CN101027307B - 通过还原烷基化作用制备鸦片止痛剂 - Google Patents
通过还原烷基化作用制备鸦片止痛剂 Download PDFInfo
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- 238000005932 reductive alkylation reaction Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229940035676 analgesics Drugs 0.000 title description 3
- 239000000730 antalgic agent Substances 0.000 title description 3
- 229940127240 opiate Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 229910052727 yttrium Inorganic materials 0.000 claims description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052721 tungsten Inorganic materials 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 150000002576 ketones Chemical class 0.000 abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 10
- OIJXLIIMXHRJJH-KNLIIKEYSA-N Diprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)C(C)(C)O)OC)CN2CC1CC1 OIJXLIIMXHRJJH-KNLIIKEYSA-N 0.000 description 9
- 229960005118 oxymorphone Drugs 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 8
- 229950002494 diprenorphine Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229960001736 buprenorphine Drugs 0.000 description 7
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 6
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- 238000003786 synthesis reaction Methods 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229960000805 nalbuphine Drugs 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- -1 cyclic tertiary amine Chemical class 0.000 description 4
- 229960005297 nalmefene Drugs 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- STBZIDOIKQNFCQ-HSALFYBXSA-N oxilorphan Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CC1 STBZIDOIKQNFCQ-HSALFYBXSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ZFSXKSSWYSZPGQ-UHFFFAOYSA-N (2-hydroxycyclopentyl)azanium;chloride Chemical compound Cl.NC1CCCC1O ZFSXKSSWYSZPGQ-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000005002 aryl methyl group Chemical group 0.000 description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 3
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 3
- 229960001113 butorphanol Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229960000858 naltrexone hydrochloride Drugs 0.000 description 3
- 229950011178 oxilorphan Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- SVNNWKWHLOJLOK-UHFFFAOYSA-N 5-chloropentanoyl chloride Chemical compound ClCCCCC(Cl)=O SVNNWKWHLOJLOK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- IOECHPRJJXZKDO-UHFFFAOYSA-N butane;formaldehyde Chemical compound O=C.CCCC IOECHPRJJXZKDO-UHFFFAOYSA-N 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- NLBUEDSBXVNAPB-DFQSSKMNSA-N cyclorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CC1CC1 NLBUEDSBXVNAPB-DFQSSKMNSA-N 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开式(A)、(B)或(C)化合物的制备方法:其中P是H、CH3或羟基保护基团;X是O、保护的酮、OH、保护的羟基基团或H;Y是OH、保护的羟基基团或H;W是C(CH3)2OH、C(CH3)(C(CH3)3)OH或COCH3;Z是C2-C10烷基或C2-C10芳烷基;以及是单键或双键。所述方法是在氢和还原烷基化催化剂存在下的还原烷基化作用。
Description
本发明涉及纳曲酮和结构相似的化合物如纳布啡、纳美芬(nalmefene)、奥昔啡烷、布托啡诺、二丙诺啡(diprenorphine)和丁丙诺啡的制备方法。所有这些化合物都含有环叔胺。
纳曲酮(1)是一种麻醉止痛剂:
纳布啡(2)和纳美芬(3)是结构相似的化合物:
奥昔啡烷(4)和布托啡诺(5)也是相似的,但是在所谓的A环和C环间没有键连接:
二丙诺啡(6)和丁丙诺啡(7)在C环上含有乙基桥接(bridge):
US 3,332,950公开了制备这类化合物的方法。在第一个方法中,从去甲羟吗啡酮(noroxymorphone)中经过四个步骤制备纳曲酮。所述方法为了分解在被保护的去甲羟吗啡酮和环丙基碳酰氯之间形成的缩合产物而采用了危险的金属氢化物试剂。为了防止在酮官能团上发生副反应,所述方法结合了保护步骤和去保护步骤。本发明人相信从盐酸去甲羟吗啡酮起始的这类方法可提供约33%的纳曲酮。在第二个方法中,在二甲基甲酰胺中将环丙基甲基溴和去甲羟吗啡酮直接偶合而制备纳曲酮。所述方法采用高温(70℃)和延长反应时间(7天),但仍然只达到理论产量的60%。
本发明人探索能提供一种制备纳曲酮及其相似化合物的改良方法。因此,本发明提供式(A)、(B)或(C)化合物的制备方法:
其中P是H、CH3或羟基保护基团;
X是O、保护的酮、OH、保护的羟基基团或H;
Y是OH、保护的羟基基团或H;
W是C(CH3)2OH、C(CH3)(C(CH3)3)OH或COCH3;
Z是C2-C10烷基或C2-C10芳基烷基;以及
其中式(D)、(E)或(F)化合物:
其中Z如上述所定义。
本发明的方法提供比已知方法更好的产率并且避免了采用大规模生产时难以操作的危险的金属氢化物试剂。它也不需要高温和延长反应时间。
在优选的实施方案中,P是H或CH3,优选H。在另一备选实施方案中,P是羟基保护基团如烷氧基、烷氧基羰基、芳氧基羰基、芳基甲基、甲硅烷基乙基、碳酸根或硫酸根基团,并且优选烷氧基、烷氧基羰基、芳氧基羰基或芳基甲基。合适的烷氧基羰基包括丙氧基羰基和乙氧基羰基。合适的芳氧基羰基包括苯氧基羰基。合适的芳基甲基包括萘基甲基和苄基。
X优选是O(因此,在X和所述C6环之间的键是双键)或OH(因此,在X和所述C6环之间的键是单键)。X可以是被保护的酮基,例如乙缩醛(acetal)基团。如果X是被保护的羟基基团,那么所述保护基团可以是上述对P所列的羟基保护基团中的任何一种。
Y优选为OH。如果Y是被保护的羟基基团,那么所述保护基团可以是上述对P所列的羟基保护基团中的任何一种。
Z是C2-C10烷基或C2-C10芳烷基,优选C2-C5烷基。术语“烷基”包括直链烷基、支链烷基、环烷基和被取代的烷基,但优选未被取代的烷基。优选地,Z是环丙基或环丁基。
在式(A)、(B)、(D)和(E)化合物的6,7碳和7,8碳之间的键可以是双键或单键。同样地,在式(C)和(F)化合物的乙基桥接的碳之间的键可以是双键或单键。在氢和还原烷基化催化剂存在下,式(D)、(E)或(F)化合物中的任一双键可被氢化,所以具有双键的式(D)、(E)和(F)化合物可提供具有对应的单键的式(A)、(B)和(C)化合物。本领域技术人员可改变反应条件以有利于双键的氢化。
在本发明的优选实施方案中,式(D)化合物(其中P是H,X是O,以及Y是OH)与式(G)化合物(其中Z是环丙基)反应。所述反应提供式(A)化合物(其中P是H,X是O,Y是OH,以及Z是环丙基)。如果所述6,7和7,8键是单键,那么所述化合物是纳曲酮。
在本发明的另一个优选的实施例中,式(D)化合物(其中P是H,X是OH,以及Y是OH)与式(G)化合物(其中Z是环丁基)反应。所述反应提供式(A)化合物(其中P是H,X是OH,Y是OH,以及Z是环丁基)。如果6,7和7,8键是单键,那么所述化合物是纳布啡。
在本发明的另一个优选的实施方案中,式(E)化合物(其中P是H,X是O,以及Y是OH或H)与式(G)化合物(其中Z是环丙基)反应。所述反应提供式(B)化合物(其中P是H,X是O,Y是OH或H,以及Z是环丙基)。如果所述6,7和7,8键是单键,那么所述化合物是奥昔啡烷和赛克罗酚。
在本发明的另一个优选的实施方案中,式(E)化合物(其中P是H,X是H,以及Y是OH)与式(G)化合物(其中Z是环丁基)反应。所述反应提供式(B)化合物(其中P是H,X是H,Y是OH,以及Z是环丁基)。如果所述6,7和7,8键是单键,那么所述化合物是布托啡诺。
在本发明的另一个优选的实施方案中,式(F)化合物(其中P是H,以及W是C(CH3)2OH)与式(G)化合物(其中Z是环丙基)反应。所述反应提供式(C)化合物(其中P是H,W是C(CH3)2OH,以及Z是环丙基)。如果所述乙基桥接具有单键,那么所述化合物是二丙诺啡。
在本发明的另一个优选的实施方案中,式(F)化合物(其中P是H,以及W是C(CH3)(C(CH3)3)OH)与式(G)化合物(其中Z是环丙基)反应。所述反应提供式(C)化合物(其中P是H,W是C(CH3)(C(CH3)3)OH,以及Z是环丙基)。如果所述乙基桥接具有单键,那么所述化合物是丁丙诺啡。
式(D)、(E)、(F)和(G)化合物为本领域技术人员所已知并可用已知的技术制备。例如,按照Olofson等(Tet.Lett.,1977,第1567-70页)所述,可合成式(D)化合物。按照Monkovic等(J.Amer.Chem.Soc.,95,1973,第9710-12页)所述,可合成式(E)化合物。按照Bentley等(J.Amer.Chem.Soc.,89,1967,第3281-92页)所述,可合成式(F)化合物。按照Organic Syntheses(有机合成)中所述(Collective Volume 6,第312页),可合成式(G)化合物。
合适的还原烷基化催化剂为技术人员所熟知且包括铂系元素的金属催化剂(例如,铂或钯)、镍催化剂和这些催化剂的混合物。所需催化剂的量适合为2mole%或更少,优选约0.2mole%。所述方法适于在室温下或更高的温度下进行,优选在50℃左右。可向所述反应适当地提供1bar或更大压力的氢气,优选约3bar。从醇、醚、胺、酰胺、烷烃、二甲苯、氯化烷烃或其混合物中适当地选择所述溶剂。优选的溶剂是甲醇。本发明的方法可能要进行1小时左右或更长时间。
可将式(A)、(B)和(C)化合物进一步反应以提供有用的化合物,如根据本发明的方法制备的纳曲酮可进一步反应而获得纳美芬。
下述实施例用于说明而不是限制本发明。
实施例1:从去甲羟吗啡酮制备纳曲酮
向溶于甲醇(20ml)中的去甲羟吗啡酮溶液(2g,6.14mmol)中加入环丙基甲醛(0.63ml,8.43mmol)。加入5%钯碳催化剂(1mole%Pd),并将所述混合物在50℃、3bar压力的氢气下氢化1小时。在完成时,过滤除去所述催化剂,用氯仿(20ml)稀释所述反应溶液并用水洗涤(3×20ml)。蒸发所述溶剂得到纳曲酮生物碱。
实施例2:从去甲羟吗啡酮制备盐酸纳曲酮
将去甲羟吗啡酮生物碱(20.0g,相当于60.9mmol干品)加入到N-甲基吡咯烷酮(60ml)和甲醇(140ml)的混合物中。加入环丙烷甲醛(5.3ml,70.9mmol)和碳铂催化剂,并将所述混合物在40psi和50℃下氢化作用1小时。在完成时,过滤除去催化剂,用氯仿(60ml)稀释反应溶液并用水洗涤(200ml)。用氯仿(2×60ml)萃取水层并将合并的有机层用水洗涤(5×140ml)。将有机层浓缩至干,并将固体残留物重新溶解于乙醇(100ml)中。加入盐酸直至pH<4.0。过滤所得的沉淀,用乙醇(10ml)洗涤并在烘箱中干燥,得到白色固体16.7g(理论值74%)。
1H NMR(d6-DMSO,δ/ppm):0.60(1H,m),0.70(1H,m),0.80(2H,m),1.30(1H,m),1.70(2H,m),2.20(1H,m),2.30(1H,m),2.65(2H,m),2.85(1H,m),3.15(3H,br m),3.50(2H,m),4.17(1H,br d),5.20(1H,s),6.80(1H,d,J=8Hz),6.85(1H,d,J=8Hz),7.18(1H,s),9.20(1H,brs),and 9.70(1H,s).13C NMR(d6-DMSOδ/ppm):2.72,5.24,5.81,22.98,27.18,30.73,35.16,46.11,48.66,56.73,60.82,69.83,88.64,118.09,119.83,120.59,127.89,140.22,143.54,and 207.94.
HPLC和IR谱与纳曲酮参考标准一致。
实施例3:从去甲-14-羟基吗啡酮制备盐酸纳曲酮
在钯碳和铂碳催化剂的存在下,将去甲-14-羟基吗啡酮(hydroxymorphinone)(20.0g,相当于62.1mmol干品)、环丙烷甲醛(5.3ml,70.9mmol)、N-甲基吡咯烷酮(60ml)和甲醇(140ml)在40psi和50℃下氢化用2小时。过滤粗制混合物,并用氯仿(60ml)稀释,然后用水(200ml)洗涤。用氯仿(2×60ml)萃取水层,并将合并的有机层用水洗涤(5×140ml)。减压除去氯仿,并将获得的固体重新溶解于乙醇(100ml)中。用盐酸调低pH至<4.0,过滤沉淀、用乙醇(10ml)洗涤并干燥,得到白色固体19.2g(理论值83%),用HPLC分析与盐酸纳曲酮相同。
实施例4:从去甲羟吗啡酮制备纳布啡
在披钯木炭催化剂存在时,将环丁烷碳酰氯(1.44ml,25.2mmol)于N-甲基吡咯烷酮(30ml)中在40psi和室温下氢化作用2小时。通过C矿床(bed of celite)过滤环丁烷甲醛的粗制溶液。向15ml上述滤液中加入去甲羟吗啡酮(2.78g,7.96mmol),随后加入铂碳催化剂,并将混合物在40psi和50℃下氢化。2小时后过滤除去催化剂并分次加入氢硼化钠(3g)。将粗制的反应混合物与已知纳布啡样品的HPLC分析比较,证实纳布啡形成。
实施例5:从去甲二丙诺啡制备二丙诺啡
将去甲二丙诺啡(2.0g)加入到溶于甲醇(16ml)和N-甲基吡咯烷酮(5ml)中的环丙烷甲醛(0.57g)中,加入铂碳催化剂,在40psi和50℃下氢化该混合物。30分钟后,过滤除去催化剂,并用氯仿(6ml)稀释反应溶液,并用水(20ml)洗涤。用氯仿(3×6ml)从所述水相中萃取产物,并将合并的有机层用水洗涤(5×20ml)。减压除去溶剂,得到灰白色固体。残留物的HPLC分析证实所述产物和二丙诺啡生物碱的参考标准一致。
实施例6:从去甲丁丙诺啡制备丁丙诺啡
在铂碳催化剂存在时,将去甲丁丙诺啡(10.0g,24.2mmol)、环丙烷甲醛(2.2ml,29.0mmol)、N-甲基吡咯烷酮(30ml)和甲醇(70ml)在40psi和50℃下氢化2小时。在完成时,过滤除去催化剂,并加入水(200ml)。用氯仿(3×60ml)萃取产物,并用水洗涤(5×140ml)。减压除去氯仿并将残留物重新溶解于乙醇(50ml)。用盐酸调节pH至<3.0。过滤、用乙醇(5ml)洗涤产物并在烘箱中干燥,得到7.2g白色结晶固体。HPLC分析证实所述物质和盐酸丁丙诺啡一致。
Claims (14)
2.根据权利要求1的方法,其中P是H或CH3。
3.根据权利要求1或权利要求2的方法,其中X是O或OH。
4.根据权利要求1的方法,其中Y是OH。
5.根据权利要求1的方法,其中烷基是未取代的。
6.根据权利要求1的方法,其中Z是环丙基或环丁基。
7.根据权利要求1的方法,其中式(D)化合物与式(G)化合物反应得到式(A)化合物,并且其中P是H,X是O,Y是OH,以及Z是环丙基。
8.根据权利要求1的方法,其中式(D)化合物与式(G)化合物反应得到式(A)化合物,并且其中P是H,X是OH,Y是OH,以及Z是环丁基。
9.根据权利要求1的方法,其中式(E)化合物与式(G)化合物反应得到式(B)化合物,并且其中P是H,X是O,Y是OH或H,以及Z是环丙基。
10.根据权利要求1的方法,其中式(E)化合物与式(G)化合物反应得到式(B)化合物,并且其中P是H,X是H,Y是OH,以及Z是环丁基。
11.根据权利要求1的方法,其中式(F)化合物与式(G)化合物反应得到式(C)化合物,并且其中P是H,W是C(CH3)2OH,以及Z是环丙基。
12.根据权利要求1的方法,其中式(F)化合物与式(G)化合物反应得到式(C)化合物,并且其中P是H,W是C(CH3)(C(CH3)3)OH,以及Z是环丙基。
13.根据权利要求1的方法,其中该方法在溶剂中进行,且其中所述溶剂选自醇、醚、胺、酰胺、烷烃、二甲苯、氯化烷烃或其混合物。
14.根据权利要求1的方法,其中该方法在溶剂中进行,且其中所述溶剂选自酰胺和醇。
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