CN101081842B - 2-(6-取代的1,3-二噁烷-4-基)乙酸衍生物的制备方法 - Google Patents

2-(6-取代的1,3-二噁烷-4-基)乙酸衍生物的制备方法 Download PDF

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CN101081842B
CN101081842B CN2007101118797A CN200710111879A CN101081842B CN 101081842 B CN101081842 B CN 101081842B CN 2007101118797 A CN2007101118797 A CN 2007101118797A CN 200710111879 A CN200710111879 A CN 200710111879A CN 101081842 B CN101081842 B CN 101081842B
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J·H·M·H·科伊斯特拉
H·J·M·泽格尔斯
D·明克
J·M·C·A·穆尔德斯
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Abstract

本发明涉及式(2a)的化合物，和式1b或式3b的(4R,6S)-2-(6-取代的1,3-二噁烷-4-基)乙酸衍生物。

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2-(6-取代的1,3-二噁烷-4-基)乙酸衍生物的制备方法
本申请是2001年7月12日提交的题为“2-(6-取代的1，3-二噁烷-4-基)乙酸衍生物的制备方法”的PCT/NL01/00535号发明专利申请的分案申请，原申请进入中国国家阶段获得的国家申请号为01812999.4。 
本发明涉及式1的2-(6-取代的1，3-二噁烷-4-基)乙酸衍生物的制备方法： 
Figure S071B1879720070703D000011
式中X代表离去基团，R1、R2和R3各自独立地代表含1-3个碳原子的烷基，该方法从式2化合物开始，使用适当的缩醛化剂，在酸催化剂的存在下进行： 
Figure S071B1879720070703D000012
式中X的定义同上。 
本发明还涉及式1的新化合物以及可由此得到的式3的盐和酸： 
Figure S071B1879720070703D000013
式中R1和R2具有上述含义，Y代表碱(土)金属或取代的或无取代的铵基团，或代表氢。 
申请人惊奇地发现2-(6-取代的1，3-二噁烷-4-基)乙酸衍生物可以有选择性地并以高收率从相应的式(2)化合物得到，可以制备这些在温和条件下较不稳定的产物。这是更有意义的，因为这可以提供一种通过相应的盐、相应的叔丁酯和2-羟甲基取代的化合物作为制备HMG-CoA还原酶抑制剂的中间体的简单路线。任选地，通过中间盐或酯进行转化(取决于所选择的反应条件)，同时使式(2)化合物中的环打开。 
本发明方法另一个优点是式(2)的起始化合物和式(3)的产物都是结晶化合物。这对于获得具有(化学和立体化学)高纯度的产物是有利的。尤其从预期的药物应用的观点来看，这是重要的。具体说，对于预期应用来说，(4R，6S)-2-(6-取代的1，3-二噁烷-4-基)乙酸衍生物是重要的。该化合物可从相应的6-取代的-2，4，6-三脱氧-D-赤己糖(erythrohexose)制备。因此，本发明也涉及式1的起始化合物，尤其其中X＝Cl者，以及这种化合物的颗粒。尤其90wt％以上的颗粒具有1∶1.5～1∶6，优选1∶2～1∶4.4的长/径比，和0.05～2mm，尤其0.1～1mm的颗粒长度。本发明也涉及这样的颗粒。式II化合物给出透明的结晶颗粒，具有73-74℃的明显熔点。按照本发明从式1的(4R，6S)-2-(6-取代的1，3-二噁烷-4-基)乙酸衍生物可以制备出式3的产物，其对映体过量(e.e.)在95％以上，尤其99.5％以上，非对应体过量(d.e.)在90％以上尤其99.5％以上。 
可用于本发明方法的合适的离去基团X的例子是卤素，尤其Cl、Br或I；甲苯磺酰基氧基；甲磺酰基氧基；酰氧基，尤其乙酰氧基、苯甲酰氧基；芳氧基，尤其苄氧基，或硝基取代的苯磺酰基。由于实践的原因，优选选择Cl作为离去基团。 
基团R1、R2和R3各自独立地代表含1-3个碳原子的烷基，优选甲基或乙基。在实践中，R1＝R2＝R3＝甲基是最优选的。 
可用于本发明方法的合适的缩醛化剂的例子是二烷氧基丙烷化合物，其中烷氧基优选各含1-3个碳原子，例如2，2-二甲氧基丙烷或2，2-二乙氧基丙烷；烷氧基丙烯，其中烷氧基优选含1-3个碳原子，例如2-甲氧基丙烯或2-乙氧基丙烯。最优选的是2，2-二甲氧基丙烷。这可任选地从丙酮和甲醇原位形成，优选同时除去水。 
作为酸催化剂可以使用缩醛化反应中已知的那些酸催化剂，优选非亲核强酸，例如磺酸，尤其甲苯磺酸、甲磺酸或樟脑磺本；含有非亲核阴离子的无机酸，例如硫酸、磷酸；酸型离子交换剂，例如DOWEX； 或固体酸，例如所谓的杂多酸。 
该缩醛化反应可以不用单独的溶剂进行，如希望的话，该反应也可在有机溶剂中进行。合适的有机溶剂的例子是酮类，尤其丙酮；烃类，尤其芳烃，例如甲苯；氯代烃，例如二氯甲烷。 
该缩醛化反应的温度优选为-20℃～60℃，尤其0℃～30℃。该缩醛化反应优选在惰性气氛中进行。 
缩醛化剂与式(2)的起始化合物的摩尔比优选为1:1～20:1，尤其3:1～5:1。使用有机溶剂时，该摩尔比尤其为1:1～2:1。 
酸催化剂与式(2)的起始化合物的摩尔比优选为1:1～0.001:1，尤其0.01:1～0.05:1。 
所得到的2-(6-取代的1，3-二噁烷-4-基)乙酸衍生物随后可在碱和水的存在下进行水解，生成相应的式3的盐： 
Figure S071B1879720070703D000031
式中Y代表碱金属、碱土金属或取代的或无取代的铵基团，优选Na、Ca或四烷基铵化合物。任选地，水解后转化成式3中Y＝H的乙酸。 
式(3)化合物的水解反应优选用碱进行，碱的用量相对于式(3)化合物而言至少为1当量，尤其1-1.5当量。原则上可以使用较大的过量的碱，但实际上通常不能提供任何优点。 
反应优选在-20℃-60℃，尤其0℃-30℃的温度下进行。 
该水解反应例如可在水中，有机溶剂中如醇中，尤其在甲醇或乙醇中，芳烃中如甲苯中，或酮中尤其丙酮或甲基异丁基酮(MI BK)中，或一种有机溶剂和水的混合物中进行，任选地使用相转移催化剂(PTC)或添加助催化剂。 
该水解反应也可以以酶催方式进行，所需的非对映体可任选地进行选择性水解。 
适用于本发明方法的酶的例子是具有脂酶或酯酶活性的酶，例如选自下列的酶：假单胞菌属，尤其荧光假单胞菌、莓实假单胞菌；伯克氏菌属，如洋葱伯克霍尔德氏菌；色杆菌属，尤其粘稠色杆菌；芽孢杆菌属，尤其热链形芽孢杆菌、地衣芽孢杆菌；产碱菌属，尤其粪产碱菌；曲霉菌属，尤其黑曲霉菌；假丝酵母菌属，尤其antartica假丝酵母菌、皱摺假丝酵母菌、解脂假丝酵母菌、cylindracea假丝酵母菌；地霉属，尤其白地霉；腐质霉属，尤其lanuginosa腐质霉；青霉属，尤其园弧青霉、娄格法尔特氏青霉、沙门氏伯干酪青霉；根粘菌属，尤其爪蛙根粘菌、米赫根粘菌；毛霉属，尤其抓硅毛霉；根霉菌属，尤其米根霉、无根根霉、德列马根霉、雪白根霉、日本根霉、爪蛙根霉；猪胰脏脂酶、麦胚脂酶、牛胰脏脂酶、猪肝脏酯酶。优选使用选自下列的酶：洋葱假单胞菌、假单胞菌sp.、洋葱伯克霍尔德氏菌、猪胰脏脂酶、米赫根粘菌、lanuginosa腐质霉、皱摺假丝酵母菌或antarctica假丝酵母，或枯草杆菌素。如果使用对映体选择性酶，则水解过程中甚至可以实现进一步的对映体富集。这些酶可用公知的技术得到。许多酶是以工业规模生产的，且可从市场购得。 
所得到的盐(或酸)是新的。因此本发明也涉及式3的这些新产物： 
Figure DEST_PATH_GSB00000062738900021
式中X代表卤素，尤其Cl、Br或I，甲苯磺酰基氧基或甲磺酰基氧基，含3-10个碳原子的酰氧基，或硝基取代的苯磺酰基，Y代表H、碱(土)金属或取代的或无取代的铵基团。 
然后可将所得到的式3的盐按本身已知的方法转化成相应的叔丁酯(式1a，R3＝叔丁基)： 
Figure DEST_PATH_GSB00000062738900022
在本发明的方法中，式(3)的化合物例如可以用下述方法进行酯化，生成叔丁酯，这些方法一般叙述于文献中： 
与异丁烯和强酸，例如对甲苯磺酸(pTS)、硫酸或强酸性离子交换剂的反应(US-A-3325466)； 
在碱，如三乙胺(Et3N)、二甲基氨基吡啶(DMAP)的存在下通过酰氯和叔丁醇的反应。酰氯可借助于例如SOCl2、POCl3、(COCl)2并用例如二甲基甲酰胺(DMF)作催化剂来制备(J.Org.Chem.35，2429(1970))； 
通过酰氯与叔丁醇锂的反应(Org.Synth.51，96(1971))； 
在强酸的影响下与乙酸叔丁酯进行的酯基转移反应(Z.Chem.12(7)264(1972))； 
盐与叔丁基溴的反应，优选在DMF、二甲基乙酰胺(DMAA)、1-甲基-2-吡咯烷酮(NMP)中进行，并使用相转移催化剂(PTC)(Te tr.Let.34(46)7409(1993))； 
酸与叔丁醇、1，3-二环己基碳化二亚胺(DCC)和DMAP的反应(Synth.Comm.9，542(1979))； 
酸与叔丁基-三氯acetami date的反应(Tetr.Let.39，1557(1998))； 
盐与羰基二咪唑(CDI)和叔丁醇的反应； 
酸与新戊酰氯和叔丁醇在DMAP和N-甲基-吗啉(NMM)存在下的反应(Bull.Chem.Soc.Japan52(7)1989(1979))； 
盐与二碳酸二叔丁酯、DMAP和叔丁醇的反应(Synthesis1063(1994))； 
酸与氰脲酰氯和吡啶或三乙胺的反应(Org Process R&D3，172(1999)；Heterocycles31 11，2055(1990))。 
所得到的2-(6-取代的1，3-二噁烷-4-基)乙酸的叔丁酯可按例如US-A-5594153或EP-A-1024139所述方法在卤化四烷基铵和/或羧酸盐的存在下，通过转化成其中R3＝叔丁基，X＝酰氧基，例如乙酰氧基的式1a化合物，再转化成2-(6-羟甲基-1，3-二噁烷-4-基)乙酸。随后按其它通常已知的方法通过溶剂分解将酰氧基转化成羟基。溶剂分解可用碱(Na2CO3、K2CO3或甲醇钠的甲醇溶液)来进行，任选地同时蒸出所生成的乙酸甲酯。
2-(6-羟甲基-1，3-二噁烷-4-基)乙酸的叔丁酯是制备各种抑制素，如ZD-4522的理想中间产物，如M.Watanabe等人的论文：Drugsof the future(未来药物)，(1999)，24(5)，511-513和Bioorg.&Med.Chem.(1997)，5(2)，437-444中所述。因此，本发明提供一种制备这些中间产物和最终产物，尤其抑制素的新的、有价值的路线。 
式2的起始化合物例如可按WO-A-96/31615中所述方法制得。 
本发明将用下列实施例进一步说明，但不为这些实施例所限制。 
实施例I
(4R，6S)-4-羟基-6-氯甲基-四氢吡喃-2-酮(化合物II；包括在式2中)的制备
在室温下在45分钟内将2.1ml溴加入到6.7g(40mmol)6-氯-2，4，6-三脱氧-D-赤-己糖(化合物I；按WO-A-96/31615所述方法制备)和6.7g碳酸氢钠在40ml二氯甲烷和10ml水中的混合物中。逸出CO2气，同时pH保持5。搅拌1小时后，根据气液色谱(GLC)分析可知起始原料已完全转化。过量的溴用固体Na2S2O3中和。相分离后水相用乙酸乙酯萃取(2×100ml)。合并的有机相用Na2SO4干燥，然后过滤。经旋转蒸发器蒸发后得到5.5g黄色油状物(相对于化合物I，X＝C1的式(2)化合物的收率为82％)。 
1H NMR(200MHz，CDCl3)： 
δ1.8-2.1(m，2H)；2.6-2.7(m，2H)；3.5-3.8(m，2H(CH2Cl))；4.4(m，1H)； 
4.9(m，1H). 
实施例II
(4R，6S)-4-羟基-6-氯甲基-四氢吡喃-2-酮(化合物II；包括在式2中)的制备
在15～25℃在3小时内往75g(450mmol)化合物I在390ml水中的溶液中加入114g(715mmol)溴。通过同时加入碳酸钠(总量88g)使反应混合物的pH维持在5-6。过量的溴用亚硫酸氢钠中和。用乙酸乙酯从水相中萃取出产物(逆流萃取)。
产物用乙酸乙酯/庚烷(125g/62g)进行结晶。冷却至0℃，滤出结晶，用50ml庚烷/乙酸乙酯(重量比＝9:1)洗涤，干燥后得到49.2g(相对于化合物I的收率为67％)无色针状结晶化合物II(m.p.73-74℃)。 
实施例III
(4R-顺式)-6-(氯甲基)-2，2-二甲基-1，3-二噁烷-4-基-乙酸甲酯(化合物III)的制备
在室温下将实施例I中得到的5.5g化合物II加入到20ml商品二甲氧基丙烷和100mg对甲苯磺酸一水合物的混合物中。在室温下搅拌1小时后，GLC分析表明已完全转化并生成透明溶液。加入500mgNaHCO3，在室温下搅拌30分钟。过滤并经旋转蒸发器蒸发后得到7.1g浅黄色油状化合物III(相对于化合物II的收率为91％)。 
1H NMR(200MHz，CDCl3)： 
δ1.25(dt，1H)；1.40(s，3H)；1.47(s，3H)； 
1.79(dt，1H)；2.42(dd，1H)；2.58(dd，1H)； 
3.40(dd，1H)；3.52(dd，1H)；3.70(s，3H)； 
4.1(m，1H)；4.35(m，1H). 
实施例IV
(4R-顺式)-6-(氯甲基)-2，2-二甲基-1，3-二噁烷-4-基-乙酸甲酯(化合物III)的制备
往49.2g(300mmol)化合物I在100ml甲苯中的溶液中加入47g(450mmol)二甲氧基丙烷和850mg对甲苯磺酸一水合物(4.5mmole)。在室温下搅拌1小时后，GLC分析表明化合物已完全转化。甲苯相用50ml0.2N NaOH水溶液洗涤。经蒸发后得到67g浅黄色油状化合物III(相对于化合物II的收率为94％)。 
实施例V
(4R-顺式)-6-(氯甲基)-2，2-二甲基-1，3-二噁烷-4-基-乙酸，钠盐(化合物IV)
55g(233mmol)化合物III加入到200ml水中。在室温下在2小 时内滴加20g50％NaOH水溶液，使pH＝12。用GLC监控水解反应。(加入)20g后pH保持恒定。加入浓盐酸使pH降低至10。水相用100ml乙酸乙酯洗涤，用旋转蒸发器蒸发。将所生成的油干燥，用无水乙醇和甲苯抽提。固体物搅拌到200ml丙酮中，过滤后用冷丙酮洗涤。经真空干燥后得到45.6g钠盐，相对于化合物III的收率为80％。 
1H NMR(200MHz，CDCl3/CD3OD)： 
δ1.21(dt，1H)；1.36(s，3H)；1.49(s，3H)； 
1.79(dt，1H)；2.25(dd，1H)；2.45(dd，1H)；3.46 
(m，2H)；4.11(m，1H)；4.36(m，1H). 
实施例VI
(4R-顺式)-6-(氯甲基)-2，2-二甲基-1，3-二噁烷-4-基-乙酸，钠盐(化合物IV)
从49.2g化合物I开始，按实施例IV所述方法制备化合物III的甲苯溶液。加入5g甲醇和25ml水。在室温下在1小时内滴加25g50％NaOH水溶液。在室温下搅拌4小时后，GLC分析表明完全水解。过量的碱用33％HCl水溶液中和至pH8.5-9.5。分离出水相，用470ml甲苯进行共沸蒸馏，使之干燥，得到65g化合物IV，呈16％重量/重量的在甲苯中的悬浮液形式，其KF<0.1％。 
该悬浮液可用于制备化合物V。 
实施例VII
(4R-顺式)-6-(氯甲基)-2，2-二甲基-1，3-二噁烷-4-基-乙酸，叔丁酯(化合物V)
45.5gIV，钠盐(186mmol)加入到159g二碳酸二叔丁酯在1400ml无水叔丁醇中的溶液中。加入6.8g二甲基氨基吡啶，在40℃搅拌16小时。将反应混合物倒入1500ml乙酸乙酯和1000ml饱和氯化铵的混合物中。水相用1500ml乙酸乙酯再萃取。合并的有机层用600ml饱和NaCl溶液洗涤。有机层用Na2SO4干燥，过滤，然后真空蒸发，得到51.9g黄色油状物(相对于化合物IV的收率为100％)。
1H NMR(200MHz，CDCl3)： 
δ1.15-1.33(m，1H)；1.40(s，3H)；1.45(s，3H)； 
1.47(s，9H)1.77(dt，1H)；2.33(dd，1H)；2.46 
(dd，1H)；3.40(dd，1H)；3.49(dd，1H)4.08(m，1H)；4.28(m，1H). 
实施例VIII
(4R-顺式)-6-[(乙酰氧)甲基]-2，2-二甲基-1，3-二噁烷-4-基-乙酸叔丁酯(化合物VI)
从实施例VII得到的33g化合物V开始，按照US-A-5457227的方法(用40g乙酸四正丁基铵在200ml DMF中)在100℃反应16小时后，从75ml庚烷中结晶后得到29g固体化合物VI。 
1H NMR(200MHz，CDCl3)： 
δ1.1-1.3(dt，1H)；1.39(s，3H)；1.45(s，9H)； 
1.47(s，3H)；1.57(dt，1H)；2.08(s，3H)；2.32 
(dd，1H)；2.46(dd，1H)；4.0-4.2(m，3H)；4.3(m，1H). 
实施例IX
(4R-顺式)-6-[羟甲基]-2，2-二甲基-1，3-二噁烷-4-基-乙酸叔丁酯(化合物VII)
从实施例V得到的29g化合物VI开始，按照US-A-5457227的方法(用6.9g碳酸钾在300ml甲醇中)得到25.0g浅黄色油状化合物VII，e.e＝100％，d.e＝99.9％(根据GLC分析)。 
1H NMR(200MHz，CDCl3)：光谱数据与文献(Synthesis1014，1995)值一致。

Claims (1)

1.式(2)的化合物，
Figure FSB00000600908800011
其中X为氯，所述化合物是4R，6S形式并且该化合物是结晶化合物。
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