CN100378091C - 2-(6-取代的1,3-二烷-4-基)乙酸衍生物的制备方法 - Google Patents
2-(6-取代的1,3-二烷-4-基)乙酸衍生物的制备方法 Download PDFInfo
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- CN100378091C CN100378091C CNB2005100657442A CN200510065744A CN100378091C CN 100378091 C CN100378091 C CN 100378091C CN B2005100657442 A CNB2005100657442 A CN B2005100657442A CN 200510065744 A CN200510065744 A CN 200510065744A CN 100378091 C CN100378091 C CN 100378091C
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- Prior art keywords
- formula
- replacement
- alkane
- benzenesulfonyl
- methanesulfonate
- Prior art date
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- 150000003839 salts Chemical class 0.000 claims abstract description 16
- -1 2-(6-substituted-1,3-dioxane-4-yl)acetic acid Chemical class 0.000 claims abstract description 15
- 239000003377 acid catalyst Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 27
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Abstract
本发明涉及式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物的制备方法,其中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,所述方法以4-羟基-6-X-取代的-甲基-四氢吡喃-2-酮化合物(X的定义同上)为原料,借助于缩醛化剂,在酸催化剂的存在下进行。本发明还涉及式1的新化合物以及要从这些化合物制备的盐和酸,其中式1中OR3基团被OY基团代替,其中X、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,并涉及式2的新化合物。所涉及的产物转化成2-(6-羟甲基-1,3-二烷-4-基)乙酸的叔丁酯后是制备抑制素的重要中间产品。
Description
本申请是2003年1月17日提交的申请号为01812999.4的中国申请的分案申请。
技术领域
本发明涉及式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物的制备方法:
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:
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:
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。
发明内容
申请人惊奇地发现2-(6-取代的1,3-二烷-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=C1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C1、Br或I;甲基磺酸根;甲磺酸根;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C1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:
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(MIBK)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:
式中X代表卤素,尤其C1、Br或I,甲苯磺酸根或甲磺酸根,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):
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)(Tetr.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acetamidate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.Japan 52(7)1989(1979));
盐与二碳酸二叔丁酯、DMAP和叔丁醇的反应(Synthesis 1063(1994));
酸与氰脲酰氯和吡啶或三乙胺的反应(Org Process R & D 3,172(1999);Heterocycles 3111,2055(1990))。
所得到的2-(6-取代的1,3-二烷-4-基)乙酸的叔丁酯可按例如US-A-5594153或BP-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。
具体实施方式
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。选出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50ml 0.2N 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20g 50%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25g 50%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pH 8.5-9.5。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-1,3-二烷-4-基-乙酸,叔
丁酯(化合物V)
45.5g IV,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-1,3-二烷-4-基-乙酸叔丁酯
(化合物VII)
从实施例VIII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(Synthesis 1014,1995)值一致。
Claims (44)
2.按照权利要求1的方法,其中X代表Cl。
3.按照权利要求1或2的方法,其中R1=R2=R3=CH3。
4.式3的盐的制备方法:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,Y代表碱金属、碱土金属或取代的或无取代的铵基团;
该方法包括:
1)从式2化合物开始,使用缩醛化剂,在酸催化剂的存在下
式中,X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,制各式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,R3独立地代表含1-3个碳原子的烷基;和
2)所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物随后在碱和水的存在下进行水解,生成式3的相应的盐。
5.按照权利要求4的方法,其中X代表Cl。
6.按照权利要求4的方法,其中R1=R2=R3=CH3。
7.按照权利要求4的方法,其中Y代表Na、Ca或四烷基铵化合物。
8.按照权利要求6的方法,其中X代表Cl。
9.按照权利要求7的方法,其中R1=R2=R3=CH3。
10.按照权利要求7的方法,其中X代表Cl。
11.按照权利要求9的方法,其中X代表Cl。
12.式3a的化合物的制备方法
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基;
该方法包括:
1)从式2化合物开始,使用缩醛化剂,在酸催化剂的存在下
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,制备式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,R3独立地代表含1-3个碳原子的烷基;和
2)所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物随后在碱和水的存在下进行水解,生成式3的盐:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,Y代表碱金属、碱土金属或取代的或无取代的铵基团;和
3)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸盐衍生物转化成式3a的相应的乙酸衍生物。
13.按照权利要求12的方法,其中X代表Cl。
14.按照权利要求12的方法,其中R1=R2=R3=CH3。
15.按照权利要求12的方法,其中Y代表Na、Ca或四烷基铵化合物。
16.按照权利要求15的方法,其中X代表Cl。
17.按照权利要求15的方法,其中R1=R2=R3=CH3。
18.按照权利要求14的方法,其中X代表Cl。
19.按照权利要求17的方法,其中X代表Cl。
20.式1a的化合物的制备方法
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基;
该方法包括:
1)从式2化合物开始,使用缩醛化剂,在酸催化剂的存在下
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,制备式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,R3独立地代表含1-3个碳原子的烷基;和
2)所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物随后在碱和水的存在下进行水解,生成式3的盐:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,Y代表碱金属、碱土金属或取代的或无取代的铵基团;和
3)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸盐衍生物转化成式1a的酯。
21.按照权利要求20的方法,其中X代表Cl。
22.按照权利要求20的方法,其中R1=R2=R3=CH3。
23.按照权利要求20的方法,其中Y代表Na、Ca或四烷基铵化合物。
24.按照权利要求23的方法,其中X代表Cl。
25.按照权利要求23的方法,其中R1=R2=R3=CH3。
26.按照权利要求22的方法,其中X代表Cl。
27.按照权利要求25的方法,其中X代表Cl。
28.式1a的化合物的制备方法
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基;
该方法包括:
1)从式2化合物开始,使用缩醛化剂,在酸催化剂的存在下
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,制备式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,R3独立地代表含1-3个碳原子的烷基;和
2)所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物随后在碱和水的存在下进行水解,生成式3的盐:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,Y代表碱金属、碱土金属或取代的或无取代的铵基团;和
3)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸盐衍生物转化成式3a的相应的乙酸衍生物:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基;和
4)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物转化成式1a的酯。
29.按照权利要求28的方法,其中X代表Cl。
30.按照权利要求28的方法,其中R1=R2=R3=CH3。
31.按照权利要求28的方法,其中Y代表Na、Ca或四烷基铵化合物。
32.按照权利要求31的方法,其中X代表Cl。
33.按照权利要求31的方法,其中R1=R2=R3=CH3。
34.按照权利要求30的方法,其中X代表Cl。
35.按照权利要求33的方法,其中X代表Cl。
36.式4的2-(6-羟甲基-1,3-二烷-4-基)乙酸叔丁酯衍生物的制备方法
式中R1和R2各自独立地代表含1-3个碳原子的烷基;
该方法包括:
1)从式2化合物开始,使用缩醛化剂,在酸催化剂的存在下
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,制备式1的2-(6-取代的1,3-二烷-4-基)乙酸衍生物
式中,X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1、R2和R3各自独立地代表含1-3个碳原子的烷基;和
2)所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物随后在碱和水的存在下进行水解,生成式3的盐:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基,Y代表碱金属、碱土金属或取代的或无取代的铵基团;和
3)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸盐衍生物转化成式3a的相应的乙酸衍生物:
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基;和
4)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸衍生物转化成式1a的酯
式中X选自卤素、甲苯磺酸根、甲磺酸根或硝基取代的苯磺酰基,R1和R2各自独立地代表含1-3个碳原子的烷基;和
5)将所得到的2-(6-取代的1,3-二烷-4-基)乙酸叔丁酯衍生物转化成式4的2-(6-羟甲基-1,3-二烷-4-基)乙酸叔丁酯衍生物。
37.按照权利要求36的方法,其中X代表Cl。
38.按照权利要求36的方法,其中R1=R2=R3=CH3。
39.按照权利要求36的方法,其中Y代表Na、Ca或四烷基铵化合物。
40.按照权利要求39的方法,其中X代表Cl。
41.按照权利要求39的方法,其中R1=R2=R3=CH3。
42.按照权利要求38的方法,其中X代表Cl。
43.按照权利要求41的方法,其中X代表Cl。
44.按照权利要求4-43中任何一项的方法,其中所制备的式3的(4R,6S)-2-(6-取代的1,3-二烷-4-基)乙酸衍生物均具有高于99%的对应体和非对应体过量。
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