CN1259122A - 制备手性3,4－脱氢脯氨酸类化合物的方法 - Google Patents
制备手性3,4－脱氢脯氨酸类化合物的方法 Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title abstract 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 5
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 4
- 239000012266 salt solution Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000003233 pyrroles Chemical class 0.000 claims description 5
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical class OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- -1 pyrrolecarboxylic acid derivative compound Chemical class 0.000 abstract 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
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- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical class OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- LSMAIBOZUPTNBR-UHFFFAOYSA-N phosphanium;iodide Chemical compound [PH4+].[I-] LSMAIBOZUPTNBR-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及制备式(Ⅰ)的手性3,4－脱氢脯氨酸类化合物的方法,式(Ⅰ)中R、R’和R”具有说明书中给出的意义。本发明的特征在于,使式(Ⅱ)的吡咯羧酸衍生物先在氨中与碱金属或碱土金属反应,然后与一种含水盐溶液或化合物(Ⅲ)反应,式中X是一个离去基团。
Description
本发明涉及制备手性3，4-脱氢脯氨酸类化合物的方法。
手性3，4-脱氢脯氨酸类化合物从4-羟基脯氨酸开始通过Chugaev反应制备(P.Grogg，Angew.Chem.92(1980)761)。除了产率较差(64％)外，该方法还要求使用高毒性化合物诸如二硫化碳、碘甲烷和甲硫醇。在180-190℃和12托下的热解分解需要很大的工业开支。
也可以代替黄原酸盐(或酯)通过热分解转化相应的碘化物、硫氧化物或硒氧化物(J.-R.Dormoy，Synthesis(1982)752)。然而，这并没有解决毒性和工业开支的那些基本问题。
非手性合成通常是从吡咯羧酸开始，用碘化鏻/碘化氢进行还原(J.W.Scott，Synth.Commun.10(1980)529)。然后通过用手性胺(S.S.Kerwar，J.Biol.Chem.251(1976)503；US4,066,658)或酒石酸(A.Corbella，Chem.Ind.(1969)583)进行结晶来拆分外消旋体。该合成方法的缺点是使用了高毒性的膦和在外消旋体的拆分中最高产率是50％。
在未先公开的德国专利申请19630082.7中，描述了消除羟基脯氨酸酯的磺酸酯和随后酶促外消旋体拆分。所述的消除伴随着脯氨酸的不对称中心的外消旋化。原则上经典的和酶促的外消旋体拆分的可能的最高产率都是50％。这只有通过用很大费用循环未拆分的对映体来改进。
A.G.Schultz(J.Am.Chem.Soc.110(1988)7828)和T.Kinoshita(J.Heterocycl.Chem.33(1996)1313)分别描述了使苯甲酸衍生物和呋喃羧酸衍生物进行烷基化不对称Birch还原。
直到现在，吡咯衍生物的Birch还原还是未知的。T.J.Donohoe首次在J.Org.Chem.61(1996)7664中描述了吡咯-2-羧酸衍生物的非手性Birch还原反应。迄今为止，已经可以仅通过经典的或酶促的外消旋体拆分将他们拆分成对映体。
现在，我们已经发现，手性3，4-脱氢脯氨酸类化合物可以通过非对映选择的Birch还原获得。
本发明涉及制备式(I)的手性3，4-脱氢脯氨酸类化合物的方法：
式中
R是一个手性基团，
R’是氢或C1-6烷基、C2-7链烯基、C7-9芳基烷基或三-C1-4烷基甲硅烷基，和
R”是一个保护基，
该方法包括，使式(II)的吡咯羧酸衍生物在氨中与碱金属或碱土金属反应，然后与一种含水盐溶液或化合物(III)反应，
R′-X III，
式中
X是一个离去基团。
特别适合的手性基团R的来源是式RH的非芳族的手性仲胺和非芳族的手性醇。具体可以提及的是下列化合物： (R＝C1-4-烷基，优选甲基)
其中，化合物D是特别优选的。
R’优选是氢、C1-3烷基、烯丙基或苄基。作为三-C1-4烷基甲硅烷基应该特别提及三甲基甲硅烷基。
对R”可以列举的保护基是Boc、C1-6酰基、甲磺酰基、苯磺酰基和甲苯磺酰基，优选Boc。
对X来说优选的离去基团是氯、溴、碘、甲磺酰氧基、甲苯磺酰氧基或三氟甲磺酰氧基(triflate)。
对于反应应该被提及的碱金属和碱土金属是镁和特别是锂、钠和钾。反应在液体或超临界氨中进行，其中也可以加入惰性溶剂。优选的溶剂是THF和C1-6醇。
反应一般在-100～+100℃范围内的温度和1～200巴的压力下进行。优选在反应混合物的沸点和1巴的条件下进行。非常特别优选在自生压力下进行反应。
当在反应混合物中不再能检测到吡咯衍生物时，反应即完成(例如通过GC、HPLC、TLC检测)。
通常，通过常规方法如蒸馏、过滤、离心或萃取来对产物进行后处理。
该新方法可以分批进行，例如在一个搅拌着的反应器中。然而，由于步骤简单，该反应也可以连续进行，例如用反应管或一组串联的搅拌着的反应器进行。
如果需要，所得初产物可以进一步例如通过结晶、萃取或层析纯化。
令人惊奇的是，吡咯-2-羧酸酯和吡咯-2-酰胺，尽管有空间要求和电子多样化手性基团，但在一些情况下还是可以被转化成相应的脱氢脯氨酸，同时具有非常高的选择性。特别令人惊奇的是，这不仅适用于反应中间体的烷基化，而且适用于其质子迁移反应。
可以通过该新方法直接制备的式(I)的手性3，4-脱氢脯氨酸类化合物是用来合成染料、作物保护剂或药物，特别是例如在PCT/WO9625426中描述的凝血酶抑制剂的有价值的中间体。
实施例1
合成N-Boc-3，4-脱氢脯氨酸-((S)-2-甲氧基甲基吡咯烷酰胺(pyrrolidinide))
将150ml氨和50ml THF在-30℃混合。然后加入0.42g(0.06mol)的锂。用5分钟的时间向该混合物中滴加溶解在20ml THF中的6.17g(0.02mol)的N-Boc-吡咯-2-羧酸-((S)-2-甲氧基甲基吡咯烷酰胺)。随后搅拌1小时后，加入10ml饱和氯化铵溶液和150ml饱和氯化钠溶液，分相，水相用二氯甲烷萃取三次，每次用50ml。合并有机相，浓缩。得到了4.8g(0.015mol，77％)的桔黄色油状的产物。1H-NMR(δ，ppm，d6-DMSO，T＝373K)：1.38(1s，积分：95∶5，叔丁基)。
实施例2
合成N-Boc-3，4-脱氢脯氨酸-((1S)-内-冰片基)酯
将150ml氨和50ml THF在-30℃混合。然后加入0.24g(0.034mol)的锂。用5分钟的时间向该混合物中滴加溶解在10ml THF中的4g(0.0115mol)的N-Boc-吡咯-2-羧酸-((1S)-内-冰片基)酯。随后搅拌1小时后，加入2ml饱和氯化铵溶液和150ml饱和氯化钠溶液，分相，水相用二氯甲烷萃取三次，每次用100ml。合并有机相，用硫酸钠干燥，浓缩。产率：3.2g(0.009mol，61％)。1H-NMR(δ，ppm，d6-DMSO，T＝358K)：1.4(2s，积分：57∶96，叔丁基)。
实施例3
合成N-Boc-3，4-脱氢脯氨酸-((1R，2S，5R)-基)酯
在-30℃将0.58g(0.084mol)的锂加到100ml氨和23ml THF中。向该混合物中滴加溶解在20ml THF中的10g(0.028mol)的N-Boc-吡咯-2-羧酸-((1R，2S，5R)-基)酯。搅拌1小时后，加入5g氯化铵、100ml的THF和7.5g的Celite，允许氨气蒸发。过滤悬浮液，浓缩滤液。产率：8.4g(0.024mol，85％)。1H-NMR(δ，ppm，CDCl3)：1.325-1.425(各2s，积分：67∶92，叔丁基)。
实施例4
合成N-Boc-3，4-脱氢脯氨酸-(1S)-2，10-樟脑磺酰胺
在-70℃将0.15g(0.023mol)的锂加到100ml氨和50ml THF中。向该混合物中滴加溶解在20ml THF中的3.2g(0.0078mol)的N-Boc-吡咯-2-羧酸-(1S)-2，10-樟脑磺酰胺。搅拌1小时后，加入4g氯化铵、25ml的THF和3g的Celite，允许氨气蒸发。过滤悬浮液，浓缩滤液。产率：4g(仍然含有LiCl)。1H-NMR(δ，ppm，CDCl3)：1.37-1.46(各2s，积分：69∶30，叔丁基)。
Claims (5)
1.制备式(I)的手性3，4-脱氢脯氨酸类化合物的方法：
式中
R是一个手性基团，
R’是氢或C1-6烷基、C2-7链烯基、C7-9芳基烷基或三-C1-4烷基甲硅烷基，和
R”是一个保护基，
该方法包括，使式(II)的吡咯羧酸衍生物在氨中与碱金属或碱土金属反应，然后与一种含水盐溶液或化合物(III)反应，
R′-X III，
式中
X是一个离去基团。
2.根据权利要求1的方法，其中R是手性胺或手性醇的残基。
3.根据权利要求2的方法，其中RH是对映异构或非对映异构形式的下述化合物中的任何一种：
(R＝C1-4-烷基)
4.根据权利要求1的方法，其中反应在惰性溶剂存在下进行。
5.根据权利要求1的方法，其中反应在1～200巴的压力和-100～+100℃的温度下进行。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19723473A DE19723473A1 (de) | 1997-06-04 | 1997-06-04 | Verfahren zur Herstellung von chiralen 3,4-Didehydroprolinen |
| DE19723473.9 | 1997-06-04 |
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| CN1259122A true CN1259122A (zh) | 2000-07-05 |
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| CN98805882A Pending CN1259122A (zh) | 1997-06-04 | 1998-06-02 | 制备手性3,4－脱氢脯氨酸类化合物的方法 |
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| Country | Link |
|---|---|
| US (1) | US6166222A (zh) |
| EP (1) | EP0986538A1 (zh) |
| JP (1) | JP2002506430A (zh) |
| KR (1) | KR20010013342A (zh) |
| CN (1) | CN1259122A (zh) |
| AU (1) | AU8335298A (zh) |
| BR (1) | BR9809726A (zh) |
| CA (1) | CA2291787A1 (zh) |
| DE (1) | DE19723473A1 (zh) |
| HU (1) | HUP0002772A3 (zh) |
| IL (1) | IL132988A0 (zh) |
| NO (1) | NO995939L (zh) |
| WO (1) | WO1998055456A1 (zh) |
| ZA (1) | ZA984814B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19913699A1 (de) * | 1999-03-26 | 2000-09-28 | Basf Ag | Verfahren zur Herstellung von 3,4-Dihydroprolinen und 3,4-Dehydropiperidinen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE19630082A1 (de) * | 1996-07-26 | 1998-01-29 | Basf Ag | Verfahren zur Herstellung von 3-Pyrrolin-2-carbonsäure-Derivaten |
-
1997
- 1997-06-04 DE DE19723473A patent/DE19723473A1/de not_active Withdrawn
-
1998
- 1998-06-02 US US09/424,933 patent/US6166222A/en not_active Expired - Fee Related
- 1998-06-02 CN CN98805882A patent/CN1259122A/zh active Pending
- 1998-06-02 IL IL13298898A patent/IL132988A0/xx unknown
- 1998-06-02 HU HU0002772A patent/HUP0002772A3/hu unknown
- 1998-06-02 WO PCT/EP1998/003284 patent/WO1998055456A1/de not_active Application Discontinuation
- 1998-06-02 JP JP50148499A patent/JP2002506430A/ja active Pending
- 1998-06-02 EP EP98933585A patent/EP0986538A1/de not_active Withdrawn
- 1998-06-02 CA CA002291787A patent/CA2291787A1/en not_active Abandoned
- 1998-06-02 AU AU83352/98A patent/AU8335298A/en not_active Abandoned
- 1998-06-02 BR BR9809726-1A patent/BR9809726A/pt not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| WO1998055456A1 (de) | 1998-12-10 |
| CA2291787A1 (en) | 1998-12-10 |
| NO995939D0 (no) | 1999-12-03 |
| MX9910984A (zh) | 2000-04-01 |
| NO995939L (no) | 1999-12-03 |
| DE19723473A1 (de) | 1998-12-10 |
| JP2002506430A (ja) | 2002-02-26 |
| IL132988A0 (en) | 2001-03-19 |
| ZA984814B (en) | 1999-12-17 |
| AU8335298A (en) | 1998-12-21 |
| EP0986538A1 (de) | 2000-03-22 |
| BR9809726A (pt) | 2000-07-11 |
| US6166222A (en) | 2000-12-26 |
| KR20010013342A (ko) | 2001-02-26 |
| HUP0002772A3 (en) | 2001-02-28 |
| HUP0002772A2 (hu) | 2000-12-28 |
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