CN1152578A - 马烯雌酮的异构化 - Google Patents
马烯雌酮的异构化 Download PDFInfo
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- CN1152578A CN1152578A CN96112035A CN96112035A CN1152578A CN 1152578 A CN1152578 A CN 1152578A CN 96112035 A CN96112035 A CN 96112035A CN 96112035 A CN96112035 A CN 96112035A CN 1152578 A CN1152578 A CN 1152578A
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- WKRLQDKEXYKHJB-UHFFFAOYSA-N Equilin Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3=CCC2=C1 WKRLQDKEXYKHJB-UHFFFAOYSA-N 0.000 title claims abstract description 32
- WKRLQDKEXYKHJB-HFTRVMKXSA-N equilin Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 WKRLQDKEXYKHJB-HFTRVMKXSA-N 0.000 title claims abstract description 32
- 238000006317 isomerization reaction Methods 0.000 title claims abstract description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910003002 lithium salt Inorganic materials 0.000 claims abstract description 8
- -1 cyclic acetal Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 8
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims 1
- 159000000002 lithium salts Chemical class 0.000 abstract description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 24
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- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical class CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 230000001076 estrogenic effect Effects 0.000 description 3
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 3
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229940063238 premarin Drugs 0.000 description 3
- 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 2
- NLLMJANWPUQQTA-UBDQQSCGSA-N 7,8-didehydro-17beta-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4C3=CCC2=C1 NLLMJANWPUQQTA-UBDQQSCGSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229940059936 lithium bromide Drugs 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Inorganic materials [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DOLVDOAPSINHRR-AYBZRNKSSA-N (9s,13s,14s)-3-methoxy-13-methyl-9,11,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-17-one Chemical compound C1C[C@]2(C)C(=O)CC[C@H]2C2=CCC3=CC(OC)=CC=C3[C@H]21 DOLVDOAPSINHRR-AYBZRNKSSA-N 0.000 description 1
- 150000000307 17β-estradiols Chemical class 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- 108010003641 statine renin inhibitory peptide Proteins 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
-
- 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
本发明涉及马烯雌酮或其衍生物异构化得到δ(8，9)-脱氢雌酮[δ(8，9)DHE]的一种方法，其特征在于用乙二胺锂盐或二甲亚砜中的氨基化锂处理马烯雌酮或其衍生物。
Description
本发明涉及马烯雌酮或其衍生物异构化的一种方法，特别是马烯雌酮的异构化成3-羟基-雌-1，3，5(10)，8(9)-四-烯-17-酮[δ(8，9)-脱氢雌酮；δ(8，9)DHE；δ8雌酮；8，9脱氢雌酮；CAS no.61612-83-71】的方法。
马烯雌酮的δ(8，9)衍生物的硫酸盐[δ(8，9)DHES]在天然共轭雌激素组成中，例如在用于激素取代物治疗的商业产品Premarin中，以约3-4％的少量存在。SCRIP no.2049(1995)，P.15提出少量的δ(8，9)DHES对共轭雌激素的效果能有显著的贡献。进一步提出与雌激素的受体有很低的亲合力的δ(8，9)DHES有高的官能团活性，其可在报道的降低LDL胆固醇的特性和在共轭雌激素，特别是Premarin对心血管影响方面起重要作用。数据表明δ(8，9)DHES贡献了18％的Premarin循环的雌激素。因此取得一种很方便地生产δ(8，9)DHE的方法是很重要的，用在现有技术中已知的方法很容易将其转换为δ(8，9)DHES的硫酸盐。
除了不方便的总的合成外，J.C.Jacquesy等，Chem.Abstr.76(1972)，154000f公开了在过量酸化的介质中马烯雌酮异构化的情况。用氟化氢或氟化氢/氟化锑在-30℃时实现转换成δ(8，9)DHE。很明显如此危险的反应情况对大规模的δ(8，9)DHE生产完全不适合也不能接收。另外，在US专利5,395,831中应用了Jacquesy的方法，但其中公开了所说的氟化氢方法不能提供纯净的δ(8，9)DHE，除此之外还有10％的不需要的δ(9，11)异构体。商业化可以接收的、不管是否通过把马烯雌酮异构化的生产方法是还没公开的。
本发明首先提供了一种通过马烯雌酮或其一种衍生物异构化到所说的衍生物未生产δ(8，9)DHE的方便和廉价的方法，其特征在于马烯雌酮或其衍生物用乙二胺锂盐或二甲亚砜中的氨基化锂处理。
马烯雌酮的化学式和所说的衍生物用化学式I表示：
其中R1是H、烷基、酰基、或甲硅烷基(烷基)3；R2是H和R3是OH、O-酰基、O-烷基或O-甲硅烷基(烷基)3；或R3是H和R2是OH、O-酰基、O-烷基或O-甲硅烷基(烷基)3；或R2和R3一起代表O；或R2和R3一起代表缩醛或环状缩醛。R1可以代表一种取代烷基，如甲氧乙氧甲基。
通式II的衍生物可以按照本发明的异构化方法制备。
式中R1、R2和R3代表先前确定的意义。
在一个优选实施方案中异构化利用乙二胺的锂盐来完成，因为该方法导致生产非常纯净的δ(8，9)DHE。用锂或烷基锂，优选地是甲基锂，处理乙二胺能够制得锂盐。可加入四氢呋喃、二甲亚砜或类似的(共)溶剂。通常在(共)溶剂加入时，可得到δ(8，9)DHE和马烯雌酮或其衍生物的混合物。在二甲基亚砜中(DMSO)氨基化锂也能提供δ(8，9)DHE和马烯雌酮或其衍生物的混合物，它们能转换成它们的硫酸盐，用在制造含共轭雌激素的药用成分上。
在化学式I的定义中所用术语烷基表示最好有1-6碳原子的有支链或非支链的烷基，如己基、异丁基、特丁基、丙基、异丙基、乙基、和优选地为甲基。术语酰基表示从烷基羧酸衍生而得的酰基基团，烷基部分有先前给出的意义，或从甲酸衍生而得的酰基基团。缩醛优选是从有1-6个碳原子的醇类衍生而得的。
当使用马烯雌酮的C3酯时，普通酯，如有1-6个碳原子的脂肪族的羧酸酯或简单的芳香羧酸酯是优选的。例如甲酸、乙酸、丙酸、苯甲酸或类似的酸的酯。乙酸酯和苯甲酸酯是优选的。在所用的反应条件下，这些酯通常同时皂化，得到游离的δ(8，9)DHE或其与马烯雌酮的混合物。如果有必要，反应产物用通常在现有技术中已知的方法进一步皂化。
如果在化学式I的化合物中，R1是甲硅烷基(烷基)3，则衍生物在反应期间将水解产生按照化学式II(其中R1是H)的化合物。相似的，如果R2或R3是O-酰基或甲硅烷基(烷基)3，化合物可以异构化，其中R2和R3是OH。
优选地，在约0℃和90℃温度之间完成异构化，如果马烯雌酮或其衍生物用乙二胺锂盐处理更优选地约在30℃，如果马烯雌酮或其衍生物用二甲基亚砜的氨基化锂处理则约在65℃。
按照本发明异构化的条件是非显而易见的。大多数直接的异构化方法似乎是在酸的条件下，如醋酸，盐酸，三氟磺酸，醚合三氟化硼或其混合物在溶剂如甲醇、乙醇、四氢呋喃、甲苯中处理马烯雌酮。
然而，没有这些条件则合适的结果就不能得到，因为根本不发生混合物反应或得到一种难处理的化合物的混合物。
在催化剂的条件下(例如钯/碳/苯甲醇)异构化都不导致合适的结果。在大多数碱性的条件下异构化也有同样结果。明显的方法如用常用溶剂中的丁基锂/叔丁醇钾、氨基化钠、叔丁醇钾或氢化钠，在二甲基甲酰胺中的氨基化锂，乙二胺中的钠或钾，和胺(二异丁基胺、戊胺、二甲基乙二胺、哌嗪、哌啶)中的锂进行异构化事实上完全不成功。在最好的情况下在各种异构体、未知的反应产物和原材料的难处理混合物中仅得到2-8％的要求的物质。吃惊地是仅利用乙二胺中的锂的异构化，它提供了95％的δ(8，9)DHE和在DMSO中的氨基化锂的异构化提供了约55％的δ(8，9)DHE和45％的原材料(马烯雌酮)，此类混合物是能够利用的，似乎是成功的。可以相信这些独特的条件提供了一种如果不是唯一的也是罕见的以商业可用的方式从马烯雌酮直接得到δ(8，9)DHE的可能性。
下面的实施例是本发明的例举说明，决不能理解为对本发明的范围的限制。
实施例1
在95℃氮气的气氛下，把锂(13g)分批加入到920ml乙二胺中，混合物在100℃搅拌30min。反应混合物冷却至23℃，之后在温度≤30℃下，把100g马烯雌酮加入混合物。混合物在30℃下再搅拌2h。悬浮液倾入2.5l的冰水中，并在温度≤25℃下加入醋酸直至PH为7。用2.5l乙酸乙酯萃取水层三次。有机层用水洗涤，加入5g活性碳(Norit)，悬浮液在21℃下搅拌30min。悬浮液在涂有dicalite涂层的过滤机上过滤，滤液在真空下蒸发直至体积约至500ml。悬浮液在温度0℃下搅拌1h，之后结晶物滤出，用乙酸乙酯洗涤并在40℃和真空下干燥，得到81g纯度约为95％的δ(8，9)-脱氢雌酮。
δ(8，9)-DHE和马烯雌酮的含量用H1NMR谱确定，它们的特征峰是对δ(8，9)-DHE为0.90ppm(C18)，对马烯雌酮是5.53ppm(C18)和0.79ppm(C18)。
实施例2
把5g氨基化锂加入到5g马烯雌酮在150ml DMSO中的，混合物内。混合物加热至65℃搅拌70min。反应混合物倾入500ml水中，用4N盐酸酸化至PH6.5。滤出结晶，用水洗涤并在真空下40℃干燥，得到5g 4∶5的马烯雌酮和δ(8，9)-脱氢雌酮的混合物。
实施例3
在氮气的气氛下温度约25℃在约15min内把6％甲基锂-溴化锂配合物的二乙醚溶液(23.5ml)加入到46ml乙二胺内。混合物的温度上升至55℃，二乙醚蒸馏出来。随后反应混合物在55℃下搅拌1h。混合物冷却至20℃，加入2.5g马烯雌酮。混合物在30℃下再搅拌90min。
悬浮液倾入冰水中，混合物用乙酸乙酯萃取。蒸发乙酸乙酯萃取液直到体积达到20ml并冷却至0℃，之后2g结晶的δ8-雌酮被分离出。
实施例4
在100℃氮气气氛下把锂(1.1g)分批加入80ml乙二胺中，混合物在100℃搅拌30min。反应混合物冷却至23℃，然后在温度≤30℃时加入4g 17β-二氢马烯雌酮。混合物在30℃下再搅拌4h。悬浮液倾入250ml冰水中，在温度≤25℃下加入醋酸至PH7。悬浮液冷却至5℃，过滤出结晶体。结晶体悬浮在150ml的水中，加入100ml的乙酸乙酯。分离各层，乙酸乙酯溶液在真空下蒸发至体积20ml。悬浮液在-15℃下搅拌1h之后结晶体过滤出来，用乙酸乙酯洗涤和在40℃真空下干燥，得到2.5g 8，9-脱氢17β-雌二醇，其纯度＞95％。
实施例5
在36℃氮气气氛下10min内把甲基锂-溴化锂的二乙醚溶液(20毫升，2.1M)加入到40毫升乙二胺中。混合物的温度上升至55℃，蒸馏出二乙醚。混合物在55℃下搅拌1h。反应混合物冷却至3℃，之后在温度小于或等于10℃下加入2g马烯雌酮-3-甲醚。混合物在12℃下搅拌2h，之后加入200毫升冰水。醋酸加入到混合物中至PH8。悬浮液在15℃下搅拌1h之后过滤出结晶体，用水洗涤，在45℃真空下干燥，得到2.0g 8，9-脱氢雌酮-3-甲醚，其纯度约为80％。
实施例6
按照在实施例5中所描述的程序，在30℃用甲基锂/乙二胺处理17β-二氢马烯雌酮3，17-二醋酸酯，定量地产生8，9-脱氢-17β-雌二醇，其纯度约90％。
实施例7
按照在实施例4中所描述的程序，在20℃用锂/乙二胺处理马烯雌酮-17-新戊基缩醛，以收率90％得到8，9-脱氢雌酮-17-新戊基缩醛，其纯度约90％。
实施例8
按照在实施例4中所描述的程序，用锂/乙二胺处理17β-二氢马烯雌酮-3，17二(三甲基硅烷醚)，定量地产生8，9-脱氢-17β雌二醇，其纯度约为90％。
Claims (5)
1.一种按照通式I的马烯雌酮或其衍生物异构化得到δ(8，9)-脱氢睢酮或其衍生物的方法，其中通式I为：
式中R1是H、烷基、酰基、或甲硅烷基(烷基)3；R2是H和R3是OH、O-酰基、O-烷基或O-甲硅烷基(烷基)3；或R3是H和R2是OH、O-酰基、O-烷基或O-甲硅烷基(烷基)3；或R2和R3一起代表O；或R2和R3一起代表缩醛或环状缩醛，
其特征在于用乙二胺锂盐或二甲亚砜中的氨基化锂处理马烯雌酮或其衍生物。
2.按照权利要求1的方法，其中R1是酰基，R2和R3一起代表O。
3.按照权利要求1或2的方法，其中用乙二胺锂盐处理马烯雌酮或其一种衍生物。
4.按照权利要求1-3的方法，其中反应温度在约0℃和90℃之间。
5.按照权利要求4的方法，其中如果马烯雌酮或衍生物用一种乙二胺锂盐处理，反应温度约在30℃，如果马烯雌酮用二甲基亚砜中的氨基化锂处理，则反应温度约为65℃。
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