CN111662318B - 一种伊洛前列素关键中间体及其制备方法 - Google Patents
一种伊洛前列素关键中间体及其制备方法 Download PDFInfo
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- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 title claims abstract description 17
- 229960002240 iloprost Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims abstract description 3
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 3
- 239000010452 phosphate Substances 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000000543 intermediate Substances 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical group C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 claims description 2
- 239000012027 Collins reagent Substances 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- RYBVCZSZPZFJOK-UHFFFAOYSA-N butyl-[butyl(dimethyl)silyl]oxy-dimethylsilane Chemical group CCCC[Si](C)(C)O[Si](C)(C)CCCC RYBVCZSZPZFJOK-UHFFFAOYSA-N 0.000 claims description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 2
- CCNWZGXOWHXIJE-UHFFFAOYSA-N ethoxyethane;oxane Chemical compound CCOCC.C1CCOCC1 CCNWZGXOWHXIJE-UHFFFAOYSA-N 0.000 claims description 2
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 claims description 2
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 claims description 2
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- -1 lactone diol Chemical class 0.000 abstract description 3
- 150000001299 aldehydes Chemical class 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000011734 sodium Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 208000002815 pulmonary hypertension Diseases 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- CRBHXDCYXIISFC-UHFFFAOYSA-N 2-(Trimethylammonio)ethanolate Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 2
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical class COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical group C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 229940105295 ventavis Drugs 0.000 description 1
Classifications
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- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
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- C—CHEMISTRY; METALLURGY
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- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于药物合成领域,涉及一种伊洛前列素关键中间体及其制备方法,具体而言,以科立内酯二醇式Ⅲ为起始原料,先保护羟基,再与磷酸酯缩合、Collins氧化、Wittig‑Horner反应生成中间体式Ⅶ,经双键还原、选择性脱保护生成中间体式Ⅸ,Dess‑Martin氧化生成醛式Ⅹ,与叶立德侧链式Ⅺ缩合得式Ⅻ,再将羰基选择性保护得关键中间体式Ⅱ‑1,相对于其它路线大大减少反应步骤,起始原料便宜易得、工艺简便易控、总收率高、易于工业化生产等优点。
Description
技术领域
本发明属于药物合成领域,涉及一种伊洛前列素关键中间体及其制备方法。
背景技术
伊洛前列素(Iloprost),由拜耳公司研究开发,商品名为Ventavis(万他维),于2004年12月29日获美国FDA批准,用于治疗肺动脉高压症(PAH),2006年经国家食药监局批准在国内上市,是目前获批用于治疗肺动脉高压的四种进口靶向药物之一。伊洛前列素化学名为5-{(E)-(1S,5S,6R,7R)-7-羟基-6-[(E)-(3S,4RS)-3-羟基-4-甲基-1-辛烯-6-炔基]-双环[3.3.0]辛-3-亚基}-戊酸,分子式为C22H32O4,结构式如下:
目前,式I化合物的合成大多会经过同一个关键中间体式II-1化合物,再经手性还原、脱保护、上TBS保护、上戊酸侧链,最后脱TBS保护制得式I化合物,关键中间体式II-1化合物结构如下所示:
例如,美国专利文献US2009325976公开了以3-羰基戊二酸二甲酯和乙二醛为起始原料经12步反应制得,由于在双环上构建6、7位手性碳时无选择性,得到的是混旋体,后通过拆分得到单一构型,使收率偏低,12步反应总收率仅约0.5%。
因此,对伊洛前列素的合成进行工艺研究,优化关键中间体式II化合物的合成路线和工艺操作,减少步骤、提高收率,对高纯度伊洛前列素的工业化生产具有十分重要的意义。
发明内容
为了解决现有技术中的问题一方面,本发明提供了一种伊洛前列素关键中间体式Ⅱ的制备方法,该方法包括将式Ⅻ化合物在新戊二醇和催化剂的存在下于溶剂中反应,
其中R为羟基保护基;优选的,R为三甲基硅醚、三乙基硅醚、叔丁基二甲基硅醚、叔丁基二苯基硅醚、三异丙基硅醚、苄醚、取代苄醚、取代甲基醚、四氢吡喃醚、烯丙基醚中的一种;进一步优选的,R为叔丁基二甲基硅基。
优选的,上述的步骤中所用的催化剂为对甲苯磺酸,对甲苯磺酸吡啶中的一种。
优选的,上述的步骤中所用的溶剂为苯,甲苯等多种取代甲苯,2-甲基四氢呋喃,1,4-二氧六环中的一种或多种,进一步优选为甲苯。
优选的,上述的步骤中的反应温度为70-120℃,进一步优选为110℃。
优选的,上述步骤中式Ⅻ化合物的合成包括如下步骤:
a、将式Ⅷ化合物在酸性催化剂存在下,选择性脱除保护基,得式Ⅸ化合物,其特征在于,酸性催化剂优选对甲苯磺酸吡啶盐(PPTS)
b、将式Ⅸ化合物在溶剂中与Dess-Martin试剂发生Dess-Martin氧化反应,得式Ⅹ化合物
c、将式Ⅹ化合物与式Ⅺ化合物在碱性条件下发生Wittig-Horner反应,得式Ⅻ化合物,其特征在于,碱性试剂选自钠氢、正丁基锂,叔丁醇钾、KHMDS、NaHMDS中的一种,优选钠氢
其中R的定义如前所述。
进一步优选的,上述步骤中的式Ⅷ化合物的合成包括如下步骤:
a-1、式Ⅲ化合物上的羟基上保护基,得式Ⅳ化合物
a-2、将式Ⅳ化合物与磷酸酯缩合,得式Ⅴ化合物
a-3、式Ⅴ化合物与Collins试剂发生Collins氧化反应,得式Ⅵ化合物
a-4、式Ⅵ化合物发生Wittig-Horner反应,得式Ⅶ化合物
a-5、式Ⅶ化合物上的双键被还原,得式Ⅷ化合物
其中R的定义如前所述。
另一方面,本发明提供了用于制备伊洛前列素关键中间体式Ⅱ的中间体,包括如下所示的化合物:
本发明的伊洛前列素关键中间体式Ⅱ的合成路线选择了科立内酯二醇式Ⅲ为起始原料,该原料双环上6、7位两个手性碳已构建好,规避了需手性合成或拆分的弊端。本发明合成路线共9步反应,总收率6.2%,相对于文献其它路线大大减少反应步骤,起始原料便宜易得、工艺简便易控、总收率高、易于工业化生产等优点。
具体实施方式
下面结合具体实施例,进一步阐述本申请。应理解,这些实施例仅用于说明本申请而不用于限制本申请的保护范围。
实施例1式IV-1化合物的合成
氮气保护下,将科立内酯二醇(III)(10.0g,58.1mmol)、咪唑(15.8g,0.23mol)加入二氯甲烷(DCM)(150ml)中,滴加溶于70ml二氯甲烷(DCM)的叔丁基二甲基氯硅烷(TBSCl)(35g,0.23mol),升温至40℃反应过夜。加入100ml水淬灭,分液,水相用二氯甲烷(DCM)萃取(100ml),合并有机相,依次用水(100ml)、饱和食盐水(100ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩得白色絮状固体(23.0g),不经纯化直接用于下步反应。
MS:401[M+H]+
实施例2式V-1化合物的合成
氮气保护下,将甲基膦酸二甲酯(18.6g,0.15mol)加入400ml无水THF中,降温至-78℃。缓慢滴加正丁基锂(n-BuLi,60ml,2.5M,0.15mol),滴毕,保温反应1h。滴加溶于80ml无水THF的化合物式IV-1(20g,50.0mmol),保温反应3h。向体系中滴加饱和氯化铵(300ml)淬灭反应,升至室温,分液,水相用乙酸乙酯萃取(100ml),合并有机相,依次用水(100ml)、饱和食盐水(100ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得淡黄色油状物(21.2g),收率81.0%。
MS:547.22[M+Na]+
实施例3式VI-1化合物的合成
柯林斯试剂的制备:氮气保护下,将CrO3(33.9g,0.34mol)分批加入吡啶(53.7g,0.68mol)与无水二氯甲烷(DCM)(500ml)的混合液中,搅拌30min,备用。
将化合物式V-1(29.7g,56.6mmol)溶于100ml无水二氯甲烷(DCM)中,滴加至上述配制的柯林斯试剂,升至40℃,回流2h。降至室温,硅藻土过滤,滤液依次用饱和CuSO4溶液(200ml硅藻)、水(200ml硅藻)、饱和食盐水(200ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得无色油状物(15.2g),收率51.5%。
MS:544.9[M+Na]+
1H NMR(400MHz,CDCl3)NMR(400MHz,CDCl油状物((件或按照制造厂商所建议的条dd,J=11.2,1.6Hz,6H),3.55(dd,J=10.0,2.8Hz,1H),3.09(s,1H),3.03(s,1H),2.87(d,J=5.2Hz,2H),2.67~2.03(m,3H),2.04~1.84(m,1H),1.17(dd,J=10.0,4.4Hz,1H),0.80(s,18H),0(d,J=7.0Hz,12H).
实施例4式VII-1化合物的合成
将化合物式VI-1(15.2g,29.1mmol)、无水碳酸钾(4.0g,29.1mmol)、18-冠-6(16.2g,61.1mmol)加入到400ml甲苯中,升温至75℃,反应6h。降至室温,依次用水(100ml依次)和饱和食盐水(100ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得无色油状物(7.75g),收率67.2%。
MS:397.15[M+H]+
实施例5式VIII-1化合物的合成
将化合物式VII-1(7.75g,19.5mmol)、甲酸(1.1g,22.9mmol)、三乙胺(3.1g,30.7mmol)、10%Pd/C(0.78g,0.1eq)依次加入至150ml甲苯中,升温至80℃,持续反应1h。降至室温,乙酸乙酯(50ml)稀释,硅藻土过滤,滤液用饱和NaHCO3(50ml藻土)、饱和食盐水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得无色油状物(6.9g),收率88.6%。
MS:399[M+H]+
实施例6式IX-1化合物的合成
将化合物VIII-1(10g,25.1mmol)、PPTS(1.3g,5.17mmol)加入到95%乙醇(200ml)中,室温搅拌24h。加入饱和NaHCO3(200ml)淬灭反应,用乙酸乙酯萃取(200ml用乙),合并有机相,依次用水(100ml相,)、饱和食盐水(100ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得无色油状物(8.2g),收率64.0%。
MS:285[M+H]+
实施例7式X-1化合物的合成
氮气保护下,将化合物IX-1(4g,14.1mmol)溶于60ml无水二氯甲烷中,降温至0℃,加入DMP(17.8g,42.0mmol)和NaHCO3(10g,0.119mol),加毕,系统升温至10℃搅拌4h。加入10%硫代硫酸钠溶液(50ml),搅拌分液,水相用二氯甲烷萃取(50ml),合并有机相,依次用水(100ml)、饱和食盐水(100ml)洗涤,无水Na2SO4干燥,硅藻土过滤,滤液减压浓缩得无色油状物4.3g,直接投入下一步反应。
MS:283[M+H]+
实施例8式XII化合物的合成
氮气保护下,将NaH(1g,25.0mmol)加入至50ml无水THF中,滴加溶于13ml无水THF的化合物式XI(5.3g,22.8mmol),室温搅拌30min,滴加溶于10ml无水THF的化合物X-1(4.3g),继续搅拌2h。加入1ml乙酸,减压浓缩,残留物用二氯甲烷(DCM)(50ml)溶解,依次用水(50ml次用)、饱和食盐水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得无色油状物(3.2g),两步收率50.6%。
1H NMR(CDCl3)δ6.79~6.73(m,1H),6.27~6.23(m,1H),4.08~4.03(dd,1H),2.89~2.72(m,2H),2.63~2.53(m,2H),2.5~2.3(m,4H),2.26~2.13(m,3H),1.75(dd,J=4.5,2.4Hz,3H),1.58~1.44(m,1H),1.17(dd,J=7.0,2.2Hz,3H),0.91~0.79(m,9H),0.00(dd,J=5.8,3.2Hz,6H);MS:389[M+H]+
注:化合物XI参考专利文献CN106573904合成。
实施例9式II化合物的合成
将化合物式XII(8g,20.6mmol)溶于100ml甲苯中,加入新戊二醇(2.6g,25.0mmol),升温至110℃,再加入PPTS(1g,3.98mmol),反应1h。降至室温,减压浓缩,残留物溶于乙酸乙酯(50ml)中,依次用水(50ml用水)和饱和食盐水(50ml)洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩后过柱纯化得无色油状物(7.5g),收率76.7%。
MS:475[M+H]+
1H NMR(CDCl3)δ6.81~6.75(dd,1H),6.25~6.20(dd,1H),3.90~3.83(m,1H),3.51~3.48(m,4H),2.93~2.9(m,1H),2.53~2.39(m,3H),2.35~2.10(m,5H),1.84~1.77(m,5H),1.55~1.48(m,1H),1.21~1.19(dd,3H),1.00~0.87(m,15H),0(m,6H)。
Claims (9)
1.一种伊洛前列素中间体的制备方法,其特征在于,包括如下步骤:
a-1、式Ⅲ化合物上的羟基上保护基,得式Ⅳ化合物
a-2、将式Ⅳ化合物与磷酸酯缩合,得式Ⅴ化合物
a-3、式Ⅴ化合物与Collins试剂发生Collins氧化反应,得式Ⅵ化合物
a-4、式Ⅵ化合物发生Wittig-Horner反应,得式Ⅶ化合物
a-5、式Ⅶ化合物上的双键被还原,得式Ⅷ化合物
a-6、将式Ⅷ化合物在酸性催化剂存在下,选择性脱除保护基,得式Ⅸ化合物,
a-7、将式Ⅸ化合物在溶剂中与Dess-Martin试剂发生Dess-Martin氧化反应,得式Ⅹ化合物,
a-8、将式Ⅹ化合物与式Ⅺ化合物在碱性条件下发生Wittig-Horner反应,得式Ⅻ化合物,
a-9、式Ⅻ化合物在新戊二醇和催化剂的存在下于溶剂中选择性地保护母核上的羰基,得到伊洛前列素中间体,
上述步骤中,其中R为三甲基硅醚、三乙基硅醚、叔丁基二甲基硅醚、叔丁基二苯基硅醚、三异丙基硅醚、苄醚、四氢吡喃醚、烯丙基醚中的一种。
2.根据权利要求1所述的制备方法,其特征在于,步骤a-6中,所述的酸性催化剂为对甲苯磺酸吡啶盐。
3.根据权利要求1所述的制备方法,其特征在于,步骤a-8中,在碱性试剂存在下反应,所述碱性试剂选自钠氢、正丁基锂,叔丁醇钾、KHMDS、NaHMDS中的一种。
4.根据权利要求3所述的制备方法,其特征在于,步骤a-8中,所述碱性试剂为钠氢。
5.根据权利要求1所述的制备方法,其特征在于,步骤a-9中,所述的催化剂为对甲苯磺酸和对甲苯磺酸吡啶中的一种。
6.根据权利要求1所述的制备方法,其特征在于,步骤a-9中,所述的溶剂为苯、甲苯、2-甲基四氢呋喃和1,4-二氧六环中的一种或多种。
7.根据权利要求6所述的制备方法,其特征在于,步骤a-9中,所述的溶剂为甲苯。
8.根据权利要求1-7任一所述的制备方法,其特征在于,步骤a-9的反应温度为70-120℃。
9.制备伊洛前列素中间体的化合物
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