Patents Assigned to Zhejiang Huahai Pharmaceutical Co., Ltd.
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Patent number: 10189760Abstract: Disclosed is a method for synthesizing a sitagliptin intermediate, the method comprising: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce a compound of formula I, wherein, an R- or S-configuration of a stereocenter is represented by *; the compound of formula I of R configuration can be used to prepare sitagliptin, and a reaction formula is as follows: R1 and R2 are each independently selected from hydrogen, C1-C12 linear or branched alkyl, C3-C12 cycloalkyl, C2-C12 alkenyl, C2-C12 alkynyl and C7-C12 arylalkyl. The method has a high yield and a high ee % value, a mild reaction condition and a low production cost, and is simple to operate, convenient to purify, environmental friendly and suitable for industrial production.Type: GrantFiled: October 9, 2015Date of Patent: January 29, 2019Assignees: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD., SHANGHAI SYNCORES TECHNOLOGIES INC. LTD.Inventors: Jian Hong, Yusheng Wang, Boyu Wang, Luning Huang, Eric Gu
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Patent number: 10173965Abstract: The present invention provides a method for preparing a pregabalin intermediate 3-carbamoymethyl-5-methylhexanoic acid without solvent. The method comprises the following steps: a) cooling an ammonia water system to a certain temperature; b) adding 3-isobutylglutaric anhydride dropwise to the system, then keeping temperature, and reacting; c) after completing the reaction, adding an acid to the system to adjust pH; d) after adjusting pH, cooling, then keeping temperature, crystallizing, then suction filtering and drying; and e) adding a solvent to the dried substance, slurrying, and suction filtering and drying to obtain the final product. The method provided in the present invention for preparing 3-carbamoymethyl-5-methylhexanoic acid is high-yield, green, environmentally-friendly, simple and convenient, and of less pollution.Type: GrantFiled: March 25, 2016Date of Patent: January 8, 2019Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD.Inventors: Musong Liu, Wenling Zhang, Peng Wang
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Patent number: 10131625Abstract: The present invention provides a method for recycling 3-carbamoylmethyl-5-methylhexanoic acid from 3-carba carbamoylmethyl moymethyl-5-methylhexanoic acid chiral resolving mother liquor. The method comprises the following steps: (a) distilling 3-carbamoylmethyl-5-methylhexanoic acid chiral resolving mother liquor, adding aromatic hydrocarbon, heating to dissolve, keeping the temperature and stirring; (b) after completing the reaction in step (a), cooling the reaction solution to 30-60° C., then adding alkali liquor dropwise, keeping the temperature and reacting; and (c) after completing the reaction in step (b), cooling the reactant to 20-30° C., layering, adjusting the pH of the separated water layer to 1 to 2, performing extraction by using an organic solvent, distilling an organic phase under a reduced pressure, and crystallizing at 0±5° C. to obtain 3-carbamoylmethyl-5-methylhexanoic acid.Type: GrantFiled: October 13, 2015Date of Patent: November 20, 2018Assignee: Zhejiang Huahai Pharmaceutical Co., Ltd.Inventors: Shudong Wang, Xuehai You, Wenling Zhang
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Publication number: 20180250305Abstract: Provided are a type of compounds that can be used for treating cardiovascular diseases and compositions containing the compounds. The compounds and the compositions can improve lipid metabolism disorders by increasing high-density lipoprotein cholesterol in blood; in addition, the compounds and the compositions can also release nitric oxide, and reduce the onset risk of cardiovascular diseases by means of relaxing blood vessels, lowering blood pressure, inhibiting platelet adhesion and aggregation and maintaining vascular tension, and thus play an important role in preventing and treating the occurrence and development of cardiovascular diseases.Type: ApplicationFiled: September 6, 2016Publication date: September 6, 2018Applicants: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD., SHANGHAI SYNERGY PHARMACEUTICAL SCIENCES CO., LTDInventors: Jian GE, Yunfei LI, Zhen ZHANG, Yijin WANG, Jiamiao WANG, Tao CHENG
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Publication number: 20180155326Abstract: The present invention uses a candesartan cyclic compound as a starting material and performs thereon a three-step reaction of forming tetrazole, hydrolysis and adding a protecting group to directly obtain trityl candesartan without separating an intermediate product via crystallization. The operating process is simple and thus is more applicable to industrial production.Type: ApplicationFiled: June 5, 2015Publication date: June 7, 2018Applicant: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD.Inventors: Enmin Lin, Mengjian Mou, Guoliang Tu, Wenfeng Huang
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Patent number: 9951036Abstract: Provide in the present invention is a method for preparing canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene. The method comprises a compound, shown as formula (II), of (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]ketone being reduced under the action of a directly used borane solution or borane locally produced by reacting alkali metal borohydride with a Lewis acid in a suitable solvent and at a suitable temperature, so as to obtain the compound of formula (I) of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene. The preparation method avoids the use of expensive reductive agents and guarantees the complete conversion of raw materials, wherein the post-treatment is simple, the purity of product obtained is high, the reaction yield is high, in the preparation method is simple and convenient, and can easily be used in industry.Type: GrantFiled: June 19, 2015Date of Patent: April 24, 2018Assignees: SHANGHAI SYNCORES TECHNOLOGIES INC. LTD., ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTDInventors: Wenjing Liao, Xiaowen Guo, Luning Huang, Eric Gu
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Patent number: 9926286Abstract: The present invention provides a new intermediate II and a method for synthesizing the same. The method comprises: (a) firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain an intermediate II; and (b) reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V. The intermediate II can be used for synthesizing Vortioxetine.Type: GrantFiled: March 25, 2015Date of Patent: March 27, 2018Assignees: SHANGHAI SYNCORES TECHNOLOGIES INC. LTD., ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTDInventors: Caide Tang, Gang Wang, Boyu Wang, Luning Huang, Eric Gu
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Patent number: 9873651Abstract: Disclosed is a method for synthesizing a sitagliptin intermediate, the method comprising: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce a compound of formula I, wherein, an R- or S-configuration of a stereocenter is represented by *; the compound of formula I of R configuration can be used to prepare sitagliptin, and a reaction formula is as follows: R1 and R2 are each independently selected from hydrogen, C1-C12 linear or branched alkyl, C3-C12 cycloalkyl, C2-C12 alkenyl, C2-C12 alkynyl and C7-C12 arylalkyl. The method has a high yield and a high ee % value, a mild reaction condition and a low production cost, and is simple to operate, convenient to purify, environmental friendly and suitable for industrial production.Type: GrantFiled: October 9, 2015Date of Patent: January 23, 2018Assignees: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD, SHANGHAI SYNCORES TECHNOLOGIES INC. LTD.Inventors: Jian Hong, Yusheng Wang, Boyu Wang, Luning Huang, Eric Gu
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Publication number: 20170334836Abstract: The present invention provides a method for recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor. The method comprises the following steps: (a) distilling 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor, adding aromatic hydrocarbon, heating to dissolve, keeping the temperature and stirring; (b) after completing the reaction in step (a), cooling the reaction solution to 30-60° C., then adding alkali liquor dropwise, keeping the temperature and reacting; and (c) after completing the reaction in step (b), cooling the reactant to 20-30° C., layering, adjusting the pH of the separated water layer to 1 to 2, performing extraction by using an organic solvent, distilling an organic phase under a reduced pressure, and crystallizing at 0±5° C. to obtain 3-carbamoymethyl-5-methylhexanoic acid. The method provided in the present invention is convenient to operate, and the recycled product is high in purity (?99.8%) and yield.Type: ApplicationFiled: October 13, 2015Publication date: November 23, 2017Applicant: Zhejiang Huahai Pharmaceutical Co., Ltd.Inventors: Shudong Wang, Xuehai You, Wenling Zhang
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Patent number: 9815801Abstract: The present invention relates to a method of refining valsartan comprising more than or equal to 10% D-isomers, the method comprising: adding a solvent to valsartan comprising more than or equal to 10% D-isomers to dissolve it, then adding a certain amount of inorganic base, separating solids out after salification, distilling a filtrate after filtration, and distilling the filtrate to remove the organic solvent; adjusting the pH of the filtrate with an acid, extracting with an organic solvent, concentrating most of the organic solvent, cooling to crystallize, and obtaining the product. The method enables isomers of the product to be below 0.5%, and produce a yield of more than or equal to 40%, being suitable for industrial production.Type: GrantFiled: February 15, 2015Date of Patent: November 14, 2017Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD.Inventors: Yongbi Chen, Wenling Zhang, Peng Wang, Jian Chen
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Publication number: 20170305822Abstract: Disclosed is a method for synthesizing a sitagliptin intermediate, the method comprising: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce a compound of formula I, wherein, an R- or S-configuration of a stereocenter is represented by *; the compound of formula I of R configuration can be used to prepare sitagliptin, and a reaction formula is as follows: R1 and R2 are each independently selected from hydrogen, C1-C12 linear or branched alkyl, C3-C12 cycloalkyl, C2-C12 alkenyl, C2-C12 alkynyl and C7-C12 arylalkyl. The method has a high yield and a high ee % value, a mild reaction condition and a low production cost, and is simple to operate, convenient to purify, environmental friendly and suitable for industrial production.Type: ApplicationFiled: October 9, 2015Publication date: October 26, 2017Applicants: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD., SHANGHAI SYNCORES TECHNOLOGIES INC.LTD.Inventors: Jian Hong, Yusheng Wang, Boyu Wang, Luning Huang, Eric Gu
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Patent number: 9745264Abstract: Provided is a method for preparing silodosin. Also provided is a method for preparing an organic acid salt of a new intermediate 3-(7-cyano-5-((R)-2-((R)-1-phenylethylamino)propyl)-1-hydrogen-indolyl) propyl alcohol (ester or ether), and a new intermediate 3-(7-cyano-5-((R)-2-(((R)-1-phenethyl)(2-(2-(trifluoroethoxy)phenoxy) ethyl)amino)propyl)1-hydrogen-indolyl)propyl alcohol (ester or ether) and a salt thereof. The method has the following advantages: raw materials are cheap and easy to obtain, the operation is simple, the intermediate and product are easy to purify, the yield is high, and the method is applicable to industrial production.Type: GrantFiled: October 20, 2014Date of Patent: August 29, 2017Assignees: Shanghai Syncores Technologies, Inc., Zhejiang Huahai Pharmaceuticals Co., Ltd.Inventors: Hong Gu, Jian Cao, Liushan Chen, Luning Huang
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Patent number: 9656958Abstract: The invention relates to a method for synthesizing an intermediate of Apixaban comprising reacting a compound of formula I with 5-chloro-valeryl chloride in the presence of inorganic base in an inert solvent to obtain a compound of formula II, with the reaction formula of (A), wherein R is selected from nitro group and the group (B). The method is mild in reaction condition, simple in operation, easy in purification, inexpensive in production cost, environmental-friendly, and suitable for industrial production.Type: GrantFiled: July 29, 2014Date of Patent: May 23, 2017Assignees: Shanghai Syncores Technologies Inc. Ltd., Zhejiang Huahai Pharmaceutical Co., Ltd.Inventors: Boyu Wang, Jinfeng Yao, Luning Huang, Jeannie Zhang
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Publication number: 20170044129Abstract: Provide in the present invention is a method for preparing canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene. The method comprises a compound, shown as formula (II), of (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]ketone being reduced under the action of a directly used borane solution or borane locally produced by reacting alkali metal borohydride with a Lewis acid in a suitable solvent and at a suitable temperature, so as to obtain the compound of formula (I) of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene. The preparation method avoids the use of expensive reductive agents and guarantees the complete conversion of raw materials, wherein the post-treatment is simple, the purity of product obtained is high, the reaction yield is high, in the preparation method is simple and convenient, and can easily be used in industry.Type: ApplicationFiled: June 19, 2015Publication date: February 16, 2017Applicants: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD., SHANGHAI SYNCORES TECHNOLOGIES INC. LTD., SHANGHAI SYNCORES TECHNOLOGIES INC. LTD.Inventors: Wenjing Liao, Xiaowen Guo, Luning Huang, Eric Gu
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Patent number: 9126990Abstract: The present invention discloses novel methods for synthesizing Rivaroxaban intermediate, i.e., 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one. The novel methods provided in the present invention involve mild reaction conditions, convenient operations, easy purification, and low production costs, and thus the process is environmental-friendly and suitable for industrial production.Type: GrantFiled: January 18, 2012Date of Patent: September 8, 2015Assignees: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD, SHANGHAI SYNCORES TECHNOLOGIES, INC.Inventors: Chunpeng Zi, Luning Huang, Jeannie Zhang
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Patent number: 9120782Abstract: A method for preparation of iloperidone is provided which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride with 1-[4-(3-chloropropoxyl)-3-methoxyphenyl]ethyl ketone in an inorganic alkaline aqueous solution. A crystallization method of iloperidone is also provided which comprises adding seed crystal to the iloperidone solution in ethyl acetate, and then iloperidone crystal is obtained with high purity by controlling the temperature and the stirring speed.Type: GrantFiled: February 26, 2014Date of Patent: September 1, 2015Assignee: Zhejiang Huahai Pharmaceutical Co., Ltd.Inventors: Shiwei Zhou, Feng Jian
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Patent number: 9067867Abstract: Disclosed is a process for preparing 5-aminosalicylic acid by gas phase catalytic carboxylation, characterized in that carbon dioxide is introduced into a system of p-acetaminophenol and a basic compound at a temperature of 150° C.˜220° C. and a pressure of 0.5˜5.0 MPa in the presence of a catalyst, so as to carry out a gas phase catalytic carboxylation reaction to form a 5-aminosalicylate, and the crude product 5-aminosalicylate is separated, and then acidified to prepare 5-aminosalicylic acid (5-ASA). Since the gas phase catalytic reaction replaces a solid phase thermo-chemical reaction, the reaction is significantly improved in terms of the process flow, reaction conditions, product quality and energy consumption. In addition, the reaction has a short reaction time, good selectivity, high yield and no formation of wastes during the reaction, and is suitable for industrial production.Type: GrantFiled: October 20, 2011Date of Patent: June 30, 2015Assignees: Zhejiang Huahai Pharmaceutical Co., Ltd., Huazhong University Of Science And TechnologyInventors: Guangxing Li, Jinjin Li, Dajian Zhu, Qiang Jiang, Lingli Cai, Yong Xie, Lixin Gan
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Patent number: 9067965Abstract: A method for preparing rocuronium is disclosed. 2?-(4-Morpholinyl)-16?-(1-pyrrolidinyl)-5?-androstan-3?-ol-17?-acetate is used as a starting material and is directly reacted with 3-bromopropene at ambient temperature to produce rocuronium.Type: GrantFiled: January 26, 2011Date of Patent: June 30, 2015Assignee: Zhejiang Huahai Pharmaceutical Co., Ltd.Inventors: Zhiwen Zeng, Wenling Zhang, Peng Wang, Xini Zhang
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Patent number: 9024013Abstract: Provided is a method for purifying rocuronium bromide, which comprises: formulating crude rocuronium bromide to be purified into an aqueous solution, distilling off excess residue solvents at reduced pressure, absorbing by adding active carbon or silica gel, then filtrating, quick freezing the filtrate into ice, and then lyophilizing to obtain rocuronium bromide.Type: GrantFiled: April 25, 2011Date of Patent: May 5, 2015Assignee: Zhejiang Huahai Pharmaceutical Co., LtdInventors: Zhiwen Zeng, Peng Wang, Wenling Zhang, Xini Zhang
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Patent number: 8802855Abstract: A method for preparation of iloperidone is provided which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride with 1-[4-(3-chloropropoxyl)-3-methoxyphenyl]ethyl ketone in an inorganic alkaline aqueous solution. A crystallization method of iloperidone is also provided which comprises adding seed crystal to the iloperidone solution in ethyl acetate, and then iloperidone crystal is obtained with high purity by controlling the temperature and the stirring speed.Type: GrantFiled: June 21, 2010Date of Patent: August 12, 2014Assignee: Zhejiang Huahai Pharmaceutical Co., Ltd.Inventors: Shiwei Zhou, Feng Jian