CN101516841B - 一种改进的9-顺-视黄酸的制备方法 - Google Patents
一种改进的9-顺-视黄酸的制备方法 Download PDFInfo
- Publication number
- CN101516841B CN101516841B CN200780036051.8A CN200780036051A CN101516841B CN 101516841 B CN101516841 B CN 101516841B CN 200780036051 A CN200780036051 A CN 200780036051A CN 101516841 B CN101516841 B CN 101516841B
- Authority
- CN
- China
- Prior art keywords
- acid
- fang
- phosphonium salt
- methylene dichloride
- vitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 title 1
- 229960001445 alitretinoin Drugs 0.000 title 1
- -1 phenyl ester Chemical class 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 150000004714 phosphonium salts Chemical class 0.000 claims description 30
- 229930002330 retinoic acid Natural products 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000012452 mother liquor Substances 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000007127 saponification reaction Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 238000005204 segregation Methods 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 241000040710 Chela Species 0.000 claims description 3
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 3
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 claims description 3
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 3
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 claims description 3
- 235000013734 beta-carotene Nutrition 0.000 claims description 3
- 239000011648 beta-carotene Substances 0.000 claims description 3
- 229960002747 betacarotene Drugs 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000004678 hydrides Chemical class 0.000 claims description 3
- 230000003020 moisturizing effect Effects 0.000 claims description 3
- 235000019155 vitamin A Nutrition 0.000 claims description 3
- 239000011719 vitamin A Substances 0.000 claims description 3
- 229940045997 vitamin a Drugs 0.000 claims description 3
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims 2
- 150000003839 salts Chemical class 0.000 abstract description 4
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 abstract 2
- 238000002955 isolation Methods 0.000 abstract 1
- 230000005588 protonation Effects 0.000 abstract 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- 229960001727 tretinoin Drugs 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine 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
- 239000002798 polar solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- AUCXIGOESXVILY-UHFFFAOYSA-N CC1(C)C(C)=C(C)CCC1 Chemical compound CC1(C)C(C)=C(C)CCC1 AUCXIGOESXVILY-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000675108 Citrus tangerina Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
-
- 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
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
产物 | 质量 | 含量(顺式RTA) | 质量100% | 摩尔质量 | 基于C-15乙烯基盐的产率(反式) |
[g] | [%] | [g] | [g/mol] | [理论产率%] | |
视黄酸 | 约14g | 约98 | 13.7 | 300.44 | 约46 |
BASF | Roche | DSM | |
基于乙烯基盐的产率 | 46% | 31% | 67% |
含量 | 65.8%Z19.0%E | 93.6%Z5%E | 98%Z2%E |
产率包括重结晶的视黄酸含量: | 25%99.5% | 15.5%??% | 40-45%>99.5% |
Claims (9)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT16052006 | 2006-09-27 | ||
ATA1605/2006 | 2006-09-27 | ||
PCT/EP2007/008399 WO2008037465A1 (en) | 2006-09-27 | 2007-09-27 | Improved method of production of 9-cis-retinoic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101516841A CN101516841A (zh) | 2009-08-26 |
CN101516841B true CN101516841B (zh) | 2014-01-22 |
Family
ID=38924424
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200780036051.8A Active CN101516841B (zh) | 2006-09-27 | 2007-09-27 | 一种改进的9-顺-视黄酸的制备方法 |
Country Status (12)
Country | Link |
---|---|
US (1) | US8536373B2 (zh) |
EP (1) | EP2066624B1 (zh) |
CN (1) | CN101516841B (zh) |
CA (2) | CA2665909C (zh) |
DK (1) | DK2066624T3 (zh) |
ES (1) | ES2529146T3 (zh) |
HK (1) | HK1135085A1 (zh) |
HU (1) | HUE024111T2 (zh) |
NO (1) | NO344470B1 (zh) |
PL (1) | PL2066624T3 (zh) |
PT (1) | PT2066624E (zh) |
WO (1) | WO2008037465A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2885309B1 (de) * | 2012-08-17 | 2017-03-15 | Basf Se | Isomerisierung olefinischer verbindungen |
US9221854B2 (en) | 2012-08-17 | 2015-12-29 | Basf Se | Isomerization of olefinic compounds |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5504230A (en) * | 1993-12-23 | 1996-04-02 | Basf Aktiengesellschaft | Preparation of 9-(Z)-retinoic acid |
CN1771227A (zh) * | 2003-04-11 | 2006-05-10 | 霍夫曼-拉罗奇有限公司 | 制造9-顺式视黄酸的方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3933334A1 (de) | 1989-10-06 | 1991-04-11 | Basf Ag | 3-substituierte 2-hydroxy-3-formyl-propionsaeureester, verfahren zu deren herstellung sowie deren verwendung zur herstellung von 3-substituierten 3-formyl-acrylsaeureestern |
-
2007
- 2007-09-27 CA CA2665909A patent/CA2665909C/en active Active
- 2007-09-27 HU HUE07818482A patent/HUE024111T2/en unknown
- 2007-09-27 ES ES07818482.7T patent/ES2529146T3/es active Active
- 2007-09-27 PT PT78184827T patent/PT2066624E/pt unknown
- 2007-09-27 WO PCT/EP2007/008399 patent/WO2008037465A1/en active Application Filing
- 2007-09-27 EP EP07818482.7A patent/EP2066624B1/en active Active
- 2007-09-27 PL PL07818482T patent/PL2066624T3/pl unknown
- 2007-09-27 DK DK07818482.7T patent/DK2066624T3/en active
- 2007-09-27 CA CA2886595A patent/CA2886595C/en active Active
- 2007-09-27 CN CN200780036051.8A patent/CN101516841B/zh active Active
- 2007-09-27 US US12/442,162 patent/US8536373B2/en active Active
-
2009
- 2009-04-27 NO NO20091657A patent/NO344470B1/no unknown
-
2010
- 2010-02-11 HK HK10101540.1A patent/HK1135085A1/zh unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5504230A (en) * | 1993-12-23 | 1996-04-02 | Basf Aktiengesellschaft | Preparation of 9-(Z)-retinoic acid |
CN1771227A (zh) * | 2003-04-11 | 2006-05-10 | 霍夫曼-拉罗奇有限公司 | 制造9-顺式视黄酸的方法 |
Also Published As
Publication number | Publication date |
---|---|
EP2066624B1 (en) | 2014-10-29 |
WO2008037465A1 (en) | 2008-04-03 |
CA2886595C (en) | 2019-05-07 |
PL2066624T3 (pl) | 2015-04-30 |
US20100217037A1 (en) | 2010-08-26 |
CN101516841A (zh) | 2009-08-26 |
NO20091657L (no) | 2009-04-27 |
HK1135085A1 (zh) | 2010-05-28 |
CA2665909A1 (en) | 2008-04-03 |
EP2066624A1 (en) | 2009-06-10 |
CA2886595A1 (en) | 2008-04-03 |
CA2665909C (en) | 2015-06-09 |
NO344470B1 (no) | 2020-01-06 |
PT2066624E (pt) | 2015-02-09 |
DK2066624T3 (en) | 2015-02-09 |
US8536373B2 (en) | 2013-09-17 |
HUE024111T2 (en) | 2016-02-29 |
ES2529146T3 (es) | 2015-02-17 |
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