CN1032062C - 3-取代呋喃糖苷化合物的不对称合成 - Google Patents
3-取代呋喃糖苷化合物的不对称合成 Download PDFInfo
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- CN1032062C CN1032062C CN92102690A CN92102690A CN1032062C CN 1032062 C CN1032062 C CN 1032062C CN 92102690 A CN92102690 A CN 92102690A CN 92102690 A CN92102690 A CN 92102690A CN 1032062 C CN1032062 C CN 1032062C
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/42—Halogenated unsaturated alcohols acyclic
- C07C33/423—Halogenated unsaturated alcohols acyclic containing only double bonds as unsaturation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
-
- 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
- C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
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Abstract
制备式I表示的3-取代呋喃糖或呋喃糖苷化合物的中间物,试剂和新方法,
其中M是氢或烷基(C1-C3),A是卤素或是下列部分式中之一:OR,SR,N3,SCR,OC-R或CN,其中R是氢,分支或不分支的烷基(C1-C4),或苯基,这些化合物具有抗病毒和其它生物活性。
Description
本发明是涉及在具有生物活性的各种改性核苷合成中,用作中间物的3-取代呋喃糖或呋喃糖苷化合物的新颖制备方法,中间物和试剂。
近来对各种改性核苷的逆转录酶抑制活性的发现以及它们在人类免疫缺损病毒(HIV)感染而致的爱滋病的实际与潜在应用中作为治疗剂的研究,已激发了改进制备这些改性核苷方法的兴趣。特别感兴趣的是制备3′-取代2′,3′-双脱氧核糖核苷类,如3′-叠氮基-3′-脱氧胸苷(AZT)和3′-脱氧-3′-氟代胸苷(FLT)的新方法,据报道这些化合物是HIV致细胞病变的强力抑制剂。对于3′-叠氮基,3′-氨基和3′-氟代嘧啶和嘌呤2′,3′-双脱氧核糖核苷类似物的生物活性和合成的广泛研究已有过报道。
通常,制造这种3′-取代核苷的方法以两种途径进行、(1)在2′-脱氧核苷中3′-OH功能团的取代,例如从胸苷合成AZT或FLT,或(2)制造-3-取代呋喃糖苷化合物,然后以一适当嘌呤或嘧啶碱基如胸腺嘧啶偶合。由于后面一种方法用较简单的原料,且提供了在3′-位置上容易以许多亲核剂取代,供作嘌呤或嘧啶碱基有效偶合所需的中间体,因此,它给大规模合成3-取代核苷提供了最大可能性。
已有过3-取代呋喃糖类几种合成方法的描述,但它们都很复杂,并需要多步反应和昂贵的试剂。Fleet等“Tetrahedron”1988,44(2)625—636叙述了从D-木糖合成甲基-5-O-叔-丁基二苯硅烷基-2-脱氧-α(β)-D-苏-呋喃戊糖苷和它转变成叠氮基糖、氟代糖和氰基糖,随后这些衍生物与保护的胸腺嘧啶碱基偶合生成胸苷化合物。Bravo等,“J.Org.Chem.”1989,54,5171—5176叙述了3-氟代呋喃糖类从下式化合物不对称合成的方法:其中在氟化的碳上用烯丙基溴单烷基化,去除辅助的亚硫酰基后进行还原加工和双链氧化开裂,提供5-O-苯甲酰基-2,3-双脱氧-3-氟代呋喃糖。
本发明描述了一种合成3-取代呋喃糖和呋喃糖苷替代的改进方法,它不复杂,使用步骤少,所用原料简单,便宜。
其中,M是氢或烷基(C1—C3),A是卤素或是部分式:OR,SR,N3,或CN中一个基团,其中,R是氢,直链或支链的烷基(C1—C4)或苯基。改进的方法可用下流程图表示:
在上面流程图I中,X可以是氯或溴。
本发明也涉及制备式Ti(OR′)nA4-n氟化剂的新方法,其中n是1到3的整数,R′是支链或直链的烷基(C1—C4),A如上所述。
按照流程图I,炔丙醇1与烯丙基氯或烯丙基溴2反应得到醇3,用氢化锂铝还原3产生烯烃4,4环氧化得到环氧乙烷5,用带有取代基A的合适亲核剂的处理,区域选择性地将5的环氧乙烷环开环,产生二醇6,6用10%钯碳作催化剂氢化,产生式7的取代戊糖化合物。
在本发明的最佳实施例中,式I的3-取代的呋喃糖由下列步骤制备:
a)炔丙醇1在pH值8-9与烯丙基氯或烯丙基溴2在温度65—70℃的水中与CuCl或CuBr一起搅拌缩合,得到己-5-烯-2-炔-1-醇3;
b)然后,化合物3,在四氢呋喃中用LiAlH4还原,生成相应的烯丙醇,4,即反-2,5-己二烯-1-醇;
c)然后,烯丙醇4在D-(-)-酒石酸二异丙酯存在下不对称环氧化,生成环氧乙烷化合物5,即2R,3R-环氧己-5-烯-1-醇;
d)然后,环氧乙烷化合物5在式Ti(OR′)nA4-n表示的适当亲核剂处理下,区域选择性地亲核开环,生成式6的二醇。Ti(oR′)nA4-n中,n为1-3的整数,R′是支链的或直链的烷基(C1—C4),A如上所述。
e)然后,二醇化合物6顺次地进行与下列各物作用:
ⅰ)臭氧;
ⅱ)以钯碳为催化剂用H2氢化还原加工;
ⅲ)醇解产生式7表示的3-取代-2,3-双脱氧-D-赤式-戊糖苷α和β异构体的混合物。
如上面步骤(c)所述的,烯丙醇化合物4通过Gao等,J.Amen.Chem.Soc,109,5765—5780(1987)所述的方法来不对称环氧化,在此作为参考引入本发明。此法从烯烃产生环氧化产物至少有94%对映体过量。在催化量的由酒石酸酯如二乙酯或二异丙酯和异丙醇钛(IV)制备的催化剂处理下,烯烃可被转变成相应的环氧化物。钛/酒石酸酯的最佳比值为1∶1.2,保持反应混合物无水是重要的,粉状的活化分子筛作此用很好。如二氯甲烷、甲苯或异辛烷可用作溶剂。反应通常在约—20℃进行,所有反应都在叔丁基过氧化氢(TBHP)存在下进行,虽然可用其它的过氧化物。
通常,酒石酸酯催化剂是通过把选用的酒石酸酯和异丙醇钛(IV)在-20℃在溶剂如二氯甲烷中混合来制备,于其中加入烯醇或叔丁基过氧化氢。不论最后加入的试剂是醇或叔丁基过氧化氢,任何情况下,这三种成份都在最后试剂加入前加入并搅拌约30分钟。所有反应都在粉状的活化分子筛存在下进行。这30分钟的搅拌称为“陈化”阶段,是得到高对映选择性的重要因素。
在上面步骤(d)中,环氧乙烷化合物5通过由式Ti(OR′)nA4-n表示的试剂的温和处理区域选择性地亲核开环,生成式6的二醇化合物。式中n是1-3的整数,R′是直链或支链的1-4个碳原子的烷基,A是如上所述。
式Ti(OR′)nA4-n的亲核试剂可以方便地由式Ti(OR′)4的钛(IV)的醇盐与适当摩尔浓度的对应酸、酸酐或三甲基硅醚反应来如下式制备:
Ti(OR′)4+R″A→Ti(OR′)nA4-n+R″(OR′)4-n
其中R″是氢,CH3CO、苯甲酰基或Si(CH3)3。例如,三异丙基氯化钛可通过异丙醇钛(IV)与三甲基硅氯化物反应得到。三异丙基叠氮化钛可由异丙醇钛(IV)在戊烷中与HN3反应得到。三异丙基硫代苯甲酸钛盐可由异丙醇钛(IV)与硫代苯甲酸反应得到。
如果A是氟时,较好的亲核剂是二氟二异丙醇钛(IV)〔TiF2(OiPr)2〕,它可由在20—25℃把异丙醇钛(IV)加于苯甲酰氟或CH3COF的己烷溶液中来制备。产物二氟二异丙醇钛(IV)在一隋性气体下过滤收集。
在取代基A不是氟化物时,开环反应的较好亲核剂是三异丙醇钛(IV)。此试剂用于在表1列出的反应条件下区域选择性地打开式表示的化合物的环。
表 1
用(iPro)3TiA的1,1-二乙氧基-3R,4R-
环氧戊-5-醇区域选择开环
A | 反应条件 | 产率,%b | 所生成的混合物的组成成份%(2) (3) | |
t/h | 溶剂 | |||
OAc 1 CHCl3 95 >98 <2OTol 1 CHCl3 90 >98 <2Cl 1 C6H6 85 >85 15SCOPh 1 CHCl3 80 >98 >2N3 1.5 CHCl3 95 >92 8 |
b加工后3-和4-取代乙缩醛的总产率。上述反应条件也同样适于化合物5即2R,3R-环氧己-5-烯-1-醇的区域选择性开环。三异丙醇钛(IV)使高效地用亲核基A在温和条件下区域选择性地打开环氧环成为可能。本方法可用于A是任何亲核基的很多环氧乙烷开环反应中。
亲核开环反应(步骤d)可在许多溶剂中进行,例如苯、甲苯、氯仿、甲醇或它们的混合物。通常最好试剂过量1.5摩尔。温度条件可从0°—130℃变化,最好是80—120℃,这时反应通常在不到1小时内完成,转化大于90%。最终产物可用色谱法把它从反应混和物中分离。
在上面步骤(e)中,式6表示的二醇化合物溶于甲醇中,在保持—60°~—70℃冷却下,将干燥臭氧通过一计泡器通入,直到反应完成。升温至0℃后,加钯碳,在氢气中进行氢化直至吸收完全。加入盐酸完成苷化,生成式7表示的3-取代-2,3-双脱氧-赤式-戊糖化合物,它是α和β异构体的混合物。
对本领域的技术人员,在对说明书和所附权利要求书的进一步研究之后,可明确本发明的进一步目的和优点。
本发明将通过下面的非限制性特定实施例更具体地阐明。
实施例1
己-5-烯-2-炔-1-醇
在室温下,将40%的氢氧化钠溶液加到250ml饱和NaCl溶液,1ml盐酸,8g氯化铜(I)和28g炔丙醇的搅拌混和物中,直至pH值调至9。反应混合物在70℃浴器中加热,将120ml烯丙基氯在80ml甲醇中的溶液滴加于其中。反应混合物的pH值小心地保持在8—9之间,如需要的话可用40%的氢氧化钠同时加入。在完全加入烯丙基氯溶液和pH值维持在8—9之后,反应混和物在70℃搅拌3.5小时。烧瓶冷却至室温后,加盐酸直到pH值为2。分离有机相,水相用50ml的醚提取3次。有机相合并,减压除去挥发物得一油状物,真空蒸镏得45克无色清澄液体的所需物,BP67-68℃/10mm,nD 201.4670.13C-NMR:137.69(C-5),115.98(C-6),82.65和81.54(C-2和C-3),50.59(C-1),23.21(C-4).C6H8O的分析计算值:C,74.97;H,8.39实测值:C,75.11;H8.18.
实施例2
反-2,5-己二烯-1-醇
将0.6克实施例1所得产物溶入50ml四氢呋喃的溶液并滴加入冷却至0℃的3.8g氢化锂铝在150ml四氢呋喃的混合物中。加完之后除去冷却浴,使温度回到室温,然后再搅拌30分钟。温度再用3小时升至45℃,然后冷却至0℃。将100ml的饱和氯化铵小心地滴入,将所得混和物过滤。滤块用20ml的***洗涤3次,滤液合并,用MgSO4干燥。挥发物减压除去,残留物真空蒸馏得7.9克无色清澄液体的所需产物,BP70-72℃/15mm,nD 201.4530.
13C-NMR:137.57(C-5),132.01和128.89(C-2,C-3),115.40(C-6),63.00(C-1),36.80(C-4).C6H10O的计算值:C,73.43;H,10.27.实测值:C,72.98;H,10.01.
实施例3
2R,3R-环氧己-5-烯-1-醇
将3.0g粉状的,活化4A分子筛和300ml干燥二氯甲烷冷却至—20℃,在连续搅拌下,顺次加入2.81g(2.36ml)D-(-)-酒石酸二异丙酯和2.84g(2.99ml)的异丙醇钛(IV),反应混合物在—20℃搅拌下,将40ml 5M TBHP的二氯甲烷溶液在5分多钟内加入。在—20℃持续搅拌30分钟,然后在保持反应温度在—25℃~20℃之间下将9.8g实施例2产物在50ml二氯甲烷中的溶液滴加其中,混合物在—25至—20℃下再搅拌8~10小时,然后用8ml预冷至—20℃的以氯化钠饱和的10%氢氧化钠水溶液(10gNaCl+10gNaOH+95ml水)中止反应。加入***使成—10%V/V的反应混合物。移开冷却浴,使搅拌的反应混合物回升至10℃,然后再搅拌10分钟,搅拌时加8g硫酸镁和1g硅藻土。再继续搅拌15分钟,然后经一硅藻土层过滤,滤块用***50ml洗涤3次。合并的滤液用硫酸镁干燥,在真空中蒸去溶剂,残留物真空蒸馏得8.9g所需的产物,BP85-87/10mm,nD 201.4458[α]D 20+23.2(C10,CH3OH).
13C-NMR:134.49(C-5),117.28(C-6),62.69(C-1),58.65(C-2),55.12(C-3),36.45(C-4).C6H8O的分析计算值:C,63.13;H,8.83实测值:C,62.88;H,8.19.
实施例4
二氟二异丙醇钛(IV)
37.4g苯甲酰氟在100ml己烷中的搅拌混合物放在一个20~25℃浴中冷却时,将28.4g的异丙醇钛(IV)滴加其中。反应进行时有升温现象,生成一种白色固体,在惰性气体中滤出,真空干燥,得13.6g白色细粉状的所需产物。
实施例5
2R,3S-3-氟代己-5-烯-1,2-二醇
将13.6g二氟二异丙醇钛(IV)在180ml干燥甲苯中的混合物在120℃油浴中搅拌回流加热。将5.8克4R,3R-环氧己-5-烯-1-醇溶在10ml干燥甲苯中的溶液滴加于此回流反应混合物中。在完全加入后移走浴。继续的搅拌至温度降到25~30℃。在激烈搅拌下加入15ml饱和碳酸氢钠溶液,搅拌持续2小时多,pH值呈中性到略偏碱性,再加饱和碳酸氢钠以调节pH值。反应混合物通过硅藻土过滤,滤块用丙酮洗涤。滤液合并用MgSO4干燥,真空除去溶剂。残留物用硅胶色谱法,用50∶1的氯仿-异丙醇淋洗纯化,得白色结晶固体的所需产物,m.p.37~38℃。TLC(9∶1氯仿-异丙醇)RF=0.41.
13C-NMR:134.85(d,JC-F3.5Hz,C-5),117.62(C-6),93.52(d,JC-F171.6Hz,C-3),73.30(d,JC-F23.1Hz,C-2),63,33(d,JC-F5.5Hz,C-1),35.98(d,JC-F21.1Hz,C-4).C6H11O2F计算值:C,53.72;H,8.27;F14.17.实测值:C,53.92;H,8.01;F,13.28.
实施例6
甲基3-氟-2,3-双脱氧-2,β-D-赤式-呋喃戊糖苷
1.5g2R,3S-3-氟己-5-烯-1,2-二醇溶于150ml甲醇的溶液冷却至-60~-70℃。经炉干燥的臭氧通于反应混合物中,历时3小时,使反应混合物升温至0℃,加0.05g的钯碳,搅拌下计有250ml氢气被吸收。过滤反应混合物,加1ml 10%盐酸的甲醇溶液。当反应从TLC(10∶1氯份-甲醇)表明已完全时,用无水碳酸钾中和反应混合物,过滤、蒸发,得1.0g所需的混合物产物。
13C-NMR:106.27(C-1,β);105.84(C-1,α),95.55(d,JC-F175.6Hz,C-3-β),94.58(d,JC-F177.6Hz,C-3-α),86.31(d,JC-F22.6Hz,C-4-β),85.51(d,JC-F23.6Hz,C-4-α),63.15(d,JC-F10.0Hz,C-5-β),62.44(d,JC-F9.6Hz,C-5-α),55.40(-OMe-β),54.68(-OMe-α),40.40(d,JC-F21.6Hz,C-2-β)40.13(d,JC-F21.1Hz,C-2-α),C6H11O3F的分析计算值:C,47.99;H,7.38;F,12.65实测值:C,47.15;H,6.69;F,11.80.
Claims (3)
b)使a步的产物与氢化铝锂反应,生成2,5-己二烯-1-醇;
c)使b步的产物在D-酒石酸二异丙酯存在下,在-25℃到-20℃反应8~10小时,生成2R,3R-环氧己-5-烯-1-醇;
e)使d步的产品与臭氧反应,然后用钯炭为催化剂氢催化还原,形成以下式表示的化合物:
2.如权利要求1所述的方法,其特征在于所述的R′是异丙基,n为2,A是氟。
3.如权利要求1所述的方法,其特征在于所述的R′为异丙基,n为1,A是氟。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US07/698,042 US5216145A (en) | 1991-05-10 | 1991-05-10 | Asymmetric synthesis of 3-substituted furanoside compounds |
US07/698,042 | 1991-05-10 |
Publications (2)
Publication Number | Publication Date |
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CN1066658A CN1066658A (zh) | 1992-12-02 |
CN1032062C true CN1032062C (zh) | 1996-06-19 |
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Application Number | Title | Priority Date | Filing Date |
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CN92102690A Expired - Fee Related CN1032062C (zh) | 1991-05-10 | 1992-04-11 | 3-取代呋喃糖苷化合物的不对称合成 |
Country Status (24)
Country | Link |
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US (2) | US5216145A (zh) |
EP (1) | EP0540807B1 (zh) |
JP (1) | JPH05170782A (zh) |
KR (1) | KR920021526A (zh) |
CN (1) | CN1032062C (zh) |
AT (1) | ATE132125T1 (zh) |
AU (1) | AU657129B2 (zh) |
CA (1) | CA2068226A1 (zh) |
CZ (1) | CZ283306B6 (zh) |
DE (1) | DE69207154T2 (zh) |
DK (1) | DK0540807T3 (zh) |
ES (1) | ES2083608T3 (zh) |
FI (1) | FI922097A (zh) |
GR (1) | GR3018671T3 (zh) |
HU (1) | HU209838B (zh) |
IE (1) | IE75888B1 (zh) |
IL (3) | IL116971A (zh) |
NO (1) | NO178113C (zh) |
NZ (1) | NZ242639A (zh) |
PH (1) | PH31630A (zh) |
PL (1) | PL168588B1 (zh) |
SK (1) | SK279311B6 (zh) |
TW (1) | TW223068B (zh) |
ZA (1) | ZA923350B (zh) |
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US5216145A (en) * | 1991-05-10 | 1993-06-01 | American Cyanamid Company | Asymmetric synthesis of 3-substituted furanoside compounds |
US5521294A (en) * | 1995-01-18 | 1996-05-28 | Eli Lilly And Company | 2,2-difluoro-3-carbamoyl ribose sulfonate compounds and process for the preparation of beta nucleosides |
TW200606159A (en) * | 2004-07-30 | 2006-02-16 | Pharmaessentia Corp | Stereoselective synthesis of β-nucleosides |
US7485716B2 (en) * | 2005-05-02 | 2009-02-03 | Pharmaessentia Corp. | Stereoselective synthesis of β-nucleosides |
EP2217247A4 (en) * | 2007-11-06 | 2011-12-28 | Pharmaessentia Corp | NEW SYNTHESIS OF BETA NUCLEOSIDES |
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US5216145A (en) * | 1991-05-10 | 1993-06-01 | American Cyanamid Company | Asymmetric synthesis of 3-substituted furanoside compounds |
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1991
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1992
- 1992-03-16 AT AT92104485T patent/ATE132125T1/de not_active IP Right Cessation
- 1992-03-16 DE DE69207154T patent/DE69207154T2/de not_active Expired - Fee Related
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- 1992-03-17 TW TW081102018A patent/TW223068B/zh active
- 1992-04-11 CN CN92102690A patent/CN1032062C/zh not_active Expired - Fee Related
- 1992-05-06 IL IL11697192A patent/IL116971A/xx not_active IP Right Cessation
- 1992-05-06 IL IL101799A patent/IL101799A/en not_active IP Right Cessation
- 1992-05-06 JP JP4139628A patent/JPH05170782A/ja active Pending
- 1992-05-07 NZ NZ242639A patent/NZ242639A/en unknown
- 1992-05-07 CZ CS921386A patent/CZ283306B6/cs not_active IP Right Cessation
- 1992-05-07 SK SK1386-92A patent/SK279311B6/sk unknown
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- 1992-05-08 NO NO921837A patent/NO178113C/no not_active IP Right Cessation
- 1992-05-08 AU AU16132/92A patent/AU657129B2/en not_active Ceased
- 1992-05-08 HU HU9201546A patent/HU209838B/hu not_active IP Right Cessation
- 1992-05-08 CA CA002068226A patent/CA2068226A1/en not_active Abandoned
- 1992-05-08 FI FI922097A patent/FI922097A/fi unknown
- 1992-05-08 PL PL92294479A patent/PL168588B1/pl unknown
- 1992-05-09 KR KR1019920007889A patent/KR920021526A/ko not_active Application Discontinuation
- 1992-07-01 IE IE921483A patent/IE75888B1/en not_active IP Right Cessation
-
1993
- 1993-03-12 US US08/031,304 patent/US5296620A/en not_active Expired - Lifetime
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1995
- 1995-01-10 PH PH49766A patent/PH31630A/en unknown
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1996
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