TWI465428B - 製備反式４－胺基－環己基乙酸乙酯ｈｃ１之方法 - Google Patents
製備反式４－胺基－環己基乙酸乙酯ｈｃ１之方法 Download PDFInfo
- Publication number
- TWI465428B TWI465428B TW098142928A TW98142928A TWI465428B TW I465428 B TWI465428 B TW I465428B TW 098142928 A TW098142928 A TW 098142928A TW 98142928 A TW98142928 A TW 98142928A TW I465428 B TWI465428 B TW I465428B
- Authority
- TW
- Taiwan
- Prior art keywords
- trans
- amino
- temperature
- acetic acid
- hydrogenation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 5
- SBVCDGKSVSHGFL-KYZUINATSA-N CCOC(=O)C[C@H]1CC[C@H](N)CC1 Chemical compound CCOC(=O)C[C@H]1CC[C@H](N)CC1 SBVCDGKSVSHGFL-KYZUINATSA-N 0.000 title 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- XVDSFSRMHSDHGJ-UHFFFAOYSA-N 2-(4-azaniumylcyclohexyl)acetate Chemical compound NC1CCC(CC(O)=O)CC1 XVDSFSRMHSDHGJ-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- -1 4-aminophenyl group Chemical group 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- XVDSFSRMHSDHGJ-LJGSYFOKSA-N N[C@H]1CC[C@H](CC(O)=O)CC1 Chemical compound N[C@H]1CC[C@H](CC(O)=O)CC1 XVDSFSRMHSDHGJ-LJGSYFOKSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 239000000047 product Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical group NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 description 1
- ZNMORCXCCZZSQB-MGCOHNPYSA-N C(C)(=O)OCC[C@@H]1CC[C@H](CC1)N Chemical compound C(C)(=O)OCC[C@@H]1CC[C@H](CC1)N ZNMORCXCCZZSQB-MGCOHNPYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical class CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZHBWMCGLXGDFAV-UHFFFAOYSA-M sodium;2-(4-nitrophenyl)acetate Chemical compound [Na+].[O-]C(=O)CC1=CC=C([N+]([O-])=O)C=C1 ZHBWMCGLXGDFAV-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/08—Saturated compounds having a carboxyl group bound to a six-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本發明有關製備反式4-胺基-環己基乙酸乙酯HCl之新穎方法。
反式4-胺基-環己基乙酸及其衍生物係合成活性藥劑之優點起始材料，因此提供可以容易進行之方式製備具有所需藥品純度及良好產率的反式4-胺基-環己基乙酸及其衍生物的經濟方法相當重要。就活性藥劑之合成而言，只能應用光學(立體異構)純反式異構物形式。
Izvesztiya Akademii Nauk SSSR(Seriya Khimicheskaya(10)，2374-9(俄羅斯)1980)揭示一種製備4-胺基-環己基乙酸及其衍生物之順式與反式異構物的方法。因此，4-胺基-環己基乙酸之順式與反式異構物係從4-硝苯乙酸鈉鹽開始，藉由在130℃與150 atm之壓力並於雷氏鎳觸媒之存在下的氫化反應而獲得。所得產物係以氯化氫鹽形式分離出來。
根據Wustrow等人(Journal of Medicinal Chemistry，1998，vol 41 No 5 768.)，反式4-胺基-環己基乙酸乙酯氯化氫鹽係藉由氫化而從4-硝苯乙酸獲得。鈉鹽之氫化首先係在含水介質中，於雷氏鎳觸媒之存在下，以49℃且在130 atm之壓力下進行，然後再於130℃且在172 atm之壓力下進行。所得之4-胺基-環己基乙酸係由約81%之反式
異構與19%之順式異構物所組成。由於分離之反式與順式4-胺基-環己基乙酸的混合物溶解於乙醇中，且以無水氫氯酸氣使之飽和並加熱至回流，故難以分離所需之反式異構物。冷卻之後，過濾該混合物，將所得之濾液濃縮，並以醚沉澱該反式產物。
上述習知製程的常見缺點係，例如該等方法僅能在相當高之溫度與壓力下且於自燃性相當高的雷氏鎳觸媒的存在下進行，因此該等工業製程不經濟又危險，且需要額外設備與極端條件。另一缺點係將鈉鹽氫化，因此難以實施加工與收回步驟。亦即，除了將該反應混合物加熱至回流且以醚沉澱產物之外，反式4-胺基-環己基乙酸乙酯氫氯酸鹽係在乙醇中無水條件下，以氫氯酸飽和而製造。由於使用腐蝕性極高的氫氯酸及易燃性醚之故，從環境觀點來看，該製程係有害的。本發明人之目的係提供以工業規模製備反式4-胺基-環己基乙酸或其可充分分離之衍生物的安全且容易處理方法，以該方法可經由簡單反應步驟製備產物，除此之外，該等步驟不需要可燃性及/或腐蝕性高之溶劑，亦不需要額外設備。
本發明人意外地發現在3-4巴超壓(在常用熱壓器中容易獲得該壓力)且於Pd/C之存在下，在含水介質中氫化4-硝苯乙酸時，獲得順式/反式4-胺基-環己基醋酸之混合物，其中順式產物對反式產物的比大約為70%。本發明
人之提高反式選擇性的研究意外顯示出當氫化作用係於Pd/C之存在下以兩步驟進行時，即，當硝基之還原與苯環之飽和係以分開的步驟進行時，則該反式選擇性提高。當硝基之還原係在介於40-50℃(較佳為44-46℃)之溫度且在至少0.6巴之超壓下進行時，苯基保持未反應，然後將於原位獲得之4-胺基苯基乙酸在介於50-60℃(較佳為55-58℃)之溫度且在至少4巴超壓下進一步氫化。在該情況下，反式→順式變得更有利，且反式異構物之轉化率達到60-70%。除此之外，本發明人已發現在質子性溶劑中(例如在水、甲醇、乙醇、丙醇、或在其混合物中，較佳係在水中)進行呈自由酸形式之4-硝苯乙酸的氫化作用，此二氫化步驟均可進行。使用所述習用製程，僅能以低效率且難以實施之方式進行順式與反式環己基乙酸的分離與純化。但本發明人已意外發現，當製備環己基乙酸烷酯衍生物，例如甲酯、乙酯、丙酯衍生物時，可以良好之反式產物產率將順式/反式乙酯氫氯酸之混合物分離成反式與順式產物。一種用於酯化胺基酸的習知一般方法係將胺基酸溶解在酯化醇中並添加亞硫醯氯，其中獲得無副產物的胺基酯。根據上述已知方法，該乙酯HCl鹽係在以氯化氫氣飽和之無水介質中製造，並添加可燃性極高之醚溶劑以沉澱該最終產物。
本發明人已意外發現，當反式4-胺基-環己基乙酸乙酯之製備係在乙醇介質中使用10-30莫耳%(較佳為20莫耳%)過量之氫氯酸進行時，形成等莫耳量之最終產物，
且不會形成副產物。本發明之方法的另一優點係不需要無水反應條件，因此介質的水含量可達到4-硝苯乙酸之起始體積的15 v%。
除此之外，本發明人已意外發現當以乙腈處理根據本發明所製備4-胺基-環己基乙酸乙酯HCl鹽之順式/反式混合物時，可以極高純度與良好產率分離出反式產物。
本發明有關製備反式4-胺基-環己基乙酸乙酯HCl之方法，其中該方法包括以下步驟：步驟1：在介於40-50℃之溫度且於0.1-0.6巴之超壓下，在質子性溶劑中及Pd/C之存在下氫化4-硝苯乙酸；步驟2：將步驟1中於原位獲得之4-胺基苯基乙酸在介於50-60℃之溫度且於1-4巴之超壓下進一步氫化；步驟3：在鹽酸酒精中將步驟2獲得之4-胺基-環己基乙酸加熱至回流1-3小時，且藉由真空蒸餾去除溶劑之後，將乙腈添加至所得之殘留物，並且將之餾除。將餾出物冷卻至介於-5-0℃之溫度，並以乙腈清洗沉澱之晶體。
茲以下列非限制性實施例舉例說明本發明。
在室溫且於氮氣氛之下，在2500l之搪瓷熱壓器中裝入1000kg之去離子水與210kg(1.16kM)之4-硝苯基-乙酸。以氮惰化之後，在所得混合物中添加21kg之10%
Pd/C於20kg之去離子水中的懸浮液，且以額外20kg之去離子水沖洗觸媒測量規。以氫氣沖洗反應容器之後，在介於44-46℃之溫度且於至高達0.6巴之超壓下進行氫化，直到氫之吸收變慢為止。在硝基還原之後，將溫度提高到55-58℃，且將氫壓力保持在最大值4.0巴之超壓持續該氫化作用。當氫之吸收完成之後，將該混合物冷卻至介於25-30℃之溫度，以氮吹洗，並在加壓氮之下於Spakler過濾器上過濾觸媒。以額外200g之去離子水清洗該反應容器、過濾器與管線。混合該等濾液，且在2500l之搪瓷二倍器中，在真空下且於至高達80℃之內部溫度蒸餾1200kg之餾出物。將所得之殘留物冷卻至低於30℃之溫度，並添加430kg之乙醇，然後在真空下且至於高達80℃收集500l之餾出物。
在蒸餾完成之後，將該混合物冷卻至介於25-30℃之溫度，(水含量最大值為10w%，絕對值為約32kg)，並添加550kg之乙醇，接著添加170kg之30%鹽酸酒精，並將該反應混合物加熱至回流約2小時。當酯化作用完成時，在真空下且於至高達80℃餾除800l之溶劑。添加額外800l之乙醇，並在真空下以至高達80℃餾除另外之750-800l的溶劑。在所得之殘留物中添加700kg之乙腈，並在真空下且於至高達80℃收集140l之餾出物。藉由導入氮停止該真空，並將該溶液冷卻至介於0-(-)5℃之溫度。將所得之晶體離心分離，以100kg分成兩部分之乙腈清洗，於該期間溫度係保持在0-(-)5℃。在至高為
60℃之下將所得之固體乾燥至恆重。
以此方式，獲得90kg之標題產物。
產率：40%。
熔點：173-176℃。
Claims (4)
- 一種製備反式4-胺基-環己基乙酸乙酯HCl之方法，其特徵在於a)在質子性溶劑中在介於40-50℃之溫度、於Pd/C存在且於0.1-0.6巴之超壓下氫化4-硝基苯基乙酸，且b)在介於50-60℃之溫度且在1-4巴之超壓下進一步氫化於步驟a)中原位獲得之4-胺基苯基乙酸，然後c)將步驟b)獲得之4-胺基-環己基乙酸在鹽酸酒精中加熱至回流1-3小時，且視需要於移除該溶劑之後，將乙腈添加於所獲得之殘留物，然後蒸餾掉。
- 如申請專利範圍第1項之方法，其中使用水作為溶劑。
- 如申請專利範圍第1項之方法，其中於步驟a)中，該氫化作用係在介於44-46℃之溫度下進行。
- 如申請專利範圍第1項之方法，其中於步驟b)中，該氫化作用係在介於55-58℃之溫度下進行。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0800762A HU229858B1 (en) | 2008-12-17 | 2008-12-17 | Process for the preparation of trans 4-amino-cyclohexyl acetic acid ethyl ester hcl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201033170A TW201033170A (en) | 2010-09-16 |
| TWI465428B true TWI465428B (zh) | 2014-12-21 |
Family
ID=89988671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW098142928A TWI465428B (zh) | 2008-12-17 | 2009-12-15 | 製備反式４－胺基－環己基乙酸乙酯ｈｃ１之方法 |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US8802888B2 (zh) |
| EP (1) | EP2358661B1 (zh) |
| JP (1) | JP5667576B2 (zh) |
| CN (1) | CN102224130B (zh) |
| AU (1) | AU2009329293B2 (zh) |
| BR (1) | BRPI0923004A2 (zh) |
| CA (1) | CA2743921C (zh) |
| CY (1) | CY1115047T1 (zh) |
| DK (1) | DK2358661T3 (zh) |
| EA (1) | EA020350B1 (zh) |
| ES (1) | ES2468365T3 (zh) |
| GE (1) | GEP20125710B (zh) |
| HK (1) | HK1160836A1 (zh) |
| HR (1) | HRP20140532T1 (zh) |
| HU (1) | HU229858B1 (zh) |
| IL (1) | IL212597A (zh) |
| MX (1) | MX2011006584A (zh) |
| NZ (1) | NZ592753A (zh) |
| PL (1) | PL2358661T3 (zh) |
| PT (1) | PT2358661E (zh) |
| RS (1) | RS53311B (zh) |
| SG (1) | SG171715A1 (zh) |
| SI (1) | SI2358661T1 (zh) |
| TW (1) | TWI465428B (zh) |
| UA (1) | UA107073C2 (zh) |
| WO (1) | WO2010070368A1 (zh) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL2317852T3 (pl) | 2008-07-16 | 2015-05-29 | Richter Gedeon Nyrt | Preparaty farmaceutyczne zawierające ligandy receptora dopaminy |
| CN103214384B (zh) * | 2013-04-10 | 2015-04-01 | 淮阴师范学院 | 对氨基苯乙酸的制备方法 |
| ITMI20131693A1 (it) | 2013-10-14 | 2015-04-15 | Chemo Res S L | Derivati della 1,4-cicloesilammina e loro preparazione |
| CN106543039A (zh) * | 2015-09-22 | 2017-03-29 | 江苏恩华药业股份有限公司 | 一种用于制备卡利拉嗪的化合物及其制备方法 |
| CN106565510B (zh) * | 2015-10-09 | 2018-04-27 | 浙江京新药业股份有限公司 | 反式4-氨基-环己基乙酸酯衍生物的制备方法 |
| CN106083631B (zh) * | 2016-06-02 | 2018-11-16 | 平光制药股份有限公司 | 一种对氨基苯乙酸的制备方法 |
| HU231173B1 (hu) * | 2016-07-08 | 2021-06-28 | Richter Gedeon Nyrt. | Ipari eljárás cariprazine előállítására |
| US11274087B2 (en) | 2016-07-08 | 2022-03-15 | Richter Gedeon Nyrt. | Industrial process for the preparation of cariprazine |
| CN106543017B (zh) * | 2016-11-10 | 2018-04-06 | 中国科学院青岛生物能源与过程研究所 | 一种4‑氨基‑环己乙酸的制备方法 |
| WO2019124011A1 (ja) | 2017-12-22 | 2019-06-27 | 三菱ケミカル株式会社 | 樹脂組成物、塗料組成物、塗装物 |
| CN110240548A (zh) * | 2018-03-09 | 2019-09-17 | 上虞京新药业有限公司 | 一种卡利拉嗪中间体的制备方法 |
| CN108586389B (zh) * | 2018-06-29 | 2020-06-12 | 成都福柯斯医药技术有限公司 | 一种合成卡利拉嗪的方法 |
| US11547707B2 (en) | 2019-04-10 | 2023-01-10 | Richter Gedeon Nyrt. | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder |
| CN114645027A (zh) * | 2020-12-21 | 2022-06-21 | 上海合全药物研发有限公司 | 一种来源于巨大芽孢杆菌的氨基转移酶突变体及其应用 |
| AU2022347282A1 (en) | 2021-09-15 | 2024-05-02 | Budapesti Műszaki és Gazdaságtudományi Egyetem | PROCESS TO PRODUCE (1r,4r)-4-SUBSTITUTED CYCLOHEXANE-1-AMINES |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4719203A (en) * | 1985-11-13 | 1988-01-12 | Boehringer Mannheim Gmbh | Diphosphonic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1148344C (zh) * | 2000-09-06 | 2004-05-05 | 胡国宜 | 4，4'－二 氨基苯酰替苯胺的制备方法 |
| KR100641825B1 (ko) | 2003-11-05 | 2006-11-02 | 주식회사 코오롱 | 4-바이페닐아세트산의 제조 방법 |
-
2008
- 2008-12-17 HU HU0800762A patent/HU229858B1/hu not_active IP Right Cessation
-
2009
- 2009-12-15 TW TW098142928A patent/TWI465428B/zh active
- 2009-12-17 RS RS20140244A patent/RS53311B/en unknown
- 2009-12-17 GE GEAP200912299A patent/GEP20125710B/en unknown
- 2009-12-17 AU AU2009329293A patent/AU2009329293B2/en active Active
- 2009-12-17 SG SG2011029204A patent/SG171715A1/en unknown
- 2009-12-17 EP EP09797144.4A patent/EP2358661B1/en active Active
- 2009-12-17 CN CN200980146417.6A patent/CN102224130B/zh active Active
- 2009-12-17 US US13/140,237 patent/US8802888B2/en active Active
- 2009-12-17 EA EA201170811A patent/EA020350B1/ru unknown
- 2009-12-17 MX MX2011006584A patent/MX2011006584A/es active IP Right Grant
- 2009-12-17 CA CA2743921A patent/CA2743921C/en not_active Expired - Fee Related
- 2009-12-17 PT PT97971444T patent/PT2358661E/pt unknown
- 2009-12-17 ES ES09797144.4T patent/ES2468365T3/es active Active
- 2009-12-17 WO PCT/HU2009/000107 patent/WO2010070368A1/en active Application Filing
- 2009-12-17 JP JP2011541612A patent/JP5667576B2/ja active Active
- 2009-12-17 NZ NZ592753A patent/NZ592753A/xx unknown
- 2009-12-17 UA UAA201109014A patent/UA107073C2/ru unknown
- 2009-12-17 BR BRPI0923004A patent/BRPI0923004A2/pt active IP Right Grant
- 2009-12-17 PL PL09797144T patent/PL2358661T3/pl unknown
- 2009-12-17 DK DK09797144.4T patent/DK2358661T3/da active
- 2009-12-17 SI SI200930947T patent/SI2358661T1/sl unknown
-
2011
- 2011-05-01 IL IL212597A patent/IL212597A/en active IP Right Grant
-
2012
- 2012-02-08 HK HK12101218.0A patent/HK1160836A1/zh unknown
-
2014
- 2014-05-06 CY CY20141100322T patent/CY1115047T1/el unknown
- 2014-06-06 HR HRP20140532AT patent/HRP20140532T1/hr unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4719203A (en) * | 1985-11-13 | 1988-01-12 | Boehringer Mannheim Gmbh | Diphosphonic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
Non-Patent Citations (1)
| Title |
|---|
| Wustrow et al, Journal of Medicinal Chemistry, 1998,41, p760-771 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI465428B (zh) | 製備反式４－胺基－環己基乙酸乙酯ｈｃ１之方法 | |
| US9783506B2 (en) | Process for the large scale production of 1H-[1,2,3]triazole and its intermediate 1-benzyl-1H-[1,2,3]triazole | |
| AU2009218414A1 (en) | Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates | |
| AU2017200463B2 (en) | The process for the preparation of metaraminol | |
| HUE032621T2 (en) | Preparation of 1 - ([1,3] dioxolan-4-ylmethyl) -1H-pyrazol-3-ylamine \ t | |
| US8242311B2 (en) | Process for preparing 2,2-difluoroethylamine and salts thereof proceeding from difluoroacetonitrile | |
| CA1319707C (en) | Process for the preparation of serinol | |
| PL192489B1 (pl) | Nowy sposób wytwarzania ketiminy | |
| US9650337B2 (en) | Method of synthesising 4-piperidin-4-yl-benzene-1,3-diol and the salts of same and novel compound tert-butyl 4-(2,4-dihydroxy-phenyl)-4-hydroxy-piperidine-1-carboxylate | |
| US2373438A (en) | Manufacture of 3,4-xylidine | |
| JP3193421B2 (ja) | ２−アミノ−４−フルオロ安息香酸の製造方法 | |
| KR101059275B1 (ko) | 개선된 4-[2-(디-엔-프로필아미노)에틸]-1,3-디하이드로-2에이치-인돌-2-온의 제조 방법 | |
| BRPI0923004B1 (pt) | Process for the preparation of ethyl esters of trans 4-amino-cyclohexyl acetic acid | |
| Juhasz et al. | Mathe et al. | |
| US3165553A (en) | Production of n-methyl substituted ethylene diamine | |
| TWI583688B (zh) | 雙環辛烷四羧酸二酐的製備方法 | |
| JP3971875B2 (ja) | トランス−４−（４’−オキソシクロヘキシル）シクロヘキサノール類の製造方法 | |
| KR20170088068A (ko) | 2-벤질아닐린의 신규 제조방법 | |
| ITMI20010556A1 (it) | Aldeido acidi o loro derivati impiegabili per la preparazione di amminoacidi ciclici |