CN106414475A - 生产21-甲氧基-11-β-苯基-19-去甲-孕甾-4, 9-二烯-3, 20-二酮衍生物的方法 - Google Patents
生产21-甲氧基-11-β-苯基-19-去甲-孕甾-4, 9-二烯-3, 20-二酮衍生物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 25
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 20
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 29
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000004305 biphenyl Substances 0.000 claims description 8
- 235000010290 biphenyl Nutrition 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 7
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
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- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 38
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000376 reactant Substances 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
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- 150000002118 epoxides Chemical class 0.000 description 12
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
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- 208000035126 Facies Diseases 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- ATOMTHYGEJDUAK-UHFFFAOYSA-N [Li]COC Chemical compound [Li]COC ATOMTHYGEJDUAK-UHFFFAOYSA-N 0.000 description 2
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- 229910021529 ammonia Inorganic materials 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- CDKCEZNPAYWORX-UHFFFAOYSA-N 1-tert-butyl-4-(4-tert-butylphenyl)benzene Chemical group C1=CC(C(C)(C)C)=CC=C1C1=CC=C(C(C)(C)C)C=C1 CDKCEZNPAYWORX-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 208000009738 Connective Tissue Neoplasms Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
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- VOQUDDBLGWLXNL-UHFFFAOYSA-N [Li]COCC Chemical compound [Li]COCC VOQUDDBLGWLXNL-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001911 anti-progestational effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- CAURZYXCQQWBJO-UHFFFAOYSA-N bromomethyl-chloro-dimethylsilane Chemical compound C[Si](C)(Cl)CBr CAURZYXCQQWBJO-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
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- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- YPRFGPKFFMJKRB-UHFFFAOYSA-N lead;propan-2-one Chemical compound [Pb].CC(C)=O YPRFGPKFFMJKRB-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940100892 mercury compound Drugs 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及合成式(I)的化合物的方法,(I)其中R的含义是二甲基氨基或乙酰基基团,使用式(III)或(IV)的化合物,其中R’的含义是二甲基氨基或2‑甲基‑1,3‑二噁烷‑2‑基基团,作为起始材料且甲氧基甲基锂作为试剂。(III)(IV)。
Description
发明领域
本发明涉及使用甲氧甲基锂试剂合成式(I)的21-甲氧基-孕甾烷衍生物的新方法,
其中R的含义是二甲基氨基或乙酰基基团,
还涉及式(III)的中间体,其中R'的含义是2-甲基-1,3-二噁烷-2-基基团。
发明背景
具有显著抗孕激素活性的21-烷氧基-孕甾烷化合物首次描述于专利申请No.WO97041145和WO01074840中。醋酸特拉司酮(Telapristone acetate)(CDB-4124)是该类型的化合物,其目前处于临床开发的III期研究中。根据至今为止公开的结果,其特别有希望用于治疗子宫纤维瘤(结缔组织的良性肿瘤)。
式(I)的21-甲氧基-孕甾烷衍生物的合成首次描述于专利申请No.WO97041145(见图1)中。
式(I)(R=二甲基氨基基团)的化合物的合成以如下方式进行:
首先,在17位引入侧链,然后通过格林尼亚(Grignard)反应,得到的化合物在11位被取代。
用(溴甲基)二甲基氯甲硅烷甲硅烷基化市售可得的3,3-[1,2-乙二基-双-(氧基)]-17α-羟基-雌-5(10),9(11)-二烯-17β-腈的17位羟基。然后在-78℃,使用二异丙基氨基锂将17-甲硅烷氧基溴化合物转化为21-溴化合物。21位甲氧基基团的引入以相当复杂、多步的方法进行:经由21-乙酰氧基和21-羟基衍生物,使用6当量过量的三甲基鎓四氟硼酸盐与质子海绵(SNAP反应)一起。一方面,该方法是昂贵的,另一方面,除去质子海绵是困难的,在很多情况下需要在几个步骤中纯化产品。
该方法进一步的缺点是,格林尼亚反应所需的环氧化物是在第七步合成的。这是不经济的,因为根据NMR光谱,在环氧化物形成中形成了四种环氧化物的同分异构体。
与上述相同的式(I)(R=乙酰基)的化合物之一的合成描述于专利申请No.WO01074840中。
部分不同的合成描述于专利申请No.WO01047945中。在该情况下,也在17位形成侧链,然后通过格林尼亚反应在11位引入取代基。在该方法中,环氧化物的合成也在反应序列的后期中进行。如前述专利申请所描述的在21位进行甲氧基的引入。
工业方法描述于专利申请No.WO2009001148(图2)中。该方法与前述方法的区别在于首先在11位引入取代基,然后在17位形成侧链。该方法的优点是环氧化物的形成是在反应序列开始进行的,与前述方法相比这带来更少的材料损失。在17位侧链形成期间,通过还原将腈转化为甲醛。在格林尼亚反应中,将得到的甲醛甲氧基甲基化。然后进行20位羟基的氧化以得到式(II)的化合物,其是酰化的。
与前述方法相比,甲氧基的引入在更少的步骤中进行,但是在格林尼亚反应期间,使用汞化合物,其从环境保护的角度是不容易管理的。
甲氧基甲基锂试剂的合成首次描述于1964年的出版物中(Tetrahedron Letters(1964),24,1503-6)。锂与甲缩醛中的甲氧基甲基氯在(-25)-(-30)℃反应。将这样得到的试剂的溶液与含有羰基基团的化合物(酮、醛和羧酸酯)反应,这样合成含有甲氧基甲基基团的醇。
类似的方法描述于1967(Liebigs Ann.Chem.704,120-125(1967))中。根据该出版物,该试剂在类似的反应中使用。
在1996年,于出版物(Tetrahedron 52(5),1643-1650,(1996))中描述了一种原位合成乙氧基甲基锂方法,其中,在-90℃,在于四氢呋喃中的4,4’-二-叔-丁基联苯基催化剂存在下,从氯甲基乙基醚和锂,其与含有羰基基团的化合物或苄腈反应。
烷氧基甲基锂试剂至今没有在甾族化合物合成中使用。
发明概述
本发明涉及合成式(I)的21-甲氧基-孕甾烷衍生物的新方法,其具有比如上所述的已知方法更少的步骤,是工业上可实现的、安全和经济的。该方法与专利申请No.WO2009001148中描述的方法区别在于,17位侧链的引入是以不同的方式进行的,特别关于21位甲氧基基团的引入。令人惊讶地发现,如果式(III)和(IV)的化合物是与甲氧基甲基锂反应-优选原位合成-在合适的条件下,甲氧基基团的引入可以以更简单的方式,以与上述方法相比更少的步骤进行。在下一步骤中,通过酸水解和脱水除去得到的中间体的保护基,然后乙酰化17位的羟基。这种方式,式(I)的化合物以与前述方法相比更简单、快速和更经济的方法得到。
本发明还涉及式(III)的中间体,其中R'的含义是2-甲基-1,3-二噁烷-2-基基团。
发明详述
本发明涉及合成式(I)的21-甲氧基-孕甾烷衍生物的新方法(图3)
其中R的含义是二甲基氨基或乙酰基基团,涉及在该方法中使用的甲氧基甲基锂试剂的合成,还涉及式(III)的中间体,其中R'的含义是2-甲基-1,3-二噁烷-2-基基团。
本发明方法的优点是它与前述已知方法相比具有更少的步骤,它是工业上可实现的、安全和经济的。
根据本发明的方法,式(IV)的化合物的5位羟基,
其中R'的含义是二甲基氨基或2-甲基-1,3-二噁烷-2-基基团,并根据描述于专利申请No.WO2009001148中的方法合成,是于卤代溶剂或四氢呋喃或甲苯,优选地在二氯甲烷中的咪唑存在下,在室温,用氯-三甲基硅烷甲硅烷基化,以得到式(III)的化合物,其中R'的含义如上所述。
在下一步骤中,合成甲氧基甲基锂试剂。将稠合或共轭的芳香烃,在给定情况下用烷基基团取代,例如,萘,烷基萘,蒽,4,4'-二-叔丁基-联苯,优选联苯,溶解于醚,脂肪族或芳香烃或甲醛二烷基乙缩醛类型溶剂中,例如四氢呋喃,甲基四氢呋喃,二乙醚,二异丙基醚,甲基-叔丁基醚,甲苯,二甲氧基乙烷,二乙氧基乙烷,优选四氢呋喃,且在惰性气氛下,向这样得到的溶液中加入锂金属。剧烈搅拌反应混合物0.5-5小时,优选3小时,直到锂在0-20℃,优选在5-10℃溶解。然后溶液冷却至(-78)-(-40)℃,优选至-55℃,且将在甲氧基甲基氯本身或将其在上述任何溶剂中的溶液加入至混合物中,以保持反应温度在(-78)-(-30)℃之间,优选在(-55)-(-40)℃之间这样的速率。向这样得到的溶液中于温度在(-78)-(-30)℃之间,优选在(-55)-(-50)℃之间加入式(III)或(IV)的化合物的溶液。反应混合物于温度在(-78)-(-30)℃之间,优选(-48)-(-52)℃之间搅拌0.5-3小时,优选2小时。
然后以保持反应温度低于0℃,优选在-10℃这样的速率向反应混合物中加入水。在加入水之后,剧烈搅拌反应混合物10-120分钟,优选30分钟,同时将温度升至10-15℃。在沉降后相分离,含有被保护的中间体的溶液用强酸,例如盐酸,硫酸,对甲苯磺酸,高氯酸,甲磺酸,磷酸,硫酸氢钾,优选硫酸氢钠处理,以产生式(II)的化合物的溶液,从中以合适的方式分离式(II)的化合物,
其中R的含义是二甲基氨基或乙酰基基团。得到的产物在给定情况下通过色谱纯化。根据描述于专利申请No.WO2009001148中的方法17位羟基被乙酰化,得到式(I)的最终产物,
其中R的含义如上所述。
实施例
本发明是通过以下非限制性实施例解释。
实施例1
11β-[(4-二甲基氨基)苯基]-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的合成:
将146.8g(0.95M)联苯溶解于920ml四氢呋喃中,这样得到的溶液冷却至0℃并在氩气气氛下向溶液中加入6.0g(0.84M)锂金属颗粒。剧烈搅拌反应混合物3小时,直到锂在5-10℃溶解。然后黑色溶液冷却至-55℃。在此期间,将34.6ml(0.45M)甲氧基甲基氯溶解于140ml甲苯中,且将这样得到的溶液加入(约20分钟)至反应混合物中,同时保持温度在(-55)-(-40)℃之间。这样得到的甲氧基甲基锂试剂的溶液冷却至-55℃。将20.0g(32.1mM)11β-[4-(二甲基氨基)苯基]-3,3-亚乙二氧基-5α,17α-双-[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈(WO2009001148的实施例5)溶解于60ml甲苯中,且在约10分钟的期间将该溶液加入至甲氧基甲基锂试剂中,同时保持反应混合物温度在(-55)-(-50)℃之间。然后在(-52)-(-48)℃搅拌反应混合物2小时。这之后,在约10分钟的期间加入240ml水,反应混合物变为无色并升温至-10℃。加入水之后,剧烈搅拌反应混合物30分钟,同时升温至10-15℃。保持惰性气氛直到完成后处理(work-up)。停止搅拌,且20分钟后,沉降相分离。向含有甾类化合物的上层有机相中加入150ml水并搅拌混合物5分钟,20分钟后沉降相分离。然后在5-10分钟期间,向含有甾类化合物的上层有机相中加入于500ml水中的35g硫酸氢钠的15-20℃溶液。在水解期间,反应混合物的温度保持在15-20℃。2小时之后,停止搅拌,且沉降相分离之后,用2x100ml约10v/v%的硫酸洗涤上层有机相,并合并水相。含有甾类化合物的合并的水相用2x100ml的环己烷萃取。然后在10-15分钟的期间,将水相加入至于3L水中的83.73g碳酸钠的溶液中。在搅拌30分钟之后滤出析出的结晶,用水洗涤几次直到中性pH。产物在真空烘箱中于40℃干燥直到恒重以得到14.5g(97.44%)的标题化合物。
总杂质:根据HPLC 7.15%
1H NMR(DMSO-d6,500MHz)δ:6.94-7.06(m,2H),6.62(s,2H),5.66(s,1H),5.37(s,1H),4.51(d,J=18.4Hz,1H),4.30-4.39(m,1H),4.21(d,J=18.4Hz,1H),3.26(s,3H),2.82(s,6H),2.75(dt,J=14.9,5.1Hz,1H),2.39-2.66(m,6H),2.28-2.38(m,1H),2.07-2.26(m,2H),1.89-2.06(m,3H),1.63-1.75(m,1H),1.32-1.51(m,2H),1.20-1.30(m,2H),0.19ppm(s,3H)
13C NMR(CDCl3,125MHz)δ:208.8,197.9,156.5,148.2,146.5,132.0,128.1,127.2,121.9,112.5,88.6,75.4,58.3,50.0,47.0,40.1,38.7,37.9,36.5,36.3,32.9,30.3,27.7,25.2,23.4,15.8ppm
实施例2
11β-[(4-二甲基氨基)苯基]-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的合成:
将121.8g(0.95M)萘溶解于920ml四氢呋喃中,这样得到的溶液冷却至0℃且将切成小片的6.0g(0.84M)锂金属在氩气气氛下加入至溶液中。在5-10℃搅拌反应混合物直到锂溶解。然后黑色溶液冷却至-55℃并向反应混合物中加入于140ml甲苯中的34.6ml(0.45M)氯甲基甲基醚的溶液,同时保持温度低于-40℃,这样得到的溶液冷却至-55℃并加入20.0g(32.1mM)于60ml甲苯中的11β-[4-(二甲基氨基)苯基]-3,3-亚乙二氧基-5α,17α-双-[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈的溶液,同时保持反应混合物的温度低于-50℃。然后在-50℃搅拌反应混合物3小时。
这之后加入240ml水并使反应混合物升温至20℃。在搅拌10分钟后,相分离。向上层有机相中加入500ml 0.3M硫酸并在20℃搅拌混合物2小时。相分离,上层有机相用2x100ml 10%的硫酸洗涤,并合并水相。合并的水相用2x100ml环己烷萃取。然后将水相加入至3L 0.3M碳酸钠溶液中。滤出析出的结晶,用水洗涤并干燥以得到14.5g(97.4%)的标题化合物。
实施例3
11β-[(4-二甲基氨基)苯基]-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的合成:
将146.8g(0.95M)联苯溶解于920ml四氢呋喃中,这样得到的溶液冷却至0℃并将切成小片的6.0g(0.84M)锂金属在氩气气氛下加入至溶液中。在5-10℃搅拌反应混合物直到锂溶解。然后黑色溶液冷却至-55℃并向反应混合物中加入34.6ml(0.45M)于140ml甲苯中的氯甲基甲基醚的溶液,同时保持温度低于-40℃。这样得到的溶液冷却至-55℃并加入于120ml四氢呋喃中的16.6g(30.1mM)11β-[4-(二甲基氨基)苯基]-3,3-亚乙二氧基-5α-羟基-17α-[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈的溶液,同时保持反应混合物的温度低于-50℃。然后在-50℃搅拌反应混合物3小时。这之后加入240ml水并使反应混合物升温至20℃。在搅拌10分钟之后,相分离。向上层有机相中加入500ml 0.3M硫酸并在20℃搅拌混合物2小时。相分离,上层有机相用2x100ml 10%硫酸洗涤,并合并水相。合并的水相用2x100ml环己烷萃取。然后将水相加入至3L 0.3M碳酸钠溶液中。滤出析出的结晶,用水洗涤并干燥以得到13.3g(95.2%)的标题化合物。
实施例4
11β-(4-乙酰基苯基)-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的合成:
将146.8g(0.952M)联苯溶解于920ml四氢呋喃中,这样得到的溶液冷却至0℃并将切成小片的6.0g(0.84M)锂金属在氩气气氛下加入至溶液中。在5-10℃搅拌反应混合物直到锂溶解。然后黑色溶液冷却至-55℃并向反应混合物中加入于140ml甲苯中的34.6ml(0.452M)氯甲基甲基醚溶液,同时保持温度低于-40℃。这样得到的溶液冷却至-55℃并加入于80ml甲苯中的21.0g(31.5mM)3,3-亚乙二氧基-11β-[4-(2-甲基-1,3-二氧戊环-2-基)苯基]-5α,17α-双-[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈的溶液,同时保持反应混合物的温度低于-50℃。然后在-50℃搅拌反应混合物3小时。这之后加入240ml水并使反应混合物升温至20℃。搅拌10分钟之后,相分离。将500ml 5%硫酸加入至上层有机相并在20℃搅拌混合物2小时。相分离,且水相用2x100ml甲苯萃取。合并的有机相用3x 100ml水和1x100ml盐水洗涤,用无水硫酸钠干燥并浓缩。残余物从甲醇结晶以除去相当数量的联苯(约115g)。将甲醇母液浓缩(约48g)并使用500g硅胶和95:5二氯甲烷和丙酮的混合物通过柱色谱法纯化。将含产物的部分浓缩且残余物从丙酮结晶以得到11.87g(81.4%)的标题化合物。
1H NMR(800MHz,CDCl3)δ:7.84-7.90(m,2H),7.25-7.28(m,2H),5.79(s,1H),4.49(m,1H),4.43(m,1H),4.27(m,1H),3.45(s,3H),2.71-2.75(m,1H),2.59-2.65(m,3H),2.57(s,3H),2.53-2.57(m,1H),2.54(s,1H),2.43(ddd,J=16.3,11.6,5.9Hz,1H),2.35(dt,J=16.3,5.5Hz,1H),2.24-2.30(m,1H),2.18(s,6H),2.05-2.10(m,2H),1.84-1.91(m,1H),1.61(ddd,J=15.2,9.3,6.2Hz,1H),1.50-1.57(m,1H),1.38(qd,J=11.7,6.4Hz,1H),0.34(s,3H)
13C NMR(201MHz,CDCl3)δ:208.2,199.2,197.5,156.2,150.3,144.2,134.9,129.8,128.7,127.0,123.2,89.6,77.0,59.3,49.8,48.3,40.4,38.2,36.7,36.6,33.5,30.9,30.9,27.8,26.5,25.7,23.9,16.3
实施例5
11β-(4-乙酰基苯基)-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的合成:
将146.8g(0.952M)联苯基溶解于920ml四氢呋喃中,这样得到的溶液冷却至0℃并将切成小片的6.0g(0.84M)锂金属在氩气气氛下加入至溶液中。在5-10℃搅拌反应混合物直到锂溶解。然后黑色溶液冷却至-55℃并向反应混合物中加入于140ml甲苯中的34.6ml(0.452M)氯甲基甲基醚的溶液,同时保持温度低于-40℃。这样得到的溶液冷却至-55℃并加入于80ml甲苯中的17.8g(30.0mM)3,3-亚乙二氧基-11β-[4-(2-甲基-1,3-二氧戊环-2-基)苯基]-5α-羟基-17α-[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈的溶液同时保持反应混合物的温度低于-50℃。然后在-50℃搅拌反应混合物3小时。这之后加入240ml水并使反应混合物升温至20℃。搅拌10分钟之后,相分离,向上层有机相中加入500ml 5%硫酸并在20℃搅拌混合物2小时。相分离,且水相用2x100ml甲苯萃取。合并的有机相用3x100ml水和1x100ml盐水洗涤,用无水硫酸钠干燥并浓缩。残余物从甲醇结晶以除去相当数量的联苯(约115g)。将甲醇母液浓缩(约48g)并使用500g硅胶和95:5的二氯甲烷和丙酮的混合物通过柱色谱法纯化。浓缩含有产物的部分且残余物从丙酮结晶以得到10.5g(75.7%)的标题化合物。
实施例6
3,3-亚乙二氧基-11β-[4-(2-甲基-1,3-二氧戊环-2-基)-苯基]-5α,17α-双[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈的合成:
将25g(41.68mM)3,3-亚乙二氧基-11β-[4-(2-甲基-l,3-二氧戊环-2-基)苯基]-5α-羟基-17α-[(三甲基甲硅烷基)氧基]-雌-9-烯-17-腈(WO0174840的实施例25)溶解于125ml二氯甲烷中并将5g咪唑加入至溶液中。在20℃,向这样得到的溶液中滴加8.4ml三甲基氯硅烷。在20-25℃搅拌反应混合物1小时,然后用70ml二氯甲烷稀释并加入70ml水。剧烈搅拌10分钟后,相分离,有机相用2x50ml水洗涤,用无水硫酸钠干燥并浓缩。残余物从甲醇结晶以得到22.2g(80.0%)的标题化合物。
1H NMR(800MHz,CDCl3)δ:7.34(m,2H),7.16(m,2H),4.33(m,1H),3.99-4.05(m,2H),3.96(m,1H),3.88-3.94(m,1H),3.83-3.88(m,1H),3.77-3.83(m,2H),3.73-3.77(m,1H),2.37-2.46(m,1H),2.24-2.35(m,3H),2.21(dd,J=14.4,2.6Hz,1H),2.12-2.18(m,1H),2.04(m,1H),2.08(dd J=14.4,0.9Hz,1H)1.97(ddd,J=14.8,9.1,5.5Hz,1H),1.75-1.88(m,2H),1.65-1.73(m,4H),1.64(s,3H),1.47-1.57(m,1H),1.34(m,1H),1.20(td,J=12.8,4.0Hz,1H),0.48(s,3H),0.26(s,9H),0.18(s,9H)
13C NMR(201MHz,CDCl3)δ:145.9,140.3,136.2,132.6,126.9,125.1,120.9,108.8,108.4,78.8,73.5,64.5,64.5,64.4,63.4,50.1,49.0,47.2,38.9,38.6,38.6,38.5,35.6,34.9,27.4,24.6,24.5,23.5,17.0,2.6,1.1
实施例7
17α-乙酰氧基-11β-[(4-二甲基氨基)苯基]-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮(CDB-4124)的合成:
将21ml(222mM)乙酸酐冷却至(-25)-(-20)℃并加入2.8ml(33mM)70%高氯酸,同时保持温度低于-15℃。在(-25)-(-20)℃,向酰化混合物中加入于32ml二氯甲烷中的7g(15.1mM)11β-[(4-二甲基氨基)苯基]-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮溶液。加入完成之后,在(-25)-(-20)℃搅拌反应混合物30分钟,然后将其加入至35ml25%氨水和55ml水的0-(-5)℃的冷却的混合物中。用30ml二氯甲烷稀释这样得到的混合物,并在20-25℃搅拌30分钟。相分离,有机层用2x25ml水洗涤,然后用硫酸钠干燥,过滤并浓缩。得到的粗产物(7.5g)使用1∶1环己烷和乙酸乙酯的混合物通过柱色谱法纯化。将含有产物的部分浓缩且残余物从甲醇结晶以得到4.9g(64%)的标题化合物。
熔点:201-204℃
NMR:1H NMR(500MHz,CDCl3(TMS),δ(ppm)):0.40(3H,s,18-CH3);2.10(3H,s,O-CO-CH3);2.90(6H,s,N-CH3);3.41(3H,s,O-CH3);4.09(1H,d,Hx-21);4.38(1H,m,H-11);4.20(1H,d,Hy-21);5.77(1H,br,H-4);6.62(2H,m,H-3’&H-5’);6.96(2H,m,H-2’&H-6’)
13C NMR(125MHz,CDCl3(TMS),δ(ppm)):15.6(C-18);21.1(O-CO-CH3);(39.3(C-11);40.6(N-CH3);59.4(O-CH3);76.0(C-21);93.9(C-17);112.8(C-3’&C-5’);123.0(C-4);127.3(C-2’&C-6’);129.4(C-10);131.3(C-1’);145.5(C-9);148.7(C-4’);156.4(C-5);170.7(O-CO-CH3);199.4(C-3);202.7(C-20)
实施例8
17α-乙酰氧基-11β-(4-乙酰基苯基)-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮(CDB-4239)的合成:
将25ml(264mM)乙酸酐冷却至(-25)-(-20)℃并加入3.4ml(40mM)70%高氯酸,同时保持温度低于-15℃。在(-25)-(-20)℃,向酰化混合物中加入于90ml二氯甲烷中的8.5g(18.4mM)11β-(4-乙酰基苯基)-17α-羟基-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的溶液。加入完成之后,在(-25)-(-20)℃搅拌反应混合物30分钟,然后将其加入至42ml25%氨水和70ml水的0-(-5)℃的冷却的混合物中。在20-25℃搅拌反应混合物30分钟,然后相分离,有机相用2x30ml水洗涤,用硫酸钠干燥,在真空下过滤并浓缩。得到的粗产物(8.5g)使用1∶1环己烷和乙酸乙酯的混合物通过柱色谱法纯化。将含有产物的部分浓缩且残余物从甲醇结晶以得到6.8g(73%)的标题化合物。
熔点:110-116℃。
Claims (9)
1.合成式(I)的化合物的方法
其中R的含义是二甲基氨基(dimetilamino)或乙酰基团,
其特征在于
a)用甲氧基甲基锂与式(III)或(IV)的化合物反应,
其中R'的含义是二甲基氨基或2-甲基-1,3-二噁烷-2-基基团,
b)除去这样得到的中间体的保护基,
c)酰化这样得到的式(II)的化合物的17位上的羟基。
2.根据权利要求1的方法,其特征在于以如下方式合成甲氧基甲基锂试剂:
a)将单独的或稠合的环芳烃溶解于醚类型的溶剂中,
b)在惰性气氛下向这样得到的溶液中加入锂金属,
c)在0-20℃搅拌混合物直到锂溶解,
d)将混合物冷却至(-78)-(-40)℃并加入甲氧基甲基氯。
3.根据权利要求1-2中任一项的方法,其特征在于使用萘或联苯作为单独的或稠合的环芳烃。
4.根据权利要求1-3中任一项的方法,其特征在于使用四氢呋喃作为醚类型溶剂。
5.根据权利要求1-4中任一项的方法,其特征在于在温度介于5-10℃之间进行权利要求2的步骤c)的反应。
6.根据权利要求1-5中任一项的方法,其特征在于在温度-55℃进行权利要求2的步骤d)的反应。
7.根据权利要求1-2中任一项的方法,其特征在于通过酸水解和脱水除去保护基。
8.根据权利要求1-3中任一项的方法,其特征在于原位合成甲氧基甲基锂试剂。
9.式(III)的中间体
其中R'的含义是2-甲基-1,3-二噁烷-2-基基团。
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WO2009001148A2 (en) * | 2007-06-27 | 2008-12-31 | Richter Gedeon Nyrt. | INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11β-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS |
WO2009134718A1 (en) * | 2008-04-28 | 2009-11-05 | Repros Therapeutics Inc. | Pregesteron antagonists such as cdb-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer etc |
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CA2668824A1 (en) | 1996-05-01 | 1997-11-06 | The Government Of The United States Of America, Represented By The Secre Tary Of The Department Of Health And Human Services | 21-substituted progesterone derivatives as new antiprogestational agents |
WO2001047945A1 (en) | 1999-12-29 | 2001-07-05 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Process for preparing 17alpha-acetoxy-11beta-[4-n,n-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates |
ES2546291T3 (es) | 2000-03-17 | 2015-09-22 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | 17-Alfa-sustituida, 11-beta-sustituida-4-arilo y 21-sustituida 19-norpregnadienodionas como agentes antiprogestacionales |
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WO2009001148A2 (en) * | 2007-06-27 | 2008-12-31 | Richter Gedeon Nyrt. | INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11β-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS |
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WO2015121840A1 (en) | 2015-08-20 |
CN106414475B (zh) | 2018-04-10 |
EP3107925B1 (en) | 2018-05-16 |
EA201691661A1 (ru) | 2016-12-30 |
EA032651B1 (ru) | 2019-06-28 |
US20160326211A1 (en) | 2016-11-10 |
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