TWI293951B - Process for the production of 9-cis-retinoic acid - Google Patents
Process for the production of 9-cis-retinoic acid Download PDFInfo
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- TWI293951B TWI293951B TW093109532A TW93109532A TWI293951B TW I293951 B TWI293951 B TW I293951B TW 093109532 A TW093109532 A TW 093109532A TW 93109532 A TW93109532 A TW 93109532A TW I293951 B TWI293951 B TW I293951B
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- 238000000034 method Methods 0.000 title claims description 17
- 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 claims description 8
- 229960001445 alitretinoin Drugs 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- -1 alkyl methacrylate Chemical compound 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- QPFVAKLVWFPTSX-UHFFFAOYSA-N 2-methyl-4-oxobut-2-enoic acid Chemical compound OC(=O)C(C)=CC=O QPFVAKLVWFPTSX-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- QOMQVYYQBYOOMQ-UHFFFAOYSA-N 3-methyl-1,8-naphthyridine Chemical compound N1=CC=CC2=CC(C)=CN=C21 QOMQVYYQBYOOMQ-UHFFFAOYSA-N 0.000 claims 1
- 241000220259 Raphanus Species 0.000 claims 1
- 235000006140 Raphanus sativus var sativus Nutrition 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- FPVGTPBMTFTMRT-NSKUCRDLSA-L fast yellow Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(N)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 FPVGTPBMTFTMRT-NSKUCRDLSA-L 0.000 claims 1
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 239000000725 suspension Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 3
- 235000021419 vinegar Nutrition 0.000 description 3
- 239000000052 vinegar Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 241000288906 Primates Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 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 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FJAKCEHATXBFJT-UHFFFAOYSA-N ethyl 2-oxobutanoate Chemical compound CCOC(=O)C(=O)CC FJAKCEHATXBFJT-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1293951 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種用於製造9-順視黃酸（9_(z)_ra)之新 穎工業應用方法。 【先前技術】 9-(Z)-RA係一種多用途化合物，據稱其可用於治療多種 皮膚疾病，例如，如W0 "/09969中所揭示。 ερ_α 〇 659739揭示一種用於製備9_(Z)_RA之方法，其特
生維蒂希反應（WiUig_reaCti〇n)，且隨後與鹼進行皂化作用 因此形成之視黃酸醋。 此方法存在如下缺點：其需要兩個涉及 黃酸醋之溶劑的步驟。由於皂化需要相 件H亦已觀察會大量形成非吾人所要
【發明内容】 因此’水^縣"E 其需要兩個涉及改變用於皂化視 由於皂化需要相當急劇的溫度條 ‘形成非吾人所要之異構體。 本發明之目的係找到一種用於製造 代方法’該方法不包括自先前技術 改良之替代方法，該 知的缺點。 種用於製造9_(Z)_Ra之經 自先如技術之已知方法得 目的， μ曰的，其中該方法之特徵在於： 甲基-4-氧代丁烯酸之鹼金屬鹽： 本發明之方法已達成該 在驗存在下，使式I之3-甲
與式11之(^ 其中’ Μ代表納或鉀， 5’ 一本基鱗鹽的順式 92053.doc 1293951 異構體反應：
Ph 其中’ Ph代表苯基，且χ代表鹵素。 【實施方式】 在:較佳實施例中’甲基_4_氧代了賴之驗金屬鹽係在 驗性氫氧化物存在下，原位水解3_甲基_4_氧代丁烯酸烧醋 (alkyl-3-methyl_4_〇x〇cr〇t〇nate)而製得，且其無需分離便可 用於隨後的反應步驟。 ^而，甲基-4·氧代丁烯酸之鹼金屬鹽當然亦須在其與式 Π的Cl5-三苯基鱗鹽之順式異構體反應之前進行分離。 甲基-4-氧代丁烯酸之鉀鹽最佳係藉由弘甲基氧代丁 烯駄乙S曰（ethyM-methyl-4-oxocrotonate)與氫氧化鉀發生 水解而製備。 吾人已發現，水解較佳在介於·1〇1與1〇。〇之間的温度（理 μ為”於0C與5°C之間）下於低碳數醇類（最佳為乙醇）存在 下執行k佺的氫氧化鉀係以水溶液形式（例如方便地 施用。
Ca三苯基鱗鹽之順式異構體係與反式異構體一起形成 異構二合物之形式存在於母液巾，其中該母液係在製傷卜 胡蘿蔔素時獲得。（Rtiegg等人，Helv.44,985(1961))。 92053.doc 1293951 氧化鉀。 反應混合物的處理可按下列步驟進行： a) 以有機溶劑進行萃取，較佳者二氯甲烷； b) 以適當無機酸（諸如磁丙參、脸 1居如％駄）將水相的pH值設定為約3至 4 ； c) 以二氯甲烷進行萃取； )藉由X顧出_氯甲烧，且較佳在同時連續導入甲醇， 將溶劑換成甲醇； ' e)分離自混合物中所結晶之9_(z)_ra。 在低碳數醇類（較佳者異丙醇）中進行再結晶作用可進一 步純化9-(Z)_RA。 由於反應物及產物之敏感性，在排除光及氧的情況下進 行主要反應步驟是很重要的。 下列貫例係說明本發明而非限制本發明。 實例 實例1 : a)9-順-Cw三苯基氯化鱗之分離 取2000克含有9_順-與9_反_Cis_三苯基氯化鱗之異構混合 物（反式含量為18%，順式含量為36%)之油性濃縮物，並在 2(TC至25°C及氬氣氛下將其與4〇〇毫升二氣甲烷混合。分離 水相，並接著在15 C至25°C下用5至1〇分鐘添加1000毫升乙 酸乙酯。接著，將35毫升正丁醇添加至先前所獲得之澄清 橙褐色溶液中。在28它至33。(：/180至200毫巴下蒸餾出乙酸 乙酯及二氯曱烷，藉此以16〇〇毫升乙酸乙酯來代替所蒸餾 92053.doc 1293951 出之量。在30°C至35°C下以〇.2毫升9_順·Ch三苯基氯化鱗 之懸浮液來引發9-順三苯基氯化鱗之結晶。接著，在％ °0：至35它下再攪拌懸浮液2至3小時。接著過濾晶體，以*⑼ 毫升乙酸乙酯進行洗滌，然後在4〇。〇 /25毫巴下真空乾燥。 獲得62.06克（以油性濃縮物計31 ·〇%)白色晶體形式之、順 -(：15二苯基氯化鱗（含量為93.6%順式異構體（1^?]^€))。 b)9-順視黃酸之製備 在氬氣氛中，將40.4克（278.5毫莫耳）3甲基_4_氧代丁烯酸 乙酯溶解於80毫升乙醇中。接著，用2〇分鐘小心添加 克（272.7¾莫耳）50%之氫氧化鉀水溶液，從而將反應溫度 保持在0°C到5°C之間。接著，在此溫度下攪拌混合物直至 酯在HPLC色譜中消失。之後，用2〇分鐘小心添加258 〇克9_ 順-Ca三苯基氯化鱗（含量為38 8%，199·5毫莫耳）之乙醇溶 液。在添加過程中使反應溫度保持在至5。〇。接著，用 20分鐘小心添加29.8克（265.6毫莫耳）50%氫氧化鉀水溶 液’從而使反應溫度保持在〇t：與5。〇之間。接著，在此溫 度下攪拌混合物直至鱗鹽在HPLC色譜中消失。在因此所形 成之橙色懸浮液中添加900毫升去離子水，藉此形成澄清的 橙色溶液。再攪拌混合物10分鐘，接著添加4〇〇毫升去離子 水及260毫升二氯甲烷，並再攪拌1〇分鐘。有機相被分離； 接著，用總體積為540毫升的二氯甲烷來萃取水相三次。有 機相被分離。藉由21毫升之85°/。磷酸將水相調節至3 5到4 〇 之pH值’並在氬氣氛及2〇1至3〇它下攪拌2〇分鐘。接著， 藉由200毫升二氯甲烷來萃取水相，並藉由總共為16〇毫升 92053.doc -10- 1293951 之一氯甲燒來進一步举取水相兩次。過據組合之有機相。 藉由在30°C/250毫巴（起始時）及在4〇t/700毫巴（終止時）下 蒸德出二氯甲烷並同時添加800毫升甲醇來達成溶劑向甲 醇之交換。在蒸餾期間9-順視黃酸開始結晶出來。接著， 將懸浮液冷卻至0°C至5°C並攪拌2小時。過濾黃橙色懸浮 液，以0 C至5°c下的總共為170毫升之甲醇洗滌，並將因此 而獲得之晶體在40°C至5(TC/30毫巴下真空乾燥一夜。獲得 10.6克（17_7%)產物，其為黃色結晶形式且其含量為98 5%。 c)9-順視黃酸之結晶 在約20°C及氬氣氛下，將28·〇克9-順視黃酸溶解於112〇 毫升異丙醇中。將懸浮液加熱至6(rcs7(rc，藉此形成澄 清的黃色溶液。藉由緩慢冷卻至〇。〇至而發生結晶。接 著，過濾懸浮液，以冷異丙醇來洗滌，並將因此而獲得之 晶體在40°C至50°C /30毫巴下真空乾燥一夜。獲得24·4克 (87 ·3 /ί>)貝色日日體形式之分析純9_順視黃酸。 92053.doc
Claims (1)
- 號專利申請案 v中文申請專利範圍替換本(％年11月） 十、申請專利範圍： —種製備9-順視黃酸（9_(z)姻in〇icacid)之方*，其特徵 在於：在驗存在下’將式U甲基_4氧代丁稀酸之驗 金屬鹽M+ _ 1 0 其中’ Μ代表納或鉀， 〃、式Π之（：！5-二苯基鱗鹽之順式異構體反應其中Χ代表自素，且Ph代表苯基； 二’鹼|±氫氧化物之存在下，甲基_4·氧代丁烯酸之鹼 至屬鹽係水解弘甲基_4_氧代丁烯酸烷酯（alkyl-methyM-〇x〇cr〇t〇nate)原位製得。 2. 3. 申明專利範圍第1項之方法，其特徵在於：Μ代表鉀， 氧代丁稀酸之卸鹽係在氫氧化卸存在下，水解 3 -甲基-4-氧你 X 丁細酉夂乙酯（ethyl-3-methyl-4-oxocrotonate) 原位製得。 申月專和範圍第1項之方法，其特徵在於··式II中的X 代表氣。 92053-961127.doc 1293951 4·如申請專利範圍第1項之方 鱗鹽之脂々 y / ，，、特徵在於·· Ci5-三苯基 之：、：一構體係分離自β，蘿蔔素合成作用所使用 J二广該母液含有順式異構體與反式異構體之異 稱此合物，該方法包含步驟： a) 以二氯甲料取該母液—濃縮物； b) 將有機相溶解在乙酸乙酯/正丁醇中； c) 蒸餾出乙酸乙酯/二氣甲規； d) 以乙酸乙酯替換所蒸顧出的量； e) 結晶出該順式異構體；及 0過濾並乾燥。 5. 6· 如申請專利範圍第1至4項中任一項之方法， 於：該反應係在-15°C與15°C之間的溫度下執行 如申請專利範圍第1至4項中任一項之方法， 於· 4反應係在C! ·6-醇類之存在下執行。 其特徵在 〇 其特徵在如申請專利範圍第丨至4項中任一項之方法，其特徵在 於·该驗為驗性氫氧化物。 8.如申請專利範圍第7項之方法，其特徵在於：該鹼為氫氧 化卸。 9.如申請專利範圍第1至4項中任一項之方法，苴 於··該反應混合物按照以下步驟處理： a) 以二氯甲烷進行萃取； b) 以無機酸設定水相pH值自3至4 ; c) 以二氣甲烷進行萃取； d) 蒸餾出二氯甲烷及連續導入甲醇將溶劑換成甲醇. 92053-961127.doc 1293951 e)分離自該混合物中所結晶之9-順視黃酸。 92053-961127.doc
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