WO2016180275A1 - Ahu-377 intermediates and method for preparing ahu-377 and ahu-377 intermediates - Google Patents

Ahu-377 intermediates and method for preparing ahu-377 and ahu-377 intermediates Download PDF

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WO2016180275A1
WO2016180275A1 PCT/CN2016/081244 CN2016081244W WO2016180275A1 WO 2016180275 A1 WO2016180275 A1 WO 2016180275A1 CN 2016081244 W CN2016081244 W CN 2016081244W WO 2016180275 A1 WO2016180275 A1 WO 2016180275A1
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compound
ahu
preparing
group
reaction
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王鹏
李丕旭
谷向永
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苏州鹏旭医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide

Definitions

  • the invention relates to the field of small molecule medicines, and more particularly to a preparation method of AHU-377, an AHU-377 intermediate and a preparation method of the AHU-377 intermediate.
  • AHU-377 (CAS No. 149709-62-6) is an enkephalinase inhibitor, which is a prodrug that can lose ethyl ester groups by hydrolysis and transform into pharmaceutically active LBQ657 with inhibition.
  • the role of endorphinase (NEP) the main biological effect of NEP is to invalidate the degradation of natriuretic peptide, bradykinin and other vasoactive peptides.
  • AHU-377 and angiotensin valsartan constituted LCZ696 in a molar ratio of 1:1.
  • LCZ696 is an angiotensin receptor enkephalinase inhibitor that lowers blood pressure and may become a new drug for the treatment of heart failure. Clinical data show that LCZ696 is more effective in treating hypertension than valsartan alone.
  • the reaction is based on a non-natural D-type tyrosine derivative as a substrate, which is relatively expensive, and a Pd-catalyzed Suzuki coupling reaction is used in the second step of synthesis, so the cost of AHU-377 prepared by this route is relatively high. high.
  • the succinimide is used to introduce a nitrogen atom through the Mitsunobu reaction, and the succinic acid is removed by hydrolysis with hydrochloric acid, followed by conversion to Boc protection, and in the final synthesis of AHU377.
  • the Boc is deprotected and then reacted with succinic anhydride to introduce the succinic acid moiety of the product structure, thus the atomic economy and step economics of this process are low.
  • the present invention provides a preparation method of AHU-377, an intermediate of AHU-377 and a preparation method of AHU-377 intermediate.
  • the method of the invention has the advantages of convenient operation, good safety and low cost, and is suitable for industrial production.
  • the invention provides a method of preparing AHU-377, comprising the steps of:
  • compound (3) is deprotected by a catalyst under the action of a catalyst in an organic solvent to form a compound (4);
  • the reaction temperature is -20 to 0 ° C; and/or in the step (b), the reaction temperature is -10 to 35 ° C; and/or in the step (d), the reaction temperature is -10 ⁇ 25°C; and/or in step (b), the Mitsunobu reaction is in triphenylphosphine or trimethylphosphine, and diisopropyl azodicarboxylate or diethyl azodicarboxylate or azodicarboxylic acid. It is carried out in the presence of a methyl ester.
  • the oxidizing agent is Dess-Martin periodinane or sodium hypochlorite.
  • the acid is hydrochloric acid, acetic acid or a mixture thereof.
  • the present invention provides an intermediate for the preparation of AHU-377, which is a compound represented by the following formula (III):
  • R 4 represents a C 1 -C 6 alkyl group
  • R 5 represents a substituted or unsubstituted aryl group.
  • R 4 is an ethyl group
  • R 5 is a phenyl group
  • the intermediate is specifically a compound represented by the following formula (8) or formula (9):
  • the present invention also provides a method for preparing an AHU-377 intermediate of the following formula (6), comprising the steps of: the compound (4) is hydrolyzed under acidic or basic conditions to form a compound (5) , the Boc protecting group on the compound (5) gives the compound (6),
  • the present invention provides a method for preparing an AHU-377 intermediate of the following formula (6), comprising the steps of: reacting the compound (3) with hydrazine hydrate or a strong acid or a strong base in an organic solvent; The compound (11) is produced, and the compound (11) is reacted with di-tert-butyl dicarbonate in an organic solvent to form a compound (12), and the compound (12) is formed into an organic solvent to form a compound (6) under the action of a catalyst.
  • the method for preparing the AHU-377 intermediate of formula (6) further comprises the following steps:
  • the reaction temperature is -20 to 25 ° C; and/or in the step (b), the reaction temperature is -10 to 35 ° C; and/or in the step (b), the Mitsunobu reaction It is carried out in the presence of triphenylphosphine or trimethylphosphine, and diisopropyl azodicarboxylate or diethyl azodicarboxylate or methyl azodicarboxylate.
  • the present invention also provides an intermediate for preparing the compound (6) which is a compound represented by the following formula (IV):
  • R 6 represents H or a tert-butoxycarbonyl group
  • R 7 represents a benzyl group or a substituted benzyl group
  • R 8 represents a substituted or unsubstituted aryl group.
  • R 6 is H or t-butoxycarbonyl
  • R 7 is benzyl
  • R 8 is phenyl
  • the intermediate is specifically a compound represented by the following formula (11) or (12):
  • the present invention provides a method for preparing AHU-377, which comprises using compound (6) as an intermediate, and the method further comprises preparing the compound represented by the following formula (6) by the above method (6) ,
  • the present invention also provides an intermediate for preparing AHU-377 or Compound (6) which is a compound represented by the following formula (II):
  • X is a hetero atom and the hetero atom is N or O;
  • R 1 represents H or a succinyl or phthalimido group
  • R 2 represents a benzyl group or a substituted benzyl group
  • R 3 represents a substituted or unsubstituted aryl group.
  • X is O
  • R 1 is H
  • R 2 is benzyl
  • R 3 is phenyl
  • the intermediate is specifically a compound represented by the following formula (2):
  • X is N
  • R 1 is a phthalimide group
  • R 2 is a benzyl group
  • R 3 is a phenyl group
  • the intermediate is specifically a compound represented by the following formula (3):
  • the solvent used in the above respective steps of the present invention may be replaced with another solvent having an equivalent function, and is not limited to the solvent, and those skilled in the art may selectively use it according to actual needs.
  • the starting materials and reagents used in the various steps of the present invention can be purchased commercially or synthetically according to conventional chemical means.
  • the compound (3) can be directly purchased or synthesized by the above method.
  • the present invention has the following advantages:
  • the invention provides a preparation method of AHU-377, an intermediate for preparing AHU-377 and a preparation method of an intermediate of AHU-377, and the method of the invention avoids using expensive unnatural amino acid raw material tyrosine, and is convenient and safe to operate.
  • the raw material used in the reaction route of the invention is low in price and easy to obtain, does not involve solvents harmful to the environment, and the intermediate and the product are easy to separate and purify, the route is short, the cumbersome protection and deprotection process is reduced, and it is suitable for large-scale production.
  • the order of the catalytic hydrogenation reaction and the deamination protection reaction is adjusted, and after the compound 3 is obtained, the reaction solution can be directly subjected to the amino deprotection reaction without treatment, thereby realizing the continuous operation of the reaction. Simple, efficient, and high continuous yield.
  • compound 1 (10 g, 1 eq) was added to a 500 mL three-necked flask at room temperature. After dissolving in 90 mL of THF, CuI (4.814 g, 0.1 eq) was added, and the system was moved to a low temperature bath to cool to -20 °C. At the beginning, the biphenyl magnesium bromide was added dropwise, and the internal temperature was controlled not higher than -10 °C. The cooling was turned off after the dropwise addition, and the reaction was returned to room temperature overnight. Completion of the reaction, the reaction mixture was poured into saturated NH 4 Cl (10vol, 100mL) was stirred at room temperature for 0.5h.
  • the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separating funnel to separate the liquid.
  • the aqueous phase was extracted with EA (10 vol ⁇ 2, 100 mL ⁇ 2), and the organic phases were combined, saturated NaHCO 3 , NH 4 Cl, and Brine. After washing once with 150 mL (15 vol), dried over anhydrous MgSO 4
  • the product obtained by column purification was 15.2 g, and the yield was 78%.
  • the nuclear magnetic data of the product is as follows:
  • Ph3P (18.54g, 2eq) to a 500mL three-necked flask at room temperature, dissolve in 240mL DCM, add succinimide (6.44g), compound 2 (15g), and cool to 0°C in ice water bath. Left and right, dropwise addition of DIAD (14 mL) was completed, and the reaction was transferred to room temperature for reaction. The reaction of the starting material was complete. The reaction was quenched by adding water (100 mL) to the system, and the mixture was stirred for 10 min.
  • the liquid phase was extracted with DCM (100 mL ⁇ 2), and the organic phase was combined, saturated Brine 100 mL ⁇ 2) and dried over anhydrous MgSO 4 , suction filtration, spin-drying to obtain a white solid; the product was purified by column to obtain 15.4 g, yield 82%.
  • the nuclear magnetic data of the product is as follows:
  • compound 3 (18.81 g) was added to a 1 L three-necked flask at room temperature, 470 mL of EtOH was dissolved, Pd/C was added, H 2 was replaced three times, and the mixture was transferred to an oil bath and heated at 60 ° C for reaction. The reaction of the starting material was complete, the system was removed from the oil bath, and the reaction mixture was filtered with celite and concentrated to give a crude material. The column was purified to obtain 11.8 g of pure product in a yield of 81.2%.
  • the nuclear magnetic data of the product is as follows:
  • Dess-Martin oxidant (767.7 mg) was added to a 25 mL three-necked flask at room temperature, 10 mL of DCM was dissolved, the system was cooled to -10 ° C, and 4 (500 mg) was added. The reaction of the starting material was completed. 5 mL of saturated NaHCO3 and Na2S2O3 were added to the system, and the reaction was quenched and stirred for 10 min. The aqueous phase was extracted with DCM (10 mL ⁇ 3), and the organic phase was combined, and 30 mL of saturated NaHCO3 and Brine were washed and dried over anhydrous MgSO4. Filter by suction and spin dry to obtain a crude product, which was directly used for the next reaction.
  • the nuclear magnetic data of the product is as follows:
  • the nuclear magnetic data of the product is as follows:
  • Example 8-1 Compound 4 (1 eq) was added to a reaction flask, water (2 Vol), concentrated hydrochloric acid (2 Vol), and the reaction was heated at 110 ° C overnight in an oil bath. The conversion of the starting material was complete and the HPLC peak area was 97%. Add 10% NaOH solution to adjust the pH to 10 or so, filtered products. The yield was 85%.
  • Example 8-2 Compound 4 (1 eq) was added to the reaction flask to add ethanol (5 Vol), water (5 Vol), potassium hydroxide (8 eq), and the reaction was heated at 110 ° C overnight in an oil bath. The conversion of the starting material was complete and the HPLC peak area was 99%. Water (5Vol) was added and the product was filtered. The yield was 95%. The product was dissolved in toluene, and hydrochloric acid ethanol was added to precipitate the hydrochloride salt of Compound 5.
  • the nuclear magnetic data of the product is as follows:
  • the nuclear magnetic data of the product is as follows:
  • a solution of glycidyl benzyl ether (50 g) in THF (200 mL) was prepared.
  • Biphenylmagnesium bromide (365 mmol) was added to a solution of THF (1020 mL) under inert gas and added to a reaction flask to cool in a low temperature bath at -40 °C.
  • cuprous iodide (0.1 eq) was added.
  • the internal temperature continued to drop to -23 ° C, and the THF solution of glycidyl benzyl ether was added dropwise.
  • the internal temperature of the dropwise addition process was not higher than -15 ° C, and the reaction was stirred for 47 min.
  • the system was cooled to -20 ° C and quenched with 1N aqueous HCl solution and stirred at ⁇ 10 ° C for 30 min.
  • the layers were separated and the aqueous phase was extracted with THF. Wash with saturated ammonium chloride (250 mL) and saturated brine (250 mL).
  • the THF was removed by rotary distillation, and water (200 mL) was added and the mixture was evaporated. Drain filtration to obtain a crude product.
  • the crude product was beaten by adding 2Vol n-heptane, and the product was obtained by suction filtration, the yield was 90-95%, and the HPLC peak area was 94%.
  • the column was purified to obtain a pure product, the yield of the column was 88.6%, and the HPLC was 99.1%.
  • the compound 2 (5 g) prepared in Example 9 was weighed into a reaction flask, and toluene (80 mL), phthalimide (2.55 g) and triphenylphosphine (5.35 g) were added to the reaction flask to replace the nitrogen gas. protection.
  • the ice salt bath was cooled to -5 ° C, and DIAD (4.12 g) was added dropwise. The dropping process was exothermic and the internal temperature was raised to 5 ° C.
  • the nuclear magnetic data of the product is as follows:
  • the nuclear magnetic data of the product is as follows:
  • the nuclear magnetic data of the product is as follows:
  • the nuclear magnetic data of the product is as follows:

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

Abstract

Disclosed are AHU-377 intermediates and a method for preparing AHU-377 and AHU-377 intermediates. The above-mentioned method for preparing AHU-377 uses a chiral glycidyl benzyl ether as the starting raw material. Intermediate compound (3) is produced by an addition reaction with a biphenyl Grignard reagent and a Mitsunobu reaction with a succimide or a phthalimide. Intermediate compound (4) is obtained after the benzyl protection has been removed. Intermediate compound (4) is oxidised to form an aldehyde, and then is reacted with a phosphorus ylide reagent to obtain target intermediate compound (8). Intermediate (9) is obtained under a selective catalytic hydrogenation condition. Target compound (10), i.e. AHU-377, is obtained by the hydrolysis of the single amide bond. The use of an expensive non-natural amino acid raw material tyrosine can be avoided in the method of the present application, and the method has a convenient operation and high safety.

Description

AHU-377的制备方法、AHU-377中间体及AHU-377中间体的制备方法Preparation method of AHU-377, AHU-377 intermediate and preparation method of AHU-377 intermediate 技术领域Technical field
本发明涉及小分子药物领域，更特别涉及一种AHU-377的制备方法、AHU-377中间体及AHU-377中间体的制备方法。The invention relates to the field of small molecule medicines, and more particularly to a preparation method of AHU-377, an AHU-377 intermediate and a preparation method of the AHU-377 intermediate.
背景技术Background technique
心力衰竭是一个死亡率非常高的综合征，对于心力衰竭患者，目前为止还没有药物能够显著改善死亡率和发病率，因而一种新型的治疗药物是非常必要的。AHU-377(CAS号149709-62-6)是一种脑啡肽酶抑制剂，它是一种前体药物，可以通过水解反应失去乙酯基团，转变成有药物活性的LBQ657，有抑制内啡肽酶(NEP)的作用，NEP的主要生物学效应是使钠尿肽、缓激肽和其他血管活性肽等降解失效。AHU-377与血管紧张素缬沙坦按照摩尔比1∶1组成LCZ696。LCZ696是一种血管紧张素受体脑啡肽酶抑制剂，它可以降低血压，可能成为一个治疗心力衰竭新的药物。临床数据显示，LCZ696对于治疗高血压比单独使用缬沙坦更加有效。Heart failure is a very high mortality syndrome. For patients with heart failure, no drug has been able to significantly improve mortality and morbidity so far, so a new type of treatment is very necessary. AHU-377 (CAS No. 149709-62-6) is an enkephalinase inhibitor, which is a prodrug that can lose ethyl ester groups by hydrolysis and transform into pharmaceutically active LBQ657 with inhibition. The role of endorphinase (NEP), the main biological effect of NEP is to invalidate the degradation of natriuretic peptide, bradykinin and other vasoactive peptides. AHU-377 and angiotensin valsartan constituted LCZ696 in a molar ratio of 1:1. LCZ696 is an angiotensin receptor enkephalinase inhibitor that lowers blood pressure and may become a new drug for the treatment of heart failure. Clinical data show that LCZ696 is more effective in treating hypertension than valsartan alone.
专利US 5,217,996和US 5,354,892最早报道了AHU-377的合成，合成路线如下：The synthesis of AHU-377 was first reported in US 5,217,996 and US 5,354,892. The synthetic route is as follows:
Figure PCTCN2016081244-appb-000001
Figure PCTCN2016081244-appb-000001
其反应以非天然的D型酪氨酸衍生物为底物，价格较昂贵，同时在合成第二步就要用到Pd催化的Suzuki偶联反应，因此由此路线制备的AHU-377成本较高。The reaction is based on a non-natural D-type tyrosine derivative as a substrate, which is relatively expensive, and a Pd-catalyzed Suzuki coupling reaction is used in the second step of synthesis, so the cost of AHU-377 prepared by this route is relatively high. high.
上述路线的专利US 8,115,016又报道了由焦谷氨酸出发，经过多步反应制备AHU-377的方法，该方法甲基化反应比较困难，且收率不高。专利US 8,580,974又报道了在羰基的a-位引入N，N-二甲基烯胺转化为甲基，然而上述路线对于甲基手性中心的构建都存在一些问题，不适合放大生产，合成路线如下：The above-mentioned route US Pat. No. 8,115,016 also reports a method for preparing AHU-377 from a multi-step reaction starting from pyroglutamic acid, which is difficult to methylate and has a low yield. Patent US 8,580,974 further reports the conversion of N,N-dimethylenamine into a methyl group at the a-position of a carbonyl group. However, the above route has some problems for the construction of a methyl chiral center, and is not suitable for scale-up production, synthetic routes. as follows:
Figure PCTCN2016081244-appb-000002
Figure PCTCN2016081244-appb-000002
关于最新的AHU377中间体的合成方法，专利WO2014032627A1报道了利用格氏试剂与环氧氯丙烷反应，较快捷的得到了化合物AHU377合成的重要中间体，合成路线如下：Regarding the synthesis method of the latest AHU377 intermediate, the patent WO2014032627A1 reports that the reaction of the Grignard reagent with epichlorohydrin is used to obtain an important intermediate for the synthesis of the compound AHU377, and the synthesis route is as follows:
Figure PCTCN2016081244-appb-000003
Figure PCTCN2016081244-appb-000003
然而，这个合成路线的第二步中利用丁二酰亚胺通过Mitsunobu反应引入氮原子，用盐酸水解将丁二酸除去，随后转换为Boc保护，在AHU377的最后合成过程中又要 将Boc脱保护，然后又跟丁二酸酐反应引入产品结构中的丁二酸部分，因而这种方法的原子经济性和步骤经济性都较低。However, in the second step of this synthetic route, the succinimide is used to introduce a nitrogen atom through the Mitsunobu reaction, and the succinic acid is removed by hydrolysis with hydrochloric acid, followed by conversion to Boc protection, and in the final synthesis of AHU377. The Boc is deprotected and then reacted with succinic anhydride to introduce the succinic acid moiety of the product structure, thus the atomic economy and step economics of this process are low.
发明内容Summary of the invention
为了克服现有技术中的上述问题，本发明提供了一种AHU-377的制备方法、AHU-377中间体及AHU-377中间体的制备方法。本发明的方法操作方便，安全性好且成本低，适合工业化生产。In order to overcome the above problems in the prior art, the present invention provides a preparation method of AHU-377, an intermediate of AHU-377 and a preparation method of AHU-377 intermediate. The method of the invention has the advantages of convenient operation, good safety and low cost, and is suitable for industrial production.
本发明采用的技术方案是：The technical solution adopted by the invention is:
在一方面，本发明提供一种AHU-377的制备方法，包括以下步骤：In one aspect, the invention provides a method of preparing AHU-377, comprising the steps of:
(a)化合物(1)S-缩水甘油苄醚与联苯基格氏试剂在有机溶剂中发生反应生成化合物(2)；(a) compound (1) S-glycidyl benzyl ether and biphenyl Grignard reagent reacted in an organic solvent to form compound (2);
(b)化合物(2)与丁二酰亚胺或邻苯二甲酰亚胺在有机溶剂中发生Mitsunobu反应生成化合物(3)；(b) compound (2) and succinimide or phthalimide in the organic solvent Mitsunobu reaction to form compound (3);
(c)化合物(3)在有机溶剂中在催化剂的作用下脱去苄基保护生成化合物(4)；(c) compound (3) is deprotected by a catalyst under the action of a catalyst in an organic solvent to form a compound (4);
(d)化合物(4)与氧化剂在有机溶剂中发生氧化反应生成化合物(7)；(d) compound (4) and an oxidizing agent are oxidized in an organic solvent to form compound (7);
(e)化合物(7)与磷叶立德试剂在有机溶剂中反应生成化合物(8)；(e) compound (7) and phosphorus ylide reagent are reacted in an organic solvent to form compound (8);
(f)化合物(8)在有机溶剂中选择性催化氢化生成化合物(9)；及(f) selective catalytic hydrogenation of compound (8) in an organic solvent to form compound (9);
(g)化合物(9)在有机溶剂中在酸存在的条件下发生酰胺水解反应生成化合物(10)，即AHU-377；(g) compound (9) in an organic solvent in the presence of acid amide hydrolysis reaction to form compound (10), namely AHU-377;
Figure PCTCN2016081244-appb-000004
Figure PCTCN2016081244-appb-000004
Figure PCTCN2016081244-appb-000005
Figure PCTCN2016081244-appb-000005
优选地，步骤(a)中，反应温度为-20～0℃；和/或步骤(b)中，反应温度为-10～35℃；和/或步骤(d)中，反应温度为-10～25℃；和/或步骤(b)中，所述Mitsunobu反应在三苯基膦或三甲基膦，和偶氮二甲酸二异丙酯或偶氮二甲酸二乙酯或偶氮二甲酸甲酯存在的条件下进行。Preferably, in the step (a), the reaction temperature is -20 to 0 ° C; and/or in the step (b), the reaction temperature is -10 to 35 ° C; and/or in the step (d), the reaction temperature is -10 ～25°C; and/or in step (b), the Mitsunobu reaction is in triphenylphosphine or trimethylphosphine, and diisopropyl azodicarboxylate or diethyl azodicarboxylate or azodicarboxylic acid. It is carried out in the presence of a methyl ester.
优选地，在步骤(d)中，所述氧化剂为戴斯-马丁氧化剂或次氯酸钠。Preferably, in step (d), the oxidizing agent is Dess-Martin periodinane or sodium hypochlorite.
优选地，在步骤(g)中，所述酸为盐酸、醋酸或其混合物。Preferably, in step (g), the acid is hydrochloric acid, acetic acid or a mixture thereof.
在另一方面，本发明还提供一种制备AHU-377的中间体，其为如下式(III)所示的化合物：In another aspect, the present invention provides an intermediate for the preparation of AHU-377, which is a compound represented by the following formula (III):
Figure PCTCN2016081244-appb-000006
Figure PCTCN2016081244-appb-000006
其中，R4表示C1-C6烷基；Wherein R 4 represents a C 1 -C 6 alkyl group;
R5表示取代或未取代芳基基团。R 5 represents a substituted or unsubstituted aryl group.
优选地，R4为乙基，R5为苯基，所述中间体具体为如下式(8)或式(9)所示的化合物：Preferably, R 4 is an ethyl group, R 5 is a phenyl group, and the intermediate is specifically a compound represented by the following formula (8) or formula (9):
Figure PCTCN2016081244-appb-000007
Figure PCTCN2016081244-appb-000007
在又一方面，本发明还提供一种如下式(6)的AHU-377中间体的制备方法，包括以下步骤：化合物(4)在酸性或碱性条件下在发生水解反应生成化合物(5)，化合物(5)上Boc保护基得到化合物(6)， In still another aspect, the present invention also provides a method for preparing an AHU-377 intermediate of the following formula (6), comprising the steps of: the compound (4) is hydrolyzed under acidic or basic conditions to form a compound (5) , the Boc protecting group on the compound (5) gives the compound (6),
Figure PCTCN2016081244-appb-000008
Figure PCTCN2016081244-appb-000008
在又一方面，本发明还提供一种如下式(6)的AHU-377中间体的制备方法，包括以下步骤：化合物(3)与水合肼或强酸或强碱条件下，在有机溶剂中反应生成化合物(11)，化合物(11)与二碳酸二叔丁酯在有机溶剂中反应生成化合物(12)，化合物(12)在有机溶剂中在催化剂的作用下生成化合物(6)，In still another aspect, the present invention provides a method for preparing an AHU-377 intermediate of the following formula (6), comprising the steps of: reacting the compound (3) with hydrazine hydrate or a strong acid or a strong base in an organic solvent; The compound (11) is produced, and the compound (11) is reacted with di-tert-butyl dicarbonate in an organic solvent to form a compound (12), and the compound (12) is formed into an organic solvent to form a compound (6) under the action of a catalyst.
Figure PCTCN2016081244-appb-000009
Figure PCTCN2016081244-appb-000009
优选地，式(6)的AHU-377中间体的制备方法还包括以下步骤：Preferably, the method for preparing the AHU-377 intermediate of formula (6) further comprises the following steps:
(a)化合物(1)S-缩水甘油苄醚与联苯基格氏试剂在有机溶剂中发生反应生成化合物(2)；(a) compound (1) S-glycidyl benzyl ether and biphenyl Grignard reagent reacted in an organic solvent to form compound (2);
(b)化合物(2)与邻苯二甲酰亚胺在有机溶剂中发生Mitsunobu反应生成化合物(3)。(b) The compound (2) and the phthalimide are subjected to a Mitsunobu reaction in an organic solvent to give a compound (3).
更优选地，步骤(a)中，反应温度为-20～25℃；和/或步骤(b)中，反应温度为-10～35℃；和/或步骤(b)中，所述Mitsunobu反应在三苯基膦或三甲基膦，和偶氮二甲酸二异丙酯或偶氮二甲酸二乙酯或偶氮二甲酸甲酯存在的条件下进行。More preferably, in the step (a), the reaction temperature is -20 to 25 ° C; and/or in the step (b), the reaction temperature is -10 to 35 ° C; and/or in the step (b), the Mitsunobu reaction It is carried out in the presence of triphenylphosphine or trimethylphosphine, and diisopropyl azodicarboxylate or diethyl azodicarboxylate or methyl azodicarboxylate.
在又一方面，本发明还提供一种制备化合物(6)的中间体，其为如下式(IV)所示的化合物： In still another aspect, the present invention also provides an intermediate for preparing the compound (6) which is a compound represented by the following formula (IV):
Figure PCTCN2016081244-appb-000010
Figure PCTCN2016081244-appb-000010
其中，R6表示H或叔丁氧羰基；Wherein R 6 represents H or a tert-butoxycarbonyl group;
R7表示苄基或取代苄基；R 7 represents a benzyl group or a substituted benzyl group;
R8表示取代或未取代芳基基团。R 8 represents a substituted or unsubstituted aryl group.
优选地，R6为H或叔丁氧羰基，R7为苄基，R8为苯基，所述中间体具体为如下式(11)或(12)所示的化合物：Preferably, R 6 is H or t-butoxycarbonyl, R 7 is benzyl, R 8 is phenyl, and the intermediate is specifically a compound represented by the following formula (11) or (12):
Figure PCTCN2016081244-appb-000011
Figure PCTCN2016081244-appb-000011
在又一方面，本发明还提供一种AHU-377的制备方法，采用化合物(6)为中间体，所述方法还包括采用上述的方法来制备如下式(6)所示的化合物(6)，In still another aspect, the present invention provides a method for preparing AHU-377, which comprises using compound (6) as an intermediate, and the method further comprises preparing the compound represented by the following formula (6) by the above method (6) ,
Figure PCTCN2016081244-appb-000012
Figure PCTCN2016081244-appb-000012
在又一方面，本发明还提供一种制备AHU-377或化合物(6)的中间体，其为如下式(II)所示的化合物： In still another aspect, the present invention also provides an intermediate for preparing AHU-377 or Compound (6) which is a compound represented by the following formula (II):
Figure PCTCN2016081244-appb-000013
Figure PCTCN2016081244-appb-000013
其中，X为杂原子，所述杂原子为N或O；Wherein X is a hetero atom and the hetero atom is N or O;
R1表示H或丁二酰基或邻苯二甲酰亚胺基；R 1 represents H or a succinyl or phthalimido group;
R2表示苄基或取代苄基；R 2 represents a benzyl group or a substituted benzyl group;
R3表示取代或未取代芳基基团。R 3 represents a substituted or unsubstituted aryl group.
优选地，X为O，R1为H，R2为苄基，R3为苯基，所述中间体具体为如下式(2)所示的化合物：Preferably, X is O, R 1 is H, R 2 is benzyl, R 3 is phenyl, and the intermediate is specifically a compound represented by the following formula (2):
Figure PCTCN2016081244-appb-000014
Figure PCTCN2016081244-appb-000014
优选地，X为N，R1为邻苯二甲酰亚胺基，R2为苄基，R3为苯基，所述中间体具体为如下式(3)所示的化合物：Preferably, X is N, R 1 is a phthalimide group, R 2 is a benzyl group, and R 3 is a phenyl group, and the intermediate is specifically a compound represented by the following formula (3):
Figure PCTCN2016081244-appb-000015
Figure PCTCN2016081244-appb-000015
其中，在本发明的上述各步骤中所使用的溶剂可使用具有等同功能的其他溶剂代替，而不限于所述溶剂，本领域技术人员可根据实际需要选择性使用。 Among them, the solvent used in the above respective steps of the present invention may be replaced with another solvent having an equivalent function, and is not limited to the solvent, and those skilled in the art may selectively use it according to actual needs.
本发明中各步骤所使用的原料和试剂均可通过商业途径购买，也可根据常规化学手段合成，例如化合物(3)可直接购买，也可通过上述方法合成。The starting materials and reagents used in the various steps of the present invention can be purchased commercially or synthetically according to conventional chemical means. For example, the compound (3) can be directly purchased or synthesized by the above method.
与现有技术相比，本发明具有以下优点：Compared with the prior art, the present invention has the following advantages:
本发明提供了AHU-377的制备方法、制备AHU-377的中间体及AHU-377的中间体的制备方法，本发明的方法避免使用昂贵的非天然氨基酸原料酪氨酸，且操作方便，安全性好，本发明的反应路线使用的原料价格低廉易得，不涉及对环境有害的溶剂，中间体及产物分离纯化容易，路线较短，减少了繁琐的保护去保护过程，适合大规模生产。The invention provides a preparation method of AHU-377, an intermediate for preparing AHU-377 and a preparation method of an intermediate of AHU-377, and the method of the invention avoids using expensive unnatural amino acid raw material tyrosine, and is convenient and safe to operate. The raw material used in the reaction route of the invention is low in price and easy to obtain, does not involve solvents harmful to the environment, and the intermediate and the product are easy to separate and purify, the route is short, the cumbersome protection and deprotection process is reduced, and it is suitable for large-scale production.
其中，用来制备中间体化合物6的合成路线3中调整了催化氢化反应和去氨基保护反应的顺序，得到化合物3后反应液可以不经过处理直接进行氨基去保护反应，实现反应的连续操作，简单，高效，连续反应收率较高。Wherein, in the synthesis route 3 for preparing the intermediate compound 6, the order of the catalytic hydrogenation reaction and the deamination protection reaction is adjusted, and after the compound 3 is obtained, the reaction solution can be directly subjected to the amino deprotection reaction without treatment, thereby realizing the continuous operation of the reaction. Simple, efficient, and high continuous yield.
具体实施方式detailed description
下面结合具体实施例对本发明作进一步详细说明，以便本领域技术人员可更好地理解本发明，从而对本发明的保护范围做出更为清楚明确的界定。The present invention will be further described in detail with reference to the specific embodiments thereof, so that those skilled in the art can understand the invention.
实施例1Example 1
合成化合物2Synthetic compound 2
Figure PCTCN2016081244-appb-000016
Figure PCTCN2016081244-appb-000016
在惰性气体保护下，室温下向500mL三口瓶中加入化合物1(10g，1eq)，90mL THF溶解后，再加入CuI(4.814g，0.1eq)，将体系移至低温浴槽中降温至-20℃时，开始滴加联苯基溴化镁，控制内温不高于-10℃。滴毕关闭制冷，恢复至室温反应过夜。反应完全，将反应液倒入饱和NH4Cl(10vol，100mL)中室温下搅拌0.5h。抽滤，滤饼用少量EA淋洗，滤液转移至分液漏斗中分液，水相用EA(10vol×2，100mL×2)萃取，合并有机相，饱和NaHCO3、NH4Cl、Brine各150mL(15vol)洗一次，无水MgSO4干燥，抽滤，浓缩得到白色固体。过柱纯化得产品15.2g，收率78％。Under the protection of inert gas, compound 1 (10 g, 1 eq) was added to a 500 mL three-necked flask at room temperature. After dissolving in 90 mL of THF, CuI (4.814 g, 0.1 eq) was added, and the system was moved to a low temperature bath to cool to -20 °C. At the beginning, the biphenyl magnesium bromide was added dropwise, and the internal temperature was controlled not higher than -10 °C. The cooling was turned off after the dropwise addition, and the reaction was returned to room temperature overnight. Completion of the reaction, the reaction mixture was poured into saturated NH 4 Cl (10vol, 100mL) was stirred at room temperature for 0.5h. After suction filtration, the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separating funnel to separate the liquid. The aqueous phase was extracted with EA (10 vol × 2, 100 mL × 2), and the organic phases were combined, saturated NaHCO 3 , NH 4 Cl, and Brine. After washing once with 150 mL (15 vol), dried over anhydrous MgSO 4 The product obtained by column purification was 15.2 g, and the yield was 78%.
产物的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.57(d，J＝7.6Hz，2H)，7.52(d，J＝8.1Hz，2H)，7.42(t， J＝7.6Hz，2H)，7.38-7.25(m，8H)，4.62-4.47(m，2H)，4.09(dd，J＝6.7，3.5Hz，1H)，3.54(dd，J＝9.5，3.5Hz，1H)，3.43(dd，J＝9.4，6.9Hz，1H)，2.84(d，J＝6.6Hz，2H)，2.38(s，1H)。 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 7.6Hz, 2H), 7.52 (d, J = 8.1Hz, 2H), 7.42 (t, J = 7.6Hz, 2H), 7.38-7.25 (m, 8H), 4.62-4.47 (m, 2H), 4.09 (dd, J = 6.7, 3.5 Hz, 1H), 3.54 (dd, J = 9.5, 3.5 Hz, 1H), 3.43 (dd, J = 9.4 , 6.9 Hz, 1H), 2.84 (d, J = 6.6 Hz, 2H), 2.38 (s, 1H).
实施例2Example 2
合成化合物3Synthetic compound 3
Figure PCTCN2016081244-appb-000017
Figure PCTCN2016081244-appb-000017
在惰性气体保护，在室温下向500mL三口瓶中加入Ph3P(18.54g，2eq)，240mL DCM溶解，再加入丁二酰亚胺(6.44g)、化合物2(15g)，冰水浴降温至0℃左右，滴加DIAD(14mL)滴加完毕，将反应转至室温反应。原料反应完全，向体系中加入水(100mL)淬灭反应，搅拌10min；分液，水相用DCM(100mL×2)萃取，合并有机相，饱和Brine 100mL×2)洗，无水MgSO4干燥，抽滤，旋干得到白色固体；过柱纯化得产品15.4g，收率82％。Under inert gas protection, add Ph3P (18.54g, 2eq) to a 500mL three-necked flask at room temperature, dissolve in 240mL DCM, add succinimide (6.44g), compound 2 (15g), and cool to 0°C in ice water bath. Left and right, dropwise addition of DIAD (14 mL) was completed, and the reaction was transferred to room temperature for reaction. The reaction of the starting material was complete. The reaction was quenched by adding water (100 mL) to the system, and the mixture was stirred for 10 min. The liquid phase was extracted with DCM (100 mL×2), and the organic phase was combined, saturated Brine 100 mL×2) and dried over anhydrous MgSO 4 , suction filtration, spin-drying to obtain a white solid; the product was purified by column to obtain 15.4 g, yield 82%.
产物的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.56(d，J＝7.4Hz，2H)，7.49(d，J＝8.0Hz，2H)，7.42(t，J＝7.6Hz，2H)，7.37-7.30(m，3H)，7.27(d，J＝6.7Hz，3H)，7.22(d，J＝8.0Hz，2H)，4.75(s，1H)，4.56(d，J＝12.0Hz，1H)，4.45(d，J＝12.0Hz，1H)，4.06(t，J＝9.6Hz，1H)，3.70(dd，J＝10.0，5.2Hz，1H)，3.23(dd，J＝13.8，10.3Hz，1H)，3.14-3.00(m，1H)，2.48(d，J＝4.0Hz.4H)。 1 H NMR (400MHz, CDCl 3 ) δ7.56 (d, J = 7.4Hz, 2H), 7.49 (d, J = 8.0Hz, 2H), 7.42 (t, J = 7.6Hz, 2H), 7.37-7.30 (m, 3H), 7.27 (d, J = 6.7 Hz, 3H), 7.22 (d, J = 8.0 Hz, 2H), 4.75 (s, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.06 (t, J = 9.6 Hz, 1H), 3.70 (dd, J = 10.0, 5.2 Hz, 1H), 3.23 (dd, J = 13.8, 10.3 Hz, 1H) , 3.14-3.00 (m, 1H), 2.48 (d, J = 4.0 Hz. 4H).
实施例3Example 3
合成化合物4 Synthetic compound 4
Figure PCTCN2016081244-appb-000018
Figure PCTCN2016081244-appb-000018
惰性气体保护，室温下向1L三口瓶中加入化合物3(18.81g)，470mL EtOH溶解，加入Pd/C，置换H2三次，移至油浴上加热60℃反应。原料反应完全，将体系移出油浴，反应液用硅藻土抽滤，浓缩得粗品。过柱纯化得纯品11.8g，收率81.2％。Under inert gas protection, compound 3 (18.81 g) was added to a 1 L three-necked flask at room temperature, 470 mL of EtOH was dissolved, Pd/C was added, H 2 was replaced three times, and the mixture was transferred to an oil bath and heated at 60 ° C for reaction. The reaction of the starting material was complete, the system was removed from the oil bath, and the reaction mixture was filtered with celite and concentrated to give a crude material. The column was purified to obtain 11.8 g of pure product in a yield of 81.2%.
产物的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.57(d，J＝7.8Hz，2H)，7.51(d，J＝7.8Hz，2H)，7.42(t，J＝7.5Hz，2H)，7.33(t，J＝7.2Hz，1H)，7.26(d，J＝7.2Hz，2H)，4.55(d，J＝5.2Hz，1H)，4.06-3.97(m，1H)，3.86(dd，J＝12.0，3.1Hz，1H)，3.16(dd，J＝8.1，2.9Hz，2H)，2.58(t，J＝7.0Hz，4H)，1.26(s，2H)。 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 7.8Hz, 2H), 7.51 (d, J = 7.8Hz, 2H), 7.42 (t, J = 7.5Hz, 2H), 7.33 (t , J = 7.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 2H), 4.55 (d, J = 5.2 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.86 (dd, J = 12.0, 3.1 Hz, 1H), 3.16 (dd, J = 8.1, 2.9 Hz, 2H), 2.58 (t, J = 7.0 Hz, 4H), 1.26 (s, 2H).
实施例4Example 4
合成化合物7Synthetic compound 7
Figure PCTCN2016081244-appb-000019
Figure PCTCN2016081244-appb-000019
惰性气体保护，室温下向25mL三口瓶中加入Dess-Martin氧化剂(767.7mg)，10mL DCM溶解，体系降温至-10℃，加入4(500mg)。原料反应完全，向体系中加入饱和NaHCO3和Na2S2O3各5mL，淬灭反应，搅拌10min；水相用DCM(10mL×3)萃取，合并有机相，饱和NaHCO3、Brine各30mL洗，无水MgSO4干燥，抽滤，旋干得到粗品，直接用于投下一步反应。 Under inert gas protection, Dess-Martin oxidant (767.7 mg) was added to a 25 mL three-necked flask at room temperature, 10 mL of DCM was dissolved, the system was cooled to -10 ° C, and 4 (500 mg) was added. The reaction of the starting material was completed. 5 mL of saturated NaHCO3 and Na2S2O3 were added to the system, and the reaction was quenched and stirred for 10 min. The aqueous phase was extracted with DCM (10 mL×3), and the organic phase was combined, and 30 mL of saturated NaHCO3 and Brine were washed and dried over anhydrous MgSO4. Filter by suction and spin dry to obtain a crude product, which was directly used for the next reaction.
实施例5Example 5
合成化合物8Synthetic compound 8
Figure PCTCN2016081244-appb-000020
Figure PCTCN2016081244-appb-000020
惰性气体保护，室温下向500mL三口瓶中加入7(497.5mg)，10mL DCM溶解冰水浴降温，加入磷叶立德试剂(880.6mg)，将体系移出冰水浴，室温下反应。原料反应完全停止反应，向体系中加入水(5mL)淬灭反应。分液，水相用DCM(10mL×2)萃取，合并有机相，饱和Brine 20mL×2洗，无水MgSO4干燥，抽滤，旋干得粗品。过柱纯化得产品563mg，产率90％。Under inert gas protection, 7 (497.5 mg) was added to a 500 mL three-necked flask at room temperature, and 10 mL of DCM was dissolved in an ice water bath to cool, and phosphorus ylide reagent (880.6 mg) was added, and the system was removed from the ice water bath and reacted at room temperature. The reaction of the starting material was completely stopped, and water (5 mL) was added to the system to quench the reaction. The mixture was separated and the aqueous phase was extracted with DCM (10 mL×2). The product was purified by column to obtain 563 mg, yield 90%.
产物的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.60-7.53(m，2H)，7.51(d，J＝8.1Hz，2H)，7.42(t，J＝7.6Hz，2H)，7.33(d，J＝7.3Hz，1H)，7.23(d，J＝8.1Hz，2H)，7.13(dd，J＝9.2，1.5Hz，1H)，5.26(td，J＝9.5，6.9Hz，1H)，4.25-4.05(m，2H)，3.40(dd，J＝13.7，9.7Hz，1H)，3.13(dd，J＝13.8，6.7Hz，1H)，2.53(d，J＝2.2Hz，4H)，1.85(d，J＝1.4Hz，3H)，1.30(t，J＝7.1Hz，3H)。 1 H NMR (400MHz, CDCl 3 ) δ7.60-7.53 (m, 2H), 7.51 (d, J = 8.1Hz, 2H), 7.42 (t, J = 7.6Hz, 2H), 7.33 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.13 (dd, J = 9.2, 1.5 Hz, 1H), 5.26 (td, J = 9.5, 6.9 Hz, 1H), 4.25-4.05 ( m, 2H), 3.40 (dd, J = 13.7, 9.7 Hz, 1H), 3.13 (dd, J = 13.8, 6.7 Hz, 1H), 2.53 (d, J = 2.2 Hz, 4H), 1.85 (d, J) = 1.4 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H).
实施例6Example 6
合成化合物9Synthetic compound 9
Figure PCTCN2016081244-appb-000021
Figure PCTCN2016081244-appb-000021
惰性气体保护，室温下向50mL三口瓶中加入8(365mg，1eq)，9mL乙醇搅拌溶解，将体系用氢气置换三次，加入Pd/C(25％w/w)室温下反应。原料反应完全停止 反应，向体系中加入水(5mL)淬灭反应。反应液用硅藻土抽滤，浓缩得粗品。过柱纯化得产品，收率80.2％，纯度97.2％。Under inert gas protection, 8 (365 mg, 1 eq) was added to a 50 mL three-necked flask at room temperature, and 9 mL of ethanol was stirred and dissolved. The system was replaced with hydrogen three times, and Pd/C (25% w/w) was added to react at room temperature. The raw material reaction completely stopped The reaction was quenched by the addition of water (5 mL) to the system. The reaction solution was suction filtered with Celite, and evaporated. The product was purified by column, the yield was 80.2%, and the purity was 97.2%.
实施例7Example 7
合成化合物10Synthetic compound 10
Figure PCTCN2016081244-appb-000022
Figure PCTCN2016081244-appb-000022
向装有化合物9(100mg)的反应瓶中加入醋酸(9mL)，盐酸(1mL)。油浴加热80℃反应。原料反应完全停止反应，向体系中加入水(5mL)淬灭反应。饱和NaHCO3中和后用EA萃取浓缩得粗品。过柱纯化得产品90mg，收率84％。To a reaction flask containing Compound 9 (100 mg) was added acetic acid (9 mL) and hydrochloric acid (1 mL). The oil bath was heated at 80 ° C for reaction. The reaction of the starting material was completely stopped, and water (5 mL) was added to the system to quench the reaction. After neutralization with saturated NaHCO3, it was concentrated with EA to give a crude material. The product was purified by column chromatography to give a product (yield: 84%).
产物的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.61-7.54(m，2H)，7.53-7.48(m，2H)，7.41(dd，J＝10.5，4.9Hz，2H)，7.31(dd，J＝8.3，6.4Hz，1H)，7.22(d，J＝8.2Hz，2H)，5.93(t，J＝9.7Hz，1H)，4.34-4.00(m，3H)，2.91-2.71(m，2H)，2.68-2.57(m，2H)，2.55(ddd，J＝9.4，7.0，4.3Hz，1H)，2.42(dt，J＝13.3，6.8Hz，2H)，1.97-1.74(m，1H)，1.64-1.46(m，1H)，1.23(td，J＝7.1，3.3Hz，3H)，1.14(dd，J＝7.1，3.9Hz，3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 - 7.54 (m, 2H), 7.53 - 7.48 (m, 2H), 7.41 (dd, J = 10.5, 4.9 Hz, 2H), 7.31 (dd, J = 8.3 , 6.4 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 5.93 (t, J = 9.7 Hz, 1H), 4.34 - 4.00 (m, 3H), 2.91-2.71 (m, 2H), 2.68 -2.57 (m, 2H), 2.55 (ddd, J = 9.4, 7.0, 4.3 Hz, 1H), 2.42 (dt, J = 13.3, 6.8 Hz, 2H), 1.97-1.74 (m, 1H), 1.64-1.46 (m, 1H), 1.23 (td, J = 7.1, 3.3 Hz, 3H), 1.14 (dd, J = 7.1, 3.9 Hz, 3H).
实施例8Example 8
合成化合物5Synthetic compound 5
Figure PCTCN2016081244-appb-000023
Figure PCTCN2016081244-appb-000023
例8-1：反应瓶中加入化合物4(1eq)加入水(2Vol)，浓盐酸(2Vol)，油浴加热110℃反应过夜，原料转化完全，HPLC峰面积97％。加入10％的NaOH溶液调节pH至 10左右，过滤得产品。收率85％。Example 8-1: Compound 4 (1 eq) was added to a reaction flask, water (2 Vol), concentrated hydrochloric acid (2 Vol), and the reaction was heated at 110 ° C overnight in an oil bath. The conversion of the starting material was complete and the HPLC peak area was 97%. Add 10% NaOH solution to adjust the pH to 10 or so, filtered products. The yield was 85%.
例8-2：反应瓶中加入化合物4(1eq)加入乙醇(5Vol)，水(5Vol)，氢氧化钾(8eq)，油浴加热110℃反应过夜，原料转化完全，HPLC峰面积99％。加入水(5Vol)，过滤得产品。收率95％。产品溶于甲苯，加入盐酸乙醇，析出化合物5的盐酸盐。Example 8-2: Compound 4 (1 eq) was added to the reaction flask to add ethanol (5 Vol), water (5 Vol), potassium hydroxide (8 eq), and the reaction was heated at 110 ° C overnight in an oil bath. The conversion of the starting material was complete and the HPLC peak area was 99%. Water (5Vol) was added and the product was filtered. The yield was 95%. The product was dissolved in toluene, and hydrochloric acid ethanol was added to precipitate the hydrochloride salt of Compound 5.
产物的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，DMSO)δ8.31(s，3H)，7.70-7.61(m，4H)，7.47(t，J＝7.6Hz，2H)，7.42-7.31(m，3H)，4.09(dq，J＝42.6，7.1Hz，1H)，3.62-3.51(m，1H)，3.50-3.41(m，1H)，3.11-3.00(m，1H)，2.95-2.84(m，1H)，1.30-1.10(m，1H)。 1 H NMR (400MHz, DMSO) δ8.31 (s, 3H), 7.70-7.61 (m, 4H), 7.47 (t, J = 7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (dq , J=42.6, 7.1 Hz, 1H), 3.62-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.11-3.00 (m, 1H), 2.95-2.84 (m, 1H), 1.30-1.10 (m, 1H).
实施例9Example 9
合成化合物6Synthetic compound 6
Figure PCTCN2016081244-appb-000024
Figure PCTCN2016081244-appb-000024
向反应器中加入化合物5，加入无水乙醇(3vol)。外温设置30℃加热，内温达到25℃后继续搅拌20min。加入30％NaOH水溶液(1.1eq)。外温设置65℃加热，内温达到60℃后慢慢加入(Boc)2O(1.1eq)。搅拌0.5h，反应监测。反应完成后慢慢滴加入水(8vol)，关闭加热，自然降温。体系温度降至25℃后继续搅拌2h。过滤，滤饼于50℃鼓风烘箱烘干得产品。Compound 5 was added to the reactor and absolute ethanol (3 vol) was added. The external temperature was set to 30 ° C for heating, and the internal temperature reached 25 ° C and stirring was continued for 20 min. A 30% aqueous NaOH solution (1.1 eq) was added. The external temperature was set to 65 ° C for heating, and after the internal temperature reached 60 ° C, (Boc) 2 O (1.1 eq) was slowly added. Stir for 0.5 h and monitor the reaction. After the reaction was completed, water (8 vol) was slowly added dropwise, and the heating was turned off to naturally cool down. Stirring was continued for 2 h after the temperature of the system was lowered to 25 °C. After filtration, the filter cake was dried in a blast oven at 50 ° C to obtain a product.
产品的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.61-7.50(m，4H)，7.61-7.50(m，4H)，7.46-7.39(m，2H)，7.48-7.38(m，2H)，7.38-7.23(m，3H)，7.37-7.26(m，3H)，4.82(d，J＝7.9Hz，1H)，4.82(d，J＝7.9Hz，1H)，3.91(s，1H)，3.70(d，J＝11.0Hz，1H)，3.77-3.54(m，2H)，3.65-3.47(m，1H)，2.88(d，J＝7.0Hz，2H)，2.88(d，J＝7.0Hz，2H)，2.51(s，1H)，2.51(s，1H)，1.42(s，9H)，1.42(s，9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 (m, 3H), 4.82 (d, J = 7.9 Hz, 1H), 4.82 (d, J = 7.9 Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0 Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0 Hz, 2H), 2.88 (d, J = 7.0 Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).
以化合物6为中间体合成化合物10，即AHU-377，的合成路线在本发明背景技术所引用的专利申请WO2014032627A1中有详细加载，在此不做赘述。The synthetic route for the synthesis of the compound 10, that is, AHU-377, using the compound 6 as an intermediate is described in detail in the patent application WO2014032627A1, which is incorporated herein by reference.
实施例10Example 10
合成化合物2 Synthetic compound 2
Figure PCTCN2016081244-appb-000025
Figure PCTCN2016081244-appb-000025
配制缩水甘油苄醚(50g)的THF(200mL)溶液。在惰性气体保护下，将联苯基溴化镁(365mmol)加入到THF(1020mL)溶液中，加入反应瓶中置于-40℃的低温浴槽中降温。内温降至-9℃时加入碘化亚铜(0.1eq)。内温继续降至-23℃开始滴加缩水甘油苄醚的THF溶液，滴加过程控制内温不高于-15℃，用时47min，加毕关闭制冷搅拌反应过夜。将体系降温至-20℃用1N HCl水溶液淬灭，＜10℃搅拌30min转至室温。分液，水相用THF萃取，合并THF相。分别用饱和氯化铵(250mL)，饱和食盐水(250mL)洗。旋蒸除去THF，加入水(200mL)继续旋蒸1h，降温析出固体。抽滤得粗品。粗品加入2Vol正庚烷打浆，抽滤得产品，收率90～95％，HPLC峰面积94％。再过柱纯化得纯品，过柱收率88.6％，HPLC 99.1％。A solution of glycidyl benzyl ether (50 g) in THF (200 mL) was prepared. Biphenylmagnesium bromide (365 mmol) was added to a solution of THF (1020 mL) under inert gas and added to a reaction flask to cool in a low temperature bath at -40 °C. When the internal temperature dropped to -9 ° C, cuprous iodide (0.1 eq) was added. The internal temperature continued to drop to -23 ° C, and the THF solution of glycidyl benzyl ether was added dropwise. The internal temperature of the dropwise addition process was not higher than -15 ° C, and the reaction was stirred for 47 min. The system was cooled to -20 ° C and quenched with 1N aqueous HCl solution and stirred at < 10 ° C for 30 min. The layers were separated and the aqueous phase was extracted with THF. Wash with saturated ammonium chloride (250 mL) and saturated brine (250 mL). The THF was removed by rotary distillation, and water (200 mL) was added and the mixture was evaporated. Drain filtration to obtain a crude product. The crude product was beaten by adding 2Vol n-heptane, and the product was obtained by suction filtration, the yield was 90-95%, and the HPLC peak area was 94%. The column was purified to obtain a pure product, the yield of the column was 88.6%, and the HPLC was 99.1%.
实施例11Example 11
合成化合物3Synthetic compound 3
Figure PCTCN2016081244-appb-000026
Figure PCTCN2016081244-appb-000026
称取实施例9制备的化合物2(5g)加入反应瓶中，向反应瓶中加入甲苯(80mL)、邻苯二甲酰亚胺(2.55g)和三苯基膦(5.35g)，置换氮气保护。冰盐浴降温至-5℃，滴加DIAD(4.12g)，滴加过程放热，内温升高至5℃。继续反应1h取样HPLC测试原料基本反应完全。加入12g硅旋干过柱收集产品(含DIEA衍生物)。 The compound 2 (5 g) prepared in Example 9 was weighed into a reaction flask, and toluene (80 mL), phthalimide (2.55 g) and triphenylphosphine (5.35 g) were added to the reaction flask to replace the nitrogen gas. protection. The ice salt bath was cooled to -5 ° C, and DIAD (4.12 g) was added dropwise. The dropping process was exothermic and the internal temperature was raised to 5 ° C. Continue the reaction for 1 h sampling and HPLC test the starting material to complete the reaction. Add 12 g of silicon to dry the column to collect the product (containing DIEA derivative).
实施例12Example 12
合成化合物11Synthetic compound 11
Figure PCTCN2016081244-appb-000027
Figure PCTCN2016081244-appb-000027
取实施例10制备的化合物3(3g)加至反应瓶中，加入乙醇(30mL)，搅拌。再加入水合肼(2g)油浴加热回流反应1h，体系搅拌困难时补加20mL乙醇，继续反应至2.5h，HPLC显示原料反应完全。加入EA/H2O各100mL分液，水相用EA(100mL)萃取，有机相分别用水(100mL)和饱和食盐水(100mL)洗。无水硫酸镁干燥过滤旋干过柱得产品1.88g，收率88％，HPLC 94％。Compound 3 (3 g) prepared in Example 10 was added to a reaction flask, and ethanol (30 mL) was added and stirred. After further adding hydrazine hydrate (2 g) oil bath and refluxing for 1 hour, when the system was difficult to stir, 20 mL of ethanol was added, and the reaction was continued until 2.5 h. HPLC showed that the starting material was completely reacted. 100 mL of each of EA/H2O was added, the aqueous phase was extracted with EA (100 mL), and the organic phase was washed with water (100 mL) and brine (100 mL). Drying with anhydrous magnesium sulfate and spinning through a column to obtain a product 1.88 g, yield 88%, HPLC 94%.
产品的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，DMSO)δ7.64(d，J＝7.2Hz，2H)，7.57(d，J＝8.1Hz，2H)，7.45(t，J＝7.6Hz，2H)，7.39-7.32(m，5H)，7.29(d，J＝8.1Hz，3H)，4.55-4.43(m，2H)，3.38-3.23(m，3H)，3.18-3.10(m，1H)，2.82-2.74(m，1H)，2.61-2.52(m，1H)。 1 H NMR (400MHz, DMSO) δ7.64 (d, J = 7.2Hz, 2H), 7.57 (d, J = 8.1Hz, 2H), 7.45 (t, J = 7.6Hz, 2H), 7.39-7.32 ( m,5H), 7.29 (d, J=8.1Hz, 3H), 4.55-4.43 (m, 2H), 3.38-3.23 (m, 3H), 3.18-3.10 (m, 1H), 2.82-2.74 (m, 1H), 2.61-2.52 (m, 1H).
实施例13Example 13
合成化合物11Synthetic compound 11
Figure PCTCN2016081244-appb-000028
Figure PCTCN2016081244-appb-000028
向化合物2的甲苯溶液中，加入邻苯二甲酰亚胺(1.1eq)，加入三苯基膦(1.3eq)搅拌。外浴设置-10℃，给体系降温，内温降至0～5℃，开始滴加DIAD(1.3eq)，控制内温-5～5℃。滴加完成，关闭外浴制冷，在室温条件下搅拌反应。搅拌反应1～4小时。得到化合物3的反应液，直接投下一步反应。向上述反应液中加入水合肼(6eq)，加热至70～80℃，至反应完全，热过滤，取滤液。加入氢氧化钠水溶液(20vol 10％)搅拌0.5h，静置分液取甲苯相。加入水(20vol)搅拌0.5h，静置分液取甲苯相。甲苯相加入盐酸(20vol，3N)，搅拌0.5h，生成固体沉淀。过滤，烘干得到产品，即化合物11，的盐酸盐，两步反应收率60％。To a toluene solution of Compound 2, phthalimide (1.1 eq) was added, and triphenylphosphine (1.3 eq) was added and stirred. The external bath was set to -10 ° C, the system was cooled, the internal temperature was reduced to 0 ~ 5 ° C, DIAD (1.3 eq) was added dropwise, and the internal temperature was controlled -5 to 5 °C. After the dropwise addition was completed, the outer bath was closed and the reaction was stirred at room temperature. The reaction was stirred for 1 to 4 hours. The reaction liquid of the compound 3 was obtained, and the next reaction was directly carried out. To the above reaction liquid, hydrazine hydrate (6 eq) was added, and the mixture was heated to 70 to 80 ° C until the reaction was completed, and the mixture was filtered while hot. Aqueous sodium hydroxide solution (20 vol 10%) was added and stirred for 0.5 h, and the mixture was allowed to stand for liquid separation to obtain a toluene phase. Water (20 vol) was added and stirred for 0.5 h, and the liquid was separated to obtain a toluene phase. The toluene phase was added with hydrochloric acid (20 vol, 3 N) and stirred for 0.5 h to give a solid precipitate. Filtration and drying gave the product, Compound 11, the hydrochloride salt, and the yield of the two-step reaction was 60%.
产品的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，DMSO)δ8.46(s，3H)，7.63(dd，J＝16.4，7.7Hz，4H)，7.47(t，J＝7.6Hz，2H)，7.42-7.22(m，8H)，4.56(d，J＝12.1Hz，1H)，4.48(d，J＝12.1Hz，1H)，3.58(d，J＝7.9Hz，2H)，3.47(dd，J＝10.9，6.3Hz，1H)，3.11(dd，J＝13.5，4.9Hz，1H)，2.92(dd，J＝13.4，9.1Hz，1H)。 1 H NMR (400MHz, DMSO) δ8.46 (s, 3H), 7.63 (dd, J = 16.4,7.7Hz, 4H), 7.47 (t, J = 7.6Hz, 2H), 7.42-7.22 (m, 8H ), 4.56 (d, J = 12.1 Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H), 3.58 (d, J = 7.9 Hz, 2H), 3.47 (dd, J = 10.9, 6.3 Hz, 1H) ), 3.11 (dd, J = 13.5, 4.9 Hz, 1H), 2.92 (dd, J = 13.4, 9.1 Hz, 1H).
实施例14Example 14
合成化合物12Synthetic compound 12
Figure PCTCN2016081244-appb-000029
Figure PCTCN2016081244-appb-000029
称取化合物11(1.38g)加到反应瓶中。向反应瓶中加DCM(14ml)和Et3N(462mg，0.73ml)。称取(Boc)2O(1.23g)加到DCM(5ml)中溶解。室温(8℃)下，将(Boc)2O的DCM溶液滴加到反应中，用DCM(2ml)涮洗。室温下搅拌反应，通过HPLC检测，4h反应结束。用水(15ml)洗涤反应液3次，用Brine(15ml)洗涤反应液1次。无机盐干燥，浓缩后PE∶EA＝15∶1过柱纯化，得产品560mg，收率30.8％，HPLC 99.92％。Compound 11 (1.38 g) was weighed into a reaction flask. DCM (14 ml) and Et3N (462 mg, 0.73 ml) were added to the reaction flask. (Boc) 2 O (1.23 g) was weighed and dissolved in DCM (5 ml). A solution of (Boc) 2 O in DCM was added dropwise to EtOAc (2 mL). The reaction was stirred at room temperature and detected by HPLC. The reaction solution was washed three times with water (15 ml), and the mixture was washed twice with brine (15 ml). The inorganic salt was dried, and after concentration, PE:EA=15:1 was purified by column to obtain 560 mg of product, yield 30.8%, HPLC 99.92%.
产品的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.57(d，J＝7.6Hz，2H)，7.49(d，J＝7.4Hz，2H)，7.43(t，J＝7.3Hz，2H)，7.39-7.28(m，5H)，7.24(d，J＝9.0Hz，3H)，5.00-4.80(br，1H)，4.51(q，J＝11.8Hz，2H)，4.08-3.85(br，1H)， 3.43(d，J＝2.9Hz，2H)，3.02-2.77(m，2H)，1.42(s，9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 7.6Hz, 2H), 7.49 (d, J = 7.4Hz, 2H), 7.43 (t, J = 7.3Hz, 2H), 7.39-7.28 (m, 5H), 7.24 (d, J = 9.0 Hz, 3H), 5.00 - 4.80 (br, 1H), 4.51 (q, J = 11.8 Hz, 2H), 4.08 - 3.85 (br, 1H), 3.43 ( d, J = 2.9 Hz, 2H), 3.02 - 2.77 (m, 2H), 1.42 (s, 9H).
实施例15Example 15
合成化合物6Synthetic compound 6
Figure PCTCN2016081244-appb-000030
Figure PCTCN2016081244-appb-000030
称取化合物12(250mg)和甲醇(9ml)加到反应瓶中。加Pd/C(138mg、1/4w/w、含水量55％)。H2置换3次，50℃加热搅拌反应。HPLC检测反应，30h反应结束。过滤除去Pd/C，40℃减压浓缩除去甲醇。PE∶EA＝3∶1过柱纯化，得产品196mg，收率100％，纯度99.34％。Compound 12 (250 mg) and methanol (9 ml) were weighed into a reaction flask. Pd/C (138 mg, 1/4 w/w, water content 55%) was added. The H 2 was replaced 3 times, and the reaction was stirred with heating at 50 °C. The reaction was detected by HPLC and the reaction was completed in 30 h. Pd/C was removed by filtration, and concentrated under reduced pressure at 40 ° C to remove methanol. PE:EA=3:1 was purified by column to obtain 196 mg of product, yield 100%, purity 99.34%.
产品的核磁数据如下：The nuclear magnetic data of the product is as follows:
1H NMR(400MHz，CDCl3)δ7.61-7.50(m，4H)，7.61-7.50(m，4H)，7.46-7.39(m，2H)，7.48-7.38(m，2H)，7.38-7.23(m，3H)，7.37-7.26(m，3H)，4.82(d，J＝7.9Hz，1H)，4.82(d，J＝7.9Hz，1H)，3.91(s，1H)，3.70(d，J＝11.0Hz，1H)，3.77-3.54(m，2H)，3.65-3.47(m，1H)，2.88(d，J＝7.0Hz，2H)，2.88(d，J＝7.0Hz，2H)，2.51(s，1H)，2.51(s，1H)，1.42(s，9H)，1.42(s，9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 (m, 3H), 4.82 (d, J = 7.9 Hz, 1H), 4.82 (d, J = 7.9 Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0 Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0 Hz, 2H), 2.88 (d, J = 7.0 Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).
以上对本发明的特定实施例进行了说明，但本发明的保护内容不仅仅限定于以上实施例，在本发明的所属技术领域中，只要掌握通常知识，就可以在其技术要旨范围内进行多种多样的变更。 The specific embodiments of the present invention have been described above, but the protection content of the present invention is not limited to the above embodiments. In the technical field of the present invention, as long as the general knowledge is grasped, various types can be performed within the scope of the technical gist thereof. Variety of changes.

Claims (16)

  1. 一种AHU-377的制备方法，其特征在于，包括以下步骤：A method for preparing AHU-377, comprising the steps of:
    (a)化合物(1)S-缩水甘油苄醚与联苯基格氏试剂在有机溶剂中发生反应生成化合物(2)；(a) compound (1) S-glycidyl benzyl ether and biphenyl Grignard reagent reacted in an organic solvent to form compound (2);
    (b)化合物(2)与丁二酰亚胺或邻苯二甲酰亚胺在有机溶剂中发生Mitsunobu反应生成化合物(3)；(b) compound (2) and succinimide or phthalimide in the organic solvent Mitsunobu reaction to form compound (3);
    (c)化合物(3)在有机溶剂中在催化剂的作用下脱去苄基保护生成化合物(4)；(c) compound (3) is deprotected by a catalyst under the action of a catalyst in an organic solvent to form a compound (4);
    (d)化合物(4)与氧化剂在有机溶剂中发生氧化反应生成化合物(7)；(d) compound (4) and an oxidizing agent are oxidized in an organic solvent to form compound (7);
    (e)化合物(7)与磷叶立德试剂在有机溶剂中反应生成化合物(8)；(e) compound (7) and phosphorus ylide reagent are reacted in an organic solvent to form compound (8);
    (f)化合物(8)在有机溶剂中选择性催化氢化生成化合物(9)；及(f) selective catalytic hydrogenation of compound (8) in an organic solvent to form compound (9);
    (g)化合物(9)在有机溶剂中在酸存在的条件下发生酰胺水解反应生成化合物(10)，即AHU-377；(g) compound (9) in an organic solvent in the presence of acid amide hydrolysis reaction to form compound (10), namely AHU-377;
    Figure PCTCN2016081244-appb-100001
    Figure PCTCN2016081244-appb-100001
  2. 根据权利要求1所述的AHU-377的制备方法，其特征在于：步骤(a)中，反应温度为-20～0℃；和/或步骤(b)中，反应温度为-10～35℃；和/或步骤(d)中，反应温度为-10～25℃；和/或步骤(b)中，所述Mitsunobu反应在三苯基瞵或三甲基瞵，和偶氮二甲酸二异丙酯或偶氮二甲酸二乙酯或偶氮二甲酸甲酯存在的条件下进行。 The method for preparing AHU-377 according to claim 1, wherein in the step (a), the reaction temperature is -20 to 0 ° C; and/or in the step (b), the reaction temperature is -10 to 35 ° C. And/or in step (d), the reaction temperature is -10 to 25 ° C; and / or in step (b), the Mitsunobu reaction is in triphenylsulfonium or trimethylsulfonium, and azodicarboxylic acid diiso It is carried out in the presence of propyl ester or diethyl azodicarboxylate or methyl azodicarboxylate.
  3. 根据权利要求1所述的AHU-377的制备方法，其特征在于：在步骤(d)中，所述氧化剂为戴斯-马丁氧化剂或次氯酸钠。The method of preparing AHU-377 according to claim 1, wherein in the step (d), the oxidizing agent is Dess-Martin periodinane or sodium hypochlorite.
  4. 根据权利要求1所述的AHU-377的制备方法，其特征在于：在步骤(g)中，所述酸为盐酸、醋酸或其混合物。The method for producing AHU-377 according to claim 1, wherein in the step (g), the acid is hydrochloric acid, acetic acid or a mixture thereof.
  5. 一种制备AHU-377的中间体，其为如下式(III)所示的化合物：An intermediate for the preparation of AHU-377 which is a compound of the following formula (III):
    Figure PCTCN2016081244-appb-100002
    Figure PCTCN2016081244-appb-100002
    其中，R4表示C1-C6烷基；Wherein R 4 represents a C 1 -C 6 alkyl group;
    R5表示取代或未取代芳基基团。R 5 represents a substituted or unsubstituted aryl group.
  6. 根据权利要求5所述的制备AHU-377的中间体，其特征在于：R4为乙基，R5为苯基，所述中间体具体为如下式(8)或式(9)所示的化合物：The intermediate for preparing AHU-377 according to claim 5, wherein R 4 is an ethyl group and R 5 is a phenyl group, and the intermediate is specifically represented by the following formula (8) or formula (9). Compound:
    Figure PCTCN2016081244-appb-100003
    Figure PCTCN2016081244-appb-100003
  7. 一种如下式(6)的AHU-377中间体的制备方法，其特征在于，包括以下步骤：化合物(4)在酸性或碱性条件下在发生水解反应生成化合物(5)，化合物(5)上Boc保护基得到化合物(6)， A method for preparing an AHU-377 intermediate of the following formula (6), which comprises the steps of: the compound (4) is hydrolyzed under acidic or basic conditions to form a compound (5), the compound (5) The above Boc protecting group gives the compound (6),
    Figure PCTCN2016081244-appb-100004
    Figure PCTCN2016081244-appb-100004
  8. 一种如下式(6)的AHU-377中间体的制备方法，其特征在于，包括以下步骤：化合物(3)与水合肼或强酸或强碱条件下，在有机溶剂中反应生成化合物(11)，化合物(11)与二碳酸二叔丁酯在有机溶剂中反应生成化合物(12)，化合物(12)在有机溶剂中在催化剂的作用下生成化合物(6)，A method for preparing an AHU-377 intermediate of the following formula (6), which comprises the steps of: reacting a compound (3) with a hydrazine hydrate or a strong acid or a strong base in an organic solvent to form a compound (11) Compound (11) is reacted with di-tert-butyl dicarbonate in an organic solvent to form compound (12), and compound (12) is formed into an organic compound in the presence of a catalyst to form compound (6).
    Figure PCTCN2016081244-appb-100005
    Figure PCTCN2016081244-appb-100005
  9. 根据权利要求8所述的AHU-377中间体的制备方法，其特征在于，还包括以下步骤：The method for preparing an AHU-377 intermediate according to claim 8, further comprising the steps of:
    (a)化合物(1)S-缩水甘油苄醚与联苯基格氏试剂在有机溶剂中发生反应生成化合物(2)；(a) compound (1) S-glycidyl benzyl ether and biphenyl Grignard reagent reacted in an organic solvent to form compound (2);
    (b)化合物(2)与丁二酰亚胺或邻苯二甲酰亚胺在有机溶剂中发生Mitsunobu反应生成化合物(3)。(b) Compound (2) is reacted with succinimide or phthalimide in an organic solvent to form compound (3).
  10. 根据权利要求9所述的AHU-377中间体的制备方法，其特征在于，The method for preparing an AHU-377 intermediate according to claim 9, wherein
    步骤(a)中，反应温度为-20～25℃；和/或步骤(b)中，反应温度为-10～35℃；和/或步骤(b)中，所述Mitsunobu反应在三苯基瞵或三甲基瞵，和偶氮二甲酸二异丙酯或偶氮二甲酸二乙酯或偶氮二甲酸甲酯存在的条件下进行。In the step (a), the reaction temperature is -20 to 25 ° C; and/or in the step (b), the reaction temperature is -10 to 35 ° C; and/or in the step (b), the Mitsunobu reaction is in the triphenyl group. It is carried out in the presence of hydrazine or trimethyl hydrazine, and diisopropyl azodicarboxylate or diethyl azodicarboxylate or methyl azodicarboxylate.
  11. 一种制备化合物(6)的中间体，其为如下式(IV)所示的化合物： An intermediate for preparing compound (6) which is a compound represented by the following formula (IV):
    Figure PCTCN2016081244-appb-100006
    Figure PCTCN2016081244-appb-100006
    其中，R6表示H或叔丁氧羰基；Wherein R 6 represents H or a tert-butoxycarbonyl group;
    R7表示苄基或取代苄基；R 7 represents a benzyl group or a substituted benzyl group;
    R8表示取代或未取代芳基基团。R 8 represents a substituted or unsubstituted aryl group.
  12. 根据权利要求11所述的制备化合物(6)的中间体，其特征在于：R6为H或叔丁氧羰基，R7为苄基，R8为苯基，所述中间体具体为如下式(11)或(12)所示的化合物：The intermediate for preparing the compound (6) according to claim 11, wherein R 6 is H or a tert-butoxycarbonyl group, R 7 is a benzyl group, and R 8 is a phenyl group, and the intermediate is specifically the following formula: Compounds shown in (11) or (12):
    Figure PCTCN2016081244-appb-100007
    Figure PCTCN2016081244-appb-100007
  13. 一种AHU-377的制备方法，采用化合物(6)为中间体，其特征在于：所述方法还包括采用权利要求7至10中任一项权利要求所述的方法来制备如下式(6)所示的化合物(6)，A method for preparing AHU-377, which comprises using compound (6) as an intermediate, characterized in that the method further comprises the following formula (6) by using the method according to any one of claims 7 to 10. Compound (6) shown,
    Figure PCTCN2016081244-appb-100008
    Figure PCTCN2016081244-appb-100008
  14. 一种制备AHU-377或化合物(6)的中间体，其为如下式(II)所示的化合物： An intermediate for the preparation of AHU-377 or compound (6) which is a compound represented by the following formula (II):
    Figure PCTCN2016081244-appb-100009
    Figure PCTCN2016081244-appb-100009
    其中，X为杂原子，所述杂原子为N或O；Wherein X is a hetero atom and the hetero atom is N or O;
    R1表示H或丁二酰基或邻苯二甲酰亚胺基；R 1 represents H or a succinyl or phthalimido group;
    R2表示苄基或取代苄基；R 2 represents a benzyl group or a substituted benzyl group;
    R3表示取代或未取代芳基基团。R 3 represents a substituted or unsubstituted aryl group.
  15. 根据权利要求14所述的制备AHU-377或化合物(6)的中间体，其特征在于：X为O，R1为H，R2为苄基，R3为苯基，所述中间体具体为如下式(2)所示的化合物：The intermediate for preparing AHU-377 or compound (6) according to claim 14, wherein X is O, R 1 is H, R 2 is benzyl, R 3 is phenyl, and the intermediate is specifically Is a compound represented by the following formula (2):
    Figure PCTCN2016081244-appb-100010
    Figure PCTCN2016081244-appb-100010
  16. 根据权利要求14所述的制备AHU-377或化合物(6)的中间体，其特征在于：X为N，R1为邻苯二甲酰亚胺基，R2为苄基，R3为苯基，所述中间体具体为如下式(3)所示的化合物：The intermediate for preparing AHU-377 or compound (6) according to claim 14, wherein X is N, R 1 is a phthalimide group, R 2 is a benzyl group, and R 3 is a benzene group. The intermediate is specifically a compound represented by the following formula (3):
    Figure PCTCN2016081244-appb-100011
    Figure PCTCN2016081244-appb-100011
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