CN1520411A - 霉酚酸莫啡酯的制备方法 - Google Patents
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- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 title claims abstract description 24
- 229960004866 mycophenolate mofetil Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims description 20
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 claims abstract description 16
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 claims abstract description 15
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 claims abstract description 15
- 229960000951 mycophenolic acid Drugs 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000009835 boiling Methods 0.000 claims description 8
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 238000000926 separation method Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- -1 2- (4-morpholinyl) ethyl group Chemical group 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 description 2
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- GRSZFWQUAKGDAV-KQYNXXCUSA-N IMP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-KQYNXXCUSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 235000013902 inosinic acid Nutrition 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229950007856 mofetil Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940046781 other immunosuppressants in atc Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Furan Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明提供了式(I)聚酚酸莫啡酯的合成方法,其中R1为2-(-吗啉基)乙基,R2为氢,包括在适当的溶剂中在水的共沸分离点下霉酚酸与4-(2-羟基乙基)吗啉反应。
Description
发明领域
本发明涉及根据式I的霉酚酸莫啡酯(Mycophenolate Mofetil)的制备方法:
其中,
R1是2-(4-吗啉基)乙基,
R2是氢原子。
霉酚酸莫啡酯(I)被用作一种与其他免疫抑制剂(环孢霉素A、***)一起用于预防治疗的免疫抑制剂,或用于治疗肾移植后患者的顽固性排斥。化学上,霉酚酸莫啡酯是霉酚酸(R1=R2=H)的2-(4-吗啉基)乙基酯,其具有细胞生长繁殖抑制作用。它表现肌苷一磷酸脱氢酶选择性抑制作用,同理还选择性抑制鸟嘌呤核苷酸重新合成途径及它们合并入DNA。同理对淋巴细胞生长繁殖抑制作用高于其他细胞。
背景技术
在基本专利EP 281 713 B1(1987)和其他几个专利:US No.4 808592(1989)、US No.4 753 935(1988)、US No.4 952 579(1990)、US No.4 984 793(1990)、US No.4 786 637(1988)中描述了依照式I(R1=2-吗啉代乙基,R2=H)的霉酚酸莫啡酯的合成。依照这些专利,霉酚酸莫啡酯可用两个标准的酯化方法(参见SyntheticOrganic Chemistry,R.B.Wagner and H.d.Zook(Wiley,New York),1952,pages 479 to 532)制备:霉酚酰氯与过量的2-吗啉代乙醇反应和用二环己基碳二亚胺(DDC)浓缩。以盐酸为媒介的酯化作用是基于过量的2-吗啉代乙醇与用适当的氯化剂(亚硫酰(二)氯、草酰氯等)从霉酚酸制备的霉酚酸酰氯反应。使用过量的2-吗啉代乙醇(至多3当量),形成二聚物(约2%,R1=H或2-吗啉代乙基,R2=霉酚酸)表现了二步方法的缺点,还有产物的颜色问题。形成不能分辩量的杂质和仅利用色谱法可从反应混合物中消除的二环己基脲是DDC用作激动剂的缺点。
1993年的美国专利No.5 247 083描述通过在适当溶剂或溶剂混合物中共沸水分离下回流霉酚酸和2-吗啉代乙醇制备霉酚酸莫啡酯。在权利要求和实施例中举出二氯甲烷、苯、甲苯、二甲苯和高级烃。最适当的溶剂是甲苯、二甲苯和它们1∶1比例的混合物。为达到充分的转化率必需的长反应期(根据所用的溶剂约60-100小时)和产物的颜色(淡紫色结晶)是此方法的缺点。
2000年的国际申请WO 00/34503的目的是以酶催化霉酚酸与2-吗啉代乙醇酯化。按此方法,可得到高的霉酚酸莫啡酯产出率和纯度,可是,这种方法不可以应用在工业中。在此专利中,描述了无任何溶剂,通过在2-吗啉代乙醇中煮沸酯化霉酚酸的方法,但是考虑到2-吗啉代乙醇的价格,该方法也不适合。
发明的公开
在通过水共沸分离下以2-吗啉代乙醇直接酯化霉酚酸制备霉酚酸莫啡酯的优化中,意外的由于二丁醚的使用,和甲苯和二甲苯不同,反应轻微加速。由于高级醚的使用,在甲苯和二甲苯中监测到的产物颜色问题被消除。霉酚酸莫啡酯在高级醚中的低溶解度也是一个有利的特性,因为它使产物更容易从高沸溶剂中分离。这就是被提议的方法对美国专利No.5 247 083描述的方法表现出最有利的代用性的原因。
依照本发明方法解决霉酚酸莫啡酯的制备如下:
在水共沸分离下及在使用过量的2-吗啉代乙醇下(1.01-3摩尔当量)下,通过在醚(通式R3OR4,其中R3、R4=烷基、芳基)中回流,其沸点最低为120℃,酯化霉酚酸。反映时间在5-50小时范围内,根据所使用的溶剂反应温度高于120℃。霉酚酸∶所用溶剂的比率是在1g∶2ml到1g∶5ml范围内。转化率是在80-98%范围内。原产物再结晶后,得到最低纯度99.0%、最低产出率70%的霉酚酸莫啡酯。
实施例
本发明用下面的实施例说明,可是它们不以任何方式限制本发明的范围。
实施例1
霉酚酸莫啡酯;使用二丁醚作为溶剂
将10g霉酚酸与20ml二丁醚一起放入带有回流冷却器的反应瓶。剧烈地搅拌下将混合物加热直至50-80℃,然后滴入4ml 2-吗啉代乙醇。反应混合物在水共沸分离下加热直至沸点。48小时后混合物冷却直至实验室温度,并以20ml二氯甲烷稀释。该溶液用10ml 0.5M含水K2CO3提取2次,并以10ml水提取1次。然后,真空下蒸馏掉二氯甲烷,将悬浮液冷却直至10-15℃。通过抽滤除去结晶的霉酚酸莫啡酯并从乙酸乙酯中重结晶。抽滤干燥后,得到11g(78%)纯度>99.0%(HPLC)的霉酚酸莫啡酯结晶。
实施例2
霉酚酸莫啡酯;使用二戊基醚作为溶剂
将10g霉酚酸与20ml二戊基醚一起放入带有回流冷却器的反应瓶。剧烈地搅拌下将混合物加热直至50-60℃,然后滴入4ml 2-吗啉代乙醇。反应混合物在水共沸分离下加热直至沸点。6小时后混合物冷却直至实验室温度,并以20ml二氯甲烷稀释。该溶液用10ml 0.5MK2CO3水溶液提取2次,并以10ml水提取1次。然后,真空下蒸馏掉二氯甲烷,将悬浮液冷却直至10-15℃。抽滤除去结晶的霉酚酸莫啡酯并从乙酸乙酯中重结晶。抽除干燥后,得到10g(71%)纯度>99.0%(HPLC)的霉酚酸莫啡酯结晶。
实施例3
霉酚酸莫啡酯;使用过量的2-吗啉代乙醇
将10g霉酚酸与20ml二丁醚一起放入带有回流冷却器的反应瓶。剧烈地搅拌下将混合物加热直至50-60℃,然后加入4.8ml 2-吗啉代乙醇。反应混合物在水共沸分离下加热直至沸点。15小时后混合物冷却直至实验室温度,并以25ml二氯甲烷稀释。该溶剂用10ml 1%的氨水提取2次,并以10ml水提取1次。然后,真空下蒸馏掉二氯甲烷,将悬浮液冷却直至10-15℃。抽滤除去结晶的霉酚酸莫啡酯并从乙酸乙酯中重结晶。抽除干燥后,得到11.1g(82%)纯度>99.0%(HPLC)的霉酚酸莫啡酯结晶。
Claims (8)
1.通过直接酯化霉酚酸和2-吗啉代乙醇制备霉酚酸莫啡酯的方法,其特征是在沸点下在醚中进行酯化。
2.权利要求1的方法,其特征是使用通式R3OR4的醚作为溶剂,其中R3和R4独立地是烷基或芳基。
3.权利要求2的方法,其特征是使用沸点高于120℃的醚作为溶剂。
4.权利要求1的方法,其特征是使用1.01直到3.0摩尔当量的2-吗啉代乙醇。
5.权利要求3的方法,其特征是使用二丁醚作为惰性溶剂。
6.权利要求5的方法,其特征是反应的起始温度范围在130℃和138℃之间且反应的终末温度范围在140℃和145℃之间。
7.权利要求5的方法,其特征是回流时间范围从30到80小时。
8.权利要求5的方法,其特征是霉酚酸对二丁醚的比率范围从1g/2ml到1g/5ml。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ20012071A CZ292123B6 (cs) | 2001-06-08 | 2001-06-08 | Způsob přípravy mykofenolátu mofetilu |
CZPV20012071 | 2001-06-08 |
Publications (2)
Publication Number | Publication Date |
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CN1520411A true CN1520411A (zh) | 2004-08-11 |
CN1253450C CN1253450C (zh) | 2006-04-26 |
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CNB028126998A Expired - Fee Related CN1253450C (zh) | 2001-06-08 | 2002-06-08 | 霉酚酸莫啡酯的制备方法 |
Country Status (17)
Country | Link |
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US (1) | US20050085635A1 (zh) |
EP (1) | EP1421081A4 (zh) |
JP (1) | JP2004534063A (zh) |
KR (1) | KR20040030660A (zh) |
CN (1) | CN1253450C (zh) |
AR (1) | AR041777A1 (zh) |
BR (1) | BR0210931A (zh) |
CA (1) | CA2450013A1 (zh) |
CZ (1) | CZ292123B6 (zh) |
HK (1) | HK1068630A1 (zh) |
HU (1) | HUP0400189A3 (zh) |
NZ (1) | NZ530013A (zh) |
PL (1) | PL364366A1 (zh) |
RU (1) | RU2283313C2 (zh) |
SK (1) | SK285663B6 (zh) |
TW (1) | TWI241299B (zh) |
WO (1) | WO2002100855A1 (zh) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1328272C (zh) * | 2005-08-22 | 2007-07-25 | 鲁南制药集团股份有限公司 | 一种工业化生产霉酚酸莫啡酯的方法 |
CN100402516C (zh) * | 2005-10-18 | 2008-07-16 | 深圳市东阳光实业发展有限公司 | 一种霉酚酸莫啡酯的制备方法 |
CN100484930C (zh) * | 2007-03-16 | 2009-05-06 | 重庆大新药业股份有限公司 | 一种吗替麦考酚酯的制备方法 |
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CN101671706B (zh) * | 2009-09-05 | 2013-09-18 | 山东新时代药业有限公司 | 一种霉酚酸发酵过程中补糖方法 |
CN107056736A (zh) * | 2017-05-08 | 2017-08-18 | 福建省微生物研究所 | 一种吗替麦考酚酯的制备方法 |
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DE602004015310D1 (de) * | 2003-09-11 | 2008-09-04 | Sandoz Ag | Verfahren zur herstellung von mycophenolatmofetil |
JP2007532585A (ja) * | 2004-04-26 | 2007-11-15 | テバ ジョジセルジャール ザ−トケルエン ムケド レ−スベニュタ−ルシャシャ−グ | ミコフェノール酸及びそのエステル誘導体の調製方法 |
US7358247B2 (en) | 2004-04-27 | 2008-04-15 | TEVA Gyógyszergyár Zártköruen Muködö Részvénytársaság | Mycophenolate mofetil impurity |
WO2006012385A2 (en) | 2004-07-20 | 2006-02-02 | Teva Gyógyszergyár Zàrtköruen Muködo Rèszvènytàrsasàg | Crystalline mycophenolate sodium |
ATE457358T1 (de) * | 2006-06-29 | 2010-02-15 | Ivax Pharmaceuticals Sro | Regulation der säuremetabolitproduktion |
US20080188653A1 (en) | 2007-02-04 | 2008-08-07 | Formosa Laboratories, Inc. | Process for Preparation of Mycophenolate Mofetil |
MX2008015797A (es) * | 2007-04-11 | 2009-03-06 | Teva Gyogyszergyar Zartkoeruen | Metodo para reducir el nivel de impurezas en la fermentacion del acido micofenolico. |
WO2009000834A1 (en) * | 2007-06-27 | 2008-12-31 | Dsm Ip Assets B.V. | Method for the purification of mycophenolate mofetil |
WO2009003878A1 (en) * | 2007-06-29 | 2009-01-08 | Dsm Ip Assets B.V. | Method for the preparation of mycophenolate mofetil |
WO2009010503A1 (en) * | 2007-07-18 | 2009-01-22 | Dsm Ip Assets B.V. | Mycophenolic acid recycling in a method for the preparation of mycophenolate mofetil |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4748173A (en) * | 1987-01-30 | 1988-05-31 | Syntex (U.S.A.) Inc. | Heterocyclic aminoalkyl esters of mycophenolic acid and derivatives thereof and pharmaceutical compositions |
HU203678B (en) * | 1988-09-26 | 1991-09-30 | Richter Gedeon Vegyeszet | Method for increased dewatering condensation reaction mixtures |
US5247083A (en) * | 1992-07-10 | 1993-09-21 | Syntex (U.S.A.) Inc. | Direct esterification of mycophenolic acid |
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2001
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- 2002-06-08 CN CNB028126998A patent/CN1253450C/zh not_active Expired - Fee Related
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- 2002-06-08 SK SK1506-2003A patent/SK285663B6/sk unknown
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- 2002-06-08 KR KR10-2003-7016069A patent/KR20040030660A/ko not_active Application Discontinuation
- 2002-06-08 NZ NZ530013A patent/NZ530013A/en unknown
- 2002-06-08 JP JP2003503622A patent/JP2004534063A/ja active Pending
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101035904B (zh) * | 2004-09-03 | 2011-02-02 | 波利工业化学公司 | 通过酶催化的酯交换反应制备霉酚酸吗啉乙酯的方法 |
CN1328272C (zh) * | 2005-08-22 | 2007-07-25 | 鲁南制药集团股份有限公司 | 一种工业化生产霉酚酸莫啡酯的方法 |
CN100402516C (zh) * | 2005-10-18 | 2008-07-16 | 深圳市东阳光实业发展有限公司 | 一种霉酚酸莫啡酯的制备方法 |
CN1974564B (zh) * | 2006-12-15 | 2010-05-12 | 丽珠集团新北江制药股份有限公司 | 一种霉酚酸莫啡酯的制备方法 |
CN100484930C (zh) * | 2007-03-16 | 2009-05-06 | 重庆大新药业股份有限公司 | 一种吗替麦考酚酯的制备方法 |
CN101671706B (zh) * | 2009-09-05 | 2013-09-18 | 山东新时代药业有限公司 | 一种霉酚酸发酵过程中补糖方法 |
CN103265514A (zh) * | 2013-06-08 | 2013-08-28 | 重庆理工大学 | 一种制备吗替麦考酚酯的方法 |
CN103265514B (zh) * | 2013-06-08 | 2016-01-13 | 重庆理工大学 | 一种制备吗替麦考酚酯的方法 |
CN107056736A (zh) * | 2017-05-08 | 2017-08-18 | 福建省微生物研究所 | 一种吗替麦考酚酯的制备方法 |
Also Published As
Publication number | Publication date |
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SK285663B6 (sk) | 2007-05-03 |
US20050085635A1 (en) | 2005-04-21 |
TWI241299B (en) | 2005-10-11 |
HUP0400189A2 (hu) | 2004-07-28 |
HK1068630A1 (en) | 2005-04-29 |
HUP0400189A3 (en) | 2007-05-29 |
RU2004100227A (ru) | 2005-06-27 |
EP1421081A1 (en) | 2004-05-26 |
NZ530013A (en) | 2005-05-27 |
CN1253450C (zh) | 2006-04-26 |
PL364366A1 (en) | 2004-12-13 |
CZ20012071A3 (cs) | 2003-01-15 |
EP1421081A4 (en) | 2004-11-03 |
CA2450013A1 (en) | 2002-12-19 |
BR0210931A (pt) | 2004-06-08 |
RU2283313C2 (ru) | 2006-09-10 |
KR20040030660A (ko) | 2004-04-09 |
JP2004534063A (ja) | 2004-11-11 |
SK15062003A3 (en) | 2004-11-03 |
AR041777A1 (es) | 2005-06-01 |
WO2002100855A1 (en) | 2002-12-19 |
CZ292123B6 (cs) | 2003-08-13 |
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