CN1268947A - 制备作为蛋白酶抑制剂的4-羟基-2-氧-吡喃衍生物的新方法 - Google Patents
制备作为蛋白酶抑制剂的4-羟基-2-氧-吡喃衍生物的新方法 Download PDFInfo
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- CN1268947A CN1268947A CN98808711A CN98808711A CN1268947A CN 1268947 A CN1268947 A CN 1268947A CN 98808711 A CN98808711 A CN 98808711A CN 98808711 A CN98808711 A CN 98808711A CN 1268947 A CN1268947 A CN 1268947A
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- 210000005259 peripheral blood Anatomy 0.000 description 1
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
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Abstract
本发明公开了制备式(XIX)[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺的新方法和新中间体。式(XIX)是一种用于治疗HIV病毒感染者的蛋白酶抑制剂。
Description
本发明涉及制备式(XIX)[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺的新方法和新中间体。式(XIX)是一种用于治疗HIV病毒感染者的蛋白酶抑制剂。
[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺(XIX)可以用国际专利申请WO 95/30670和WO 94/11361所述方法制备。
《药物化学杂志》(J.Med.Chem.),39(22),4349(1996),公开了外消旋形式的环酯(VI)。该文献还公开了将环酯(VI)转变成蛋白酶抑制剂(XIX)的不同合成方法。
《美国化学会志》(J.Am.Chem.Soc.),111,3627(1997),公开了氨基化合物(XVIII)。
《四面体通讯》(Tetrahedron Letters),34(2),277-280(1993),公开了β-羟基羰基化合物向类似于式(VI)和(CVI)的环转化的方法。现有技术中的β-羟基羰基化合物是仲醇,而本发明中的β-羟基羰基化合物是叔醇。而且,《四面体通讯》公开的方法完全不同于本发明制备叔醇(IV)和(CIV)的方法。
《药物化学杂志》,39(23),4630-4642(1996),公开了制备类似于制备式(VI)和(CVI)的化合物的方法,但是从起始原料制备外消旋形式不同于本发明方法且与本发明无关。
国际专利申请WO 95/14012要求保护类似于本发明环状化合物(VI)、(XVII)和(XXV)但是外消旋形式的环状化合物。本发明方法选择性制备了纯形式的这些化合物。
本发明公开了(R)-3-羟基-3-(2-苯基乙基)己酸(IV)及其可药用盐。
本发明还公开了(6R)-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮。
本发明进一步公开了[3α(R),(6R)]5,6-二氢-4-羟基-3-[1-(3-硝基苯基)丙基]-6-丙基-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVII)。
另外,还公开了3-(3-硝基苯基)戊酸(S)-甲酯。
还公开了[3α(R),(6R)]5,6-二氢-4-羟基-3-[(Z)-1-(3-硝基苯基)丙烯基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮。
本发明还公开了式(CVI)的羟基内酯的制备方法,其中R1是
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR1-1,其中R1-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;其中R2是
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR2-1,其中R2-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;该方法包括
(1)将式(CIV)的盐与酸反应制成游离酸,
(2)从反应混合物中萃取游离酸,
(3)将游离酸与活化剂反应,
(4)将游离酸/活化剂的反应混合物与丙二酸单酯和二价金属反应,
(5)将步骤(4)的反应混合物与酸反应,
(6)将步骤(5)的反应混合物在C1-C4醇,THF或DMF存在下与碱反应。
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR1-1,其中R1-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;其中R2是
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR2-1,其中R2-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;该方法包括
(2)将游离酸/活化剂的反应混合物与丙二酸单酯和二价金属反应,
(3)将步骤(2)的反应混合物与酸反应,
(4)将步骤(3)的反应混合物在C1-C4醇,THF或DMF存在下与碱反应。
本发明涉及用新中间体制备[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺(XIX)的新方法。式(XIX)是一种已知的蛋白酶抑制剂,可用于治疗HIV病毒感染者。
路线A描述了酮(I)至相应的酮-酯(II),再到相应的酸(III),到相应的盐(IV),到相应的酮-醇(V),最后再到相应的环形酯(VI)的转变过程;参见实施例1-4,优选方法见实施例18。
路线B描述了4-氯苯硫酚(VII)至相应的氯代醚(VIII),再到相应的联苯基化合物(IX)转变过程;参见实施例5和6。
路线C描述了联苯基化合物(IX)与盐(IV)缩合形成酯醚(X)的过程,以及酯醚(X)到相应的醇(XI)和到相应的醛(XII)的转变过程。还描述了光学纯硝基酯(XIII)与醛(XII)偶合生成相应的硝基醚(XIV)的过程;参见实施例7-10。
路线D描述了硝基醚(XIV)至相应的硝基酮(XV),再到相应的硝基醇(XVI),到相应的硝基-α,β-不饱和酯(XVII),到相应的氨基化合物(XVIII),最后再到相应的蛋白酶抑制剂(XIX)的转变过程;参见实施例11-15。
路线E描述了用于路线C的光学纯硝基酯(XIII)的制备过程。路线E还描述了外消旋体1-(3-硝基苯基)丙醇(XX)经过光学拆分生成相应的光学纯1-(3-硝基苯基)丙醇(XXI)及其转变成相应的磺酸甲酯(XXII),再到相应的二酯(XXIII),到相应的硝基酸(XXIV),最后到相应的光学纯硝基酯(XIII)的过程;参见制备例1-5。
路线F描述了将环酯(VI)转变成相应的硝基-α,β-不饱和酯(XVII)的另一种优选途径。在环酯(VI)中加入间硝基苯基加合物使之变成6(R)-烯烃(XXV)(见实施例16),然后用适当催化剂进行氢化,将其还原成硝基-α,β-不饱和酯(XVII)(见实施例17)。最后,用上述方法将硝基-α,β-不饱和酯(XVII)转变成蛋白酶抑制剂(XIX)。
路线G描述了式(CVI)的光学纯羟基内酯的制备方法。该方法是继实施例1-4和18之后将式(CIV)的盐转变成式(CVI)的羟基内酯。起始原料(CI)的羟基和氨基可以用本领域技术人员熟知的方法进行保护。这些保护基可以在接下来反应步骤中的各个位置或在除去后可以得到所需产物的任何阶段用本领域技术人员熟知的方法除去。本领域技术人员都很清楚,有很多制备光学纯(CIV)的方法。如何进行拆分实施例3制成的光学纯(CIV)并不重要,本发明的目的是要将光学纯(CIV)转变成光学纯(CVI)。
如果酸(III)与足够强的碱反应则形成碱加成盐。可药用盐包括无机碱盐和有机碱盐。可药用盐优于游离酸,因为它们产生的化合物具有较好的水溶性和结晶性能。优选的可药用盐包括下列碱形成的盐:例如氢氧化物,氨,氨丁三醇(THAM),2-氨基-2-(羟甲基)-1,3-丙二醇,(1R,2S)-降麻黄碱,(1S,2R)-降麻黄碱,(R)-2-氨基-2-苯基乙醇,(S)-2-氨基-2-苯基乙醇,(R)-1-苯基乙胺和(S)-1-苯基乙胺。优选的盐是(1R,2S)-降麻黄碱盐。
已知实施例15化合物[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺(XIX)(用“化合物”表示)可用于治疗HIV感染者(见国际专利申请WO 95/30670和WO94/11361)。“化合物”抑制逆转录蛋白酶,因此抑制病毒的复制。本发明的“化合物”被用于抑制人的逆转录蛋白酶。“化合物”被用于治疗感染人类逆转录病毒的病人。人类逆转录病毒包括,例如人类免疫缺陷病毒(HIV-1或HIV-2的株)或人类T细胞白血病病毒(HTLV-I或HTLV-II),这些病毒会导致获得性免疫缺陷综合征(AIDS)和/或相关疾病。
需要治疗的患者是这样的个体:(1)感染一种和多种人类逆转录病毒的人,由血清中是否有病毒的抗体或抗原存在来确定,及(2)在HIV感染情况下的无症状HIV感染或有症状AIDS定义的感染,例如,(a)播散性组织胞浆菌病,(b)异牛皮癣(isoporiasis),(c)支气管和肺念珠菌病,包括气肺(pneumocystic)肺炎,(d)非何杰金氏淋巴瘤,或(e)卡波济氏肉瘤及小于60岁;或在外周血液中绝对CD4+淋巴细胞数量少于500/mm3。治疗过程就是保持本发明“化合物”在整个患者治疗期的抑制水平。
本发明“化合物”被用于治疗感染了能导致获得性免疫缺陷综合征(AIDS)和相关疾病的人类免疫缺陷病毒(HIV)的病人。为了这个目的,这些“化合物”经口服,透皮,皮下和胃肠外(包括肌肉内和静脉内)途径以每日0.1-100mg/kg(体重)的剂量被给药。优选口服方式给药。
本领域技术人员都应该知道如何将“化合物”配制成合适的药物剂型。合适的剂型包括,例如口服剂型如片剂或胶囊剂,或胃肠外剂型如无菌溶液。
如果本发明化合物是口服给药,有效剂量是每日约0.1-100mg/kg(体重),优选剂量是每日约10-100mg/kg(体重),更优选的是每日约30-90mg/kg(体重)。优选每日给药2-5次,更优选每日3次。因此,优选剂量是约2,700-4,500mg/天。
固体剂型或液体剂型都可以用来口服给药,但优选固体剂型,更优选胶囊剂。
如果本发明化合物是胃肠外给药,则可以通过注射或静脉内滴注给药。有效剂量是每日约0.1-100mg/kg(体重)。胃肠外用溶液是将本发明化合物溶解于水性载体,并在封装在适当小瓶或安瓿中之前过滤灭菌制成的。胃肠外用悬浮液是用基本相同的方法制成,只是用的是灭菌悬浮载体,并且在将本发明化合物悬浮于载体之前用环氧乙烷或适当气体灭菌。
本领域技术人员很容易确定准确的给药途径,剂量和给药频率,另外,这些还取决于需要治疗的患者的年龄,体重,身体情况和/或其它临床症状。定义和约定
以下对术语的定义和解释贯穿整个文件,包括说明书和权利要求书。定义
所有温度均用摄氏度表示。
TLC指薄层色谱。
HPLC指高压液相色谱;4.6×250mm Zorbax C-8柱,流动相A=甲醇,流动相B=6.5g叔丁基氢氧化铵的水溶液,用乙酸调至pH 4.0,20分钟内流动相梯度变化为A/B 65/35至A/B 70/30,然后用A/B 70/30无梯度洗脱5分钟,然后再用20分钟从A/B 70/30梯度变化至A/B90/10;流速为1.0ml/分钟;在254nm处进行UV探测。
THF指四氢呋喃。
DMF指二甲基甲酰胺。
MTBE指甲基叔丁基醚。
DMSO指二甲亚砜。
盐水指饱和的氯化钠水溶液。
色谱(柱色谱和快速色谱)指化合物的纯化/分离过程,表示为(载体,洗脱剂)。应该理解,还要将合适的流出液收集起来然后浓缩,得到所要的化合物。
CMR指13C(核)磁共振谱,化学位移表示从低场TMS的ppm(δ)。
NMR指核(质子)磁共振谱,化学位移表示从低场四甲基硅烷的ppm(δ)。
MS指质谱,表示为m/e,m/z或质量/电荷单位。[M+H]+指母核加氢原子的正离子。EI指电子碰撞。CI指化学离子化反应。FAB指快原子轰击。
醚指***。
“可药用的”指这样的性质和/或物质,从药理学/毒理学角度看对于患者是可接受的,从物理学/化学角度看,关于组合物,制剂,稳定性,患者的可接受能力和生物利用度,对于制造药物的化学家来说也是可接受的。
当使用溶剂对儿时,所用溶剂的比例表示为体积/体积(v/v)。
当使用溶解在溶剂中的固体时,固体与溶剂的比例表示为重量/体积(wt/v)。
“化合物”指[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺(XIX)。
“烷基”指C1-C4烷基,包括直链和支链异构体。
W1指乙基和叔丁基。
实施例
如果没有进一步说明,本领域技术人员可以根据上述描述将本发明最大限度地扩展。下面详细的实施例描述了如何制备各种化合物和/或实现本发明各种方法,但实施例仅仅是为了解释而非以任何方式限制上述公开。本领域技术人员都会迅速地理解可以对本方法进行适当变化,无论是反应物还是反应条件和工艺。制备例1将(±)-1-(3-硝基苯基)丙醇(XX)拆分成(S)-1-(3-硝基苯基)丙醇(XXI)和(R)-1-(3-硝基苯基)丙醇乙酸酯
将硅藻土作为载体的PS-30脂酶(Amano,24g)和异丙烯基乙酸酯(22.00ml,0.20mol)加到(±)-1-(3-硝基苯基)丙醇(XX,24.00g,0.13mol)的MTBE(240ml)中。将混合物在20-25℃搅拌2天。结束时过滤除去催化剂,滤饼用***洗涤,然后将混合物减压浓缩,得到乙酸酯-醇混合物。用硅胶色谱分离混合物,得到(R)-1-(3-硝基苯基)丙醇乙酸酯(13.03g),[α]D=+68.7°(乙醇,c=1)和(S)-1-(3-硝基苯基)丙醇(10.7g),[α]D=-33.0°(乙醇,c=1)。制备例2(S)-1-(3-硝基苯基)丙醇甲磺酸酯(XXII)
将二异丙基乙胺(1.07g,8.3mmol)加到(S)-1-(3-硝基苯基)丙醇(XXI,制备例1,1g,5.5mmol)的二氯甲烷(20ml)混合物中。将混合物冷却至-20℃,并加入甲磺酰氯(0.69g,6.02mmol)。将反应保持在-20℃10分钟,然后在0℃保持40分钟。用二氯甲烷稀释反应,加入碳酸氢钠(5%)并分离各相。蒸发除去二氯甲烷,得到标题化合物,[α]D=-79.9°(乙醇,c=1);TLC(硅胶GF,乙酸乙酯/己烷20/80)Rf=0.19;NMR(CDCl3,TMS)0.96-1.01,1.88-2.17,2.89,5.54-5.59,7.57-7.62,7.70-7.73和8.20-8.24δ.制备例31-[1-(3-硝基苯基)丙基]丙二酸(S)-二甲酯(XXIII)
将金属钠(1.27g,0.055mol)溶解于无水乙醇(55ml),制成乙醇钠溶液(1.0M)。在0℃将丙二酸二乙酯(8.84g,0.055mol)加到上述溶液中,然后在-20℃将(S)-1-(3-硝基苯基)丙醇甲磺酸酯(XXII,制备例2,1.43g,5.5mmol)滴加到丙二酸钠(6.4ml,6.4mmol)的上述溶液中。在20-25℃2小时后再在反应中加入一份丙二酸钠(5ml,5.0mmol),并在20-25℃搅拌过夜。浓缩反应,并在乙酸乙酯和盐酸(1N)之间分配。分离有机相,除去溶剂,得到粗产物,经色谱分离(硅胶,乙酸乙酯/己烷10/90)得到标题化合物,[α]D=+19.4°(乙醇,c=1);TLC(硅胶GF,乙酸乙酯/己烷20/80)Rf=0.48;NMR(CDCl3,TMS)0.70-0.75,0.96-1.00,1.27-1.32,1.56-1.88,3.37-3.45,3.65-3.69,3.86-3.96,4.21-4.28,7.44-7.49,7.54-7.57和8.08-8.11δ.制备例4(S)-3-(3-硝基苯基)戊酸(XXIV)
将1-[1-(3-硝基苯基)丙基]丙二酸(S)-二甲酯(XXIII,制备例3,0.73g,2.26mmol)在盐酸(6N,10ml)中回流18小时。将反应冷却,用乙酸乙酯萃取。乙酸乙酯相用水洗涤,分离并浓缩,得到标题化合物,[α]D=+13.3°(甲醇,c=1);TLC(硅胶GF,乙酸/乙酸乙酯/己烷2/20/80)Rf=0.46;
NMR(CDCl3,TMS)0.78-0.83,1.59-1.82,2.59-2.78,3.07-3.17,7.44-7.54和8.04-8.10δ.制备例5(±)-3-(3-硝基苯基)戊酸甲酯(XIII)
在(±)-3-(3-硝基苯基)戊酸(XXIV,30.21g,135mmol)的甲醇(250ml)溶液中加入浓硫酸(0.6ml)。将所得混合物加热回流3小时。冷却,将混合物在乙酸乙酯和碳酸氢钠(5%水溶液)之间分配。分离出水相,用乙酸乙酯反复萃取两次。合并的有机相用饱和氯化钠水溶液洗涤,硫酸钠干燥,过滤,然后浓缩,得到标题化合物;对于乙酸/乙酸乙酯/己烷(2/20/80),TLC(硅胶GF)Rf=0.54;对于乙酸乙酯/己烷(20/80)Rf=0.54;NMR(CDCl3,TMS)0.80,1.56-1.83,2.55-2.75,3.05-3.2,3.57,7.4-7.55和8.03-8.12δ.制备例6(S)-3-(3-硝基苯基)戊酸甲酯(XIII)
按照制备例5的一般方法并可进行非关键性变化,由(S)-3-(3-硝基苯基)戊酸(XXIV,制备例4)开始制备标题化合物。实施例13-羟基-3-(2-苯基乙基)己酸乙酯(II)
用1小时时间向-58℃的二异丙基胺(32.2ml,230mmol)的四氢呋喃(240ml)溶液中加入2.63M正丁基锂的己烷(87.4ml,230mmol)。加入乙酸乙酯(21.4ml,220mmol),将反应混合物搅拌1小时,在此期间,把反应混合物冷却到-70℃。用30分钟慢慢加入苯基-3-己酮(I,35.2g,200mmol),冷却的同时搅拌反应混合物1小时。用氯化铵水溶液(100ml)淬灭反应,然后允许其升至20-25℃。用盐酸(4M)酸化混合物,用甲基叔丁基醚萃取所要产物,硫酸镁干燥,然后浓缩,得到标题化合物。TLC Rf=0.71(乙酸乙酯/己烷,30/70);NMR(CDCl3)7.28-7.12,4.13,3.60,2.73-2.63,2.50,1.83-1.77,1.58-1.53,1.41-1.36,1.24和0.93δ;CMR(CDCl3)173.0,143.2,128.5,128.4,128.3,128.1,125.8,72.8,60.6,42.9,41.3,30.1,17.0,14.6和14.2δ;MS(CI,氨)m/z(相对强度)282(100),264(63),247(10),194(13),172(5),159(5).实施例23-羟基-3-(2-苯基乙基)己酸(III)
将3-羟基-3-(2-苯基乙基)己酸乙酯(II,实施例1,200mmol)溶解于甲醇(423ml),然后加入2M氢氧化钠(150ml,300mmol)。将反应混合物在20-25℃搅拌过夜。除去甲醇,用盐酸(4M)酸化剩下的水性混合物。用甲基叔丁基醚萃取所要产物,硫酸镁干燥,然后浓缩,得到标题化合物。TLC Rf=0.10(乙酸乙酯/己烷,30/70);NMR(CDCl3)7.43-7.13,2.77-2.62,2.06,1.87-1.76,1.63-1.57,1.45-1.31和0.93δ;CMR(CDCl3)176.9,141.9,128.4,128.3,125.9,73.4,42.7,41.4,40.9,31.9,17.0和14.5δ;MS(CI,氨)m/z(相对强度)254(100),236(28),218(3),194(3),159(5).实施例3(R)-3-羟基-3-(2-苯基乙基)己酸,(1R,2S)-降麻黄碱盐(IV)
将3-羟基-3-(2-苯基乙基)己酸(III,实施例2,2.83g,11.97mmol,根据甲基叔丁基醚调节)溶解于乙腈(15ml)。加入(1R,2S)-降麻黄碱(910mg,5.99mmol,0.5当量),并将混合物在20-25℃搅拌过夜。约1小时后产物开始沉淀。第二天早晨,在过滤收集羟基酸盐之前1小时将浆液冷却到0℃。滤饼用冷乙腈(9ml)洗涤,然后减压加热干燥,得到所要产物。
将产物(约1.5g)在乙腈(21ml)中搅拌并加热至70℃30分钟。将所得溶液逐渐冷却到20-25℃使产物沉淀。在20-25℃2小时后真空过滤收集产物。用乙腈(21ml)洗涤并在20-25℃减压干燥。
再将产物在乙腈(21ml)中搅拌并加热至70℃30分钟。将所得溶液逐渐冷却到20-25℃的室温使产物沉淀。在20-25℃2小时后真空过滤收集产物。用乙腈(21ml)洗涤并在20-25℃减压干燥,得到标题化合物。mp=113-117°;NMR(甲醇)7.41-7.08,5.18,4.98,3.15,2.65-2.60,2.34,1.79-1.73,1.56-1.52,1.43-1.37,1.06和0.92δ;CMR(甲醇)181.4,144.6,142.2,130.2-129.3,127.6,127.1,74.5,73.9,54.0,46.4,43.6,43.4,31.9,31.9,18.6,15.7和12.9δ;MS(CI,氨)m/z(相对强度)388(25),303(15),254(30),236(7),152(100);[α]25 D=16(C=1.0,甲醇).实施例4(6R)-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(VI)
通过将(R)-3-羟基-3-(2-苯基乙基)己酸,(1R,2S)-降麻黄碱盐(IV,实施例3,81g,209mmol)在乙酸乙酯(810ml)中搅拌并加入盐酸(1M,810ml),将盐转变成游离酸(R)-3-羟基-3-(2-苯基乙基)己酸。用乙酸乙酯萃取游离酸,收集乙酸乙酯相,然后浓缩成油。将所得游离酸重新溶解于四氢呋喃(490ml),并将溶液冷却到-10℃。加入羰基-二咪唑(37.3g,230mmol),冷却的同时搅拌反应混合物2小时。加入丙二酸单乙酯镁盐(65.9g,230mmol),允许反应混合物逐渐升温至20-25℃,同时搅拌过夜。用盐酸(1M,490ml)淬灭反应,然后收集有机相。用碳酸氢钠溶液洗涤有机相,并浓缩至294ml,得到5-羟基-7-苯基-5-丙基庚酸(R)-乙酯(V)。在浓缩的溶液中加入氢氧化钠溶液(0.5M,460ml,230mmol),将所得浑浊的混合物在20-25℃搅拌过夜。加入甲基叔丁基醚,收集水相。用盐酸(4M)酸化水相,然后用甲基叔丁基醚萃取产物。甲基叔丁基醚相用硫酸钠干燥,然后浓缩,得到标题化合物。TLC Rf=0.22(乙酸乙酯/己烷,50/50);NMR(CDCl3)7.29-7.13,3.39,2.70,2.71-2.62,1.98-1.93,1.74-1.66,1.45-1.34和0.93δ;CMR(CDCl3)176.89,167.5,140.4,128.6,128.4,128.2,128.2,126.3,83.2,60.1,47.1,44.3,40.7,40.4,29.6,16.8和14.5δ;MS(CI,氨)m/z(相对强度)
278(100),254(15),236(15),217(5),195(5),159(3).实施例5(4-苯基苯氧基)(4-氯苯硫氧基)甲烷(VIII)
在22℃的低聚甲醛(36.24g,1.21mol,1.58当量)的甲苯(243ml)浆液中加入氢溴酸水溶液(48.5wt%,652ml,5.86mol,7.68当量),然后用吸热物使温度降至18℃。将所得二相溶液升温至40℃,用半小时时间加入4-氯苯硫酚(VII,138.81g,0.960mol,1.26当量)的甲苯(116ml)溶液,并保持在40-43℃,然后用甲苯漂洗。将混合物升温至50℃并搅拌1小时。将混合物冷却到10℃,分离各相,水相用甲苯(250ml)洗涤。合并的有机相先后用冰水(500ml)和己烷(350ml)处理,然后分离各相。用甲苯(200ml)洗涤水相,合并的有机相用硫酸镁干燥,浓缩得到粗溴甲硫基-4-氯苯(268.01g),NMR 7.43,7.34,4.79δ;CMR 134.37,132.05,131.78,129.46,37.32δ;HRMS(EI+)C7H6BrClS,计算值=235.9063,实测值=235.9063。
在-10℃的4-苯基苯酚(129.91g,0.763mol,1.00当量)的DMF(400ml)溶液中加入叔丁醇钾的THF(20wt%,429.40g,0.765mol,1.00当量)溶液,并保持温度在5℃以下。将混合物浓缩至557g净重,然后加入DMF(33ml),接着加入上面制备的粗的溴甲硫基-4-氯苯,反应从22℃自然发热至70℃。用DMF(50ml)漂洗粗溴甲硫基-4-氯苯,并将所得浆液在80℃搅拌半小时。将混合物冷却到22℃,先后加入己烷(400ml)和水(500ml)。真空过滤收集沉淀,先后用水(1500ml)和甲醇(300ml)洗涤,在氮气流中干燥,得到固体(251.25g)。将固体溶解于二氯甲烷(1L),然后用硫酸镁干燥,二氯甲烷(200ml)洗涤。加入总体积为1.35L的甲醇使浓缩过程中体积保持恒定(1300-1800ml),最终净重为1344g。在20-25℃真空过滤收集所得沉淀,用甲醇(1L)洗涤,在65℃减压干燥,得到标题化合物。
mp=99-101°;TLC(Rf=0.64,乙酸乙酯/己烷,1/9);HPLC(rt)=9.67min;NMR(CDCl3)7.55-6.99和5.44δ;CMR(CDCl3)155.99,140.52,135.28,133.48,132.06,129.18,128.75,128.24,126.90,126.80,116.34,73.15δ;MS(CI,NH3)m/z(相对强度)346(1.7),344(3.5),328(3.8),326(8.1),201(11),200(100).实施例61-氯甲氧基-4-苯基苯
在21℃向(4-苯基苯氧基)(4-氯苯硫氧基)甲烷(VIII,实施例5,176.45g,539.9mmol)的二氯甲烷(750ml)混合物中加入磺酰氯(73.32g,543.2mmol,1.01当量)的二氯甲烷(150ml)溶液,并保持在23℃以下8分钟。将混合物在20℃搅拌11分钟,然后冷却到3℃。在3-5℃用10分钟加入环己烯(60.7ml,599mmol,1.11当量)的二氯甲烷(100ml)混合物,然后升温至19℃并搅拌10分钟。将混合物整个体积浓缩至600ml后加入己烷(500ml)。再将混合物浓缩至500ml,然后加入己烷(300ml)。将所得浆液浓缩至500ml,然后加入戊烷(1.3L)。将浆液冷却到-50℃,通过真空过滤收集沉淀,用-30℃戊烷(700ml)洗涤,干燥后得到固体(115.28g)。将一部分固体(110.34g)溶解于二氯甲烷(200ml)。加入己烷(1L),并将混合物浓缩至949g。再加入己烷(200ml),并将混合物浓缩至589g。再加入己烷(500ml),将浆液冷却到-30℃,通过真空过滤收集沉淀,用己烷(300ml)洗涤,干燥后得到标题化合物。mp 67-70°;TLC Rf=0.68(乙酸乙酯/己烷,8/92);HPLC rt=6.45min;NMR 7.80-7.13和5.89δ;CMR(CDCl3)155.03,140.34,136.49,128.78,128.35,127.10,126.88,116.39和77.16δ;HRMS(EI+)C13H11ClO,计算值=218.0498,实测值=218.0493。实施例7(R)-(4-苯基苯氧基)甲基-3-(2-苯基乙基)-3-[(4-苯基苯氧基)甲氧基]己酸酯(X)
在20-25℃向(R)-3-羟基-3-(2-苯基乙基)己酸(-)-降麻黄碱盐(IV,实施例4,25.04g,64.62mmol)的水(185ml)和MTBE(185ml)浆液中加入盐酸水溶液(37.5wt%,7.51g,77.24mmol,1.20当量),将pH从8.04调整到1.30。分离各相,水相用MTBE(185ml)洗涤。有机相用硫酸镁干燥,然后浓缩。在浓缩物中加入甲苯(77ml),N,N-二异丙基乙胺(96ml,551mmol,8.53当量)和1-氯甲氧基-4-苯基苯(IX,实施例6,71.88g,328.68mmol,5.09当量)。将混合物升温至110℃,并在110-117℃搅拌5小时。将混合物冷却到65℃并加入甲醇(800ml)。将所得浆液冷却到-30℃,然后真空过滤收集产物。用甲醇(200ml)洗涤,干燥后得到粗产物。色谱分离(乙酸乙酯/己烷)得到分析样品,结晶后得到标题化合物。mp=104.0-105.5°;TLC Rf=0.50(15%乙酸乙酯/己烷);HPLC rt=13.8min;NMR(CDCl3)7.51-7.04,5.78,5.32,2.75,2.64-2.58,2.03-1.97,1.78-1.72,1.41-1.28 and0.86δ;CMR(CDCl3)169.38,157.14,156.14,142.04,140.71,140.41,135.85,134.56,128.75,128.68,128.35,128.29,128.09,126.97,126.81,126.73,125.78,116.13,87.34,85.20,80.40,41.19,38.80,38.61,29.73,16.74,14.35δ;MS(CI,NH3)m/z(相对强度)620(1.7),619(7.8),618(19),418(13),266(100);[α]25 D=-4(C=1.0,二氯甲烷).实施例8(R)-3-(2-苯基乙基)-3-[(4-苯基苯氧基)甲氧基]己醇(XI)
向(R)-(4-苯基苯氧基)甲基-3-(2-苯基乙基)-3-[(4-苯基苯氧基)甲氧基]己酸酯(X,实施例7,56.5wt%,49.32g,46.38mmol)的甲苯(500ml)浆液中加入二异丁基氢化铝的甲苯溶液(1.52M,85ml,129.2mmol,2.79当量),并保持在-20℃。用2.5小时将混合物慢慢升温至1℃,然后搅拌0.5小时。加入丙酮(8.0ml,108.5mmol,2.34当量),然后经过套管将混合物加到18℃的柠檬酸一水合物(136g,647.2mmol,14.0当量)的水(433ml)溶液中并控制放热至28℃。用甲苯(100ml)漂洗,将混合物在20-25℃搅拌1.5小时,然后真空滤去不溶物质。用甲苯洗涤。分离滤液中各相,水相用甲苯洗涤(2×300ml)。有机相用硫酸镁干燥,然后用氢氧化钠水溶液(0.5M,2×500ml)洗涤。将有机相浓缩至净重137g,然后加入甲醇(250ml)。浓缩所得浆液,再加入甲醇(250ml)。再次浓缩混合物,并加入甲醇(250ml)。将浆液冷却到-60℃,过滤除去不溶物。浓缩滤液至净重60g,加入己烷(500ml),再将混合物浓缩至净重22g。加入己烷(500ml),再将混合物浓缩至净重40g。加入二氯甲烷(25ml),然后慢慢加入己烷(500ml)和戊烷(250ml),同时冷却到-55℃。过滤收集产物,用戊烷(200ml)洗涤,并在氮气流中干燥,得到所要产物。色谱分离(乙酸乙酯/己烷)得到分析样品,结晶(二氯甲烷/己烷)后得到标题化合物。mp=49-53°;TLC Rf=0.14(15%乙酸乙酯/己烷);HPLC rt=9.18min;NMR(CDCl3)7.56-7.07,5.36,3.76-3.74,2.63-2.58,1.94-1.88,1.70-1.65,1.38-1.30,0.93δ;CMR(CDCl3)157.05,142.25,140.73,134.68,128.70,128.42,128.29,128.21,126.76,125.85,116.07,87.05,81.85,58.89,38.77,38.60,38.23,29.90,17.04,14.62δ;MS(CI,NH3)m/z(相对强度)423(2.3),422(9.9),252(100);[α]25 D=6(C=1.0,二氯甲烷)实施例9(R)-3-(2-苯基乙基)-3-[(4-苯基苯氧基)甲氧基]己醛(XII)
向0℃的粗(R)-3-(2-苯基乙基)-3-[(4-苯基苯氧基)甲氧基]己醇(XI,实施例8,91.1wt%,15.40g,34.68mmol)的二氯甲烷(47ml)混合物中加入溴化钾(0.4057g,3.409mmol,0.098当量)和碳酸氢钠(1.557g,18.53mmol,0.53当量)的水(20.5ml)溶液,然后加入游离基团4-羟基-2,2,6,6-四甲基哌啶氧基(0.3060g,1.776mmol,0.051当量)。用注射泵在1小时内加入次氯酸钠水溶液(13.4wt%/vol,26.6ml,47.88mmol,1.38当量)并保持在1-5℃。加入硫代硫酸钠(0.5182g,2.088mmol,0.0602当量)的水(14ml)溶液。在0℃分离各相,水相用二氯甲烷洗涤(2×50ml)。立即用酸式硫酸镁(50.25g)过滤有机相,用二氯甲烷(400ml)彻底漂洗。将萃取物浓缩成油(30g),然后加入己烷(500ml)。将混合物浓缩至净重250g,并加入己烷(100ml)。将混合物浓缩至净重186g,并加入戊烷(300ml)。将所得浆液冷却到-50℃,真空过滤收集所得产物,用-50℃戊烷(100ml)洗涤,干燥得到固体。纯化后得到标题化合物。mp=47.0-48.5°;TLC Rf=0.41(乙酸乙酯/己烷,10/90);HPLC rt=10.95min;NMR(CDCl3)9.79,7.53,7.40,7.26,7.20-7.08,5.40,2.67,2.65-2.56,1.99,1.76,1.38,0.93δ;CMR(CDCl3)201.83,156.90,141.69,140.68,134.82,128.72,128.47,128.29,128.24,126.77,125.99,116.03,87.19,80.36,50.14,39.21,39.14,29.74,16.86,14.45δ;MS(CI,NH3)m/z(相对强度)420(3.5),220(100);[α]25 D=14(C=1.0,二氯甲烷)。实施例10(3S),(7R)-4-甲酯基-3-(3-硝基苯基)-7-(2-苯基乙基)-7-[(4-苯基苯氧基)甲氧基]癸-5-醇(在C-4和C-5位的非对映体的混合物)(XIV)
用7分钟向-80℃的(S)-3-(3-硝基苯基)戊酸甲酯(XIII,制备例6,3.78g,15.932mmol)的THF(55ml)混合物中加入六甲基二硅烷叠氮化钠的THF溶液(0.935M,17.5ml,16.36mmol,1.027当量),同时保持在-80--85℃。将所得混合物升温至-74℃,然后在-74--76℃搅拌18分钟。将混合物冷却到-90℃,用10分钟加入(R)-3-(2-苯基乙基)3-[(4-苯基苯氧基)甲氧基]己醛(XII,实施例9,6.50g,16.147mmol,1.013当量)的THF(20ml)溶液,同时保持在-85--90℃。用THF(20ml)漂洗,然后将混合物升温至-71℃。加入饱和氯化铵水溶液(90ml),接着加入水(90ml)和MTBE(90ml),并将混合物加热至20-25℃。分离各相,水相用MTBE(90ml)洗涤。萃取物用硫酸镁干燥,然后浓缩成油。色谱分离(乙酸乙酯/己烷)得到分析样品,得到标题化合物。TLC Rf=0.16,0.24(乙酸乙酯/己烷10/90);HPLC保留时间=12.52,12.68,12.97分钟;MS(电喷射,乙酸钠)m/z(相对强度)662.5(100)。实施例11(3S),(7R)-4-甲酯基-3-(3-硝基苯基)-7-(2-苯基乙基)-7-[(4-苯基苯氧基)甲氧基]癸-5-酮(在C-4位的非对映体的混合物)(XV)
将(3S),(7R)-4-甲酯基-3-(3-硝基苯基)-7-(2-苯基乙基)-7-[(4-苯基苯氧基)甲氧基]癸-5-醇(XIV,实施例10,11.12g,79.0wt%,13.73mmol)的二氯甲烷(530ml)溶液加到氯铬酸吡啶鎓(16.099g,74.685mmol,5.44当量),乙酸钠(6.984g,85.14mmol,6.20当量)和硅酸镁载体(5.181g)研磨的混合物中,并保持温度在11℃以下。将混合物升温至21℃,然后在20-25℃搅拌20小时。经酸式硅酸镁(47.7g)过滤所得浆液,用二氯甲烷(375ml)漂洗。将滤液浓缩成油。色谱分离(乙酸乙酯/己烷)得到标题化合物的分析样品。TLC Rf=0.34乙酸乙酯/己烷,10/90);HPLC rt=13.02,13.23min;NMR(CDCl3)8.05-8.01,7.60-7.00,5.37,5.21,4.03,3.94,3.75,3.58-3.43,3.39,2.96,2.78-1.37,1.20,0.91,0.71-0.61δ;CMR(CDCl3)200.89,200.60,168.29,167.81,157.10,157.05,148.38,148.30,143.58,143.32,141.99,141.93,140.73,140.69,135.29,135.01,134.78,129.38,129.23,128.75,128.45,128.36,128.23,126.77,125.91,125.80,122.96,122.80,122.04,122.00,116.16,87.14,86.92,80.93,80.44,66.34,65.92,52.79,52.35,49.02,48.62,46.28,46.20,38.70,38.51,38.43,37.99,30.10,29.52,26.92,26.71,16.64,16.39,14.39,14.16,11.81,11.58;MS(CI,氨)m/z(相对强度)656(2.8),655(6.1),136(100).实施例12(3S),(7R)-4-甲酯基-7-羟基-3-(3-硝基苯基)-7-(2-苯基乙基)-癸-5-酮(在C-4位的非对映体的混合物)(XVI)
向23℃的(3S),(7R)-4-甲酯基-3-(3-硝基苯基)-7-(2-苯基乙基)-7-[(4-苯基苯氧基)甲氧基]癸-5-酮(XV,实施例11,9.14g,83.7wt%,11.995mmol)的THF(20ml)混合物中加入硫酸的甲醇溶液(0.524M,20ml,10.48mmol,0.87当量)。将混合物放置在23℃22小时,然后相继加入碳酸氢钠(3.52g,41.90mmol,3.49当量)的水(50ml)溶液和MTBE(50ml)。分离各相,水相用MTBE(30ml)洗涤。合并的有机相用5℃氢氧化钠水溶液(0.5M,2×50ml)洗涤,然后用水(2×10ml)洗涤,再用饱和氯化铵水溶液(15ml)和水(35ml)的混合物洗涤两次。有机相用硫酸镁干燥,然后浓缩成油。色谱分离(乙酸乙酯/己烷)得到标题化合物的分析样品。
TLC Rf=0.39(乙酸乙酯/己烷,25/75);HPLC rt=8.15,8.50min;NMR(CDCl3)8.15-7.85,7.48-7.01,3.99,3.92,3.78,3.50-3.39,3.38,3.32-1.21,0.82 and 0.74-0.67δ;CMR(CDCl3)205.20,204.99,168.00,167.46,148.38,143.10,142.04,141.97,135.23,134.99,129.47,129.33,128.46,128.41,128.28,128.18,125.85,122.82,122.58,122.17,73.83,73.49,66.63,66.36,52.92,52.50,50.79,50.60,46.25,46.17,41.57,41.01,40.83,30.03,29.60,26.95,17.05,16.90,14.55,14.43,11.74和11.47δ.实施例13[3α(R),6(R)]5,6-二氢-4-羟基-3-[1-(3-硝基苯基)丙基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVII)
将4℃的氢氧化钠水溶液(1M,11.4ml,11.4mmol,1.89当量)的甲醇(35ml)溶液加到粗(3S),(7R)-4-甲酯基-7-羟基-3-(3-硝基苯基)-7-(2-苯基乙基)-癸-5-酮(XVI,实施例12,73.3wt%,3.740g,6.018mmol)中,然后用甲醇(45ml)漂洗并保持温度在5℃以下。将混合物剧烈搅拌使大部分粗油溶解,然后在0-5℃适度搅拌67小时。将混合物冷却到-5℃并加入己烷(90ml)。在5℃以下分离各相,有机相在5℃以下用甲醇(50ml)和水(7ml)的混合物洗涤。在5℃以下用乙酸(1.52g,25.31mmol,4.21当量)将合并的水相的pH从12.55调节到6.24。浓缩水相,用二氯甲烷萃取(2×40ml),硫酸镁干燥,浓缩得到粗产物。在粗产物样品(0.401g)中加入***(1.0ml)。将所得浆液冷却到-30℃,真空过滤收集沉淀,冷***洗涤,氮气流干燥,得到标题化合物。TLC Rf=0.49(乙酸乙酯/己烷,1/1);HPLC rt=6.93min;NMR(CDCl3/CD3OD,1/1)8.08,7.80,7.56,7.22,7.07-6.88,3.98,3.33-3.30,2.50-2.37,1.92-1.70,1.58-1.50,1.22-1.14,0.76和0.72δ;CMR(CDCl3/CD3OD,1/1)169.05,166.66,148.66,147.79,141.99,135.30,129.21,129.02,128.70,126.55,123.51,121.23,105.13,81.39,42.58,40.39,40.09,36.76,30.38,24.95,17.44,14.54和13.04δ.实施例14[3α(R),6(R)]-3-[1-(3-氨基苯基)丙基]-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVIII)
向[3α(R),6(R)]5,6-二氢-4-羟基-3-[1-(3-硝基苯基)丙基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVII,实施例13,0.6993g,1.651mmol)的THF(50ml)溶液中加入钯炭(5%,50%水湿度,0.2574g,0.06048mmol,0.0366当量),然后将混合物在50psi在Parr摇动器中氢化21小时。加入硅藻土(2.07g),真空过滤除去催化剂,然后用THF漂洗。浓缩滤液得到标题化合物。TLC Rf=0.45(乙酸乙酯/己烷,1/1);HPLC Rt=5.18分钟。实施例15[R-(R*,R*)]-N-[3-[1-[5,6-二氢-4-羟基-2-氧-6-(2-苯基乙基)-6-丙基-2H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)-2-吡啶磺酰胺(XIX)
在-25--30℃用2小时时间向[3α(R),6(R)]-3-[1-(3-氨基苯基)丙基]-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVIII,实施例14,粗重0.555g,相对于标题化合物XIX为1.378mmol)的二氯甲烷(3.10ml),DMSO(0.100ml,1.409mmol,1.02当量)和吡啶(0.56ml,6.92mmol,5.02当量)的混合物中加入以上制备的5-(三氟甲基)-2-吡啶磺酰氯的二氯甲烷粗混合物(5.23ml,相对于硫醇约为2.3mmol,约1.7当量),与5-(三氟甲基)-2-吡啶磺酰氯混合物一起研磨,直到HPLC显示残余的[3α(R),6(R)]-3-[1-(3-氨基苯基)丙基]-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVIII,实施例14)面积剩下1.4%。加入盐酸水溶液(1M,6.2ml,6.2mmol,4.50当量)和乙酸乙酯(5.2ml),然后分离各相。水相用二氯甲烷(10ml)洗涤。合并的有机相用硫酸镁干燥,然后浓缩。将浓缩物放在装有乙酸乙酯/己烷(10/90)的硅胶柱(9.76g硅胶)上,接下来产物用乙酸乙酯的己烷混合物梯度洗脱(50ml 10%,100ml 20%,100ml 30%及50ml40%)。合并洗脱液,并与乙酸乙酯相一起浓缩成油。加入乙酸乙酯(5.2ml),通过慢慢加入庚烷(15ml)产生沉淀。将所得浆液冷却到-30℃,真空过滤收集沉淀,用-30℃的乙酸乙酯(1ml)和庚烷(4ml)的混合物洗涤,氮气流干燥,得到标题化合物。mp=86-89°;TLC Rf=0.66(乙酸乙酯/己烷,50/50);NMR(CD3OD)8.94,8.19,8.02,7.25-6.97,3.93,2.68-2.52,2.15-2.09,1.96-1.64,1.33,0.88和0.83δ;CMR(CD3OD)169.9,167.0,161.6,148.1,147.6,142.8,137.7,137.0,130.1,129.5,129.3,127.0,126.1,124.2,122.6,120.3,106.2,81.9,43.6,40.5,40.5,37.4,30.9,25.8,17.9,14.7和13.3δ;MS(CI,氨)m/z(相对强度)621(1.7),620(5.4),604(1.1),603(3.4),411(12),394(12),148(100);IR(研磨)1596,1413,1359,1326,1177,1149,1074和720cm-1(用同样的固态形式作为参考)实施例16[3α(R),6(R)]5,6-二氢-4-羟基-3-[(Z)-1-(3-硝基苯基)丙烯基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XXV,主要部分)和[3α(R),6(R)]5,6-二氢-4-羟基-3-[(E)-1-(3-硝基苯基)丙烯基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XXV,次要部分)
将(6R)-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(VI,实施例4,50.0g,187mmol)与间硝基苯基·乙基酮(33.5g,187.2mmol)和THF(375ml)混合。加入吡啶(31.0ml,374mmol)。搅拌所得混合物并将其冷却到-5℃以下。在80ml甲苯中加入四氯化钛(31ml,280mmol)制成溶液,并控制地将该溶液加到混合物中以保证反应温度在10℃以下。用甲苯(15ml)漂洗整个四氯化钛溶液,结束时将反应混合物升温至35-45℃并保持这种状态约16小时。将反应混合物冷却到0℃,一次性加入200ml水。搅拌混合物直到所有固体溶解。将混合物升温到至少15℃,然后将其转移到分液漏斗中,用水(250ml)和乙酸乙酯(500ml)稀释。分离出水相,用乙酸乙酯(150ml)萃取,然后丢弃。最初的有机相依次用盐酸(1N,2×150ml),水(150ml)和饱和碳酸氢钠溶液(150ml)洗涤。每次洗涤后清理前用乙酸乙酯(150ml)萃取。这时将最初的有机相与萃取液合并,然后减压浓缩,得到浓缩物。将浓缩物溶解于二氯甲烷(350ml),然后用总共500ml 1N氢氧化钠(4×50ml及3×100ml)萃取。将合并的萃取液用总共500ml二氯甲烷(4×50ml及3×100ml)洗涤,之后用盐酸(3N,150ml)处理。酸化的混合物用二氯甲烷(400ml及6×100ml)萃取,然后将合并的有机萃取液用水(200ml)洗涤。用无水硫酸钠干燥后用酸式硅酸镁饼过滤混合物,然后减压浓缩,得到标题化合物,TLC:对Z异构体,Rf=0.18;对E异构体,Rf=0.28(乙酸乙酯/己烷,1/1);CMR(CDCl3)166.93,166.53,148.27,142.53,142.39,140.96,132.23,132.12,131.82,131.74,129.87,129.12,128.55,128.14,126.16,121.67,120.56,101.09,81.77,39.78,35.23,29.73,16.91,15.75,15.69和14.23δ;MS(CI+NH3)m/z(相对强度)439(100),422(18),409(9),392(9),278(9),194(10),136(9).实施例17[3α(R),6(R)]5,6-二氢-4-羟基-3-[1-(3-硝基苯基)丙基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVII)
将[3α(R),6(R)]5,6-二氢-4-羟基-3-[(Z)-1-(3-硝基苯基)丙烯基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XXV,实施例16,4.24g,10mmol)和[(1,5-环辛二烯)铑(I)-1,2-双(2R,5R)-二甲基-膦(phospholano)苯]四氟硼酸盐(6.0mg,0.01mmol)在惰性气体中混合,然后溶解在20ml脱氧甲醇中。用80psig或更高压力的氢气代替惰性气体,然后将反应升温至55℃并搅拌24小时。搅拌结束时将反应冷却到20-25℃,然后用惰性气体代替氢气。减压浓缩反应混合物,剩余物从甲醇/水(3/1)结晶,得到标题化合物,TLC Rf=0.49(乙酸乙酯/己烷,1/1);
HPLC rt=6.93min;NMR(CDCl3/CD3OD,1/1)8.08,7.80,7.56,7.22,7.07-6.88,3.98,3.33-3.30,2.50-2.37,1.92-1.70,1.58-1.50,1.22-1.14,0.76和0.72δ;CMR(CDCl3/CD3OD,1/1)169.05,166.66,148.66,147.79,141.99,135.30,129.21,129.02,128.70,126.55,123.51,121.23,105.13,81.39,42.58,40.39,40.09,36.76,30.38,24.95,17.44,14.54和13.04δ.实施例18(6R)-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(CVI)
通过在二氯甲烷(1100ml)中搅拌(R)-3-羟基-3-(2-苯基乙基)己酸,(1R,2S)-降麻黄碱盐(CIV,180g,486mmol)并加入盐酸(2M,720ml),将该盐转变成(R)-3-羟基-3-(2-苯基乙基)己酸。用二氯甲烷萃取该游离酸,并用递增的二氯甲烷(总共700ml)通过常压蒸馏以共沸干燥混合物。将该游离酸混合物(350ml)加到-10-0℃的羰基-二咪唑(90.5g,558mmol)的二氯甲烷(80ml)和吡啶(210ml)浆液中。将混合物升温至0℃并搅拌1小时。
通过将丙二酸钾一乙酯(144g,在350ml丙酮中为846mmol)的丙酮浆液加到氯化镁(72g,756mmol)浆液中制成丙二酸一乙酯镁盐浆液,其中,氯化镁浆液是将丙酮(250ml)慢慢加到氯化镁的二氯甲烷(100ml)浆液中制成的。经常压蒸馏使体积达到350ml,完成丙二酸盐的制备。
将由羰基-二咪唑活化反应得到的(R)-3-羟基-3-(2-苯基乙基)己酰基咪唑混合物加到10-20℃的乙基丙二酸镁浆液中。将混合物升温至20-25℃并搅拌约16小时。通过加入盐酸(5N,850ml)来淬灭反应。加入二氯甲烷(125ml)并分离各相。含有机相的产物先后用盐酸(1N,400ml)和饱和碳酸氢钠溶液(500ml)洗涤。真空浓缩有机相至约200ml,加入甲醇(700ml),然后继续浓缩使体积最终达到150ml。在(R)-5-羟基-3-氧-5-(2-苯基乙基)辛酸乙酯的甲醇化溶液中加入15-20℃的氢氧化钾的甲醇化溶液(59.5g,85%,溶解于200ml甲醇中为902mmol)。将混合物在20℃搅拌16小时。加水(350ml),含水相的产物用甲基叔丁基醚(2×350ml)洗涤。水相用盐酸(6M,220ml)酸化,产物用甲苯(550ml)萃取。所得甲苯混合物用水(150ml)洗涤,然后减压浓缩至200ml。分批加入辛烷使产物结晶(分两次加入约400ml,使得在两次添加之间产生结晶)。冷却的同时真空过滤分离产物,用辛烷分批洗涤,在20-25℃干燥,得到标题化合物。实施例195,6-二氢-4-羟基-6-[1-(2-(4-取代的)苯基)乙基]-6-异丙基-2H-吡喃-2-酮(CVI)
依照实施例1-4的普遍方法并可进行非关键性变化,但必须从4-羟基-,4-氨基-,4-一烷基氨基-或4-二烷基氨基-苯基-2-甲基-3-戊酮(CI)开始制备,得到标题化合物。实施例20(6S)-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-苯基-2H-吡喃-2-酮(CVI)
依照实施例1-4的普遍方法并可进行非关键性变化,但必须从1,3-二苯基-1-丙酮(CI)开始制备,得到标题化合物。实施例213-羟基-3-(2-苯基乙基)己酸叔丁酯(II)
依照实施例1的普遍方法并可进行非关键性变化,但必须用乙酸叔丁酯代替乙酸乙酯,得到标题化合物。优选使用乙酸叔丁酯。
反应路线A
Claims (49)
1.(R)-3-羟基-3-(2-苯基乙基)己酸(IV)及其可药用盐。
2.根据权利要求1的化合物,其中可药用盐选自由氢氧化物,氨,氨丁三醇(THAM),2-氨基-2-(羟甲基)-1,3-丙二醇,(1R,2S)-降麻黄碱,(1S,2R)-降麻黄碱,(R)-2-氨基-2-苯基乙醇,(S)-2-氨基-2-苯基乙醇,(R)-1-苯基乙胺和(S)-1-苯基乙胺构成的盐。
3.根据权利要求1的化合物是(R)-3-羟基-3-(2-苯基乙基)己酸(1R,2S)-降麻黄碱盐。
4.(6R)-5,6-二氢-4-羟基-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮。
5.[3α(R),6(R)]5,6-二氢-4-羟基-3-[1-(3-硝基苯基)丙基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮(XVII)。
6.(S)-3-(3-硝基苯基)戊酸甲酯。
7.[3α(R),6(R)]5,6-二氢-4-羟基-3-[(Z)-1-(3-硝基苯基)丙烯基]-6-[1-(2-苯基)乙基]-6-丙基-2H-吡喃-2-酮。
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR1-1,其中R1-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;其中R2是
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR2-1,其中R2-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;该方法包括
(1)将式(CIV)的盐与酸反应制成游离酸,
(2)从反应混合物中萃取游离酸,
(3)将游离酸与活化剂反应,
(4)将游离酸/活化剂的反应混合物与丙二酸单酯和二价金属反应,
(5)将步骤(4)的反应混合物与酸反应,
(6)将步骤(5)的反应混合物在C1-C4醇,THF或DMF存在下与碱反应。
9.根据权利要求8的式(CVI)羟基内酯的制备方法,其中步骤(1)的酸是无机酸或有机酸。
10.根据权利要求9的式(CVI)羟基内酯的制备方法,其中的酸选自盐酸,硫酸,磷酸,氢溴酸,氢碘酸,柠檬酸,三氟乙酸,氯乙酸,硫酸氢钠,硫酸氢钾。
11.根据权利要求10的式(CVI)羟基内酯的制备方法,其中的酸是盐酸。
12.根据权利要求8的式(CVI)羟基内酯的制备方法,其中游离酸的萃取过程可用非极性有机溶剂进行。
13.根据权利要求12的式(CVI)羟基内酯的制备方法,其中的非极性有机溶剂选自二氯甲烷,甲苯,苯,乙酸甲酯,乙酸乙酯,甲基叔丁基醚,***和己烷。
14.根据权利要求13的式(CVI)羟基内酯的制备方法,其中的溶剂是二氯甲烷。
15.根据权利要求8的式(CVI)羟基内酯的制备方法,其中的活化剂是羰基-二咪唑。
16.根据权利要求8的式(CVI)羟基内酯的制备方法,其中步骤(3)是在碱存在下进行。
17.根据权利要求16的式(CVI)羟基内酯的制备方法,其中的碱选自吡啶,4-N,N-二甲氨基吡啶,二甲基苯胺,二乙基苯胺,2,6-二甲基吡啶,三乙胺,三丁胺和三甲吡啶。
18.根据权利要求17的式(CVI)羟基内酯的制备方法,其中的碱是吡啶。
19.根据权利要求8的式(CVI)羟基内酯的制备方法,其中的丙二酸一酯选自KO-CO-CH2-CO-O-Re,其中Re是C1-C4烷基或苯基。
20.根据权利要求19的式(CVI)羟基内酯的制备方法,其中的丙二酸一酯是C1或C2酯。
21.根据权利要求8的式(CVI)羟基内酯的制备方法,其中的二价金属选自Mg+2,Ca+2和Zn+2。
22.根据权利要求21的式(CVI)羟基内酯的制备方法,其中的二价金属是Mg+2。
23.根据权利要求22的式(CVI)羟基内酯的制备方法,其中的二价金属是MgCl2。
24.根据权利要求8的式(CVI)羟基内酯的制备方法,其中步骤(5)中的酸选自无机酸和有机酸。
25.根据权利要求24的式(CVI)羟基内酯的制备方法,其中的酸选自盐酸,硫酸,磷酸,氢溴酸,氢碘酸,柠檬酸,三氟乙酸,氯乙酸,硫酸氢钠,硫酸氢钾。
26.根据权利要求25的式(CVI)羟基内酯的制备方法,其中的酸是盐酸。
27.根据权利要求8的式(CVI)羟基内酯的制备方法,其中步骤(6)中的碱选自有机碱和无机碱。
28.根据权利要求27的式(CVI)羟基内酯的制备方法,其中的碱选自氢氧化物,C1-C4醇盐和碳酸盐。
29.根据权利要求28的式(CVI)羟基内酯的制备方法,其中的碱是氢氧化物。
30.根据权利要求8的式(CVI)羟基内酯的制备方法,其中过量的丙二酸一酯在步骤(6)之前通过萃取除去。
31.根据权利要求30的式(CVI)羟基内酯的制备方法,其中丙二酸一酯用碱萃取除去,所说碱选自氢氧化物,叔胺碱,碳酸盐和碳酸氢盐。
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR1-1’其中R1-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;其中R2是
C1-C6烷基,
环己基,
苯基,
-CH2-CH2-φR2-1,其中R2-1是
-OH(及其保护形式),
-NH2(及其保护形式),
-H,
-NH-CO-CH3,
-N(-CO-CH3)2;该方法包括
(1)将式(CIV)的阴离子或其游离酸形式与活化剂反应,
(2)将游离酸/活化剂的反应混合物与丙二酸单酯和二价金属反应,
(3)将步骤(2)的反应混合物与酸反应,
(4)将步骤(3)的反应混合物在C1-C4醇,THF或DMF存在下与碱反应。
33.根据权利要求32的式(CVI)羟基内酯的制备方法,其中的活化剂是羰基-二咪唑。
34.根据权利要求32的式(CVI)羟基内酯的制备方法,其中的步骤(1)在碱存在下进行。
35.根据权利要求34的式(CVI)羟基内酯的制备方法,其中的碱选自吡啶,4-N,N-二甲氨基吡啶,二甲基苯胺,二乙基苯胺,2,6-二甲基吡啶,三乙胺,三丁胺和三甲吡啶。
36.根据权利要求35的式(CVI)羟基内酯的制备方法,其中的碱是吡啶。
37.根据权利要求32的式(CVI)羟基内酯的制备方法,其中的丙二酸一酯选自KO-CO-CH2-CO-O-Re,其中Re是C1-C4烷基或苯基。
38.根据权利要求37的式(CVI)羟基内酯的制备方法,其中的丙二酸一酯是C1或C2酯。
39.根据权利要求32的式(CVI)羟基内酯的制备方法,其中的二价金属选自Mg+2,Ca+2和Zn+2。
40.根据权利要求39的式(CVI)羟基内酯的制备方法,其中的二价金属是Mg+2。
41.根据权利要求40的式(CVI)羟基内酯的制备方法,其中的二价金属是MgCl2。
42.根据权利要求32的式(CVI)羟基内酯的制备方法,其中步骤(3)中的酸选自无机酸和有机酸。
43.根据权利要求42的式(CVI)羟基内酯的制备方法,其中的酸选自盐酸,硫酸,磷酸,氢溴酸,氢碘酸,柠檬酸,三氟乙酸,氯乙酸,硫酸氢钠,硫酸氢钾。
44.根据权利要求43的式(CVI)羟基内酯的制备方法,其中的酸是盐酸。
45.根据权利要求32的式(CVI)羟基内酯的制备方法,其中步骤(4)中的碱选自有机碱和无机碱。
46.根据权利要求45的式(CVI)羟基内酯的制备方法,其中的碱选自氢氧化物,C1-C4醇盐和碳酸盐。
47.根据权利要求46的式(CVI)羟基内酯的制备方法,其中的碱是氢氧化物。
48.根据权利要求32的式(CVI)羟基内酯的制备方法,其中过量的丙二酸一酯在步骤(4)之前通过萃取除去。
49.根据权利要求48的式(CVI)羟基内酯的制备方法,其中丙二酸一酯用碱萃取除去,所说碱选自氢氧化物,叔胺碱,碳酸盐和碳酸氢盐。
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CN100448836C (zh) * | 2005-06-03 | 2009-01-07 | 浙江中贝化工有限公司 | 一种抗艾滋病药物关键中间体的制备方法 |
WO2013016840A1 (zh) * | 2011-07-29 | 2013-02-07 | 安徽省新星药物开发有限责任公司 | 用于合成他喷他多或其类似物的新中间体 |
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PT1161427E (pt) | 1999-03-18 | 2003-03-31 | Upjohn Co | Processo melhorado para hidrogenacao assimetrica |
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US6500963B2 (en) | 2001-02-22 | 2002-12-31 | Boehringer Ingelheim Pharma Kg | Process for preparing optically active dihydropyrones |
DE10108470A1 (de) * | 2001-02-22 | 2002-09-05 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung optisch aktiver Dihydropyrone |
US6987123B2 (en) | 2001-07-26 | 2006-01-17 | Cadila Healthcare Limited | Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine |
JP4108611B2 (ja) * | 2002-02-07 | 2008-06-25 | 住友化学株式会社 | (r)−3−ヒドロキシ−3−(2−フェニルエチル)ヘキサン酸の製造方法 |
DE10313118A1 (de) | 2003-03-24 | 2004-10-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Enantioselektive Hydrierung von Intermediaten bei der Tipranavir-Synthese |
US7512945B2 (en) * | 2003-12-29 | 2009-03-31 | Intel Corporation | Method and apparatus for scheduling the processing of commands for execution by cryptographic algorithm cores in a programmable network processor |
EP1928878A1 (en) * | 2005-08-24 | 2008-06-11 | Pfizer Inc. | Methods for the preparation of hcv polymerase inhibitors |
EP2232608B1 (en) * | 2007-11-30 | 2018-08-15 | Semiconductor Energy Laboratory Co, Ltd. | Light-emitting element, light-emitting device, and electronic device |
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CN100448836C (zh) * | 2005-06-03 | 2009-01-07 | 浙江中贝化工有限公司 | 一种抗艾滋病药物关键中间体的制备方法 |
WO2013016840A1 (zh) * | 2011-07-29 | 2013-02-07 | 安徽省新星药物开发有限责任公司 | 用于合成他喷他多或其类似物的新中间体 |
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