CN1231667A - 麻醉性镇痛剂的制备 - Google Patents

麻醉性镇痛剂的制备 Download PDF

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CN1231667A
CN1231667A CN97198338A CN97198338A CN1231667A CN 1231667 A CN1231667 A CN 1231667A CN 97198338 A CN97198338 A CN 97198338A CN 97198338 A CN97198338 A CN 97198338A CN 1231667 A CN1231667 A CN 1231667A
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B·穆德赖克
J·坎特
C·萨皮诺
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Johnson Matthey PLC
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    • 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
    • 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
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Abstract

本发明公开了一种采用催化量的均相有机金属配合物制备诸如二氢可待因酮和二氢吗啡酮之类麻醉镇痛药的新方法。

Description

麻醉性镇痛剂的制备
本发明涉及利用催化量的均相有机金属配合物制备诸如二氢可待因酮和二氢吗啡酮之类麻醉性镇痛剂的新方法。
二氢可待因酮和二氢吗啡酮都是半合成的阿片类(opioid)镇痛剂，它们具有与可待因和吗啡类似性质的多种作用，包括对中枢神经系统和平滑肌的作用。这些阿片剂的确切作用机理尚不清楚，但据信与中枢神经系统中的阿片受体有关。
过去已经存在多种制备二氢可待因酮和二氢吗啡酮的方法，这些方法包括氢化可待因酮(Arch.Pharm.(1920),258,295)、氧化二氢可待因(DE 415097；US 2715626)、氧化二氢吗啡(有机化学杂志(J.Org.Chem.)(1950)15,1103,US 2628962；US 2654756；US2649454)、电解还原吗啡(日本药物科学杂志(J.Pharm.Soc.Japan)(1936),56,44和(1942),62,347)或催化重排可待因或吗啡(DE623821，应用放射性同位素(App.Radiat.Isot.)(1987)38,651)。但所有这些方法都是高成本低效率的两步法。
采用钯黑催化重排吗啡的方法已有记载。但是，这种方法除得到所需产物外，还得到30-35％不希望的O-脱甲基蒂巴因酮，因而这一方法不可能以适合生产的大规模方式进行。而且纯净产物的分离过程也十分冗长，并需要广泛提纯。
本发明人现已发现一种新的一步法制备二氢可待因酮和二氢吗啡酮的方法，其产率大于80％，而且纯化也只需通过简单方法极简单地进行。
因此，本发明提供了一种制备式(Ⅰ)化合物的新方法：
Figure A9719833800041
其中R1代表氢，甲基或通常用于保护酚和醇的保护基；R2代表氢，甲基，烯丙基，环丁基甲基，苄基，三烷基甲硅烷基或胺保护基；R3代表氢，羟基或氨基；该方法包括使式(Ⅱ)化合物：其中R1,R2和R3的定义同上，与式(Ⅲ)有机金属配合物反应：
Figure A9719833800052
其中M代表金属；Ar各自代表芳基，n代表2-5,X代表BF4 -或ClO4 -，且solv代表甲醇，二氯甲烷/甲醇，四氢呋喃或乙醇。
R1定义内的醇或酚保护基的实例包括醚(如甲氧基甲基、苄氧基甲基、2-(三甲基甲硅烷基)-乙氧基甲基醚、四氢吡喃基、苯甲酰甲基、烯丙基、三乙基甲硅烷基、叔丁基二甲基甲硅烷基)，酯(例如乙酸酯、新戊酸酯(pivaloate)、苯甲酸酯)，碳酸酯(例如苄基、甲基)和磺酸酯(例如甲磺酸酯，甲苯磺酸酯)。
R2定义内的胺保护基的实例包括氨基甲酸酯(例如甲基、2,2,2-三氯乙基、2-甲基甲硅烷基、三乙基甲硅烷基、叔丁基、苄基)，酰胺(例如甲酰基、乙酰基、苯甲酰基、环丁基)，磺酸酯和氨基乙醛缩衍生物。
适宜的R1为氢或甲基。
适宜的R2为氢或甲基，优选氢。
适宜的R3为氢。
适宜的M为铑，钯，铂，铱或铁，优选铑。
适宜的Ar为苯基或环己基基团，优选Ar为苯基。
优选n为4。
反应适宜在极性溶剂或溶剂混合物中进行，例如甲醇，甲醇/二氯甲烷，四氢呋喃，丙酮或乙醇。优选反应在甲醇/二氯甲烷混合物中进行。
反应适宜在5℃-50℃的非极限温度下进行。优选反应在室温(例如25℃-27℃)的温度下进行。
式(Ⅱ)化合物为市售品，式(Ⅲ)化合物则可以采用Boshich等在美国化学会会志(J.Am.Chem.Soc.)(1991),113,958和有机金属(Organometallics)(1988),7,936中所述的类似方法通过有机金属化合物与式(Ⅳ)化合物反应而制得：
Figure A9719833800061
本发明在此通过实施例加以说明，但本发明并不局限于此。
                     实施例1
             大规模制备二氢可待因酮
将配有机械搅拌器、通气管、排气管和温度计的2升四颈圆底烧瓶用氮气冲洗，加入无水甲醇(500ml)。向溶剂中鼓氮气脱氧10-15分钟。然后在氮气氛下加入四氟硼酸双(二环[2.2.1]庚-2,5-二烯)合铑(I)(1.88g,0.005M)和1,4-双(二苯膦基)丁烷(2.17g,0.0051M)，在室温下搅拌所得溶液30分钟。通氢气氢化溶液30分钟，此时溶液的颜色从橙色变为褐黄。
向溶液中鼓氮气10分钟以除去过量氢气，接着在氮气流及搅拌下向溶液中加入可待因(150g,0.5M)。搅拌反应混合物5-15分钟，二氢可待因酮开始以细微结晶形式沉淀析出。加入二氯甲烷(300ml)以溶解所有固体。搅拌暗红色均匀溶液1小时。反应完成之后，在室温下真空浓缩溶液至大约其原始体积的一半。滤出沉淀出的产物，在滤器上用冷甲醇(100ml)浆化，再用甲醇(1×100ml)洗涤，在60-70℃下真空干燥16小时后，得到124.5g(83％)二氢可待因酮游离碱。1H NMR(CDCl3):δ1.26(qd,J=4.3Hz和13.0Hz,1H)；1.75-1.90(m,2H)；2.06(td,J=4.6Hz和12.0Hz,1H)；2.20(td,J=3.4Hz和12.0Hz,1H)；2.30(dd,J=6.0Hz和18.5Hz,1H)；2.36(td,J=4.7Hz和13.7Hz,1H)；2.38-2.48(m,1H)；2.43(s,3H)；2.51-2.61(m,2H)；3.03(d,J=18.5Hz,1H)；3.17(dd,J=2.8和5.4Hz,1H)；3.91(s,3H)；4.65(s,1H)；6.63(d,J=8.2Hz,1H)；6.70(d,J=8.2Hz,1H).13CNMR(CDCl3):δ19.8；25.3；35.3；40.0；42.4；42.7；46.58；46.65；56.6；58.9；91.2；114.5；119.5；126.2；127.2；142.5；145.2；207.5.
                      实施例2
                 制备二氢吗啡酮
将配有磁力搅拌器、气体入口管、排气管和温度计的100ml三颈圆底烧瓶用氮气冲洗，尔后加入无水甲醇(10ml)和二氯甲烷(5ml)。向溶剂中鼓入干燥氮气脱氧10分钟。然后在氮气氛下加入四氟硼酸双(二环[2.2.1]庚-2,5-二烯)合铑(Ⅰ)(112mg,0.0003M)和1,4-双(二苯膦基)丁烷(130mg,0.00031M)，在室温下搅拌所得溶液15分钟。接着通氢气氢化溶液10分钟，向溶液中鼓入氮气5分钟以除去过量氢气。温热催化剂溶液到40℃，在缓和氮气流下加入吗啡(2.14g,0.0075M)。将暗黑色溶液在40℃搅拌4小时。粗制物的1H NMR表明存在88％二氢吗啡酮，8％未反应的吗啡和3-4％未确定的副产物。真空除去溶剂后，通过快速色谱(乙酸乙酯/甲醇3∶1)分离粗制二氢吗啡酮，得到一棕色固体(1.21g,56％)，进而将其用乙醇(25ml)重结晶纯化，得到＞98％纯净二氢吗啡酮(0.75g,35％)。1H NMR(CDCl3-CD3OD～10:1):δ1.25(qd,J=4.5Hz和13.0Hz,1H)；1.79(ddd,J=1.8,3.4和12.3Hz,1H)；1.88(dq,J=4.1和13.0Hz,1H)；2.09(td,J=4.7Hz和12.3Hz,1H)；2.25(td,J=3.5Hz和12.1Hz,1H)；2.35(dd,J=5.6Hz和18.6Hz,1H)；2.38-2.53(m,2H)；2.44(s,3H)；2.55-2.64(m,2H)；3.03(d,J=18.6Hz,1H)；3.19(dd,J=2.7和5.6Hz,1H)；4.67(s,1H)；6.61(d,J=8.1Hz,1H)；6.70(d,J=8.1Hz,1H).13C NMR(d6-DMSO):δ19.5；25.0；34.8；39.6；41.4；42.5；46.2；46.3；58.3；90.3；116.9；119.1；124.4；127.3；139.2；143.9；208.6.

Claims (11)

1．制备式(Ⅰ)化合物的新方法：
Figure A9719833800021
其中R1代表氢，甲基或通常用于保护酚和醇的保护基；R2代表氢，甲基，烯丙基，环丁基甲基，苄基，三烷基甲硅烷基或胺保护基；R3代表氢，羟基或氨基；
该方法包括使式(Ⅱ)化合物：其中R1,R2和R3的定义同上，与式(Ⅲ)有机金属配合物反应：
Figure A9719833800023
其中M代表金属；Ar各自代表芳基，n代表2-5,X代表BF4 -或ClO4 -，且solv代表甲醇，二氯甲烷/甲醇，四氢呋喃，丙酮或乙醇。
2．根据权利要求1的方法，其中R1代表氢或甲基。
3．根据权利要求1或2的方法，其中R2代表氢或甲基。
4．根据权利要求3的方法，其中R2代表氢。
5．根据权利要求1-4中任一项的方法，其中R3代表氢。
6．根据权利要求1-5中任一项的方法，其中M代表铑，钯，铂，铱或铁。
7．根据权利要求6的方法，其中M代表铑。
8．根据权利要求1-7中任一项的方法，其中Ar代表苯基或环已基。
9．根据权利要求8的方法，其中Ar代表苯基。
10．根据权利要求1-9中任一项的方法，其中n代表4。
11．式(Ⅲ)金属配合物在制备式(Ⅰ)化合物中的应用。
CN97198338A 1996-08-01 1997-07-18 麻醉性镇痛剂的制备 Expired - Lifetime CN1105721C (zh)

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TW396157B (en) 2000-07-01
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US5847142A (en) 1998-12-08
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JP4316674B2 (ja) 2009-08-19
EP0915884B1 (en) 2002-04-10
PL331525A1 (en) 1999-07-19
WO1998005667A1 (en) 1998-02-12
PL186307B1 (pl) 2003-12-31
CN1105721C (zh) 2003-04-16
ES2175438T3 (es) 2002-11-16
JP2001500846A (ja) 2001-01-23
ZA976853B (en) 1998-02-11
ATE215955T1 (de) 2002-04-15
JP2009161557A (ja) 2009-07-23
GB9616253D0 (en) 1996-09-11
AU3629197A (en) 1998-02-25
EP0915884A1 (en) 1999-05-19
MY117858A (en) 2004-08-30

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