CN1031568C - 四氢-5-取代-3-亚甲基-2-呋喃甲醇的立体、对映选择合成法 - Google Patents
四氢-5-取代-3-亚甲基-2-呋喃甲醇的立体、对映选择合成法 Download PDFInfo
- Publication number
- CN1031568C CN1031568C CN92102602A CN92102602A CN1031568C CN 1031568 C CN1031568 C CN 1031568C CN 92102602 A CN92102602 A CN 92102602A CN 92102602 A CN92102602 A CN 92102602A CN 1031568 C CN1031568 C CN 1031568C
- Authority
- CN
- China
- Prior art keywords
- methyl
- product
- methylene radical
- furfuralcohol
- diethoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
- 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
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- 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
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
制备用作合成各种具有抗病毒和其它生物活性的改性核苷的中间体的四氢-5-羟基-3-亚甲基-2-呋喃甲醇和四氢-5-〔低级烷氧基(C1-C3)〕-3-亚甲基-2-呋喃甲醇的新方法和中间体。
Description
本发明指出了制备用作合成各种具有生物活性的改性核苷中间体的四氢-5-羟基-3-亚甲基-2-呋喃甲醇和四氢-5-〔低级烷氧基(C1—C3)〕-3-亚甲基-2-呋喃甲醇的新方法和中间体。
新近发现,具有抑制各种改性的核苷和它们作为有关人类免疫缺陷病毒(HIV)传染的获得性免疫缺陷综合征(AIDS)治疗中的治疗剂的实际可能有用的活性的反转录酶,这些发现引起了人们对制备这种核苷新方法的兴趣。特别感兴趣的是,制备已报道的作为HIV-诱导细胞病原性的有效抑制剂的3′-叠氮基-3′-脱氧胸苷(AZT)和3′-脱氧-3′-氟代胸苷(FLT)的新方法。对3′-叠氮基,3′-氨基和3′氟嘧啶和嘌呤2′,3′-二脱氧核糖核苷类似物的合成法和生物活性的广泛研究已报道过。
一般,制备如3′-取代核苷的方法有二个独立的途径:(1)在2′-脱氧核苷中的3′-OH官能团的取代反应,如由胸苷合成AZT或FLT,或(2)制备3-取代呋喃糖苷化合物,随后联结一合适的嘌呤或嘧啶碱如胸腺嘧啶。后一种方法因它使用更简单的原材料,为3′-位置上简单取代大量的亲核物质作准备并提供适合于与嘌呤或嘧啶碱有效偶联的中间体后显示出其无疑的优点。因而,后一种方法为合成大量的3′-取代核苷提供了最大的可能性。
合成3-取代呋喃糖苷糖的几种方法已描述过,但它们是很复杂的,并且需要多步反应和昂贵的试剂。Fleet,G.W.et al;《四面体》1988,44(2)625—636描述了甲基-5-O-叔-丁基二苯基甲硅烷基-2-脱氧-α(β)-D-苏型五呋喃糖苷的合成法,它是从D-木糖与其转变成叠氮基、氟代和氰基糖,随后与一些经保护的胸腺嘧啶的衍生物偶合而产生胸苷化合物。Bravo,P.et al.,J.Org.Chem.1989,54,5171—5176描述了用下述化合物作原料的3-氟呋喃糖的不对称合成法。在氟取代碳上用烯丙基溴将其单烷基化,除去亚磺酰基助剂,随后经一还原过程和双键的氧化断裂,得到5-O-苯甲酰基-2,3-二脱氧-3-氟-呋喃糖。
包含一环外双键的单糖在合成接枝和官能取代的碳水化合物过程中同样是有用的化合物。四面体快报,22(43),4315—4318(1981)描述了几种在合成过程中使用碳水化合物的大环内酯抗生素的合成方法。
尽管如此,四氢-5-取代-3-亚甲基-2-呋喃甲醇用作合成3′-取代核苷的有用中间体还是新的和未知的。
本发明描述了一种立体和对映选择合成四氢-5-羟基-3-亚甲基-2-呋喃甲醇和四氢-5-〔低级烷氧基(C1—C3)]-3-亚甲基-2-呋喃甲醇的改进的另一种方法。此方法是新的,不复杂的,经少量步骤并使用简单、便宜的原材料。
本发明涉及了如式I的新颖的四氢-5-羟基-3-亚甲基-2-呋喃甲醇和四氢-5-〔低级烷氧基(C1—C3)〕-3-亚甲基-2-呋喃甲醇,这些化合物作为制备接枝和3′-官能团取代核苷的中间体是有用的。
本发明同样涉及一种改进的立体、对映选择合成如下式的四氢-5-取代-3-亚甲基-2-呋喃甲醇的方法。其中R代表H或低级烷基(C1—C3)。改进方法可用下面反应示意图I来表示:
通常,3-甲基-2-丁烯醛1与三甲基氯硅烷反应到2。2与原甲酸三烷基(C1—C3)酯反应产生3。3与二(2-甲氧基乙氧基)氢化铝钠反应到达4。4的环氧化产生环氧乙烷5。5经一催化量的异丙醇钛(IV)处理后产生6。6经痕量HCl乙醇溶液处理后产生7和8的混合物,水解6产生9。
按照前面的示意图I,式I化合物通过下述步骤来制备:
(a)3-甲基-2-丁烯醛与三甲基氯硅烷采用P.Cazeau et al.,《四面体》43,2075—2088(1987)的方法,在含三乙胺和无水碘化钠的乙腈中,在40—45℃进行反应,生成1-三甲基甲硅烷氧基-3-甲基-1,3-丁二烯2;
(b)室温下化合物2与原甲酸三烷基(C1—C3)酯在15%的氯化锌的乙酸乙酯溶液中经多于1小时的反应产生1,1-二乙氧基-3-甲基-4-戊烯醛3;
(c)化合物3随后在0°至5℃的甲苯中被二(2-甲氧基乙氧基)氢化铝钠还原得到烯丙醇4,即1,1-二乙氧基-3-甲基-4-戊烯-5-醇;
(d)烯丙醇4在D-(—)-酒石酸二异丙酯,异丙醇钛(IV),4°A分子筛和叔丁基过氧化氢的存在下发生不对称的环氧化作用,在-20℃的二氯甲烷中产生新的环氧乙烷化合物5,即反式-(+)-1,1-二乙氧基-3-甲基-3,4-环氧戊-5-醇;
(e)环氧乙烷化合物5用催化量的异丙醇钛(IV)处理,在苯中回流3小时以上,发生开环生成6,即(s)-5,5-二乙氧基-3-亚甲基-1,2-戊二醇;
(f)二醇化合物6在室温下经10%的HCl乙醇溶液处理30分钟得到7(2S-顺式)-四氢-5-乙氧基-3-亚甲基-2-呋喃甲醇和8(2S-反式)-四氢-5-乙氧基-3-亚甲基-2-呋喃甲醇的混合物;
(g)二醇化合物6在室温下经一酸式离子交换树脂水溶液处理3小时生成化合物9四氢-5-羟基-3-亚甲基-2-呋喃甲醇。
如上所述的第四步(d)中,烯丙醇化合物4用Y.Gao et al.,《J.Amer.Chem.Soc.》,109,5765-5780(1987)的方法不对称环氧化,并结合参考本发明。这种方法是在至少过量94%对映体的烯烃中制得环氧化物。烯烃经一以催化量的从酒石酸酯如酒石酸二乙酯或二异丙酯和异丙醇钛制得的催化剂处理后可转变成相应的环氧化物,钛/酒石酸酯的最佳比率为1∶1.2。保持混合物在无水的情况下反应是很重要的,(这样)粉状活化分子筛就能正常起作用。溶剂如二氯甲烷、甲苯或异辛烷是可以使用的。反应通常是在大约-20℃的温度下进行的,尽管其它的一些过氧化物也成功地使用过,但所有的反应必须在叔丁基过氧化氢(TBHP)存在下进行。
一般,催化剂是这样来制备的:将选出的酒石酸和异丙醇钛(IV)在-20℃于溶剂如二氯甲烷中混合,然后加入烯醇或叔丁基过氧化氢,总之,将这三种组分混合并在最后一种试剂加入前搅拌约30分钟,这最后一种试剂是烯醇或叔丁基过氧化氢,所有反应必须在粉状活化分子筛存在的情况下进行。30分钟的搅拌称为“老化”期,它对得到高对映选择性是一个很重要的因素。
四氢-5-乙氧基-3-亚甲基-2-呋喃甲醇化合物7和8以及四氢-5-乙氧基-3-亚甲基-2-呋喃甲醇化合物9对制备各种3′-取代核苷化合物如3′-叠氮基-3′-脱氧胸苷(AZT)或3′-脱氧-3′-氟代胸苷(FLT)的前体是有用的,这些化合物作为HIV诱导细胞病原性抑制剂的使用而熟知。一般,式I呋喃甲醇化合物可与各种氮杂杂环在Lewis酸的条件下,如三甲基硅三氟甲烷磺酸盐,氯化锌或氯化锡,发生标准偶合反应。于是,呋喃甲醇(式I)与亲电子试剂在新形成的双键位置上可发生进一步的官能反应,如硼氢化反应,锇酰化反应或卤代醇生成反应。
在研究下面的说明书和附加权利要求,进一步的论题和本发明的优点将明显地体现在文本中。
本发明将结合下面非限制性的具体实施例作更详细的描述。
实施例1
1-三甲基甲硅烷氧基-3-甲基-1,3-丁二烯
室温下在180g溶于300ml无水乙腈的无水碘化钠的悬浮液中加入112g三乙胺和84g 3-甲基-2-丁烯醛溶于400ml戊烷溶液。在35~38℃时,将109g三甲基氯硅烷滴加到上述溶液中,并且在40~45℃的温度下混合搅拌4小时,过滤所得固体,用400ml戊烷洗涤并蒸发溶剂直至残液。将残液蒸馏得到112g的标题产物,B.P.56~60℃/35mm,nD 201.4496。
分析:C8H16OSi的计算值:C,61.48;H,10.32;Si,17.97.
实测值:C,61.59;H,10.24;Si,17.68.
实施例2
1,1-二乙氧基-3-甲基-4-戊烯醛
室温下在104g的原甲酸三乙酯和15%氯化锌的乙酸乙酯溶液的混合物中加入109g实施例1的产物,边滴加边搅拌,然后再搅拌1小时,小心地加入600ml饱和的碳酸氢钠水溶液。过滤所得沉淀,并用600ml***洗涤滤饼,分开水相,用200ml饱和的碳酸氢钠水溶液洗涤有机相,用碳酸钾干燥,蒸发至残液。将残液蒸馏得到78g油状的标题产物。
B.P.:68~70℃/3mm,n20 D1.4590.13C-NMR:δ191.12(C-5),159.71(C-3),129.85(C-4),101.74(C-1),61.75(OC-2H5),45.13(C-2),18.13(CH3),15.46(OC2H5)-trans;191.20(C-5),159.04(C-3),130.27(C-4),62.61(OC2H5),38.00(C-2),26.17(CH3),15.56(OC2H5)-cis.
分析:C10H18O3:计算值:C,64.49;H,9.74.
实测值:C,64.72;H,9.89.
实施例3
1,1-二乙氧基-3-甲基-4-戊烯-5-醇
0℃时,在200ml浓度为30%的二(2-甲氧基乙氧基)氢化铝钠的甲苯溶液中边搅拌边滴加入50g实施例2产物溶于50ml***的溶液。混合物在0℃~5℃搅拌1小时。在0℃~5℃时滴加饱和的氯化铵水溶液,然后在10℃~15℃时搅拌30分钟。过滤所得固体并用300ml***洗涤。分离有机相,用碳酸钾干燥并蒸至残液,残液在真空中蒸馏得到41g油状的标题产物。
BP 93~96℃/0.5mm,n20 D1.4550.13C-NMR:δ133.44(C-3),128.45(C-4),102.76(C-1),61.32(OC2H5),58.96(C-5),44.31(C-2),16.90(CH3),15.54(OC2H5)-trans;134.25(C-3),128.51(C-4),102.61(C-1),62.11(OC2H5),58.69(C-5)(C-5),37.45(C-2),21.62(CH3),15.60(OC2H5)-cis.
分析:C10H20O3:计算值:C,63.79;H,10.71.
实测值:C,63.71;H,10.75
实施例4
反式—(+)-1,1-二乙氧基-3-甲基-3,4-环氧-5-戊醇
将5g粉状,4°A活化分子筛置于300ml二氯甲烷的混合物冷至-20℃,然后加入2.84gD-(-)酒石酸二异丙酯,3.51g异丙醇钛(IV)和45.5ml叔丁基过氧化氢,然后在-20℃的温度下搅拌30分钟。再加入18.8g的实施例3产物溶于20ml二氯甲烷的溶液。保持-20℃的温度下搅拌8小时,然后加入8ml 10%用氯化钠饱和的氢氧化钠水溶液。在10℃时加入8g无水硫酸镁和1g硅藻土,此混合物搅拌15分钟后静置1小时,悬浮液通过硅藻土垫板过滤,滤饼用***(3×50ml)洗涤,将滤液和洗涤液合并,用无水硫酸镁干燥,蒸发至残液。残液通过硅胶柱色谱、用己烷-***来梯度洗脱而达到提纯,得13.7g的油状标题产物。
n20 D1.4465,[α]D+19°(C3.5,甲醇)
分析:C10H20O4:计算值:C,58.80;H,9.87.
实测值:C,58.76;H,9.88.
实施例5
(S)-5,5-二乙氧基-3-亚甲基-1,2-戊二醇
20℃时,在2.04g实施例4产物溶于80ml苯的溶液中加1.42g异丙醇钛,将此混合物回流3小时后冷至室温,加入30ml***和2ml饱和碳酸氢钠水溶液,搅拌30分钟,悬浮液通过硅藻土垫板过滤,垫板用***(3×10ml)洗涤,蒸发溶剂至残液,残液通过硅胶柱色谱,用20∶1的氯仿-甲醇洗脱而达到提纯,得1.78g浆状标题产物。
[α]D+12°(C2.2,甲醇)
分析:C10H20O4:计算值:C,58.80;H,9.87.
实测值:C,58.83;H,9.85.
实施例6
(2S-顺式)-四氢-5-乙氧基-3-亚甲基-2-
呋喃甲醇和(2S-反式)-四氢-5-乙氧基-3-
亚甲基-2-呋喃甲醇
室温下,在1.75g实施例5产物溶于230ml无水乙醇的溶液中加入0.22ml10%的HCl乙醇溶液,将此混合物搅拌30分钟后加入0.1g碳酸钾,再搅拌1小时,过滤混合物,滤饼用无水***(3×10ml)洗涤。蒸发合并的滤液,将残液通过硅胶柱色谱,用氯仿洗脱而达到提纯,得到0.84g标题产物。
[α]D+218°(C2.0,甲醇)
分析:C8H14O3:计算值:C,69.74;H,8.92.
实测值:C,69.78;H,8.96
实施例7
(2S-顺式)-四氢-5-羟基-3-亚甲基-2-
呋喃甲醇和(2S-反式)-四氢-5-羟基-3-亚甲基
-2-呋喃甲醇
在2.04g实施例5产物溶于40ml水的溶液中加入0.4gQU-2离子交换树脂,室温下将此混合物搅拌3小时,过滤,用水(2×5ml)洗涤固体。在合并的滤液和洗涤液中加入0.6g碳酸钡,将此混合物搅拌30分钟,过滤固体,蒸发滤液得到1.09g浆状标题产物。
[α]d+4°(C2.0,H2O).
分析:C6H10O3:计算值:C,55.37;H,7.75.
实测值:C,55.33;H,7.70.
Claims (1)
1.一种制备如下式所示的化合物的方法:其中R代表H或C1~C3烷基,其特征在于:包括:a)在40—50℃时,3-甲基-2-丁烯醛与三甲基氯硅烷在含三乙胺和碘化钠的乙腈中反应生成1-三甲基甲硅烷氧基-3-甲基-1,3-丁二烯;
b)室温下,将步骤a的产物与原甲酸三烷基(C1—C3)酯在氯化锌于乙酸乙酯中经多于1小时的反应生成1,1-二乙氧基-3-甲基-4-戊烯醛;
c)在0~5℃时,将步骤b的产物与二(2-甲氧基乙氧基)氢化铝在甲苯中反应生成1,1-二乙氧基-3-甲基-4-戊烯-5-醇;
d)在-20℃时,将步骤c的产物与D-(—)酒石酸二异丙酯,异丙醇钛(IV),叔丁基过氧化氢和4A分子筛在二氯甲烷中反应生成反式-(+)-1,1-二乙氧基-3-甲基-3,4-环氧-5-戊醇;
e)将步骤d的产物与催化量的异丙醇钛(IV)在回流苯中经多于3小时的反应生成(S)-5,5-二乙氧基-3-亚甲基-1,2-戊二醇;
f)室温下,将步骤e的产物与10%HCl乙醇溶液经30分钟的反应生成(2S-顺式)-四氢-5-乙氧基-3-亚甲基-2-呋喃甲醇和(2S-反式)-四氢-5-乙氧基-3-亚甲基-2-呋喃甲醇;
g)室温下,将步骤e的产物与酸式离子交换树脂QU-2的水溶液经3小时的反应生成四氢-5-羟基-3-亚甲基-2-呋喃甲醇。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/698,041 US5153337A (en) | 1991-05-10 | 1991-05-10 | Stereo and enantioselective synthesis of tetrahydro-5-substituted-3-methylene-2-furanmethanols |
US07/698,041 | 1991-05-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1066659A CN1066659A (zh) | 1992-12-02 |
CN1031568C true CN1031568C (zh) | 1996-04-17 |
Family
ID=24803681
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN92102602A Expired - Fee Related CN1031568C (zh) | 1991-05-10 | 1992-04-08 | 四氢-5-取代-3-亚甲基-2-呋喃甲醇的立体、对映选择合成法 |
Country Status (24)
Country | Link |
---|---|
US (1) | US5153337A (zh) |
EP (1) | EP0512222B1 (zh) |
JP (1) | JPH05148255A (zh) |
KR (1) | KR920021525A (zh) |
CN (1) | CN1031568C (zh) |
AR (1) | AR248404A1 (zh) |
AT (1) | ATE134370T1 (zh) |
AU (1) | AU645199B2 (zh) |
CA (1) | CA2068247A1 (zh) |
CZ (1) | CZ282920B6 (zh) |
DE (1) | DE69208386T2 (zh) |
DK (1) | DK0512222T3 (zh) |
ES (1) | ES2085508T3 (zh) |
FI (1) | FI922096A (zh) |
GR (1) | GR3019057T3 (zh) |
HU (1) | HU215157B (zh) |
IE (1) | IE75889B1 (zh) |
IL (1) | IL101800A (zh) |
NO (1) | NO178112C (zh) |
NZ (1) | NZ242638A (zh) |
PL (1) | PL168623B1 (zh) |
SK (1) | SK279424B6 (zh) |
TW (1) | TW223069B (zh) |
ZA (1) | ZA923349B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5153337A (en) * | 1991-05-10 | 1992-10-06 | American Cyanamid Company | Stereo and enantioselective synthesis of tetrahydro-5-substituted-3-methylene-2-furanmethanols |
CN1039121C (zh) * | 1994-10-18 | 1998-07-15 | 北京医科大学药学院 | 具有嘧啶或嘌呤取代基的氢化呋喃衍生物及其制法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5929678A (ja) * | 1982-08-11 | 1984-02-16 | Eisai Co Ltd | 光学活性化合物およびその製造方法 |
JPS6034961A (ja) * | 1983-08-06 | 1985-02-22 | Suntory Ltd | ラベル化メバロン酸合成中間体及びラベル化メバロン酸の製造法 |
DE3629116A1 (de) * | 1986-08-27 | 1988-03-10 | Asta Pharma Ag | Verfahren zur herstellung enantiomerenreiner r-(+)-(alpha)-liponsaeure und s-(-)-(alpha)-liponsaeure (thioctsaeure) sowie nonen- beziehungsweise mesylderivate als zwischenprodukte hierfuer |
US5153337A (en) * | 1991-05-10 | 1992-10-06 | American Cyanamid Company | Stereo and enantioselective synthesis of tetrahydro-5-substituted-3-methylene-2-furanmethanols |
-
1991
- 1991-05-10 US US07/698,041 patent/US5153337A/en not_active Expired - Fee Related
-
1992
- 1992-03-16 DK DK92104487.1T patent/DK0512222T3/da active
- 1992-03-16 AT AT92104487T patent/ATE134370T1/de not_active IP Right Cessation
- 1992-03-16 EP EP92104487A patent/EP0512222B1/en not_active Expired - Lifetime
- 1992-03-16 DE DE69208386T patent/DE69208386T2/de not_active Expired - Fee Related
- 1992-03-16 ES ES92104487T patent/ES2085508T3/es not_active Expired - Lifetime
- 1992-03-17 TW TW081101999A patent/TW223069B/zh active
- 1992-04-08 CN CN92102602A patent/CN1031568C/zh not_active Expired - Fee Related
- 1992-05-06 IL IL10180092A patent/IL101800A/en not_active IP Right Cessation
- 1992-05-06 JP JP4139629A patent/JPH05148255A/ja active Pending
- 1992-05-07 CZ CS921387A patent/CZ282920B6/cs unknown
- 1992-05-07 NZ NZ242638A patent/NZ242638A/en unknown
- 1992-05-07 SK SK1387-92A patent/SK279424B6/sk unknown
- 1992-05-08 ZA ZA923349A patent/ZA923349B/xx unknown
- 1992-05-08 AU AU16133/92A patent/AU645199B2/en not_active Ceased
- 1992-05-08 CA CA002068247A patent/CA2068247A1/en not_active Abandoned
- 1992-05-08 HU HU9201547A patent/HU215157B/hu not_active IP Right Cessation
- 1992-05-08 NO NO921838A patent/NO178112C/no unknown
- 1992-05-08 AR AR92322306A patent/AR248404A1/es active
- 1992-05-08 FI FI922096A patent/FI922096A/fi unknown
- 1992-05-08 PL PL92294478A patent/PL168623B1/pl unknown
- 1992-05-09 KR KR1019920007888A patent/KR920021525A/ko active IP Right Grant
- 1992-07-01 IE IE921484A patent/IE75889B1/en not_active IP Right Cessation
-
1996
- 1996-02-22 GR GR950402378T patent/GR3019057T3/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1136224C (zh) | 具有类胰岛素作用的肌醇聚糖 | |
WO1998040390A2 (de) | Oligosaccharide und deren derivate sowie ein chemo-enzymatisches verfahren zu deren herstellung | |
CN1193022C (zh) | 在制备他汀类的过程中的内酯化方法 | |
CN1031568C (zh) | 四氢-5-取代-3-亚甲基-2-呋喃甲醇的立体、对映选择合成法 | |
CN1032062C (zh) | 3-取代呋喃糖苷化合物的不对称合成 | |
CN1184228C (zh) | 一种脱氧尿苷衍生物的制备方法 | |
CN1030141C (zh) | 4’-去甲基表鬼臼脂素葡萄糖苷-4’-磷酸酯的制备方法 | |
CN1228313C (zh) | 醋丁酰心安的合成方法 | |
CN1944407A (zh) | 3,4,5-三羟基哌啶生物碱的制备方法 | |
CN1025033C (zh) | 制备烷氧亚甲基表鬼臼毒葡糖苷的方法 | |
Zamojski et al. | Iron complexes in carbohydrate chemistry | |
SU1011655A1 (ru) | Способ получени @ - @ -октилглюкозида | |
JP4212087B2 (ja) | C,c−グリコピラノシル化合物とその製造法 | |
JPH059194A (ja) | レチニルグルコシドの製法 | |
CN1264711A (zh) | 香菇多糖单体衍生物、其制备方法及应用 | |
JP2005225775A (ja) | 免疫活性剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |