公开(公告)号：US09139507B2

公开(公告)日：2015-09-22

申请号：US14239976

申请日：2013-12-09

Applicant: KingChem LLC.

Inventor： Zheqing Wang ,  Angang Wang ,  Yongcan Wang ,  Zhenwei Li

IPC: C07D231/00 ,  C07C67/54 ,  C07C67/343 ,  C07C67/313 ,  C07D231/14

CPC classification number: C07D231/14 ,  C07C67/313 ,  C07C67/343 ,  C07C67/54 ,  C07C69/732 ,  C07C69/716 ,  C07C69/738

Abstract: The disclosure provides a process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-caboxylate and its analogs. The process includes a reaction workup method for Claisen condensation, wherein the enolate salt is acidified after removing remaining starting material and byproducts such as, ethanol and excessive ethyl acetate. The process also includes a method for completely drying alkyl difluoroacetoacetate and its analogs before use in the next step by reacting trialkyl orthoformate with the residual water. The process includes using Na2CO3 and/or K2CO3 to promote the ring-closure reaction to produce the alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. The process also includes effectively removing the regioisomer, alkyl 3-difluoromethyl-2-methyl-1H-pyrazole-4-caboxylate formed as a byproduct of the ring closure by a precipitation in a mixed solvent system and thereby eliminating the need for recrystallization of the final product.

Abstract translation: 本公开提供了制备3-二氟甲基-1-甲基-1H-吡唑-4-羧酸烷基酯及其类似物的方法。 该方法包括用于Claisen缩合的反应处理方法，其中将烯醇盐在除去剩余的原料和副产物如乙醇和过量的乙酸乙酯后酸化。 该方法还包括一种通过使三甲基原甲酸酯与残留水反应而在下一步骤中完全干燥二氟乙酰乙酸烷基酯及其类似物的方法。 该方法包括使用Na 2 CO 3和/或K 2 CO 3促进闭环反应以产生3-二氟甲基-1-甲基-1H-吡唑-4-羧酸烷基酯。 该方法还包括通过在混合溶剂体系中沉淀而有效地除去形成为闭环的副产物的区域异构体烷基3-二氟甲基-2-甲基-1H-吡唑-4-甲酰氧基化物，从而不需要重结晶 完成品。

公开(公告)号：US20150158808A1

公开(公告)日：2015-06-11

申请号：US14239976

申请日：2013-12-09

Applicant: KingChem LLC.

Inventor： Zheqing Wang ,  Angang Wang ,  Yongcan Wang ,  Zhenwei Li

IPC: C07C67/54 ,  C07C67/313 ,  C07D231/14 ,  C07C67/343

CPC classification number: C07D231/14 ,  C07C67/313 ,  C07C67/343 ,  C07C67/54 ,  C07C69/732 ,  C07C69/716 ,  C07C69/738

Abstract: The disclosure provides a process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate and its analogs. The process includes a reaction workup method for Claisen condensation, wherein the enolate salt is acidified after removing remaining starting material and byproducts such as, ethanol and excessive ethyl acetate. The process also includes a method for completely drying alkyl difluoroacetoacetate and its analogs before use in the next step by reacting trialkyl orthoformate with the residual water. The process includes using Na2CO3 and/or K2CO3 to promote the ring-closure reaction to produce the alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. The process also includes effectively removing the regioisomer, alkyl 3-difluoromethyl-2-methyl-1H-pyrazole-4-carboxylate formed as a byproduct of the ring closure by a precipitation in a mixed solvent system and thereby eliminating the need for recrystallization of the final product.

Abstract translation: 本公开提供了制备3-二氟甲基-1-甲基-1H-吡唑-4-羧酸烷基酯及其类似物的方法。 该方法包括用于Claisen缩合的反应处理方法，其中将烯醇盐在除去剩余的原料和副产物如乙醇和过量的乙酸乙酯后酸化。 该方法还包括一种通过使三甲基原甲酸酯与残留水反应而在下一步骤中完全干燥二氟乙酰乙酸烷基酯及其类似物的方法。 该方法包括使用Na 2 CO 3和/或K 2 CO 3促进闭环反应以产生3-二氟甲基-1-甲基-1H-吡唑-4-羧酸烷基酯。 该方法还包括通过在混合溶剂体系中的沉淀，有效地除去作为闭环的副产物形成的3-二氟甲基-2-甲基-1H-吡唑-4-羧酸烷基酯，从而不需要重结晶 完成品。

公开(公告)号：US08871947B2

公开(公告)日：2014-10-28

申请号：US14145073

申请日：2013-12-31

Applicant: KingChem LLC

Inventor： Zheqing Wang ,  Angang Wang

IPC: C07C67/343 ,  C07D231/14 ,  C07C67/313 ,  C07C67/36

CPC classification number: C07D231/14 ,  C07C67/313 ,  C07C67/343 ,  C07C67/36 ,  C07C69/732 ,  C07C69/738 ,  C07C69/716

Abstract: The present disclosure provides a novel and economically advantageous process for preparation of compounds of Formula I, such as alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester. The process includes acidification of the sodium enolate of alkyl difluoroacetoacetate by carbonic acid generated in situ by reacting carbon dioxide with water. The disclosure also includes promoting the ring closure reaction in which alkyl 2-alkomethylene-4,4-difluoro-3-oxobutyrate is reacted with methylhydrazine in two phase system with a weak base such as Na2CO3 or K2CO3.

Abstract translation: 本公开内容提供了制备式I化合物的新颖且经济上有利的方法，例如3-二氟甲基-1-甲基-1H-吡唑-4-甲酸烷基酯。 该方法包括通过二氧化碳与水反应原位产生的碳酸来酸化二氟乙酰乙酸烷基酯的烯醇化钠。 本公开还包括促进闭环反应，其中2-烷基亚甲基-4,4-二氟-3-氧代丁酸烷基酯与二碱系中的甲基肼与弱碱如Na 2 CO 3或K 2 CO 3反应。

公开(公告)号：US20150353501A1

公开(公告)日：2015-12-10

申请号：US14830190

申请日：2015-08-19

Applicant: KingChem LLC.

Inventor： Zheqing Wang ,  Angang Wang ,  Yongcan Wang ,  Zhenwei Li

IPC: C07D231/14

CPC classification number: C07D231/14 ,  C07C67/313 ,  C07C67/343 ,  C07C67/54 ,  C07C69/732 ,  C07C69/716 ,  C07C69/738

Abstract: The disclosure provides a process for the preparation of alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate and its analogs. The process includes a reaction workup method for Claisen condensation, wherein the enolate salt is acidified after removing remaining starting material and byproducts such as, ethanol and excessive ethyl acetate. The process also includes a method for completely drying alkyl difluoroacetoacetate and its analogs before use in the next step by reacting trialkyl orthoformate with the residual water. The process includes using Na2CO3 and/or K2CO3 to promote the ring-closure reaction to produce the alkyl 3-di-fluoromethyl-1-methyl-1H-pyrazole-4- carboxylate. The process also includes effectively removing the regioisomer, alkyl 3-difluoro methyl-2-methyl-1H-pyrazole-4-carboxylate formed as a byproduct of the ring closure by a precipitation in a mixed solvent system and thereby eliminating the need for recrystallization of the final product.

Abstract translation: 本公开提供了制备3-二氟甲基-1-甲基-1H-吡唑-4-羧酸烷基酯及其类似物的方法。 该方法包括用于Claisen缩合的反应处理方法，其中将烯醇盐在除去剩余的原料和副产物如乙醇和过量的乙酸乙酯后酸化。 该方法还包括一种通过使三甲基原甲酸酯与残留水反应而在下一步骤中完全干燥二氟乙酰乙酸烷基酯及其类似物的方法。 该方法包括使用Na 2 CO 3和/或K 2 CO 3促进闭环反应以产生3-二氟甲基-1-甲基-1H-吡唑-4-羧酸烷基酯。 该方法还包括通过在混合溶剂体系中的沉淀，有效地除去作为闭环的副产物形成的3-二氟甲基-2-甲基-1H-吡唑-4-羧酸的区域异构体，由此不需要重结晶 最终产品。

公开(公告)号：US20140221669A1

公开(公告)日：2014-08-07

申请号：US14145073

申请日：2013-12-31

Applicant: KingChem LLC

Inventor： Zheqing Wang ,  Angang Wang

IPC: C07D231/14 ,  C07C67/36 ,  C07C67/313

CPC classification number: C07D231/14 ,  C07C67/313 ,  C07C67/343 ,  C07C67/36 ,  C07C69/732 ,  C07C69/738 ,  C07C69/716

Abstract: The present disclosure provides a novel and economically advantageous process for preparation of compounds of Formula I, such as alkyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ester. The process includes acidification of the sodium enolate of alkyl difluoroacetoacetate by carbonic acid generated in situ by reacting carbon dioxide with water. The disclosure also includes promoting the ring closure reaction in which alkyl 2-alkomethylene-4,4-difluoro-3-oxobutyrate is reacted with methylhydrazine in two phase system with a weak base such as Na2CO3 or K2CO3.

Abstract translation: 本公开内容提供了制备式I化合物的新颖且经济上有利的方法，例如3-二氟甲基-1-甲基-1H-吡唑-4-甲酸烷基酯。 该方法包括通过二氧化碳与水反应原位产生的碳酸来酸化二氟乙酰乙酸烷基酯的烯醇化钠。 本公开还包括促进闭环反应，其中2-烷基亚甲基-4,4-二氟-3-氧代丁酸烷基酯与二碱系中的甲基肼与弱碱如Na 2 CO 3或K 2 CO 3反应。