JP5870197B2 - Method for producing taxane derivative - Google Patents
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- JP5870197B2 JP5870197B2 JP2014533210A JP2014533210A JP5870197B2 JP 5870197 B2 JP5870197 B2 JP 5870197B2 JP 2014533210 A JP2014533210 A JP 2014533210A JP 2014533210 A JP2014533210 A JP 2014533210A JP 5870197 B2 JP5870197 B2 JP 5870197B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 47
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 64
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 53
- 229960003668 docetaxel Drugs 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 claims description 28
- 238000000746 purification Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- -1 taxane compound Chemical class 0.000 claims description 17
- 230000035484 reaction time Effects 0.000 claims description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 11
- 229940123237 Taxane Drugs 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000011701 zinc Substances 0.000 claims description 11
- 229910052725 zinc Inorganic materials 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 238000007142 ring opening reaction Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 239000012190 activator Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000014509 gene expression Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000006227 byproduct Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000002917 oxazolidines Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- MSVWUXLRSKRKFZ-IPMKNSEASA-N (2r,4s,5r)-2-(4-methoxyphenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-4-phenyl-1,3-oxazolidine-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1[C@@H]1N(C(=O)OC(C)(C)C)[C@@H](C=2C=CC=CC=2)[C@H](C(O)=O)O1 MSVWUXLRSKRKFZ-IPMKNSEASA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000010924 continuous production Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
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- 238000005886 esterification reaction Methods 0.000 description 2
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- 239000012467 final product Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000000383 hazardous chemical Substances 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000005741 Steglich esterification reaction Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 230000032050 esterification Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Description
本発明は、タキサン誘導体であるドセタキセルの製造方法に関し、より詳しくは、最終生成物であるドセタキセルと同じ形態の立体配置を有する特定構造の中間体を特定構造のタキサン化合物から製造した後、これを用いて、ドセタキセルを半合成することによって、単純な製造工程によって高収率及び高純度のドセタキセルを製造することができ、工業生産に非常に適したドセタキセルの製造方法に関するものである。 The present invention relates to a method for producing docetaxel, which is a taxane derivative. More specifically, an intermediate having a specific structure having the same configuration as that of the final product docetaxel is produced from a taxane compound having a specific structure. The present invention relates to a method for producing docetaxel that is capable of producing docetaxel with high yield and high purity by a simple production process by semi-synthesizing docetaxel and is very suitable for industrial production.
ドセタキセル（下記式（１）で示される化合物）は、タキソイド族に属する化合物であり、広範囲な抗腫瘍及び抗白血病活性を有する癌化学療法剤である。ドセタキセルは、ヨーロッパ又はインド樹木の葉及び皮から抽出された１０−デアセチルバッカチン（deacetylbaccatin）ＩＩＩの化学的修飾から誘導された半合成抗癌剤であり、ヨーロッパをはじめとする世界各国でその効能が認められ、乳癌及び卵巣癌などに対する治療剤として広く市販されている医薬品である： Docetaxel (a compound represented by the following formula (1)) belongs to the taxoid family and is a cancer chemotherapeutic agent having a wide range of antitumor and antileukemia activities. Docetaxel is a semisynthetic anticancer agent derived from chemical modification of 10-deacetylbaccatin III extracted from leaves and skins of European or Indian trees, and its efficacy has been recognized in various countries around the world including Europe. And are widely marketed as therapeutic agents for breast cancer, ovarian cancer and the like:
今までドセタキセルの製造のための実行可能な半合成経路及びこの化合物の製造に用いられる中間体等の製造方法を含む合成法開発に対する様々な研究が行われてきた。例えば、特許文献１は、ａ）７，１０−ジＴｒｏｃ−１０−デアセチルバッカチンＩＩＩとオキサゾリジン誘導体をトルエン溶媒下で、８０℃の温度で加熱して、エステル化反応する工程；ｂ）過剰量のギ酸を用いたオキサゾリジン環の開環工程；ｃ）側鎖アミンへのＢｏｃ（ｔ−ブトキシカルボニル基）保護基の導入工程；及びｄ）７，１０−ヒドロキシ基保護基を脱保護化する工程；からなるドセタキセルを含むタキサン誘導体製造方法を記載している。しかし、この場合、工程ａ）で、高温の縮合反応と複雑な抽出及び精製工程を経ることになっており、工程ｂ）で、開環反応と同時に、Ｂｏｃを除去する反応を経た後、技術的に難しい濃縮工程及び複雑な抽出／精製工程を行わなければ、約８５％の収率で目的化合物を得ることができないという限界がある。更に、工程ｄ）で、７，１０−ヒドロキシ基保護基の脱保護化反応は、過剰量の酢酸と粉末亜鉛を使用しているので、発熱が激しく、爆発危険性が高く、大量生産に適しない短所がある。 Until now, various studies have been conducted on development of synthetic methods including feasible semi-synthetic routes for the production of docetaxel and methods for producing intermediates used in the production of this compound. For example, Patent Document 1 discloses: a) a step of esterification by heating 7,10-diTroc-10-deacetylbaccatin III and an oxazolidine derivative in a toluene solvent at a temperature of 80 ° C .; b) excess A step of opening an oxazolidine ring using an amount of formic acid; c) a step of introducing a Boc (t-butoxycarbonyl group) protecting group into a side chain amine; and d) deprotecting a 7,10-hydroxy group protecting group A method for producing a taxane derivative comprising docetaxel comprising the steps: However, in this case, in step a), a high-temperature condensation reaction and a complicated extraction and purification step are to be performed. In step b), after the ring-opening reaction and the reaction to remove Boc, the technology Unless the difficult concentration step and complicated extraction / purification step are performed, the target compound cannot be obtained in a yield of about 85%. Furthermore, in step d), the deprotection reaction of the 7,10-hydroxy group protecting group uses an excessive amount of acetic acid and powdered zinc, so it generates a large amount of heat, has a high explosion risk, and is suitable for mass production. There are no disadvantages.
特許文献２は、ａ）７，１０−ジＴｒｏｃ−１０−デアセチルバッカチンＩＩＩとオキサゾリジン誘導体［（２Ｒ，４Ｓ，５Ｒ）−３（ｔｅｒｔ−ブトキシカルボニル）−２−（４−メトキシフェニル）−４-フェニルオキサゾリジン−５−カルボン酸］をトルエン溶媒下、２０℃でエステル化反応する工程；ｂ）塩酸を用いたオキサゾリジン環の開環工程；及びｃ）７，１０−ヒドロキシ基保護基を脱保護化する工程；からなるオキサゾリジン誘導体を用いたドセタキセルの製造方法を開示している。しかし、この場合、工程ａ）で用いられるトルエンはＩＣＨガイドラインＱ３Ｃ（Guideline Impurities: Guideline for residual solvents）でクラス２に該当する物質であり、一般的に興奮、幻覚又は麻酔作用を引き起こす有害化学物質（幻覚物質）として規定されているところ、その使用が制限されている。また、各工程ａ）〜ｃ）で、異なる溶媒を使用しているので、大量生産時、これらを除去する時間が長くなり、生産コストが増大するという問題点がある。 Patent Document 2 describes a) 7,10-diTroc-10-deacetylbaccatin III and an oxazolidine derivative [(2R, 4S, 5R) -3 (tert-butoxycarbonyl) -2- (4-methoxyphenyl)- 4-phenyloxazolidine-5-carboxylic acid] in a toluene solvent at 20 ° C .; b) ring opening step of oxazolidine ring using hydrochloric acid; and c) 7,10-hydroxy group protecting group is removed. A method for producing docetaxel using an oxazolidine derivative comprising a protecting step is disclosed. However, in this case, toluene used in step a) is a substance that falls under Class 2 according to ICH Guidelines Q3C (Guideline Impurities: Guideline for residual solvents), and is generally a hazardous chemical substance that causes excitement, hallucination or anesthetic action ( Its use is restricted where it is prescribed as a hallucinogen. In addition, since different solvents are used in the respective steps a) to c), there is a problem that the time for removing them becomes longer during mass production, and the production cost increases.
特許文献３は、４−及び５−位の炭素原子がＳ，Ｓ立体配置を有するオキサゾリジン誘導体［（２Ｒ，４Ｓ，５Ｓ）−３−（ｔｅｒｔ−ブトキシカルボニル）−２−（４−メトキシフェニル）−４-フェニルオキサゾリジン−５−カルボン酸］と７，１０−ジＴｒｏｃ−１０−デアセチルバッカチンＩＩＩを無水トルエン溶媒下、７４℃で２４時間、エステル化反応して、エピマー混合物を得る工程；ｂ）７，１０−ヒドロキシ基保護基を脱保護化して、エピマー混合物を精製工程で所望の目的化合物として分離する工程；及びｃ）塩酸を用いて、オキサゾリジン環を開環した後、精製する工程を含む、低い収率でドセタキセルを製造する方法を記載している。しかし、この場合、別途のエピマー混合物分離工程が必要とされ、有害物質であるトルエンを用い、７４℃で２４時間という長時間反応しなければならなく、工業生産に適しないという問題がある。 Patent Document 3 discloses an oxazolidine derivative [(2R, 4S, 5S) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) having 4- and 5-position carbon atoms having S and S configurations. 4-phenyloxazolidine-5-carboxylic acid] and 7,10-diTroc-10-deacetylbaccatin III in an anhydrous toluene solvent at 74 ° C. for 24 hours to obtain an epimer mixture; b) a step of deprotecting the 7,10-hydroxy group protecting group and separating the epimer mixture as a desired target compound in the purification step; and c) a step of purifying after opening the oxazolidine ring using hydrochloric acid. A process for producing docetaxel in low yield is described. However, in this case, a separate epimer mixture separation step is required, and toluene, which is a harmful substance, must be reacted at 74 ° C. for 24 hours, which is not suitable for industrial production.
要約すれば、前記した従来技術は、ドセタキセルを大量生産するのに非効率的であり、医薬分野などでのドセタキセルの需要増加に適切に応じ得なく、有害化学物質の使用と低い生産性により、その適用がまた制限されている実状である。 In summary, the prior art described above is inefficient to mass-produce docetaxel, cannot adequately respond to the increasing demand for docetaxel in the pharmaceutical field, etc., due to the use of hazardous chemicals and low productivity, Its application is also limited.
そこで、ドセタキセルを高収率で大量生産しうる効率的な製造方法に対する技術の開発が切実に求められている。 Therefore, there is an urgent need for development of a technique for an efficient manufacturing method capable of mass-producing docetaxel in a high yield.
本発明は、前記した従来技術の問題点を解決するためのものであり、単純な製造工程によって高収率及び高純度でドセタキセルを製造しうるドセタキセルの製造方法を提供することを技術的課題とする。 The present invention is to solve the above-described problems of the prior art, and to provide a method for producing docetaxel capable of producing docetaxel with high yield and high purity by a simple production process. To do.
前記した技術的課題を達成するための本発明は、下記式（３）で示される化合物の保護基を、脱保護化反応によって除去して、下記式（２）で示される化合物を製造し、
得られた下記式（２）で示される化合物を中間体として用いて、下記式（１）で示されるドセタキセルを製造することを特徴とする、下記式（１）で示されるドセタキセルの製造方法である。
The present invention for achieving the above-mentioned technical problem produces a compound represented by the following formula (2) by removing a protecting group of a compound represented by the following formula (3) by a deprotection reaction.
Using the obtained compound represented by the following formula (2) as an intermediate, docetaxel represented by the following formula (1) is produced by the method for producing docetaxel represented by the following formula (1). is there.
本発明に係る製造方法は、最終生成物であるドセタキセルと同じ形態の立体配置を有するように製造された中間体を用いる単純な工程によって、高収率のドセタキセルを製造することができる。従って、製造時間及び製造コストが低減され、ドセタキセルの工業生産に非常に適している。また、本発明によって製造された半合成ドセタキセルは、簡単なクロマトグラフィー工程などによって容易に精製でき、最終的に高い純度のドセタキセルを提供することができる。 The production method according to the present invention can produce docetaxel in a high yield by a simple process using an intermediate produced so as to have the same configuration as that of the final product docetaxel. Therefore, manufacturing time and manufacturing cost are reduced, and it is very suitable for industrial production of docetaxel. In addition, the semi-synthetic docetaxel produced according to the present invention can be easily purified by a simple chromatography step and the like, and finally high-purity docetaxel can be provided.
本発明は、特定構造のオキサゾリジン側鎖−含有タキサン化合物（式（３））から脱保護化反応によってドセタキセルと同じ形態の立体配置を有する特定構造の化合物（式（２））を製造した後、この時、得られた式（２）の化合物を中間体として用いて、ドセタキセル（式（１））を製造する方法に関するものである。本発明において、式（２）の化合物は、式（３）の化合物から製造され、好ましくは、下記反応式１に示される、式（４）を出発物質として、式（３）を経て、式（２）化合物を得ることができる。従って、本発明の好ましい一具体例によれば、（ａ）式（４）で示される７，１０−ヒドロキシ基が保護された１０−デアセチルバッカチンＩＩＩと式（５）で示されるオキサゾリジン酸誘導体を縮合反応して、式（３）で示されるオキサゾリジン側鎖−含有タキサン化合物を製造する工程；（ｂ）前記工程（ａ）で得られたオキサゾリジン側鎖−含有タキサン化合物の７，１０−位の保護基を除去して、式（２）で示される７，１０−ヒドロキシタキサン化合物を製造する工程；及び（ｃ）前記工程（ｂ）で得られた７，１０−ヒドロキシタキサン化合物を酸性媒体の存在下で、開環反応する工程；を含み、ドセタキセル粗生成物を製造する。 The present invention produces a specific structure compound (formula (2)) having the same configuration as docetaxel by deprotection reaction from an oxazolidine side chain-containing taxane compound (formula (3)) having a specific structure. The present invention relates to a method for producing docetaxel (formula (1)) using the obtained compound of formula (2) as an intermediate. In the present invention, the compound of the formula (2) is produced from the compound of the formula (3), and preferably represented by the following reaction formula 1, using the formula (4) as a starting material, via the formula (3), (2) A compound can be obtained. Therefore, according to one preferred embodiment of the present invention, (a) 10-deacetylbaccatin III in which the 7,10-hydroxy group represented by formula (4) is protected and oxazolidine acid represented by formula (5) A step of producing a oxazolidine side chain-containing taxane compound represented by the formula (3) by condensation reaction of the derivative; (b) 7,10- of the oxazolidine side chain-containing taxane compound obtained in the step (a); Removing the protecting group at the position to produce a 7,10-hydroxytaxane compound represented by the formula (2); and (c) acidifying the 7,10-hydroxytaxane compound obtained in the step (b). Carrying out a ring-opening reaction in the presence of a medium to produce a crude docetaxel product.
このような本発明のドセタキセル製造方法の具体例に対する全工程を下記反応式１に概略的に示した。 The entire process for the specific example of the method for producing docetaxel of the present invention is schematically shown in the following reaction formula 1.
（本明細書に記載された全ての式及び反応式において、Ｔｒｏｃは２，２，２−トリクロロエトキシカルボニル、Ａｃはアセチル、Ｂｚはベンゾイル（Ｃ６Ｈ５−Ｃ（＝Ｏ）−）、Ｐｈはフェニル、Ｂｏｃはｔ−ブトキシカルボニル、Ｍｅはメチルを表す。）
以下では、前記した本発明によるドセタキセルの好ましい製造方法を工程別に更に詳細に説明する。
(In all formulas and reaction formulas described herein, Troc is 2,2,2-trichloroethoxycarbonyl, Ac is acetyl, Bz is benzoyl (C 6 H 5 -C (═O) —), Ph Represents phenyl, Boc represents t-butoxycarbonyl, and Me represents methyl.)
Below, the preferable manufacturing method of the above-mentioned docetaxel by this invention is demonstrated in detail according to process.
工程（ａ）：式（３）で示されるオキサゾリジン側鎖−含有タキサン化合物の製造
本工程は、７−及び１０−位のヒドロキシ基がＴｒｏｃ基で保護された１０−デアセチルバッカチンＩＩＩ（下記式（４）;７，１０−ジＴｒｏｃ-１０−デアセチルバッカチンＩＩＩ）と側鎖として保護基が導入されたオキサゾリジン酸誘導体（下記式（５）;［（２Ｒ，４Ｓ，５Ｒ）−３−（ｔｅｒｔ−ブトキシカルボニル）−２−（４−メトキシフェニル）−４-フェニルオキサゾリジン−５−カルボン酸］）とを、エステル化反応によって縮合（カップリング）して、４−及び５−位の炭素原子がＳ、Ｒ立体配置を有するオキサゾリジン側鎖−含有タキサン化合物（下記式（３））を製造する工程である：
Step (a): Production of Oxazolidine Side Chain-Containing Taxane Compound represented by Formula (3) This step is for 10-deacetylbaccatin III in which the 7- and 10-position hydroxy groups are protected with a Troc group (described below) Formula (4); 7,10-diTroc-10-deacetylbaccatin III) and an oxazolidine acid derivative having a protecting group introduced as a side chain (formula (5) below: [(2R, 4S, 5R) -3 -(Tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyloxazolidine-5-carboxylic acid]) by an esterification reaction to form 4- and 5-positions. It is a step of producing an oxazolidine side chain-containing taxane compound (the following formula (3)) in which the carbon atom has S, R configuration:
式（３）で示される化合物は、式（４）で示される化合物と式（５）で示される化合物とを用いて、当該分野で周知の縮合方法（例えば、Steglichエステル化）で製造することができる。 The compound represented by the formula (3) is produced by a condensation method well known in the art (for example, Steglich esterification) using the compound represented by the formula (4) and the compound represented by the formula (5). Can do.
式（５）で示されるオキサゾリジン酸誘導体は、式（４）で示される１０−デアセチルバッカチンＩＩＩ １当量に対して１〜２当量、より好ましくは１．２〜１．５当量の量で使用することが好ましい。その使用量が１０−デアセチルバッカチンＩＩＩ １当量に対して１当量未満のとき、反応が完結しないことがあり、その使用量が１０−デアセチルバッカチンＩＩＩ １当量に対して２当量を超えると、反応に必要な量以上に高価な試薬を過剰に添加することになり、経済的な側面から好ましくない。 The oxazolidine acid derivative represented by the formula (5) is used in an amount of 1 to 2 equivalents, more preferably 1.2 to 1.5 equivalents relative to 1 equivalent of 10-deacetylbaccatin III represented by the formula (4). It is preferable to use it. When the amount used is less than 1 equivalent with respect to 1 equivalent of 10-deacetylbaccatin III, the reaction may not be completed, and the amount used exceeds 2 equivalents with respect to 1 equivalent of 10-deacetylbaccatin III. In such a case, an excessive amount of reagent more than the amount necessary for the reaction is added, which is not preferable from the economical aspect.
本工程の縮合反応において、縮合剤としては、ジシクロヘキシルカルボジイミド（ＤＣＣ）、ジイソプロピルカルボジイミド（ＤＩＣ）及びエチル−３−（３-ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）から選択される１種以上が挙げられるが、これらに限定されることはない。好ましくは、安価なジシクロヘキシルカルボジイミドを使用する。縮合剤は１０−デアセチルバッカチンＩＩＩ １当量に対して１〜４当量、より好ましくは１．７〜２．２当量の量で使用することが好ましい。その使用量が１０−デアセチルバッカチンＩＩＩ １当量に対して１当量未満のとき、縮合剤を追加投入しなければならない不便を生じることがあり、その使用量が１０−デアセチルバッカチンＩＩＩ １当量に対して４当量を超えると、試薬の過剰添加によって製造コストが増加し、副生成物、例えば、ウレアが多量に生成し、精製工程に困難を生じることがある。 In the condensation reaction in this step, examples of the condensing agent include one or more selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). However, it is not limited to these. Preferably, inexpensive dicyclohexylcarbodiimide is used. The condensing agent is preferably used in an amount of 1 to 4 equivalents, more preferably 1.7 to 2.2 equivalents, relative to 1 equivalent of 10-deacetylbaccatin III. When the amount used is less than 1 equivalent with respect to 1 equivalent of 10-deacetylbaccatin III, it may cause inconvenience that a condensing agent must be additionally added, and the amount used is 10-deacetylbaccatin III 1. When the amount exceeds 4 equivalents, the production cost increases due to excessive addition of reagents, and a by-product such as urea is produced in a large amount, which may make the purification process difficult.
本工程の反応に使用可能な溶媒としては、酢酸エチル、酢酸メチル、ジクロロメタン、トルエン、キシレン、テトラヒドロフランなどが挙げられるが、これらに限定されることはない。好ましくは、環境親和性に優れた酢酸エチルを使用する。 Examples of the solvent that can be used for the reaction in this step include, but are not limited to, ethyl acetate, methyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, and the like. Preferably, ethyl acetate having excellent environmental compatibility is used.
本工程の反応には、活性化剤が更に添加されていてもよい。活性化剤としては、４−ジメチルアミノピリジン（ＤＭＡＰ）、ピリジンなどのアミン類を単独又は２種以上混合して使用することができるが、これらに限定されることはなく、好ましくは、４−ジメチルアミノピリジンを使用する。活性化剤は、１０−デアセチルバッカチンＩＩＩに対して化学量論的な当量以下の量、例えば、０．３〜０．５当量の量で使用することが好ましい。その使用量が１０−デアセチルバッカチンＩＩＩ １当量に対して０．３当量未満のとき、反応が完結せず、活性化剤を追加投入しなければならない不便を生じることがあり、その使用量が１０−デアセチルバッカチンＩＩＩ １当量に対して０．５当量を超えると、副生成物が多量に生成し、精製工程に困難を生じることがある。 An activating agent may be further added to the reaction in this step. As the activator, amines such as 4-dimethylaminopyridine (DMAP) and pyridine can be used alone or in admixture of two or more kinds. However, the activator is not limited to these and is preferably 4- Dimethylaminopyridine is used. The activator is preferably used in an amount less than or equal to the stoichiometric equivalent to 10-deacetylbaccatin III, for example, 0.3 to 0.5 equivalent. When the amount used is less than 0.3 equivalents relative to 1 equivalent of 10-deacetylbaccatin III, the reaction may not be completed, resulting in inconvenience that additional activator must be added. Is more than 0.5 equivalents relative to 1 equivalent of 10-deacetylbaccatin III, a by-product may be produced in a large amount, which may make the purification process difficult.
本工程の好ましい反応温度は０〜６０℃、より好ましくは２０〜３０℃である。反応温度が０℃未満のとき、反応が進まないか、又は反応時間が過度に長くなり、反応温度が６０℃を超えると、反応中、副生成物の生成が増加して純度が低下（例えば、５〜１０％低下）することがある。 The preferable reaction temperature of this process is 0-60 degreeC, More preferably, it is 20-30 degreeC. When the reaction temperature is less than 0 ° C., the reaction does not proceed or the reaction time becomes excessively long, and when the reaction temperature exceeds 60 ° C., the production of by-products increases during the reaction and the purity decreases (for example, 5-10%).
本工程の好ましい反応時間は、２０〜３０分である。反応時間が２０分未満のとき、目的化合物が十分に製造されず、反応時間が３０分を超えると、副生成物の生成が増加することがある。 The preferred reaction time for this step is 20 to 30 minutes. When the reaction time is less than 20 minutes, the target compound is not sufficiently produced, and when the reaction time exceeds 30 minutes, the production of by-products may increase.
前記工程（ａ）で、各種反応物、添加剤及び溶媒の使用量と反応温度及び反応時間を適宜調節すれば、副生成物の生成が最小限に抑えられ、得られた式（３）で示される化合物を更に分離／精製することなく、次の工程である工程（ｂ）で直ちに使用することができ、このような連続工程により、ドセタキセルの全体的な製造時間は顕著に短縮される。 In the step (a), by appropriately adjusting the usage amount of various reactants, additives and solvents, the reaction temperature and the reaction time, the production of by-products can be minimized, and the obtained formula (3) The compounds shown can be used immediately in the next step, step (b), without further separation / purification, and such continuous steps significantly reduce the overall production time of docetaxel.
工程（ｂ）：式（２）で示される７，１０−ヒドロキシタキサン化合物の製造
本工程は、前記工程（ａ）で得られたオキサゾリジン側鎖−含有タキサン化合物（前記式（３））の７−及び１０−位の保護基（即ち、Ｔｒｏｃ基）を、脱保護化反応によって除去して、７，１０−ヒドロキシタキサン化合物（下記式（２））を製造する工程である：
Step (b): Production of a 7,10-hydroxytaxane compound represented by the formula (2) This step is for the oxazolidine side chain-containing taxane compound obtained in the step (a) (7 in the formula (3)). A step of producing a 7,10-hydroxytaxane compound (the following formula (2)) by removing the protecting group at the − and 10-positions (ie, the Troc group) by a deprotection reaction:
本発明の一具体例で、本工程の脱保護化反応は、式（３）で示される化合物を適切な反応溶媒、例えば、酢酸の存在下で、亜鉛と反応することによって遂行される。この場合、酢酸は（式（３）で示される化合物が１００％生成するものと仮定する場合）、式（３）で示される化合物に対して重量比で０．２〜５倍量、より好ましくは０．３〜０．６倍量で使用することが好ましい。その使用量が、式（３）で示される化合物の重量に対して、０．２倍量未満のとき、反応が完結せず、その使用量が式（３）で示される化合物の重量に対して、５倍量を超えると、抽出及び精製工程で過剰量の酢酸が残留するという問題が生じることがある。また、亜鉛は式（３）で示される化合物に対して、重量比で０．３〜１倍量、より好ましくは０．４〜０．６倍量で使用することが好ましい。その使用量が式（３）で示される化合物重量に対して、０．３倍量未満のとき、反応が完結しないことがあり、その使用量が式（３）で示される化合物重量に対して、１倍量を超えると、不純物の増加によって追加的な精製工程が必要となることがある。 In one embodiment of the present invention, the deprotection reaction in this step is performed by reacting the compound represented by formula (3) with zinc in the presence of a suitable reaction solvent, for example, acetic acid. In this case, acetic acid (assuming that 100% of the compound represented by formula (3) is produced) is 0.2 to 5 times by weight, more preferably the compound represented by formula (3). Is preferably used in an amount of 0.3 to 0.6 times. When the amount used is less than 0.2 times the weight of the compound represented by formula (3), the reaction is not completed, and the amount used is based on the weight of the compound represented by formula (3). If the amount is more than 5 times, there may be a problem that an excessive amount of acetic acid remains in the extraction and purification steps. Zinc is preferably used in an amount of 0.3 to 1 times, more preferably 0.4 to 0.6 times the weight of the compound represented by formula (3). When the amount used is less than 0.3 times the weight of the compound represented by Formula (3), the reaction may not be completed, and the amount used is based on the weight of the compound represented by Formula (3). Above the 1-fold amount, additional purification steps may be required due to increased impurities.
本工程の反応に使用可能な溶媒としては、酢酸エチル、メタノール又はこれらの混合物が挙げられるが、これらに限定されることはない。 Examples of the solvent that can be used in the reaction of this step include, but are not limited to, ethyl acetate, methanol, or a mixture thereof.
本工程の反応には、反応中、亜鉛の凝集現象を改善及び解消するために、セライトが更に添加されていてもよい。セライトは、式（３）で示される化合物に対して重量比で０．３〜１倍量、より好ましくは、０．４〜０．８倍量で使用することが好ましい。その使用量が、式（３）で示される化合物重量に対して、０．３倍量未満のとき、亜鉛の凝集現象改善効果が小さく、その使用量が式（３）で示される化合物重量に対して、１倍量を超えると、抽出及び精製工程で過剰量のセライトが残留するという問題が生じることがある。 Celite may be further added to the reaction in this step in order to improve and eliminate the phenomenon of zinc aggregation during the reaction. Celite is preferably used in an amount of 0.3 to 1 times, more preferably 0.4 to 0.8 times the weight ratio of the compound represented by formula (3). When the amount used is less than 0.3 times the weight of the compound represented by formula (3), the effect of improving the agglomeration phenomenon of zinc is small, and the amount used is reduced to the weight of the compound represented by formula (3). On the other hand, if the amount exceeds 1 time, there may be a problem that an excessive amount of celite remains in the extraction and purification steps.
本工程の好ましい反応温度は、４０〜７０℃、より好ましくは４５〜６５℃である。反応温度が４０℃未満のとき、反応性に劣り、反応時間が過度に長くなり、反応中の発熱により瞬間的な爆発が生じ、反応温度が７０℃を超えると、副生成物の増加によって追加的な精製工程が必要となることがある。 The preferable reaction temperature of this process is 40-70 degreeC, More preferably, it is 45-65 degreeC. When the reaction temperature is less than 40 ° C, the reactivity is inferior, the reaction time becomes excessively long, an instantaneous explosion occurs due to heat generation during the reaction, and when the reaction temperature exceeds 70 ° C, additional by-products are added. Purification steps may be required.
本工程の好ましい反応時間は、１０分以内、より具体的に５〜１０分である。反応時間が１０分を超えると、不純物増加により追加的な精製工程が必要となることがある。 The preferred reaction time for this step is within 10 minutes, more specifically 5-10 minutes. If the reaction time exceeds 10 minutes, additional purification steps may be required due to increased impurities.
前記工程（ｂ）で、各種反応物、添加剤及び溶媒の使用量（特に、亜鉛及び酢酸の使用量）、反応温度及び反応時間を適宜調節すれば副生成物の生成が最小限に抑えられ、得られた式（２）の化合物を更に分離／精製することなく、次の工程である工程（ｃ）で直ちに使用することができる。従って、このような連続工程により、ドセタキセルの全体的な製造時間は顕著に短縮される。 In the step (b), by adjusting the usage amounts of various reactants, additives and solvents (especially the usage amounts of zinc and acetic acid), reaction temperature and reaction time, the formation of by-products can be minimized. The resulting compound of formula (2) can be used immediately in the next step, step (c), without further separation / purification. Thus, such a continuous process significantly reduces the overall production time of docetaxel.
工程（ｃ）：ドセタキセル粗生成物の製造
本工程は、前記工程（ｂ）で得られたオキサゾリジン側鎖−含有７，１０−ヒドロキシタキサン化合物（前記式（２）の化合物）を中間体として、これを酸性媒体の存在下で開環反応によってオキサゾリジン環を開環して、最終的にドセタキセル（下記式（１）の化合物）粗生成物を製造する工程である：
Step (c): Production of crude docetaxel product In this step, the oxazolidine side chain-containing 7,10-hydroxytaxane compound (compound of formula (2)) obtained in the step (b) is used as an intermediate. This is a step of opening the oxazolidine ring by a ring-opening reaction in the presence of an acidic medium to finally produce a docetaxel (compound of the following formula (1)) crude product:
本工程の開環反応に使用可能な酸性媒体としては、塩酸、硫酸、酢酸及びメタンスルホン酸などが挙げられるが、これらに限定されることはなく、好ましくは塩酸を使用する。酸性媒体は、工程（ｃ）の反応物の全体積に対して、２〜５％（ｖ／ｖ）の量で使用することが好ましい。その使用量が反応物の全体積に対して、２％未満のとき、反応が完結しないか、又は反応時間が過度に長くなることがあり、その使用量が反応物の全体積に対して５％を超えると、副生成物が増加し、抽出工程で酸を除去するための追加的な精製工程が必要となることがある。 Examples of the acidic medium that can be used for the ring-opening reaction in this step include hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, and the like, but are not limited thereto, and hydrochloric acid is preferably used. The acidic medium is preferably used in an amount of 2 to 5% (v / v) based on the total volume of the reactants in step (c). When the amount used is less than 2% with respect to the total volume of the reactants, the reaction may not be completed or the reaction time may be excessively long. Beyond%, by-products increase and an additional purification step may be required to remove the acid in the extraction step.
本工程で使用可能な反応溶媒としては、メタノール、エタノール、イソプロピルアルコール、酢酸エチル又はこれらの混合物が挙げられるが、これらに限定されることはない。 Examples of the reaction solvent that can be used in this step include, but are not limited to, methanol, ethanol, isopropyl alcohol, ethyl acetate, or a mixture thereof.
本工程の好ましい反応温度は、０〜４０℃、より好ましくは２０〜３０℃である。反応温度が０℃未満のとき、反応が進まないか、又は反応時間が長くなり過ぎ、反応温度が４０℃を超えると、副生成物の生成が増加することがある。 The preferable reaction temperature of this process is 0-40 degreeC, More preferably, it is 20-30 degreeC. When the reaction temperature is less than 0 ° C., the reaction does not proceed or the reaction time becomes too long, and when the reaction temperature exceeds 40 ° C., the production of by-products may increase.
本工程の好ましい反応時間は１〜２時間である。反応時間が１時間未満のとき、反応が完結せず、塩酸を更に投入しなければならないという問題が生じ、反応時間が２時間を超えると、副生成物の生成が増加することがある。 The preferred reaction time for this step is 1-2 hours. When the reaction time is less than 1 hour, there is a problem that the reaction is not completed and hydrochloric acid must be further added. When the reaction time exceeds 2 hours, the production of by-products may increase.
前記工程（ａ）〜（ｃ）から得られたドセタキセル粗生成物については、当該分野で一般的な方法によって、反応溶媒をろ過及び濃縮し、更に精製してもよい。ドセタキセル粗生成物を精製する方法は、特に制限されることはなく、カラムクロマトグラフィーなど当該分野で一般的な方法によって精製すればよい。本発明によって製造された半合成ドセタキセルは、簡単なクロマトグラフィー工程によって容易に精製される。従って、最終的に高い純度のドセタキセルを提供することができる。 About the docetaxel crude product obtained from the said process (a)-(c), you may further refine | purify by filtering and concentrating a reaction solvent by a general method in the said field | area. The method for purifying the docetaxel crude product is not particularly limited, and may be purified by a general method in the art such as column chromatography. Semi-synthetic docetaxel produced according to the present invention is easily purified by a simple chromatographic process. Therefore, finally high-purity docetaxel can be provided.
以下、本発明を実施例によって詳細に説明する。これらの実施例は本発明の理解を容易にするものであって、本発明の範囲はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in detail by way of examples. These examples facilitate understanding of the present invention, and the scope of the present invention is not limited to these examples.
実施例１：式（３）で示される化合物の製造
反応器に、酢酸エチル０．３Ｌを加え、式（５）で示される化合物２９ｇ（ＨＰＬＣ純度９８％以上、（２Ｒ，４Ｓ，５Ｒ）−３（ｔｅｒｔ−ブトキシカルボニル）−２−（４−メトキシフェニル）−４-フェニルオキサゾリジン−５−カルボン酸）、４−ジメチルアミノピリジン（ＤＭＡＰ）３ｇ及び式（４）で示される化合物５０ｇ（ＨＰＬＣ純度９８％以上）を加えた。ジシクロヘキシルカルボジイミド（ＤＣＣ）２１ｇを２０℃で加えた後、黄色の反応物を３０分間撹拌した。反応終結後、反応物をセライトパッドでろ過し、ろ液を炭酸ナトリウム水溶液で洗浄した後、得られた有機層を無水硫酸マグネシウムで脱水し、ろ過及び減圧濃縮して、黄色の目的化合物を得た。追加的な精製のために、室温で酢酸エチル０．０５Ｌを加え、撹拌しながらヘキサン１Ｌを滴下して、結晶化した。室温で、１時間撹拌し、沈澱物をろ過した後、４０℃で真空乾燥して、白色の目的化合物（６８ｇ、収率９５％）を得た（ＨＰＬＣ純度９７％）。
Example 1: Production of a compound represented by the formula (3) 0.3 L of ethyl acetate was added to a reactor, and 29 g of a compound represented by the formula (5) (HPLC purity of 98% or more, (2R, 4S, 5R)- 3 (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyloxazolidine-5-carboxylic acid), 3 g of 4-dimethylaminopyridine (DMAP) and 50 g of the compound represented by formula (4) (HPLC purity) 98% or more) was added. After adding 21 g of dicyclohexylcarbodiimide (DCC) at 20 ° C., the yellow reaction was stirred for 30 minutes. After completion of the reaction, the reaction product was filtered through a celite pad, and the filtrate was washed with an aqueous sodium carbonate solution. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a yellow target compound. It was. For additional purification, 0.05 L of ethyl acetate was added at room temperature, and 1 L of hexane was added dropwise with stirring to crystallize. The mixture was stirred at room temperature for 1 hour, the precipitate was filtered, and then vacuum dried at 40 ° C. to obtain the white target compound (68 g, yield 95%) (HPLC purity 97%).
高性能液体クロマトグラフィー（ＨＰＬＣ）分析条件及び分析法は下記通りである。 High performance liquid chromatography (HPLC) analysis conditions and analysis methods are as follows.
実施例２：式（２）で示される化合物の製造
反応器に、メタノール０．２５Ｌを加え、５０〜５５℃で酢酸０．０３４Ｌ、セライト５０ｇ及び亜鉛（亜鉛末、１０μｍ以下）３３ｇを加えた後、１０分間撹拌した。メタノール０．２５Ｌに溶解した前記実施例１で得られた式（３）で示される化合物６８ｇを反応液に加え、５０〜６０℃で１０分間撹拌した。反応終結後、高温状態で反応物を、セライトパッドでろ過し、追加的にメタノール０．２５Ｌを用いて、セライトパッドを洗浄、ろ過した後、ろ液を更に精製することなく、次の反応に用いた（ろ液のＨＰＬＣ純度８５％）。
−ＨＰＬＣ分析条件及び分析法は前記実施例１と同じである。
Example 2 Production of Compound Represented by Formula (2) 0.25 L of methanol was added to a reactor, and 0.034 L of acetic acid, 50 g of celite, and 33 g of zinc (zinc powder, 10 μm or less) were added at 50 to 55 ° C. After that, it was stirred for 10 minutes. 68 g of the compound represented by the formula (3) obtained in Example 1 dissolved in 0.25 L of methanol was added to the reaction solution and stirred at 50 to 60 ° C. for 10 minutes. After completion of the reaction, the reaction product is filtered through a celite pad at a high temperature, and the celite pad is additionally washed with 0.25 L of methanol and filtered, and then the filtrate is further purified without further purification. Used (HPLC purity of the filtrate 85%).
-HPLC analysis conditions and analysis method are the same as in Example 1.
実施例３：式（１）で示される化合物の製造
反応器に、前記実施例２で得られたろ液を加えた後、２０℃で濃塩酸０．０２７Ｌを加えた。反応液を２０〜２５℃で維持しながら、９０分間撹拌した後、反応液にジクロロメタン０．５Ｌと精製水０．５Ｌを加えて抽出した。
Example 3 Production of Compound Represented by Formula (1) The filtrate obtained in Example 2 was added to a reactor, and then 0.027 L of concentrated hydrochloric acid was added at 20 ° C. The reaction solution was stirred for 90 minutes while maintaining at 20 to 25 ° C., and then extracted by adding 0.5 L of dichloromethane and 0.5 L of purified water to the reaction solution.
得られた有機層を無水硫酸マグネシウムで脱水し、ろ過及び減圧濃縮した後、４５℃で真空乾燥して、黄色の目的化合物（５２．５ｇ、２工程収率１２２％）を得た（ＥＰ分析法（European Pharmacopoeia 6.6. 01-2010: 2449）による含量６５％）。 The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then vacuum-dried at 45 ° C. to obtain a yellow target compound (52.5 g, 2-step yield 122%) (EP analysis). 65% content according to the law (European Pharmacopoeia 6.6. 01-2010: 2449)).
実施例４：連続工程による式（１）で示される化合物の製造
（ａ）反応器に、酢酸エチル２．５Ｌを加え、式（５）で示される化合物２９０ｇ（ＨＰＬＣ純度９９％）、４−ジメチルアミノピリジン（ＤＭＡＰ）３０ｇ及び式（４）で示される化合物５００ｇ（ＨＰＬＣ純度９８％）を加えた。ジシクロヘキシルカルボジイミド（ＤＣＣ）２３０ｇを２０℃で加えた後、黄色の反応物を３０分間撹拌した。反応終結後、反応物をセライトパッドでろ過し、ろ液を炭酸ナトリウム水溶液で洗浄した後、得られた有機層を無水硫酸マグネシウムで脱水し、ろ過及び減圧濃縮して、黄色の目的化合物を得た（ろ液のＨＰＬＣ純度９３％）。
Example 4: Production of compound represented by formula (1) by continuous process (a) To a reactor, 2.5 L of ethyl acetate was added, and 290 g of compound represented by formula (5) (HPLC purity 99%), 4- 30 g of dimethylaminopyridine (DMAP) and 500 g of a compound represented by the formula (4) (HPLC purity 98%) were added. After adding 230 g of dicyclohexylcarbodiimide (DCC) at 20 ° C., the yellow reaction was stirred for 30 minutes. After completion of the reaction, the reaction product was filtered through a celite pad, and the filtrate was washed with an aqueous sodium carbonate solution. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a yellow target compound. (HPLC purity 93% of filtrate).
（ｂ）得られた式（３）で示される化合物を含むろ液を反応器に加え、５５℃で酢酸０．３５Ｌとセライト５００ｇを加えた。亜鉛（亜鉛末、１０μｍ以下）３３０ｇを反応液にゆっくり加え、１０分間撹拌した後、高温状態で反応物をセライトパッドでろ過した。酢酸エチル２Ｌを用いて、追加的にセライトパッドを洗浄、ろ過した後、ろ液を更に精製することなく、次の反応に用いた（ろ液のＨＰＬＣ純度８２％）。 (B) The filtrate containing the compound represented by the formula (3) obtained was added to the reactor, and 0.35 L of acetic acid and 500 g of celite were added at 55 ° C. After slowly adding 330 g of zinc (zinc powder, 10 μm or less) to the reaction solution and stirring for 10 minutes, the reaction product was filtered through a celite pad in a high temperature state. The celite pad was additionally washed with 2 L of ethyl acetate and filtered, and the filtrate was used in the next reaction without further purification (HPLC purity of the filtrate: 82%).
（ｃ）得られた式（２）で示される化合物を含むろ液を反応器に加えた後、２０℃で濃塩酸０．３５Ｌを加えた。反応液を２０〜２５℃で維持しながら、９０分間撹拌した後、反応液を、精製水５Ｌを用いて、２回洗浄した。無水硫酸マグネシウムで有機層を脱水し、ろ過及び減圧濃縮した後、４５℃で真空乾燥して、黄色の目的化合物（４８２ｇ，３工程全収率１０７％）を得た（ＥＰ分析法による含量６５％）。 (C) After adding the obtained filtrate containing the compound represented by the formula (2) to the reactor, 0.35 L of concentrated hydrochloric acid was added at 20 ° C. After stirring for 90 minutes while maintaining the reaction solution at 20 to 25 ° C., the reaction solution was washed twice with 5 L of purified water. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then vacuum dried at 45 ° C. to obtain a yellow target compound (482 g, total yield of 3 steps 107%) (content by EP analysis: 65 %).
実施例５：連続工程を介した式（１）で示される化合物の製造
（ａ）反応器に、酢酸エチル２．５Ｌを加え、式（５）で示される化合物２９０ｇ（ＨＰＬＣ純度９９％）、４−ジメチルアミノピリジン（ＤＭＡＰ）３０ｇ及び式（４）で示される化合物５００ｇ（ＨＰＬＣ純度９８％）を加えた。ジシクロヘキシルカルボジイミド（ＤＣＣ）２３０ｇを２０℃で加えた後、黄色の反応物を３０分間撹拌した。反応終結後、反応物をセライトパッドでろ過し、ろ液を炭酸ナトリウム水溶液で洗浄した後、得られた有機層を無水硫酸マグネシウムで脱水し、ろ過した後、全体積が約０．８〜１Ｌになるように減圧濃縮した。
Example 5: Preparation of compound represented by formula (1) through continuous process (a) To a reactor, 2.5 L of ethyl acetate was added, and 290 g of compound represented by formula (5) (HPLC purity 99%), 30 g of 4-dimethylaminopyridine (DMAP) and 500 g of the compound represented by the formula (4) (HPLC purity 98%) were added. After adding 230 g of dicyclohexylcarbodiimide (DCC) at 20 ° C., the yellow reaction was stirred for 30 minutes. After completion of the reaction, the reaction product was filtered through a celite pad, and the filtrate was washed with an aqueous sodium carbonate solution. The obtained organic layer was dehydrated with anhydrous magnesium sulfate and filtered, and the total volume was about 0.8 to 1 L. The solution was concentrated under reduced pressure.
（ｂ）メタノール２．５Ｌを反応器に加え、５０℃で酢酸０．３５Ｌ、セライト５００ｇ及び亜鉛（亜鉛末、１０μｍ以下）３５０ｇを加え、１０分間撹拌した。得られた式（３）で示される化合物を含むろ液をメタノール２．５Ｌに溶解し、反応器に加え、１０分間撹拌した後、高温状態で反応物をセライトパッドでろ過した。メタノール２Ｌを用いて、追加的にセライトパッドを洗浄、ろ過した後、ろ液を更に精製することなく、次の反応に用いた（ろ液のＨＰＬＣ純度８３％）。 (B) 2.5 L of methanol was added to the reactor, 0.35 L of acetic acid, 500 g of celite and 350 g of zinc (zinc powder, 10 μm or less) were added at 50 ° C., and the mixture was stirred for 10 minutes. The obtained filtrate containing the compound represented by the formula (3) was dissolved in 2.5 L of methanol, added to the reactor, stirred for 10 minutes, and then the reaction product was filtered through a celite pad in a high temperature state. The celite pad was additionally washed with 2 L of methanol and filtered, and the filtrate was used in the next reaction without further purification (HPLC purity of filtrate: 83%).
（ｃ）得られた式（２）で示される化合物を含むろ液を反応器に加えた後、２０℃で濃塩酸０．２８Ｌを加えた。反応液を２０〜２５℃で維持しながら、９０分間撹拌した後、反応液にジクロロメタン７．５Ｌと精製水５Ｌを加えて抽出した。得られた有機層を無水硫酸マグネシウムで脱水し、ろ過及び減圧濃縮した後、４５℃で真空乾燥して、黄色の目的化合物（４８８ｇ、３工程全収率１０８％）を得た（ＥＰ分析法による含量７１％）。 (C) After adding the obtained filtrate containing the compound represented by the formula (2) to the reactor, 0.28 L of concentrated hydrochloric acid was added at 20 ° C. The mixture was stirred for 90 minutes while maintaining the reaction solution at 20 to 25 ° C., and extracted with 7.5 L of dichloromethane and 5 L of purified water. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then vacuum dried at 45 ° C. to obtain a yellow target compound (488 g, total yield of 3 steps, 108%) (EP analysis method) Content 71%).
半合成ドセタキセル（式（１）で示される化合物）の精製
前記実施例５で得られた半合成ドセタキセル４５０ｇをメタノール２．５Ｌに完全に溶解した後、精製水１３Ｌに滴下して結晶化させた。生成した白色の結晶を３０分間、３０〜３５℃で撹拌した後、ろ紙でろ過し、精製水２．５Ｌで白色の結晶を洗浄した。得られた濡れた白色の結晶化合物を６５℃で真空乾燥して、白色の目的化合物（４１５ｇ）を得た（ＥＰ分析法による含量８４％）。
Purification of semi-synthetic docetaxel (compound represented by formula (1)) 450 g of semi-synthetic docetaxel obtained in Example 5 was completely dissolved in 2.5 L of methanol, and then dropped into 13 L of purified water for crystallization. . The produced white crystals were stirred for 30 minutes at 30 to 35 ° C., and then filtered through filter paper, and the white crystals were washed with 2.5 L of purified water. The obtained wet white crystalline compound was vacuum-dried at 65 ° C. to obtain a white target compound (415 g) (content by EP analysis: 84%).
シリカゲル（６０〜１００μｍ、Timely、Japan）が充填されたカラム（２５×９０ｃｍ）で液体クロマトグラフィーにより分離精製を実施した。移動相２．５％メタノール／９７．５％ジクロロメタン溶液を用いて、流速３．４Ｌ／分で平衡を保たせ、試料３００ｇをジクロロメタンに溶解し、これら全てを注入した。移動相溶媒を流し続け、ＵＶ検出器を利用して該当するピークを分取した後、減圧濃縮した。４０℃で真空乾燥して、白色の固体として目的化合物（２２７ｇ、ＨＰＬＣ純度９９．５％、個々の関連物質０．１％以下）を得た。得られたドセタキセルに対して、次のような分析を行った。 Separation and purification were performed by liquid chromatography on a column (25 × 90 cm) packed with silica gel (60-100 μm, Timely, Japan). A mobile phase 2.5% methanol / 97.5% dichloromethane solution was used to equilibrate at a flow rate of 3.4 L / min, and a 300 g sample was dissolved in dichloromethane, all of which was injected. The mobile phase solvent was allowed to flow, and the corresponding peak was collected using a UV detector, and then concentrated under reduced pressure. Vacuum drying at 40 ° C. gave the target compound (227 g, HPLC purity 99.5%, individual related substances 0.1% or less) as a white solid. The following analysis was performed on the obtained docetaxel.
１．比旋光度（specific optical rotation）[α]（ＥＰ薬方局の分析法に基づく）
[α]２３ Ｄ＝−４０．０１゜（ｃ＝０．１、ＭｅＯＨ）
1. Specific optical rotation [α] (based on EP Pharmacopoeia analysis)
[α] 23 D = −40.01 ° (c = 0.1, MeOH)
２．ＮＭＲ ４００ＭＨｚ（ＣＤＣｌ３）
2. NMR 400 MHz (CDCl 3 )
３．高分解能質量分析（High Resolution Mass Spectroscopy, HRMS）（機器名-Shimadzu LCMS-IT-TOF, Kyoto, Japan）
3. High Resolution Mass Spectroscopy (HRMS) (Instrument name-Shimadzu LCMS-IT-TOF, Kyoto, Japan)
Claims (12)
（ｂ）前記工程（ａ）で得られたオキサゾリジン側鎖−含有タキサン化合物を更に分離精製することなく直ちに使用して７，１０−位の保護基を除去して、下記式（２）で示される７，１０−ヒドロキシタキサン化合物を製造する工程と、
（ｃ）前記工程（ｂ）で得られた７，１０−ヒドロキシタキサン化合物を酸性媒体の存在下で開環反応して、ドセタキセル粗生成物を製造する工程と、
を含むことを特徴とする、下記式（１）で示されるドセタキセルの製造方法：
（式中、Ｔｒｏｃは２，２，２−トリクロロエトキシカルボニル、
Ａｃはアセチル、
Ｂｚはベンゾイル、
Ｐｈはフェニル、
Ｂｏｃはｔ−ブトキシカルボニル、
Ｍｅはメチルを表す。） (A) A 10-deacetylbaccatin III in which a 7,10-hydroxy group represented by the following formula (4) is protected and an oxazolidine acid derivative represented by the following formula (5) are subjected to a condensation reaction, and the following formula ( A step of producing an oxazolidine side chain-containing taxane compound represented by 3);
(B) The oxazolidine side chain-containing taxane compound obtained in the step (a) is immediately used without further separation and purification to remove the protective group at the 7,10-position, and is represented by the following formula (2). Producing a 7,10-hydroxytaxane compound,
(C) ring-opening reaction of the 7,10-hydroxytaxane compound obtained in the step (b) in the presence of an acidic medium to produce a docetaxel crude product;
Characterized in that it comprises a method of docetaxel represented by the following following formula (1):
(In the formula, Troc is 2,2,2-trichloroethoxycarbonyl,
Ac is acetyl,
Bz is benzoyl,
Ph is phenyl,
Boc is t-butoxycarbonyl,
Me represents methyl. )
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