisting of tetrahydrofuran, N, N-dimethylformamide, and N, N-dimethylformamide.
  • the method for preparing a compound represented by the formula (III), a compound represented by the formula (II), and a compound represented by the formula (I) provided by the present invention further includes conditions for the presence of a compound of the formula (V) in a condensing agent and a solvent
  • the condensing agent is selected from N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, N-hydroxysuccinimide, benzo Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, dichlorosulfoxide, oxalyl chloride, N, N'-carbonyldiimidazole, 1-hydroxybenzotriazole, O- At least one of benzotriazole-N, N, N ', N'-tetramethylurea tetrafluoroborate, 1-hydroxy-7-azobenzotriazole, 1-propyl phosphoric anhydride, N, N'-carbonyldiimidazole is preferred;
  • the solvent is selected from one or more of diethyl ether, tetrahydrofuran, isopropanol, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, benzene, and toluene, preferably dichloride.
  • the reaction system optionally contains an organic base selected from at least one of triethylamine, trimethylamine, diisopropylethylamine, pyridine, or p-dimethylaminopyridine;
  • the method for preparing a compound represented by formula (IV), a compound represented by formula (III), a compound represented by formula (II), and a compound represented by formula (I) provided by the present invention is characterized in that R 1 is methyl or benzyl; R 2 is a C 1 -C 10 linear or branched alkyl group; R 3 is a halogen-substituted phenyl group; L is CH 2 , n is 1, and X is bromine.
  • the method for preparing a compound represented by formula (IV), a compound represented by formula (III), a compound represented by formula (II), and a compound represented by formula (I) provided by the present invention is characterized in that R 1 is methyl; R 2 is Methyl; R 3 is p-chlorophenyl; L is CH 2 , n is 1, and X is bromine.
  • the preparation process of the compound represented by (IV), the compound represented by Formula (III), the compound represented by Formula (II), and the compound represented by Formula (I) is as follows:
  • the present invention provides a compound represented by the following formula (IVa)
  • the present invention further provides a method for preparing a compound represented by formula (IVa), which is characterized by comprising a step of generating a compound represented by formula (IVa) in the presence of a condensing agent and a solvent,
  • the condensing agent is selected from N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, N-hydroxysuccinimide, benzo Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, dichlorosulfoxide, oxalyl chloride, N, N'-carbonyldiimidazole, 1-hydroxybenzotriazole, O- At least one of benzotriazole-N, N, N ', N'-tetramethylurea tetrafluoroborate, 1-hydroxy-7-azobenzotriazole, 1-propyl phosphoric anhydride, N, N'-carbonyldiimidazole is preferred;
  • the solvent is selected from one or more of diethyl ether, tetrahydrofuran, isopropanol, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, benzene, and toluene, preferably dichloride.
  • the reaction system optionally contains
  • organic base is selected from at least one of triethylamine, trimethylamine, diisopropylethylamine, pyridine, or p-dimethylaminopyridine.
  • the present invention provides a compound represented by formula (III-A),
  • R 1 is as described above.
  • the present invention provides a compound represented by formula (IIIa),
  • the hydroxy-protecting group of the present invention is a suitable group for hydroxy-protection known in the art, see the hydroxy-protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts).
  • the hydroxyl protecting group may be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc .; may be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl, benzyl , Methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc .; may be (C 1-10 alkyl or aromatic) acyl, for example: formyl, acetyl, benzoyl Ac
  • Carboxylic acid protecting groups are suitable groups for carboxylic acid protection known in the art, see carboxylic acid protecting groups in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts), As an example, preferably, the carboxylic acid protecting group may be a substituted or unsubstituted C 1-10 straight or branched alkyl group, or a substituted or unsubstituted C 2-10 straight or branched alkenyl group.
  • alkynyl, substituted or unsubstituted C 3-8 cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl) 3 silane C 1-6 is preferably a straight or branched alkyl group of C 1-6 , and more preferably a straight or branched alkyl group of C 1-4 .
  • IVa 600g
  • tetrahydrofuran 1.6kg
  • triethylamine 400g
  • cuprous iodide 7.5g
  • bis (triphenylphosphine) dichloride were sequentially added to a 10-L reaction kettle.
  • Palladium 27.8g
  • the temperature was raised to about 65 ° C, and a solution of 3-p-chlorophenoxypropyne (495g) in tetrahydrofuran (534g) was slowly added dropwise.
  • the mixture was kept under stirring until the HPLC showed that the reaction was complete.
  • the tetrahydrofuran was concentrated by evaporation under reduced pressure, and then it was sequentially added to the residual liquid.
  • N, N-dimethylacetamide (2.8kg), IIIa (600g), anhydrous lithium chloride (327g) were sequentially added to the 20-L reaction kettle, and the reaction temperature was raised to 80-130 ° C.
  • HPLC After the reaction was completed, the temperature was lowered to 50 ° C, and 724 g of a 17% wt.
  • Sodium hydroxide aqueous solution was slowly added dropwise. After the hydrolysis was completed, the temperature was lowered to room temperature.
  • Water (600 g), ethyl acetate (13.5 kg) were sequentially added, and concentrated hydrochloric acid was slowly added dropwise. (1.56 kg), continue to stir for 1 h, filter, separate the phases, and concentrate the organic phase under reduced pressure.
  • Ethyl acetate (75 mL) was added and suction filtered. The filtrate was added with water and 6M hydrochloric acid to adjust the pH to 3-5 and the phases were separated. The aqueous phase continued to be extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Ethyl acetate (30 mL) was added to the solution under reflux, and methyl tert-butyl ether (115 mL) was added dropwise at 35 ° C, and the temperature was lowered to 0 ° C and stirred overnight. . After filtering and drying, 10.1 g of off-white solid was obtained with a yield of 55% and a purity of 98.3%.
  • 70 ° C, 80 ° C, and 90 ° C are the results of the continuous reaction of the same batch of stepwise temperature rises. It can be seen that as the reaction temperature increases, the raw materials will react completely, but the impurities will become larger and larger in the post-treatment. It is difficult to remove, and the yield of the two steps of the new route is 65% in total, resulting in lower product purity.

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Abstract

提供一种用于制备炔基吡啶类脯氨酰羟化酶抑制剂的方法。具体而言，涉及的方法以不同保护基团保护的3-取代-5-溴吡啶-2-甲酸为原料，经缩合、Sonogashira偶联、脱保护制得目标化合物。工艺反应条件简单，无苛刻反应条件，可操作性强，且放大稳定。

Description

一种用于制备炔基吡啶类脯氨酰羟化酶抑制剂的方法 技术领域
本发明涉及用于制备炔基吡啶类脯氨酰羟化酶抑制剂的方法。
背景技术
炔基吡啶类脯氨酰羟化酶(prolyl hydroxylase，PHD)抑制剂是一类用于治疗和预防贫血症以及缺血性疾病(如慢性肾病贫血、心肌缺血、脑缺血、中风等)的潜在疗法。其作用机制是通过抑制PHD，提高低氧诱导因子(hypoxia inducible factor，HIF)α亚基的含量，从而增加促红细胞生成素(erythropoietin，EPO)的生成与分泌，促进红细胞成熟及提升血液输送氧气的能力，改善贫血或缺血症状。
CN105130888A公开了一种制备该类化合物的方法，示例如下：
Figure PCTCN2019088150-appb-000001
以3-羟基-5-溴吡啶-2-甲酸为起始原料，与甘氨酸甲酯盐酸盐成酰胺，所得酰胺与取代丙炔在碘化亚铜和二氯(二三苯基膦)鈀作用下，经微波反应得到偶联产物，后酯基脱保护得终产品。但该工艺路线存在以下问题：1)起始原料3-羟基-5-溴吡啶-2-甲酸的制备方法中由5-溴-3-硝基-2-氰基吡啶到5-溴-3-羟基-2-氰基吡啶的步骤放热剧烈，产生大量杂质，不适宜工业生产，且使用酚羟基未保护的化合物在下一步中容易发生原料本身的酯化反应；2)成酰胺的步骤中使用1-羟基苯并三唑(HOBT)做缩合剂，该试剂价格昂贵，易残留，故增加了生产成本，且无水的HOBT易发生爆炸，带来安全隐患，3)路线中使用微波反应无法实现工业化；4)终产品的收率低；5)缩合、偶联步骤所得产物需经硅胶柱层析纯化，不适宜大量生产。
发明内容
本发明提供一种式(Ⅲ)所示化合物的制备方法，其特征在于式(Ⅳ)所示化合物与式(Ⅵ)所示化合物在钯催化剂、铜催化剂及碱存在条件下反应后得到，
Figure PCTCN2019088150-appb-000002
其中R 1为羟基保护基；
R 2为羧基保护基；
R 3为C 1-C 4烷基、苯基、取代苯基、含氧或氮的5～6元芳杂环、取代的含氧或氮的5～6元芳杂环，所述取代基是C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、卤素、氰基，
Figure PCTCN2019088150-appb-000003
苯基或含氧或氮的5～6元芳杂环，其中R 4为C 1-C 4烷基；R 5、R 6各自独立地选自氢或C 1-C 4烷基，或者R 5、R 6连接形成3～7元含氮杂环；
L为-CH 2-、-CH 2O-或
Figure PCTCN2019088150-appb-000004
R 7选自氢，C 1-C 4烷基或者苯基；
n选自0或1；
X为碘、溴、氯或三氟甲磺酸酯基。
本发明提供的式(Ⅲ)所示化合物的制备方法，其特征所述的钯催化剂选自Pd 2(dba) 3、Pd(dba) 2、Pd(OAc) 2、Pd(tfa) 2、Pd(Piv) 2、Pd(OTf) 2、Pd(PPh 3) 4、PdCl 2、Pd(PPh 3) 2Cl 2、Pd(dppf)Cl 2，优选Pd(PPh 3) 2Cl 2中的至少一种；所述铜催化剂选自CuI、CuBr、CuCl、CuF中的至少一种，优选CuI；所述碱选自三乙胺、三甲胺、二异丙基乙胺中的至少一种，优选三乙胺。
本发明提供的式(Ⅲ)所示化合物的制备方法，其特征在于所述的钯催化剂与式(Ⅳ)所示化合物的物质的量比为0.001:1-1:1，优选0.01:1-0.05:1；铜催化剂与钯催化剂的物质的量比为10:1-1:10，优选2:1-1:2。
本发明提供式(Ⅲ)所示化合物的制备方法，其特征在于所述的反应溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、六甲基磷酰三胺、1,3-二甲基-2-咪唑啉酮中的至少一种，优选四氢呋喃。
本发明提供一种式(Ⅰ)所示化合物的制备方法，其特征在于包含式(Ⅲ)所示化合物所述化合物的制备方法，进一步包含脱除R 1和R 2的步骤，
Figure PCTCN2019088150-appb-000005
其中R 1、R 2、R 3、L、n如上所述。
一种式(Ⅱ)所示化合物的制备方法，其特征在于包含式(Ⅲ)所示化合物在反应助剂条件下脱除R 1得式(Ⅱ)所示化合物的步骤，
Figure PCTCN2019088150-appb-000006
其中R 1、R 2、R 3、L、n如上所述。
本发明提供的式(Ⅱ)所示化合物的制备方法，其特征在于所述反应助剂选自氯化锂、二氯化锡、四氯化锡、三氯化铈、五氯化锑、氯化铁、三氟化硼乙醚、三氯化硼，三溴化硼中的至少一种，优选氯化锂；反应的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、六甲基磷酰三胺、1,3-二甲基-2-咪唑啉酮中的至少一种，优选N,N-二甲基乙酰胺。
本发明提供的式(Ⅱ)所示化合物的制备方法，其特征在于所述的反应助剂与式(Ⅲ)所示化合物的物质的量比为10:1-1:1，优选7:1-3:1。
本发明提供的式(Ⅰ)所示化合物的制备方法，进一步包含上述制备式(Ⅱ)所示化合物的步骤。
本发明提供的式(Ⅰ)所示化合物、式(Ⅱ)所示化合物、式(Ⅲ)所示化合物的制备方法，进一步包含式(Ⅱ)所示化合物碱性条件下水解得式(Ⅰ)所示化合的步骤，
Figure PCTCN2019088150-appb-000007
其中R 2、R 3、L、n如上所述。
本发明提供的制备方法中，式(Ⅱ)所示化合物水解得式(Ⅰ)所示化合物的步骤中，所述的碱为氢氧化钠、氢氧化钾、氢氧化锂、甲醇钠、乙醇钠中的至少一种，优选氢氧化钠。
本发明提供的制备方法中，式(Ⅱ)所示化合物水解得式(Ⅰ)所示化合物的步骤中，反应溶剂选自四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、六甲基磷酰三胺、1,3-二甲基-2-咪唑啉酮或其与水组成的混合溶剂，优选N,N-二甲基乙酰胺/水或四氢呋喃/水混合溶剂。
本发明提供的式(Ⅲ)所示化合物、式(Ⅱ)所示化合物、式(Ⅰ)所示化合物制备方法，其特征在于还包括式(Ⅴ)所示化合物在缩合剂及溶剂存在的条件下生成式(Ⅳ)所示化合物的步骤，
Figure PCTCN2019088150-appb-000008
其中所述缩合剂选自N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐、二环己基碳二亚胺、N-羟基琥珀酰亚胺、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、二氯亚砜、草酰氯、N,N’-羰基二咪唑、1-羟基苯并三唑、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸、1-羟基-7-偶氮苯并三氮唑、1-丙基磷酸酐中的至少一种，优选N,N’-羰基二咪唑；
所述溶剂选自乙醚、四氢呋喃、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、1,4-二氧六环、苯、甲苯中的一种或几种，优选二氯甲烷；
反应体系任选含有有机碱，所述的有机碱选自三乙胺、三甲胺、二异丙基乙胺、吡啶或对二甲氨基吡啶中的至少一种；
其中X、R 1、R 2如上所述。
本发明提供的式(Ⅳ)所示化合物、式(Ⅲ)所示化合物、式(Ⅱ)所示化合物、式(Ⅰ)所示化合物制备方法，其特征在于R 1为甲基或苄基；R 2为C 1-C 10的直链或支链烷基；R 3为卤素取代的苯基；L为CH 2，n为1，X为溴。
本发明提供的式(Ⅳ)所示化合物、式(Ⅲ)所示化合物、式(Ⅱ)所示化合物、式(Ⅰ)所示化合物制备方法，其特征在于R 1为甲基；R 2为甲基；R 3为对氯苯基；L为CH 2，n为1，X为溴。
本发明的一个优选实施例中(Ⅳ)所示化合物、式(Ⅲ)所示化合物、式(Ⅱ)所示化合物、式(Ⅰ)所示化合物制备过程如下所示：
Figure PCTCN2019088150-appb-000009
本发明提供一种如下式(Ⅳa)所示的化合物
Figure PCTCN2019088150-appb-000010
本发明进一步提供一种式(Ⅳa)所示化合物的制备方法，其特征在于包括式(Ⅴa)所示化合物在缩合剂及溶剂存在的条件下生成式(Ⅳa)所示化合物的步骤，
Figure PCTCN2019088150-appb-000011
其中所述缩合剂选自N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐、二环己基碳二亚胺、N-羟基琥珀酰亚胺、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、二氯亚砜、草酰氯、N,N’-羰基二咪唑、1-羟基苯并三唑、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸、1-羟基-7-偶氮苯并三氮唑、1-丙基磷酸酐中的至少一种，优选N,N’-羰基二咪唑；
所述溶剂选自乙醚、四氢呋喃、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、1,4-二氧六环、苯、甲苯中的一种或几种，优选二氯甲烷；
反应体系任选含有
有机碱，所述的有机碱选自三乙胺、三甲胺、二异丙基乙胺、吡啶或对二甲氨基吡啶中的至少一种。
本发明提供一种式(Ⅲ-A)所示的化合物，
Figure PCTCN2019088150-appb-000012
其中R 1如上所述。
本发明提供一种式(Ⅲa)所示的化合物，
Figure PCTCN2019088150-appb-000013
本发明所使用的术语，除有相反的表述外，具有如下的含义：
本发明的羟基保护基是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts) 中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。
“羧酸保护基”是本领域已知的适当的用于羧酸保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羧酸保护基团，作为示例，优选地，所述的羧酸保护基可以是取代或非取代的C 1-10的直链或支链烷基、取代或非取代的C 2-10的直链或支链烯基或炔基、取代或非取代的C 3-8的环状烷基、取代或非取代的C 5-10的芳基或杂芳基、或(C 1-8烷基或芳基) 3硅烷基；优选C 1-6的直链或支链烷基，更优选C 1-4的直链或支链烷基。
Figure PCTCN2019088150-appb-000014
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，本发明的实质和范围并不局限于此。
其中式(Ⅴa)所示制备方法参考专利WO2010018458A中的方法制备，(Ⅴc)参考专利CN104276999A中的方法制备。
实施例1
Figure PCTCN2019088150-appb-000015
向20-L反应釜中依次加入Ⅴa(650g)，二氯甲烷(6.9kg)，室温下缓慢加入 N,N’-羰基二咪唑(500g)，加完并继续室温搅拌1h，缓慢加入甘氨酸甲酯盐酸盐(387g)，HPLC显示反应完全后，加水萃取，有机相减压浓缩，室温下滴加正庚烷(3.536kg)，过滤，烘干后得到产品719g，纯度为98.5％，收率为84％。
实施例2
Figure PCTCN2019088150-appb-000016
氮气保护下，向10-L的反应釜中依次加入Ⅳa(600g)，四氢呋喃(1.6kg)，三乙胺(400g)，碘化亚铜(7.5g)、二(三苯基膦)二氯化钯(27.8g)。升温至65℃左右，缓慢滴入3-对氯苯氧基丙炔(495g)的四氢呋喃(534g)溶液，继续保温搅拌至HPLC显示反应完全，减压浓缩蒸出四氢呋喃，然后向残留液中依次加入乙酸乙酯(4.32kg)，水(1.2kg)，1％wt盐酸水溶液(1.5kg)，调节pH至2-3。加入水(0.9kg)，静置分相。水相继续以乙酸乙酯萃取。合并后的有机相用水洗涤，过滤。滤液减压浓缩后，依次滴加甲基叔丁基醚(4.44kg)，正庚烷(1.224kg)，室温搅拌过夜。过滤，烘干后得到棕色固体672g，收率87％，纯度98.8％。
实施例3
Figure PCTCN2019088150-appb-000017
氮气保护下，向20-L反应釜中依次加入N,N-二甲基乙酰胺(2.8kg)，Ⅲa(600g)，无水氯化锂(327g)，升温至80-130℃反应，HPLC显示反应完全后降温至50℃，缓慢滴加724g 17％wt.氢氧化钠水溶液，水解完全后，降至室温，依次加入水(600g)、乙酸乙酯(13.5kg)，缓慢滴加浓盐酸(1.56kg)，继续搅拌1h，过滤，分相，有机相减压浓缩后，室温下向残留液中加入异丙醇(7kg)，水(3.6kg)，抽滤，干燥得产品Ⅰa 408g，纯度为96.5％，收率为71％。
实施例4
Figure PCTCN2019088150-appb-000018
参照实施例2，用3-对氟苯氧基丙炔替换3-对氯苯氧基丙炔。氮气保护下，向反应瓶中依次加入Ⅳa(15g)，四氢呋喃(45mL)，三乙胺(10g)，碘化亚铜(0.15g)、二(三苯基膦)二氯化钯(0.556g)。升温至65℃左右，缓慢滴入3-对氟苯氧基丙炔(12.6g)的四氢呋喃(36mL)溶液，继续保温搅拌至HPLC显示反应完全。加入乙酸乙酯(75mL)，抽滤。滤液加水、6M盐酸调pH 3-5后分相。水相继续以乙酸乙酯萃取。合并后的有机相用水洗涤，无水硫酸钠干燥，减压浓缩干，加入乙酸乙酯(30mL)回流溶清，35℃滴加甲基叔丁基醚(115mL)，降温至0℃搅拌过夜。过滤，烘干后得到类白色固体10.1g，收率55％，纯度98.3％。
Figure PCTCN2019088150-appb-000019
参照实施例3步骤操作，氮气保护下，向反应瓶中依次加入Ⅲb(25g)，N,N-二甲基乙酰胺(125mL)，无水氯化锂(17.1g)，升温至105-110℃反应，HPLC显示反应完全后降温至50℃，缓慢滴加33.4g 16％wt.氢氧化钠水溶液，水解完全后，降至室温，依次加入水(250g)、乙酸乙酯(625mL)，缓慢滴加浓盐酸(56mL)，分相，有机相水洗、减压浓缩后，室温下向残留液中加入乙腈(40mL)，水(150mL)，抽滤，干燥得类白色固体Ⅰb 16.7g，2步收率72％，纯度98.6％。
实施例5
Figure PCTCN2019088150-appb-000020
将化合物Ⅲa(5g)溶于四氢呋喃/水(25/5mL)中，加入氢氧化锂(0.63g)，室温下反应。反应结束后，依次加入乙酸乙酯(200mL)，水(50mL)，浓盐酸(10mL)，有机相水洗，无水硫酸钠干燥，减压蒸馏后，用甲基叔丁基醚打浆，抽滤干燥后得产物IIa-1 4.0g，产率83％，纯度97.5％。
Figure PCTCN2019088150-appb-000021
氮气保护下，向反应瓶中依次加入IIa-1(2g)，无水氯化锂(1.2g)，N,N-二甲基乙酰胺(10mL)，90℃反应完全。降温，依次加入水(20g)、乙酸乙酯(50mL)，缓慢滴加浓盐酸调pH为1，分相萃取，有机相干燥、减压浓缩后，向残 留液中加入乙腈(5mL)，水(20g)，抽滤，干燥得产品Ⅰa 1.5g，纯度为83％，收率为78％。
不同反应温度HPLC
Figure PCTCN2019088150-appb-000022
上表中70℃、80℃、90℃为同一批次阶梯升温连续反应的结果，由此可知随着反应温度升高原料会反应完全，但杂质会越来越大，且在后处理中很难除去，新路线两步收率合计65％，得到产品纯度较低。
实施例6
Figure PCTCN2019088150-appb-000023
将中间体Vc(20g)溶于二氯甲烷400mL中，依次加入三乙胺(27mL)，1-羟基苯并三唑(12.0g)，搅拌10min后加入N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐(16.5g)，甘氨酸甲酯盐酸盐(8.64g)，室温反应6h。反应结束后，反应液用饱和碳酸氢钠、水、饱和食盐水依次洗涤。无水硫酸钠干燥，减压蒸馏后，粗品用硅胶柱层析分离纯化。该步反应重复5次，合并一次18g中间体Vc的投料，共得白色固体化合物85.5g，收率58.9％。
Figure PCTCN2019088150-appb-000024
将IVc((25.0g)溶于500mL的二氯甲烷中，向反应瓶中加入三氟化硼乙醚70mL。加热至45℃反应6h。反应结束后，加入饱和氯化铵溶液300mL搅拌2h。分液，有机相依次用水、饱和食盐水洗洗涤，减压蒸馏除去有机溶剂得粗品，该步反应重复3次，并合并一次10.5g中间体IVc的投料，所得粗品用二氯甲烷重结晶后共得到淡黄色固体产物34.4g，收率52.7％。
Figure PCTCN2019088150-appb-000025
于微波管中加入化合物N-(5-溴-3-羟基-吡啶-2-甲酰基)甘氨酸甲酯(4.0g)，3-对氯苯氧基丙炔(3.2mL)，三乙胺5mL，二(三苯基膦)二氯化钯(700mg)，碘化亚铜(700mg)和N,N-二甲基甲酰胺(5mL)。将微波反应管放入CEM微波反应器中，在微波功率为300W，温度为120℃的条件下反应20min。同时此部分反应也可使用常温加热80℃反应8-10h。用空气流将反应器降至室温后，将反应混合物用二氯甲烷稀释，硅藻土抽滤，滤饼用二氯甲烷洗涤。有机相水洗、饱和食盐水洗，无水硫酸钠干燥。该步反应重复10次，合并后柱层析分离纯化得白色固体产物27.5g，产率52.8％。
Figure PCTCN2019088150-appb-000026
将化合物Ⅱa(27.0g)溶于10％的四氢呋喃水溶液中，加入氢氧化锂，加热至35℃反应。反应结束后，浓缩反应液，加入适量水完全溶解，10％的稀盐酸中和至固体完全析出，抽滤干燥后得产物Ⅰa 20.5g，产率78.9％。

Claims (19)

  1. 一种式(Ⅲ)所示化合物的制备方法，其特征在于式(Ⅳ)所示化合物与式(Ⅵ)所示化合物在钯催化剂、铜催化剂及碱存在条件下反应得到，
    Figure PCTCN2019088150-appb-100001
    其中R 1为羟基保护基；
    R 2为羧基保护基；
    R 3为C 1-C 4烷基、苯基、取代苯基、含氧或氮的5～6元芳杂环、取代的含氧或氮的5～6元芳杂环，所述取代基是C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、卤素、氰基，
    Figure PCTCN2019088150-appb-100002
    苯基或含氧或氮的5～6元芳杂环，其中R 4为C 1-C 4烷基；R 5、R 6各自独立地选自氢或C 1-C 4烷基，或者R 5、R 6连接形成3～7元含氮杂环；
    L为-CH 2-、-CH 2O-或
    Figure PCTCN2019088150-appb-100003
    R 7选自氢，C 1-C 4烷基或者苯基；
    n选自0或1；
    X为碘、溴、氯或三氟甲磺酸酯基。
  2. 根据权利要求1所述的制备方法，其特征所述的钯催化剂选自Pd 2(dba) 3、Pd(dba) 2、Pd(OAc) 2、Pd(tfa) 2、Pd(Piv) 2、Pd(OTf) 2、Pd(PPh 3) 4、PdCl 2、Pd(PPh 3) 2Cl 2、Pd(dppf)Cl 2中的至少一种，优选Pd(PPh 3) 2Cl 2；所述铜催化剂选自CuI、CuBr、CuCl、CuF中的至少一种，优选CuI；所述碱选自三乙胺、三甲胺、二异丙基乙胺中的至少一种，优选三乙胺。
  3. 根据权利要求1所述的制备方法，其特征在于所述的钯催化剂与式(Ⅳ)所示化合物的物质的量比为0.001:1-1:1，优选0.01:1-0.05:1；铜催化剂与钯催化剂的物质的量比为10:1-1:10，优选2:1-1:2。
  4. 根据权利要求1所述的制备方法，其特征在于所述的反应溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、六甲基磷酰三胺、1,3-二甲基-2-咪唑啉酮中的至少一种，优选四氢呋喃。
  5. 一种式(Ⅰ)所示化合物的制备方法，其特征在于包含权利要求1-4任一项所述的式(Ⅲ)所示化合物的制备方法，进一步包含脱除R 1和R 2的步骤，
    Figure PCTCN2019088150-appb-100004
    其中R 1、R 2、R 3、L、n如权利要求1中定义。
  6. 一种式(Ⅱ)所示化合物的制备方法，其特征在于包含式(Ⅲ)所示化合物在反应助剂条件下脱除R 1的步骤，
    Figure PCTCN2019088150-appb-100005
    其中R 1、R 2、R 3、L、n如权利要求1中定义。
  7. 根据权利要求6所述的制备方法，其特征在于所述反应助剂选自氯化锂、二氯化锡、四氯化锡、三氯化铈、五氯化锑、氯化铁、三氟化硼乙醚、三氯化硼，三溴化硼中的至少一种，优选氯化锂；反应的溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、六甲基磷酰三胺、1,3-二甲基-2-咪唑啉酮中的至少一种，优选N,N-二甲基乙酰胺。
  8. 根据权利要求7所述的制备方法，其特征在于所述的反应助剂与式(Ⅲ)所示化合物的物质的量比为10:1-1:1，优选7:1-3:1。
  9. 根据权利要求5所述的式(Ⅰ)所示化合物的制备方法，其特征在于进一步包含权利要求6-8任一项所述的制备式(Ⅱ)所示化合物的步骤。
  10. 根据权利要求5-9任一项所述的制备方法，进一步包含式(Ⅱ)所示化合物碱性条件下水解得式(Ⅰ)所示化合的步骤，
    Figure PCTCN2019088150-appb-100006
    其中R 2、R 3、L、n如权利要求1中定义。
  11. 根据权利要求10所述的制备方法，其特征在于所述的碱为氢氧化钠、氢氧化钾、氢氧化锂、甲醇钠、乙醇钠中的至少一种，优选氢氧化钠。
  12. 根据权利要求1-11任一项所述的制备方法，其特征在于还包括式(Ⅴ)所示化合物在缩合剂及溶剂存在的条件下生成式(Ⅳ)所示化合物的步骤，
    Figure PCTCN2019088150-appb-100007
    其中所述缩合剂选自N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐、二环己基碳二亚胺、N-羟基琥珀酰亚胺、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、二氯亚砜、草酰氯、N,N’-羰基二咪唑、1-羟基苯并三唑、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸、1-羟基-7-偶氮苯并三氮唑、1-丙基磷酸酐中的至少一种，优选N,N’-羰基二咪唑；
    所述溶剂选自乙醚、四氢呋喃、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、1,4-二氧六环、苯、甲苯中的一种或几种，优选二氯甲烷；
    反应体系任选含有有机碱，所述的有机碱选自三乙胺、三甲胺、二异丙基乙胺、吡啶或对二甲氨基吡啶；
    其中X、R 1、R 2如权利要求1中定义。
  13. 根据权利要求1-12任一项所述的制备方法，其特征在于R 1为甲基或苄基；R 2为C 1-C 10的直链或支链烷基；R 3为卤素取代的苯基；L为CH 2，n为1，X为溴。
  14. 根据权利要求1-12任一项所述的制备方法，其特征在于R 1为甲基；R 2为甲基；R 3为对氯苯基；L为CH 2，n为1，X为溴。
  15. 根据权利要求1-14任一项所述的制备方法，其包含以下步骤
    Figure PCTCN2019088150-appb-100008
  16. 一种式(Ⅳa)所示的化合物，
    Figure PCTCN2019088150-appb-100009
  17. 一种式(Ⅳa)所示化合物的制备方法，其特征在于包括式(Ⅴa)所示化合物在缩合剂及溶剂存在的条件下生成式(Ⅳa)所示化合物的步骤，
    Figure PCTCN2019088150-appb-100010
    其中所述缩合剂选自N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐、二环己基碳二亚胺、N-羟基琥珀酰亚胺、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、二氯亚砜、草酰氯、N,N’-羰基二咪唑、1-羟基苯并三唑、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸、1-羟基-7-偶氮苯并三氮唑、1-丙基磷酸酐中的至少一种，优选N,N’-羰基二咪唑；
    所述溶剂选自乙醚、四氢呋喃、异丙醇、二氯甲烷、N,N-二甲基甲酰胺、1,4-二氧六环、苯、甲苯中的一种或几种，优选二氯甲烷；
    反应体系任选含有有机碱，所述的有机碱选自三乙胺、三甲胺、二异丙基乙胺、吡啶或对二甲氨基吡啶中的至少一种。
  18. 一种式(Ⅲ-A)所示的化合物，
    Figure PCTCN2019088150-appb-100011
    其中R 1如权利要求1中定义。
  19. 一种式(Ⅲa)所示的化合物，
    Figure PCTCN2019088150-appb-100012
PCT/CN2019/088150 2018-05-24 2019-05-23 一种用于制备炔基吡啶类脯氨酰羟化酶抑制剂的方法 WO2019223764A1 (zh)

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