CN1040426C - 双保护的2,3-羟甲基环丁醇的制备方法 - Google Patents
双保护的2,3-羟甲基环丁醇的制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
将下式保护的环丁酮用氯化二烷基铝、二氯化烷基铝、三烷基铝化合物、在催化剂钌黑或附在氧化铝上的钌存在下的氢、在氯化三(三苯基膦)铑(1)存在下的二苯基硅烷或四氯化铱处理,得到相应的双保护的环丁醇。该化合物可用作制备抗病毒剂的中间体。
Description
本发明涉及改进的式(I)双保护的2,3-羟甲基环丁醇的制备方法,式(1)结构如下:式中Prot是保护基团;该方法包括:用还原剂处理式(II)环丁酮,得到期望的式(I)环丁醇为主产物,还得到不期望的式(III)异构体化合物;所述还原剂选自氯化二烷基铝、二氯化烷基铝、三烷基铝化合物、在催化剂钌黑或附在氧化铝上的钌存在下的氢、氯化三(三苯膦)铑(I)存在下的二苯基硅烷、以及亚磷酸存在下的四氯化铱。式(II)化合物和式(III)化合物结构如下:
本发明方法可利用旋光的(2S-反式)也称作[2S,3S]的式(II)环丁酮。在这种情况下,期望的式(I)环丁醇也将是旋光的,即[1S-(1α,2β,3β)]。然后该旋光的环丁醇可以被转化成旋光的抗病毒剂例如[1R-(1α,2β,3α)]-2-氨基-9-[2,3-双(羟甲基)环丁基-1,9-二氢-6H-嘌呤-6-酮。
本发明方法也可以利用式(II)环丁酮的外消旋化合物,在这种情况下,期望的式(I)环丁醇也将是非旋光的物质,即(1α,2β,3β)。然后可以将该外消旋的环丁醇转化成外消旋的抗病毒剂例如(±)-(1α,2β,3α)-2-氨基-9-[2,3-双(羟甲基)环丁基]-1,9-二氢-6H-嘌呤-6-酮。
在式(I)双保护的2,3-羟甲基环丁醇中,结构式示出的环丁基环上的取代基的相对立体化学表明:羟基取代基相对于邻近的-CH2-O-Prot取代基为顺式并且两个-CH2-O-Prot取代基互为反式。
通过用还原剂处理式(II)环丁酮制得相对于不期望的式(III)异构体化合物占优势的期望的式(I)双保护的2,3-二羟甲基环丁醇,所述还原剂选自氯化二烷基铝如氯化二异丁基铝、二氯化烷基铝如二氯化异丁基铝、三烷基铝化合物如三异丁基铝、催化剂钌黑或附在氧化铝上的钌存在下的氢、氯化三(三苯膦)铑(I)存在下的二苯基硅烷以及亚磷酸存在下的四氯化铱。
术语“烷基”是指1-20个碳的直链或支链基团,3-10个碳为佳。
Prot是羟基保护基团。适宜的保护基团包括受阻的甲硅烷基基团,例如叔丁基二甲基甲硅烷基、叔丁基二苯甲基硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基。适宜的保护基团也包括苄基和取代的苄基基团如对甲氧基苄基和式
酰基基团,式中R1是1-6个碳的直链或支链的低级烷基、或苯基,带苯甲酰基即R1是苯基的基团为优选的酰基保护基。
当本发明方法中所用的还原剂为氯化二烷基铝时,适宜于反应的溶剂包括惰性非质子传递溶剂例如二氯甲烷、甲苯等。反应可在约-90℃到溶剂的沸点这一温度范围内进行,约-90℃~0℃为佳,约-40℃为最好。
当用在本发明方法中的还原剂为二氯化烷基铝如二氯化异丁基铝或三烷基铝化合物如三异丁基铝时,反应适用的溶剂包括惰性非质子传递溶剂,例如二氯甲烷、甲苯等。反应可以在约-90℃到溶剂的沸点这一温度范围内进行,约-90℃~0℃为佳。若所用还原剂为三烷基铝化合物时,则保护基团Prot不能是苯甲酰基。
当用在本发明方法中的还原剂是亚磷酸存在下的四氯化铱时,反应适用的溶剂包括羟基溶剂如水、甲醇、丙醇、异丙醇等或它们的混合物如水-异丙醇。反应可以在约50℃~100℃温度下进行,约80℃为最好。
当用在本发明方法中的还原剂是催化剂钌黑存在下的氢时,反应适用的溶剂包括羟基溶剂如甲醇、异丙醇或它们的混合物,甲醇最好,反应可以在约-90℃到溶剂的沸点这一温度范围内进行,约0℃~50℃为佳,约25℃为最好。
当用在本发明方法中的还原剂是附在氧化铝上的催化剂钌存在下的氢时,反应适用的溶剂包括羟基溶剂如甲醇、乙醇等,但不包括异丙醇,优选甲醇。反应可以在约-90℃到溶剂的沸点这一温度范围内进行,0℃~50℃为佳,约25℃为最好。
当用在本发明方法中的还原剂为氯化三(三苯基膦)铑(I)存在下的二苯基硅烷时,反应适用的溶剂包括苯、甲苯、己烷、环己烷等,优选甲苯,或者反应可以在无溶剂存在的情况下进行。若反应在溶剂存在下进行,则反应进行的温度为约0℃到溶剂的沸点,约25℃为佳。若反应在无溶剂存在的情况下进行,则反应进行的温度为约0℃~120℃。
在本发明优选的方法中,还原剂是氯化二烷基铝,最好的还原剂是氯化二异丁基铝;优选的保护基团Prot是苯甲酰基,以及优选的式(II)原料环丁酮是旋光的(2S-反式)形式。
式(I)旋光的(2S-反式)双保护的2,3-羟甲基环丁酮可按下述文献所述方法制备:Bisacchi等人,美国专利5064961;Norbeck等人,欧洲专利申请366059;Ichikawa等人,欧洲专利申请358154;Pariza等人,欧洲专利申请452729;或Ahmad,欧洲专利申请458643。式(I)消旋的(反式)双保护的2,3-羟甲基环丁酮可按Slusarchyk等人在欧洲专利申请335355中以及Norbeck等人和Ichikawa等人在上述的欧洲专利申请中所述方法制备。制备式(II)旋光的环丁酮的另一种方法由Godfrey等人在美国专利第5185463中作了描述。
然后将式(IV)对甲苯磺酰化合物用式(V)苄氧基鸟嘌呤处理得式(VI)化合物,式(V)及式(VI)化合物结构如下:
除去式(VI)化合物的保护基团后得抗病毒剂[1R-(1α,2β3α)]-2-氨基-9-[2,3-双(羟甲基)环丁基]-1,9-二氢-6H-嘌呤-6-酮。
下列实施例说明本发明方法。
实施例1
[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯
将2385ml无水二氯甲烷装入机械搅拌器、内数字温度计、加料漏斗和氮气入口的3升三颈烧瓶中。冷却至-40℃后,加入氯化二异丁基铝(156.6g,886mmol,1.27moleq.)。经加料漏斗用63分钟时间向该冷溶液中滴加(2S-反式)-2,3-双[(苯甲酰氧基)甲基]环丁酮(235g,699mmol)的二氯甲烷(600ml)溶液,于-40℃再反应70分钟。通过缓慢加入甲醇(502ml)使反应终止,返期间用1小时的时间将温度从-40℃升至-32℃。去除冷浴并加入氯化铵饱和水溶液(502ml),搅拌18小时后将混合物经无水硫酸镁(502g)过滤并将滤饼用二氯甲烷充分洗涤。减压浓缩滤液,残留物于35℃用真空泵干燥,得287.3g粗产物。该略湿的固体用约2升甲醇和约400ml水结晶,得160.6g(收率:68%)[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯;mp.75-77℃,TLC(硅胶;40%乙酸乙酯/己烷)Rf=0.39,[α]D=-15.3°(C=1.1,氯仿),HPLC:HI(215nm,Zorabax-cyano柱,水-乙腈梯度洗脱)99.95%。
-理论值- C20H20O5
C,70.38;H,5.94;H2O,0.27
-实测值- C,69.92;H,5.87;H2O,0.27.
实施例2
[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苄基醚
将(2S-反式)-2,3-双[(苄氧基)-甲基]环丁酮(0.5g,1.61mmol)的甲苯(1ml)溶液于-78℃滴加到二氯化异丁基铝溶液(0.71M己烷溶液,3.41ml,2.42mmol)中。将混合物用2小时时间缓慢加热至室温,于室温搅拌30分钟后,使混合物于0℃放置过夜。反应混合物用乙酸乙酯稀释后用10%盐酸终止反应。有机相用盐水洗涤,干燥(硫酸镁)并蒸除溶剂,得[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苄基醚;TLC(50%乙酸乙酯/己烷)Rf=0.53。
实施例3
[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苄基醚
用10分钟时间将(2S-反式)-2,3-双[(苄氧基)-甲基]环丁酮(0.2g,0.645mmol)的甲苯(4ml)溶液于-40℃滴加到三异丁基铝(0.91M己烷液,0.9ml,0.816mmol)甲苯(2ml)溶液中。混合物于-50℃搅拌4小时并于-40℃搅拌1小时。将三异丁基铝溶液(1ml,0.91mmol)加到该反应混合物中,于-40℃搅拌30分钟后,向反应混合物中加入10%盐酸(2ml)使反应终止。有机相用盐水洗涤,干燥(硫酸镁)并蒸除溶剂,得[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苄基醚;TLC(30%乙酸乙酯/己烷)Rf=0.3。该产物含约5%异构体化合物;TLC(30%乙酸乙酯/己烷)Rf=0.2。
实施例4
[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苄基醚
将(2S-反式)-2,3-双[(苄氧基)-甲基]环丁酮(0.25g,0.806mmol)、四氯化铱(0.016g,0.0483mmol)、亚磷酸(0.397g,4.84mmol)和水(0.3ml)在异丙醇(3ml)中的混合物回流过夜。在旋转蒸发器上蒸除溶剂,将残留物溶于乙酸乙酯中并相继用10%盐酸、盐水和5%碳酸氢钠洗涤。有机层经干燥(硫酸镁)和蒸除溶剂,得[1S-(1α,2β,3β)]-3-羟基-1,2-环丁烷二甲醇的二苄基醚;TLC(40%乙酸乙酯/己烷)Rf=0.51。
实施例5
(1α,2β,3β)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯
将钌黑(20mg)在异丙醇(1ml)中的悬浮液于室温和1个氢气压下预氢化1小时。将(反式)-2,3-双[(苯甲酰氧基)甲基[环丁酮(200mg)异丙醇(11ml)液加到该混合物中。该混合物于室温1个氢气压下搅拌21小时后,HPLC表明存在(1α,2β,3β)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯和异构体化合物(1α,2β,3α)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯,其比率为84∶16。
实施例6
(1α,2β,3β)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸乙酯。
(反式)-2,3-双[(苯甲酰氧基)-甲基]环丁酮(50mg)和5%附在氧化铝(10mg)上的钌在甲醇(2ml)中的混合物于室温和1个氢气压下搅拌46小时后,HPLC表明存在(1α,2β,3β)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯和异构体化合物(1α,2β,3α)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯,其比率为73∶27。
实施例7
(1α,2β,3β)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯
将二苯基硅烷(27.4μ1,0.148mmol)搅拌下滴加到(反式)-2,3-双[(苯酰氧基)甲基]环丁酮(50mg,0.148mmol)和氯化三-(三苯基膦)-铑(I)(1.4mg,0.0015mmol)的甲苯(0.75ml)溶液中并于室温和氩气气氛下保持15分钟。然后将反应混合物浓缩成油状物,然后将该油与含催化量对甲苯磺酸的10%含水甲醇(1ml)一起于室温搅拌1小时。将该混合物浓缩成油状物,然后将该油在水和乙酸乙酯中进行分配。乙酸乙酯层用碳酸氢钠饱和水溶液和盐水洗涤,无水硫酸钠干燥并蒸除溶剂,得5.5mg清油。该油的HPLC表明存在(1α,2β,3β)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯和异构体化合物(1α,2β,3α)-3-羟基-1,2-环丁烷二甲醇的二苯甲酸酯,其比率为82∶18。
Claims (12)
2.权利要求1的方法,其中还原剂是氯化二烷基铝,烷基一词指3-10个碳的直链或支链基团,并且Prot是选自下述基团的受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基;或Prot是苄基、对甲氧基苄基或苯甲酰基。
3.权利要求2的方法,其中反应在选自二氯甲烷或甲苯的非质子传递溶剂存在下于约-90℃到溶剂的沸点温度下进行,还原剂是氯化二异丁基铝,并且Prot是苯甲酰基。
4.权利要求1的方法,其中还原剂是二氯化烷基铝、烷基一词指3-10个碳的直链或支链基团,并且Prot是选自以下基团的受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苄基、对甲氧基苄基或苯甲酰基。
5.权利要求4的方法,其中反应在下述条件下进行:在选自二氯甲烷或甲苯的非质子传递溶剂存在下并在约-90℃到溶剂的沸点的温度范围内而且还原剂是二氯化异丁基铝。
6.权利要求1的方法,其中还原剂是三烷基铝化合物,烷基一词指3-10个碳的直链或支链基团,并且Prot是选自以下基团的受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苄基或对甲氧基苄基。
7.权利要求6的方法。其中反应在下述条件下进行:在选自二氯甲烷或甲苯的非质子传递溶剂存在下并在约-90℃到溶剂的沸点的温度范围内而且还原剂是三异丁基铝。
8.权利要求1的方法,其中还原剂是钌黑存在下的氢,Prot是选自下述基团的受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苄基、对甲氧基苄基或苯甲酰基,并且反应在选自甲醇、异丙醇或它们的混合物的溶剂存在下于约-90℃到溶剂的沸点温度下进行。
9.权利要求1的方法,其中还原剂是附在氧化铝上的钌存在下的氢,Prot是选自下述基团的受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苯甲酰基,并且反应在选自甲醇或乙醇的溶剂存在下于约-90℃到溶剂的沸点温度下进行。
10.权利要求1的方法,其中还原剂是氯化三(三苯基膦)铑(I)存在下的二苯基硅烷,Prot是选自下述受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苄基、对甲氧基苄基或苯甲酰基,并且反应在选自苯、甲苯、己烷或环己烷的溶剂存在下于约0℃到溶剂的沸点温度下进行。
11.权利要求1的方法,其中还原剂是氯化三(三苯基膦)铑(I)存在下的二苯基硅烷,Prot是选自下述受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苄基、对甲氧基苄基或苯甲酰基,并且反应在无溶剂存在下于约0℃-120℃进行。
12.权利要求1的方法,其中还原剂是亚磷酸存在下的四氯化铱,Prot是选自下述基团的受阻的甲硅烷基基团:包括叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、甲基二异丙基甲硅烷基和三异丙基甲硅烷基,或Prot是苄基、对甲氧基苄基或苯甲酰基,并且反应在选自水、甲醇、丙醇、异丙醇或它们的混合物存在下于约50℃-100℃温度下进行。
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CN1040978A (zh) * | 1988-09-09 | 1990-04-04 | 日本化药株式会社 | 新的环丁烷衍生物及其制备方法 |
US5064961A (en) * | 1989-12-18 | 1991-11-12 | E. R. Squibb & Sons, Inc. | Process for preparing an optically active cyclobutane nucleoside |
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Publication number | Publication date |
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PL172496B1 (pl) | 1997-09-30 |
NO931897L (no) | 1993-11-29 |
NO179101C (no) | 1996-08-07 |
SG77537A1 (en) | 2001-01-16 |
FI932396A0 (fi) | 1993-05-26 |
NO931897D0 (no) | 1993-05-25 |
AU656858B2 (en) | 1995-02-16 |
US5516903A (en) | 1996-05-14 |
EP0572209A2 (en) | 1993-12-01 |
NZ247574A (en) | 1994-08-26 |
CN1082025A (zh) | 1994-02-16 |
KR930023320A (ko) | 1993-12-18 |
HU9301531D0 (en) | 1993-09-28 |
CA2096153A1 (en) | 1993-11-27 |
AU3877993A (en) | 1993-12-02 |
EP0572209A3 (zh) | 1994-04-20 |
TW234117B (zh) | 1994-11-11 |
IL105655A0 (en) | 1993-09-22 |
MX9303025A (es) | 1994-05-31 |
RU2118312C1 (ru) | 1998-08-27 |
IL105655A (en) | 1996-07-23 |
US5412134A (en) | 1995-05-02 |
ZA933223B (en) | 1993-12-08 |
HUT65115A (en) | 1994-04-28 |
NO179101B (no) | 1996-04-29 |
FI932396A (fi) | 1993-11-27 |
PL299081A1 (en) | 1994-03-21 |
HU212966B (en) | 1996-12-30 |
JPH069460A (ja) | 1994-01-18 |
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