CN1282732A - α-羟基-β-氨基酸酯及其制备方法 - Google Patents
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Abstract
通过相应于氨基醇10的噁唑烷酮制备下式10的2-[3(S)-氨基-2(R)-羟基-4-苯基丁基]-N-叔丁基-十氢-(4aS,8aS)-异喹啉-3(S)甲酰胺的方法,以及制备该方法中出现的中间体的方法。
Description
本发明涉及制备β-氨基醇,即下式10的2-〔3(S)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢(4aS,8aS)-异喹啉-3(S)甲酰胺的新方法。本发明还涉及上述方法中出现的新的中间体。本发明的方法包括:1a)将式Ⅶ的磺酸酯其中R1是低级烷基或是也可以被最多2个卤原子或低级烷基或硝基取代的苯基,在碱存在下和式8的N-叔丁基-十氢(4aS,8aS)-异喹啉-3(S)甲酰胺反应用强酸将产生的式9的噁唑酮转变成式9噁唑酮的盐,再用碱处理该盐,并且
1.b)用碱断裂产生的式9的噁唑酮,得到上述式10的氨基醇,
EPA-0432695已公开了上述化合物8和10,其分别相当于EPA-0432695中的式Ⅶ和式Ⅱ化合物,在上述专利中它们是制备有治疗活性的产品的中间体,其式Ⅱ化合物的制备方法与本发明式10的制备方法不同。
式Ⅶ的磺酸酯和酰胺8之间的反应通常是在溶剂如DMSO,烃类例如甲苯,三乙胺或低级醇例如乙醇,或酮中,优选在4-甲基-2-戊酮中,并且在碱如低级烷基胺或碱金属碳酸盐,优选三乙胺或碳酸钠存在下进行,同时加热至回流温度,优选50-150℃,特别是80-110℃。为了提纯产生的噁唑酮9,可以用加入强酸如硫酸或特别是盐酸的方法制备出其易于结晶的盐如磺酸盐,特别是对甲苯磺酸盐,对溴苯磺酸盐,对硝基苯磺酸盐。
在事先用碱优选碳酸氢钠,在溶剂中,优选在乙酸乙酯中萃取除去磺酸之后,噁唑酮9的断裂反应通常在溶剂中,如在水,乙醇或其混合物中,用碱如NaOH或KOH,加热至回流温度,优选20-100℃,特别是80℃来完成。
按照本发明,上述磺酸酯Ⅶ可用下述方法制备:
2b)还原由此得到的式Ⅴ的2-氧代-噁唑烷-5-羧酸酯中的低级烷氧羰基,并且
在本发明的范围内,术语低级烷基(单独的如R1或结合的如低级-烷醇)是指最多为6,优选为4个碳原子的直链或支链烃基,例如甲基,乙基,异丙基。α-羟基-β-氨基酸酯Ⅳ的盐的例子是和乙酸或硫酸形成的盐。
羰基试剂的例子是羰基二咪唑,氯代甲酸苯酯,三光气并且优选光气。Ⅳ或其盐的羰基化反应通常在溶剂中如CH2Cl2,甲苯或优选THF中,在温度-10~50℃之间进行,也可以有碱如三乙胺,K2CO3或NaHCO3存在。
2-氧代-噁唑烷-5-羧酸酯Ⅴ的还原反应通常是在溶剂如甲苯,THF或优选在乙醇中,于0-60℃,特别是于22℃,使用双(2-甲氧乙氧)氢化铝钠,LiAlH4或优选NaBH4来完成。
醇6的磺化反应在溶剂中如在乙酸乙酯,丙酮或优选THF中,在碱如三乙胺或优选N-甲基吗啉存在下,于0-60℃,特别是20-40之间完成。
上述α-羟基-β-氨基酸酯Ⅳ按照本发明能用下述方法制备:
3b)断裂式Ⅱ的腈中的三(低级烷基)甲硅烷基
3d)也可以游离出式Ⅱ′的亚氨基醚的盐,然后进行水解,并且
3e)先用强碱后用强酸将产生的式Ⅲ的α-羟基酸酯转变成式Ⅳ的α-羟基-β-氨基酸酯。
对于制备其中R3是氢的的腈Ⅱ,用水溶性的焦硫酸钠处理例如在甲苯中的醛Ⅰ的溶液,再将所产生的焦硫酸盐和醛Ⅰ的加成产物用NaCN处理,也可以用水或任意含水的二氯甲烷或甲苯这样的溶剂。另-方法是用三甲基甲硅烷基氰化物于-70~0℃,例于-15℃下处理醛Ⅰ和ZnBr2在溶剂如CH2Cl2中的混合物,然后通过加入柠檬酸的乙醇溶液断裂得到的氰醇的甲硅烷基醚。
为了制备R3是低级链烷酰基例如乙酰基的腈Ⅱ,将醛Ⅰ和相应的酸酐如乙酸酐的CH2Cl2溶液用NaCN在苄基三乙基胺氯化物存在下处理,并通常冷却至-10~0℃。对于制备R3是苄氧羰基的腈Ⅱ,可采用类似的方法,但用氯甲酸苄酯代替酸酐。
R3是氢的腈Ⅱ可通过在溶剂如乙醇或CH2Cl2中氢化其中R3是苄氧羰基的腈Ⅱ来得到。
式Ⅱ′的亚氨基醚的相应的盐可通过使氰醇Ⅱ和强酸例如HCl在低级烷醇R2-OH存在下,在溶剂如低级烷醇R2-OH,CH2Cl2,甲苯,叔丁基甲基醚或优选CH2Cl2或R2-OH或甲苯和R2-OH的混合物中反应,并且冷至-10~10℃,通常冷至0℃来得到。
上述盐例如用含水的乙酸乙酯,CH2Cl2或优选用含水甲苯及R2-OH水解成羟基酸酯Ⅲ。
通过将式Ⅱ′的(S,S)-亚氨基醚或α-羟基酸酯Ⅲ的盐例如盐酸盐重结晶分离异构体,并且当用CH2Cl2作溶剂时得到的异构体纯度为93-99%。当用甲苯作溶剂时,不可能分离Ⅱ′的盐的异构体。通过分别重结晶化合物Ⅳ或6,所需异构体纯度可分别达到近92%和99%。所有化合物Ⅲ都能用SiO2色谱法分离。
式Ⅳ化合物通过在溶剂如THF或优选醇如R2-OH,特别是甲醇,于-10~20℃,特别是第一步于0℃,第二步于20℃下,首先用碱如甲胺然后用强酸如HCl处理式Ⅲ化合物来制备。
作为原料的醛Ⅰ通过下述方法得到:在甲苯中和邻苯二甲酸酐-起加热L-苯基丙氨酸,使产生的N-保护的L-苯基丙氨酸和甲苯中的草酰氯及催化量的DMF反应,随后在甲苯中,在1,2-环氧丁烷存在下催化氢化(Pd/C)产生的相应于所需醛Ⅰ的酰氯。
实施例1(Ⅶ+8→9,R1=P-NO2C6H4)
A)将24.69g对硝基苯磺酸(4S,5S)4-苄基-2-氧代-噁唑烷-5-基甲基酯(实施例12),15.0gN-叔丁基-十氢-(4aS,8aS)-异喹啉-3(S)甲酰胺和10.0g碳酸钠于76ml 4-甲基-2-戊酮中,于搅拌下加热回流10小时,将悬浮液冷至80℃,用176ml 4-甲基-2-戊酮和54ml 3N盐酸稀释,冷至40℃并过滤,残留物用水和4-甲基-2-戊酰洗并干燥,得35.1g(88%)(3S,4aS,8aS)-2-〔(4S,5R)-4-苄基-2-氧代-噁唑烷-5-基甲基〕-N-叔丁基-十氢-异喹啉-3-甲酰胺对硝基苯磺酸盐,〔α〕20 D=-31.2 °(1%DMF中),
B)用三乙胺(2个当量)代替碳酸钠以89%产率也可得到该盐。实施例2(Ⅶ+→9,R1=CH3)
类似于实施例1B)的方法,使14g甲磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基-甲基酯(实施例9)和11.7gN-叔丁基十氢(4aS,8aS)异喹啉-3(S)甲酰胺反应,加1当量对甲苯磺酸后,得到11.8g(40%)(3S,4aS,8aS〕-2-〔(4S,5R)-4-苄基-2-氧代-噁唑烷-5-基-甲基〕-N-叔丁基-十氢-异喹啉-3-甲酰胺甲磺酸盐,m.p203-205℃。实施例3(Ⅶ+→9,R1=对甲苯基)
类似于实施例1B)的方法,使7.2g对甲苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲酯(实施例11)和4.8gN-叔丁基-十氢(4aS,8aS)异喹啉-3(S)甲酰胺反应,得5.4g(45%)(3S,4aS,8aS)-2-〔(4S,5R)-4-苄基-2-氧代-噁唑烷-5-基甲基〕-N-叔丁基-十氢-异喹啉-3-甲酰胺对甲苯磺酸盐。m.p.202-204℃。实施例4(Ⅶ+8→9,R1=P-BrC6H4)
类似于实施例1B)的方法,使30g对溴苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲酯(实施例13)和16.8gN-叔丁基-十氢-(4aS,8aS)-异喹啉-3(S)甲酰胺反应,得到36.5g(78%)(3S,4aS,8aS)-2-〔(4S,5R)-4-苄基-2-氧代-噁唑烷-5-基甲基〕-N-叔丁基-十氢-异喹啉-3-甲酰胺对溴苯磺酸盐。〔α〕20 D-29.9。(1%DMF中)实施例5(Ⅶ+→9,R1=O-NO2C6H4)
类似于实施例1B)的方法,使39.2g邻硝基苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基-甲酯(实施例10)和23.8gN-叔丁基-十氢-(4aS,8aS)-异喹啉-3(S)甲酰胺反应,加1当量对甲苯磺酸后,得42g(70%)(3S,4aS,8aS)-2-〔(4S,5R)-4-苄基-2-氧代-噁唑烷-5-基甲基〕-N-叔丁基-十氢-异喹啉-3-甲酰胺对甲苯磺酸盐。〔α〕20 D-34.20(1%DMF中)。
实施例6(9→10)
实施例1的34.7g产品盐在110ml乙酸乙酯和110ml饱和碳酸氢钠之间分配。水相用乙酸乙酯萃取,乙酸乙酯萃取液用110ml饱和碳酸氢钠及水洗涤,蒸发有机萃取液,残留物用55ml乙醇稀释并于搅拌下用于55ml水中的11.0g氢氧化钠溶液处理,混合物于回流下加热5小时,用55mlH2O稀释并冷至22℃。过滤悬浮液,残留物用水洗直到滤液呈中性pH,将残留物干燥得20.7g(93%)2-〔3(S)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4aS,8aS)-异喹啉-3(S)甲酰胺,m.p.175-176℃。
实施例7(Ⅳ-Ⅴ)
A)于0℃将39g光气导入于350ml THF中的43g92:8的3-氨基-2-羟基-4-苯基丁酸甲酯乙酸盐的(2S,3S)和(2R,3S)异构体混合物(实施例23B)的悬浮液中,于0℃搅拌1小时及22℃搅拌24小时后,将溶液浓缩至干,残留物溶于200ml CH2Cl2中并用水及饱和NaHCO3洗,水相用CH2Cl2萃取,合并CH2Cl2相,干燥并过滤,蒸发滤液得到粗的4-苄基-2-氧代-噁唑烷-5-甲酸甲酯的(4S,5S)和(4S,5R)异构体的92∶8的混合物,TLC(SiO2,乙酸乙酯):Rf=0.5,产率100%。
B)类似于实施例7A)的方法,使3-氨基-2-羟基-4-苯基丁酸甲酯乙酸盐(实施例23A)的(2S,3S)和(2R,3S)异构体的98∶2的混合物进行反应,得到粗的4-苄基-2-氧代-噁唑烷-5-甲酸甲酯的(4S,5S)和(4S,5R)异构体的98∶2的混合物,产率100%,TLC(SiO2,乙酸乙酯):Rf=0.5。
实施例8(Ⅴ-6)
A)实施例7B)得到的150g4-苄基-2-氧代-噁唑烷-5-甲酸甲酯的(4S,5S)和(4S,5R)异构体的98∶2混合物于15-20℃约1.5小时加入到搅拌着的于360ml乙醇中的20.8g NaBH4中并继续搅拌2小时,悬浮液于20℃用450ml水处理并用165ml3N盐酸将pH调至7,悬浮液于22℃搅拌2.5小时,于4℃静置18小时,过滤,残留物用水洗并干燥,得111.6g(84%)99%的(4S,5S)-4-苄基-5-羟甲基噁唑烷-2-酮,m.p.167.3-168.9℃,〔α〕20 D-79.4(1%甲醇中)
B)类似于实施例8A)方法,从实施例7A)得到的(4S,5S)和(4S,5R)异构体的92∶8的混合物制得99%的(4S,5S)-4-苄基-5-羟甲基-噁唑烷-2-酮(75%),m.p.167-169℃。实施例9(6→Ⅶ,R1=CH3)
于25℃将4.7ml甲磺酰氯于10ml丙酮中的溶液加到实施例8得到的10.4g醇于20ml丙酮和6.1ml N-甲基吗啉的悬浮液并将悬浮液于25℃搅3小时,再加1.1ml N-甲基吗啉并将混合物搅1小时,将悬浮液溶于80ml半饱和的NaHCO3溶液及乙酸乙酯中,分离水相并用乙酸乙酯萃取,乙酸乙酯萃取液用水洗,干燥并过滤,浓缩滤液得14.3g(100%)粗的甲磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲基酯,TLC(SiO2,乙酸乙酯):Rf=0.4;MS(E1):286(M+H+)实施例10(6→Ⅶ,R1=O-NO2C6H4)
类似于实施例9的方法,由50g从实施例8制得的醇和80g邻硝基苯磺酰氯得到88.2g(93%)邻硝基苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲基酯,TLC(SiO2,乙酸乙酯):Rf=0.38;MS(E1):393(M+M+)。实施例11(6→Ⅶ,R1=p-tolyl)
于22℃将5.6ml三乙胺加到实施例8制备的5.55g醇于27ml丙酮和6.64g对甲苯磺酰氯的搅拌着的悬浮液中,于22℃搅6.5小时,悬浮液用水处理,于10℃搅拌,过滤,残留物用水/丙酮(3∶2)溶液洗涤,干燥后得9.09g(94%)99%的对甲苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲基酯,m.p.148.7-150.3℃,〔α〕20 D+3.00(1%丙酮中)。实施例12(6→Ⅶ,R1=p-NO2C6H4)
将15.4g对硝基苯磺酰氯于20-25℃分次加到从实施例8得到的12.0g醇于35ml THF和7.66ml N-甲基吗啉的悬浮液中搅拌4.5小时,悬浮液再用0.77ml N-甲基吗啉处理并于22℃搅拌4.5小时,混合物用70ml 2%碳酸氢钠溶液处理,搅拌1.5小时,过滤,残留物用水和乙醇洗,干燥后得21.4g(94%)98.5%的对硝基苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲基酯,m.p.148-149.5℃,〔α〕20 D:10.0°(1%丙酮中)。实施例13(6→Ⅶ,R1=p-BrC6H4)
类似于实施例12的方法,由从实施例8制得的35g产品醇和56.1g对溴苯磺酰氯制得65.5g(91%)对溴苯磺酸(4S,5S)-4-苄基-2-氧代-噁唑烷-5-基甲基酯,m.p.151.6-153℃。实施例14(1→Ⅱ,R3=Ac)
于0℃及搅拌下将5g3-苯基-2(S)邻苯二甲酰亚氨基丙-1-醛和3.66g乙酸酐于30ml CH2Cl2的溶液滴加到1.76gNaCN和0.16g苄基三甲基氯化铵于30ml CH2Cl2和55ml水的混合物中,于0℃再搅7小时,水相用CH2Cl2萃取,将萃取液干燥,过滤,并浓缩滤液,残留物进行硅胶层析,用CH2Cl2∶异丙醇(100∶1)洗脱。得6.12g(98%)(2S,3S)-和(2R,3S)-3-(1,3-二氧代-1,3-二氢异吲哚-2-基〕-2-乙酰氧基-4-苯基丁腈的75∶25混合物,IR(膜):2227W(CN),1773S,1760S及1717S(酰亚胺和乙酸乙酯的C=O)。实施例15(1-Ⅱ:R3=苄基-OCO,H)
A)11.16g3-苯基-2(S)-邻苯二甲酰亚氨基丙1-醛和0.7g苄基三甲基氯化铵于70ml CH2Cl2中的溶液于-10℃搅拌下用6.2ml氯甲酸苄酯处理,滴加3.10g NaCN于50mlH2O中的溶液,于-1O℃0.5小时后将混合物温热至0℃,CH2Cl2相用水及饱和NaCl溶液洗涤,水相用CH2Cl2萃取,将CH2Cl2相干燥,过滤,将滤液浓缩,残留物含18.33g(2S,3S)-和(2R,3S)-3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-苄氧羰氧基-4-苯基丁腈的70∶30混合物。MS(E1)∶349(6,M+-C6H5CH2),288(6,M+-C6H5CH2OCOOHH),91(100,C6H5CH2);IR(膜):2240w(CN),1763S和1717S(酰亚胺和氨基甲酸酯中的C=O)
B)2gA)制备的碳酸苄酯和0.15gpd/c(10%)于12ml乙醇和2ml CH2Cl2中的悬浮液于22℃下氢化2小时,过滤,用CH2Cl2洗,浓缩滤液,得1.35g(97%)(2S,3S)-和(2R,3S)-3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁腈的73∶27混合物,IR(KBr)∶3450m(OH),2250w(C≡N),1775m和1712s(酰亚胺中的C=O)。实施例16(1-Ⅱ;R3=H)
5g3-苯基-2(S)-邻苯二甲酰亚氨基丙-1-醛和4.43gZnBr2于50ml CH2Cl2中的悬浮液于-15℃搅拌下用1.95g三甲基甲硅烷基氰化物于5ml CH2Cl2中的溶液处理5小时,于-10℃加入5g柠檬酸于50ml乙醇中的溶液断裂形成的甲硅烷基醚,浓缩混合物,用H2O处理残留物,用CH2Cl2萃取,将有机萃取液干燥,过滤,浓缩滤液。残留物中含5.45g(99%)粗的3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁腈,为74∶26的(2S,3S)和(2R,3S)的混合物,IR(KBr)∶3437m(OH),2250w(C≡N),1775m及1713s(酰亚胺的C=O)。实施例17(Ⅱ,R3=H,ViaⅠ)
A)于氩气中加热82.6gL-苯基丙氨酸和74.1g邻苯二甲酸酐于600ml甲苯中的悬浮液并回流8小时,将所得悬浮液冷至22℃并用0.5ml DMF处理,随后加入66.64g草酰氯。搅拌2小时后向悬浮液内吹入氩气。
B)将含3-苯基-2(S)邻苯二甲酰亚氨基丙酰氯的溶液用500ml甲苯稀释并用72.11g 1,2-环氧丁烷处理。往溶液中加23.5gpd/c(5%)和100ml甲苯,搅拌下将悬浮液氢化17小时,过滤,残留物用200ml甲苯洗涤。
C)95.05g焦亚硫酸钠于11水中的的溶液于22℃及搅拌下加入到含3-苯基-2(S)邻苯二甲酰亚氨基丙-1-醛的溶液中,搅拌4.5小时后,含亚硫酸氢盐和上述醛加成物的水相用甲苯洗涤,甲苯相用水萃取,往水相中加1200ml CH2Cl2,混合物于22℃及搅拌下用41.66g NaCN于330ml水中的溶液处理,搅1.2小时后加水,分离出的水相用CH2Cl2萃取,将有机相干燥,过滤,残留物用CH2Cl2洗,蒸发滤液,将残留物溶在200mlCH2Cl2中,于30℃及搅拌下将600ml己烷加到上述溶液中,然后于0℃再加600ml己烷。过滤悬浮液,残留物用己烷洗并干燥,得114.02g(74%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁腈的(2S,3S)∶(2R,3R)∶(2S,3R)=74.7∶23.5∶1.4∶0.4的混合物。m.p.127.2-130.5℃,〔α〕20 D-146.6°(1%CH2Cl2中)。实施例18(1→Ⅱ,R3=H)
47.5g焦亚硫酸钠于500ml水中的溶液于22℃搅拌下加到含实施例17B)制备的产品即3-苯基-2(S)邻苯二甲酰亚氨基丙-1-醛的溶液中,搅7.5小时后含焦亚硫酸盐和上述醛加成物的水相用甲苯洗涤,甲苯相用水洗,将24.2gNaCN于200ml水中的溶液于25℃搅拌下加入到该水相中,搅拌1小时后过滤悬浮液,残留物用水洗至中性,干燥后得112.03g(73%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁腈的(2S,3S)∶(2R,3S)=67.2∶32.8的异构体混合物,m.p.131-133℃,〔α〕20 D-150.2(1%CH2Cl2中)。实施例19(Ⅱ→Ⅲ,R2=CH3,R3=R4=H)
A)100g3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-2-羟基-4-苯基丁腈(实施例17C)于450mlCH2Cl2中的溶液于0℃加入到400g HCl于980ml甲醇的溶液中,0℃搅拌18小时后将悬浮液过滤,600ml乙酸乙酯和600ml水的混合物被加到含所产生的亚胺醚-HCl的残留物中,固体溶解后,水相用乙酸乙酯萃取,有机相用饱和NaHCO3溶液洗并用水洗后干燥,过滤悬浮液,蒸发滤液得77.15g(70%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸甲酯的(2S,3S)∶(2R,3S)异构体为93∶7的混合物,〔α〕20 D-121.5°(1%乙酸乙酯中)。
B)120gHCl于0℃加入到200g3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-2-羟基-4-苯基丁腈(实施例17C)于1200ml甲苯和106ml甲醇的溶液中,并于0℃搅拌3小时,悬浮液用1200ml水和400ml甲醇处理并于22℃搅2小时,水相用甲苯萃取,有机相用水洗,干燥,过滤,蒸发滤液得221g(100%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸甲酯的(2S,3S):(2R,3S)异构体为75∶25的混合物,〔α〕20 D-133.1°(1%乙酸乙酯中)。实施例20(Ⅱ→Ⅲ,R2=C2H5,R3=R4=H)
150ml HCl-饱和的乙醇于0℃用30g3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁腈(实施例17C)于150ml CH2Cl2中的溶液处理,0℃下4小时后将悬浮液用150ml CH2Cl2稀释,过滤,残留物用CH2Cl2洗,为了水解形成的亚氨基醚-HCl,将残留物溶在250ml甲苯,250ml水和12ml乙醇中,搅拌4小时后水相用甲苯萃取,甲苯相用水洗,干燥甲苯相,过滤并浓缩滤液,残留物含19.54g(57%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸乙酯的(2S,3S)∶(2R,3S)为95∶5的混合物。m.p.83.1-84.3℃,〔α〕20 D:-143·1°(1%乙酸乙酯中)。实施例21(Ⅱ→Ⅲ,R2=i-Pr,R3=R4=H)
A)150ml HCl-饱和的异丙醇于0℃搅拌下用30g 3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁腈(实施例17C)于150ml CH2Cl2中的溶液处理。0℃9小时后该溶液用300ml水处理并于22℃搅拌4小时,相分离后水相用CH2Cl2萃取,有机萃取液用水洗,干燥,过滤,浓缩滤液,残留物含29.73g(83%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸异丙酯的(2S,3S)和(2R,3S)异构体的70∶30混合物,〔α〕20 D=126.8°(1%乙酸乙酯中);MS(E1):368(1,M+H+),250〔100,M-CH(OH)COOCH(CH3)2〕
B)A)中制备的异构体混合物溶于180ml叔丁基甲基醚中,用60ml己烷处理,于22℃搅拌,再于0℃及-10℃搅拌并过滤,干燥后得13.13g(36.5%)(2S,3S)-3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸异丙酯,IR(膜):3463m(OH),1773m,1730s及1705s(酰亚胺及酯的C=O)实施例22(Ⅱ→Ⅲ,R2=CH3,R3=AC,R4=H)
3.39g(2S,3S)和(2R,3S)的3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-乙酰氧基-4-苯基丁腈的75∶25混合物(实施例14)于25ml甲醇中的溶液于0℃用HCl饱和并于0℃搅拌21小时,该溶液用100ml水处理并用乙酸乙酯萃取,将萃取液干燥,过滤,蒸缩滤液,残留物含3.3g(100%)3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸甲酯的(2S,3S)∶(2R,3S)异构体为75∶25的混合物。IR(膜):3362m(OH),1775m,1745s及1712s(酰亚胺和酯的C=O)。实施例23(Ⅲ→Ⅳ,R2=CH3)
A)20g3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸甲酯的(2S,3S):(2R,3S)的93∶7混合物(实施例19A)于20ml甲醇中的溶液于0℃搅拌下用11.75ml 18.7%的甲胺/甲醇溶液处理,并于0℃搅拌4小时。
44ml 20%的HCl-甲醇溶液于0℃加到上述溶液中,于22℃搅拌3小时后将悬浮液过滤,残留物用甲醇洗涤,浓缩滤液。将残留物用稀氨水于0℃调pH4。水相用乙酸乙酯洗,有机相用水萃取,合并后的水相的pH用氨水于22℃调至9.3,水相用乙酸乙酯萃取数次,将有机相干燥,过滤,滤液被浓缩至50g。残留的溶液用3.4ml乙酸处理并于0℃搅拌。过滤悬浮液,残留物用乙酸乙酯洗,干燥后得13.83g(87%)3-氨基-2-羟基-4-苯基丁酸甲酯乙酸盐的(2S,3S)和(2R,3S)异构体的98∶2混合物,m.p.113-114.5℃〔α〕20 D+15.3°(1%甲醇中)。
B)类似于实施例23A,用54.6g 3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸甲酯的(2S,3S)∶(2R,3S)异构体的75∶25混合物(实施例19B),得到28.4g(66%)3-氨基-2-羟基-4-苯基丁酸甲酯乙酸盐的(2S,3S)和(2R,3S)异构体的92∶8混合物,m.p.109-110℃,〔α〕20 D+13.6°(1%甲醇中)。实施例24(Ⅲ→Ⅳ,R2=C2H5)
类似于实施例23的方法,使10.42g 3-(1,3-二氧代-1,3-二氢异吲哚-2-基)-2-羟基-4-苯基丁酸乙酯的(2S,3S)和(2R,3S)的95∶5异构体混合物(实施例20)于10ml乙醇中与5.9ml33%甲胺/乙醇溶液反应,得5.39g(82%)(2S,3S)-3-氨基-2-羟基-4-苯基丁酸乙酯TLC(SiO2,CH2Cl2/甲醇10∶1,UV254):Rf=0.34
Claims (5)
2.制备按照权利要求1式Ⅳ的α-羟基-β-氨基酸酯的方法,该方法包括:
2b)断裂除去式Ⅱ腈中的三(低级烷基)甲硅烷基,
2c)将所产生的其中R3是H,低级链烷酰基或苄氧羰基的式Ⅱ的腈在低级链烷醇R2-OH存在下用强酸转变成式Ⅱ’的亚氨基醚的盐,其中R4是H,低级链烷酰基或苄氧羰基以及R2是低级烷基,
2d)也可以游离出式Ⅱ’的亚氨基醚的盐,然后进行水解,并且
3.按照权利要求2的方法,其中R2是乙基或异丙基,R3和R4是氢,乙酰基或苄氧羰基或者R3是三甲基甲硅烷基。
4.按照权利要求2的方法,其中R1是对硝基苯基,R2是甲基及R3和R4是H。
5.按照权利要求1的化合物,其选自:
(2S,3S)-3-氨基-2-羟基-4-苯基丁酸乙酯以及
(2S,3S)-3-氨基-2-羟基-4-苯基丁酸甲酯。
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WO2003050063A2 (en) * | 2001-12-11 | 2003-06-19 | Wyeth | PROCESS FOR THE SYNTHESIS OF CHIRALLY PURE β-AMINO-ALCOHOLS |
US6792281B2 (en) * | 2002-06-28 | 2004-09-14 | Motorola, Inc. | Method and system for patching dispatch calling parties together |
US20040191207A1 (en) * | 2003-03-31 | 2004-09-30 | Lipari John M. | Alpha-hydroxy acid ester drug delivery compositions and methods of use |
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IT1194593B (it) * | 1978-11-25 | 1988-09-22 | Nippon Kayaku Kk | Procedimento per la produzione di acidi treo-3-ammino-2-idrossibutanoilamminoacetici nonche' di loro intermedi |
IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
US4462943A (en) * | 1980-11-24 | 1984-07-31 | E. R. Squibb & Sons, Inc. | Carboxyalkyl amino acid derivatives of various substituted prolines |
JPS60199884A (ja) * | 1984-03-26 | 1985-10-09 | Microbial Chem Res Found | ベスタチン類の新規製造法 |
CA1340588C (en) * | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Amino acid derivatives |
GB8927913D0 (en) * | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Amino acid derivatives |
EP0443840B1 (en) * | 1990-02-21 | 1995-04-19 | Toda Kogyo Corp. | Superparamagnetic fine particles of iron oxide and magnetic recording media containing said particles |
JPH06184069A (ja) * | 1991-11-19 | 1994-07-05 | Lonza Ag | α−ヒドロキシ−β−アミノカルボン酸の製造方法 |
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1994
- 1994-03-09 US US08/208,420 patent/US5455353A/en not_active Expired - Fee Related
- 1994-03-11 EP EP94103735A patent/EP0635493A3/de not_active Ceased
- 1994-03-18 JP JP6072823A patent/JP2845419B2/ja not_active Expired - Lifetime
- 1994-03-23 CN CN94103347A patent/CN1099387A/zh active Pending
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1995
- 1995-03-09 US US08/401,480 patent/US5512688A/en not_active Expired - Fee Related
- 1995-03-09 US US08/401,583 patent/US5512682A/en not_active Expired - Fee Related
- 1995-03-09 US US08/401,824 patent/US5578730A/en not_active Expired - Fee Related
- 1995-03-09 US US08/401,482 patent/US5919949A/en not_active Expired - Fee Related
- 1995-03-09 US US08/401,578 patent/US5495025A/en not_active Expired - Fee Related
- 1995-03-09 US US08/401,481 patent/US5516930A/en not_active Expired - Fee Related
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1998
- 1998-07-13 JP JP10212040A patent/JP3078525B2/ja not_active Expired - Lifetime
- 1998-07-13 JP JP10212017A patent/JPH11100358A/ja active Pending
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1999
- 1999-11-17 CN CN99124439A patent/CN1282732A/zh active Pending
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3824046B1 (en) * | 2018-07-20 | 2022-08-31 | Neste Oyj | Purification of recycled and renewable organic material |
Also Published As
Publication number | Publication date |
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EP0635493A2 (de) | 1995-01-25 |
US5516930A (en) | 1996-05-14 |
US5512688A (en) | 1996-04-30 |
US5578730A (en) | 1996-11-26 |
CN1099387A (zh) | 1995-03-01 |
US5455353A (en) | 1995-10-03 |
JP2845419B2 (ja) | 1999-01-13 |
JP3078525B2 (ja) | 2000-08-21 |
US5495025A (en) | 1996-02-27 |
US5919949A (en) | 1999-07-06 |
JPH11100372A (ja) | 1999-04-13 |
CN1275567A (zh) | 2000-12-06 |
JPH11100358A (ja) | 1999-04-13 |
JPH07309840A (ja) | 1995-11-28 |
EP0635493A3 (de) | 1995-02-08 |
US5512682A (en) | 1996-04-30 |
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