CN1019486B - r-丁内酰胺的制备方法 - Google Patents
r-丁内酰胺的制备方法Info
- Publication number
- CN1019486B CN1019486B CN86106592A CN86106592A CN1019486B CN 1019486 B CN1019486 B CN 1019486B CN 86106592 A CN86106592 A CN 86106592A CN 86106592 A CN86106592 A CN 86106592A CN 1019486 B CN1019486 B CN 1019486B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- gram
- milliliters
- reaction
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 61
- 230000008569 process Effects 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- -1 Gamma butyrolactam compound Chemical class 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 230000003287 optical effect Effects 0.000 claims abstract description 9
- 230000004048 modification Effects 0.000 claims abstract description 7
- 238000012986 modification Methods 0.000 claims abstract description 7
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- HNJBEVLQSNELDL-UHFFFAOYSA-N gamma-butyrolactam Natural products O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000006345 epimerization reaction Methods 0.000 claims description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- 150000002085 enols Chemical class 0.000 claims description 2
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- 239000012442 inert solvent Substances 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 238000006317 isomerization reaction Methods 0.000 claims 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- 229920002554 vinyl polymer Polymers 0.000 description 9
- 235000006662 Lansium Nutrition 0.000 description 8
- 241001156382 Lansium Species 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 239000000052 vinegar Substances 0.000 description 5
- 235000021419 vinegar Nutrition 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000008859 change Effects 0.000 description 3
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- 125000001207 fluorophenyl group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000011733 molybdenum Substances 0.000 description 3
- 229910052750 molybdenum Inorganic materials 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 238000005502 peroxidation Methods 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
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- 125000002252 acyl group Chemical group 0.000 description 2
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- 125000004104 aryloxy group Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- KQYZOQQWBTXSDF-UHFFFAOYSA-N clausmarin a Chemical compound O1C(=O)C(C(C)(C)C=C)=CC2=C1C=C1OC3(C)CCC(C(C)(O)C)OC3CC1=C2 KQYZOQQWBTXSDF-UHFFFAOYSA-N 0.000 description 2
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- 229940124600 folk medicine Drugs 0.000 description 2
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
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- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
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- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 description 1
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- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本发明是关于一种具有抗健忘作用的γ-丁内酰胺的制备方法。已经知道在非洲某些地区使用芸香科黄皮属anicata做为民间药物〔I.Master等,Planta Medica32,81(1977)〕。还知道小叶黄皮的粗提物具有心血管活性和用薄层层析法由黄皮属Pentaphalla(Roxb.)中分离出两种香豆精衍生物Clausmarin(黄皮香豆素)A和B具有解痉活性〔Dhan Prakash等,Phyochem.17,1194(1978);和Aboo shoeb等,J.Chem.Soc.,Chem,Commun.1978,281〕。在中国的民间药物中,黄皮的水提液也被认为是一种保护肝脏的有效药剂,并被用来抵抗急慢性病毒性肝炎。还可以从这种提取物中分离出(±)3(S*),4(R*),5(R*),7(S)-3-羟基-5-α-羟苯甲基-1-甲基-4-苯基吡咯烷-2-酮(黄皮胺)作为其主要组分之一。
黄皮胺和由黄皮胺制备的衍生物在动物实验中呈现抗健忘作用和对大脑缺氧提供保护的作用。由于需要有更大量的物质来进行深入的药理学研究,另一方面,使用昂贵的抽提方法从14公斤干叶中只能得到15毫克的起始化合物,因此需要提出一种化合成方法。
本发明讲述的是制备γ-丁内酰胺的方法,它具有通式(Ⅰ)的C(3)-C(4)-反式构型
其中:
R1代表氢或烷基,芳基或芳烷基,每种可多达10个碳原子,
R2和R3可以相同或者不同,代表氢,最多达10个碳原子的烷基、芳基、芳烷基、烷氧基、芳氧基,芳烷氧基,最多达18个碳原子的酰基,三氟甲基,三氟甲氧基,硝基,羟基,卤素,氨基,羧基,磺基,在烷基上多达4个碳原子的二烷基氨基,或多达18个碳原子的酰氨基,
制得的化合物Ⅰ以其异构体,异构体混合物,外消旋物或光学对映体形式存在。该方法的特点是:在惰性溶剂中,在碱存在下,还可在辅助剂存在下,将具有通式Ⅱ的化合物氧化,
其中:
R1,R2和R3含义如上所述。
使人惊奇的是按照本发明的操作方法能以高产率全部形成C(3)-C(4)-反式构型的羟基化产物(Z)。本发明的方法具有这样的优点,即在短时间内可以制出相当大量的物质且化费低。另外,有可能靠选择起始化合物(Ⅱ)来决定最终产物的立体化学,这就是说通过控制制备方法有可能制备个别的立体异构体。
在本定义中,“烷基”和“烷氧基”最好含有多达6个碳原子,“芳基”,“芳烷基”、“芳氧基”和“芳烷氧基”最好分别指苯基,苄基,苯氧基和苄氧基,而“酰基”最好含有多达7个碳原子。
本发明特别适合于制备的式(Ⅰ)化合物如下(以它们的异构体,异构体混合物,外消旋物或光学对映体形式存在):
其中:
R1代表多达4个碳原子的烷基,R2和R3可相同或不同,代表多达4个碳原子的烷基,多达4个碳原子的烷氧基,苯基,苄基,苯氧基,苄氧基,苯甲酰基,乙酰基,三氟甲基,三氟甲氧基,硝基,氟,氯,溴,羟基,氨基,二甲氨基、二乙氨基,乙酰胺基、羧基或磺基,
例如,若用(±)4(S*),5(R*),7(S*)-5-α-羟基-苄基-1-甲基-4-苯基吡咯烷-2-酮作为起始物质,则反应过程可用如下反应方程式说明:
可以使用的氧化剂有有机的或无机的过氧化合物,例如过氧醋酸,过氯代苯甲酸或过氧化钼/吡啶络合物,以及氧、臭氧、或氧的传递剂,如2-磺酰基氧氮丙啶。
通常惰性的,在反应条件下不起变化的有机溶剂都是可用的溶剂。其中(最好的)包括烃类,例如苯、甲苯、二甲苯、己烷、环己烷或石油醚,醚类(例如二乙醚,四氢呋喃或二噁烷),醇类(例如:甲醇、乙醇、或丙醇),卤代烃类(例如二氯甲烷、氯仿、四氯化碳或1,2-二氯乙烷,冰醋酸或六甲基磷酸三胺。也可以使用上述溶剂的混合物。
通常用以形成烯醇的碱都可使用。首选的碱包括碱金属醇化物,氨基碱金属,碱金属氢化物或有机碱金属化合物,例如甲醇的钠盐或钾盐、乙醇的钠盐或钾盐、叔丁醇的钾盐,氢化钠、氨基钠、二异丙氨基锂,丁基锂或苯基锂。同样也可以使用叔胺类,例如,2,5-二氮杂双环(4,3,0)壬-5-烯或1,8-二氮杂双环(5,4,0)十一碳-7-烯。特别可取的硷是二异丙氨基锂、六甲基哌啶锂以及正-,仲-,或叔-丁基锂和苯基锂。
碱、溶剂和(如果合适)助剂的选择取决于所选定的氧化方法。
如果使用助剂,应选那些能够当场还原所形成的过氧化氢中间产物的,特别是当使用过氧化钼/吡啶或氧作为氧化剂时如此。为此最好使用亚磷酸酯,特别是三烷基或三芳基亚磷酸酯,例如三甲基亚磷酸酯、三乙基亚磷酸酯、三丙基亚磷酸酯三异丙基亚磷酸酯、三丁基亚磷酸酯或三苯基亚磷酸酯。
在六甲基磷酸三酰胺中用过氧化钼/吡啶和用氧进行氧化时使用亚磷酸酯做为助剂是特别合适的。当使用如四氢呋喃或六甲基磷酸三酰胺,或它们的适当的混合物作溶剂时,使用三乙基亚磷酸酯作为助剂,用氧进行氧化可得到特别好的产率。已经证明此处使用二异丙氨基锂或丁基锂作为碱是有好处的。
反应温度可在-100℃到+20℃之间变化。最好在温度从-78℃到0℃范围内进行反应。
按照本发明的方法可以在常压下实现羟基化,但也可以在加压或减压条件下进行。一般来说是在常压条件下进行。
按照本发明进行操作时,每摩尔的起始化合物可使用1到5摩尔,最好是1到2.5摩尔的碱,和0.5到5摩尔,最好是0.5到2摩尔的助剂。
制备(Ⅱ)的烯醇化物,通常是先在一合适的溶剂借助于碱进行的,加入亚磷酸酯并使纯氧通过溶液直到用薄层层析观察不到进一步的变化。用专家所熟悉的通常方法将反应混合物逐渐加工成产品。
式(Ⅱ)的起始化合物是新的。它们可以通过使通式为(Ⅱ)的醛与通式为(Ⅳ)的化合物反应来制备,反应在合适的溶剂中,在-20℃到+50℃(最好在-10℃到+30℃)温度下,以及(如果合适)使产物在碳原子7处差向异构体,
其中R1和R3规定如上,
其中R2规定如上,X代表MgBr,MgCl,Li或Ti〔OCH(CH3)2〕3。
式(Ⅳ)化合物的X代表MgCl,MgBr,或Ti〔OCH(CH3)2〕3是最合适的。
在有机金属试剂参加的反应中通常使用的惰性有机溶剂都是适合的。最好是醚类,如乙醚或四氢呋喃,如果合适,还与己烷混合使用。
反应可以用那些类似于文献已知的方法来实现,
例如,由D,Seebach,B.Weidmann和L.Widleir在“Modern Synthetic Methods1983”第217页及以后(Verlay Salle和Sauerlander)或在Houben Weyls“Methoden der organischen Chemie”(Methods of Organic Chemistry”)ⅩⅢ卷/2a,第289页及以后,第302页及以后,或N.L.Drake和G.B.Woke在Organic Synthesis合订本第Ⅱ卷,406页及以后(1963年)所介绍的方法。
式(Ⅲ)的化合物在反应中可以使用其异构体,异构体混合物,外消旋体或光学对映体等形式。式(Ⅲ)的C(4)-C(5)-顺式构型的化合物都是最可取的。
根据所用有机金属试剂的性质,在碳原子7上是R-构型的具有通式(Ⅱa)的化合物可以首先形成,再通过氧化作用差向异构体,成为具有通式(Ⅴ)的化合物,(Ⅴ)经还原后得到7-S-构型的具有通式(Ⅱb)的化合物:
其中R1,R2和R3规定如上;
其中R1,R2和R3规定如上;
其中R1,R2和R3规定如上。
完成(Ⅱa)到(Ⅴ)的氧化是与用二甲基亚砜作为氧化剂的已知方法相似的方法,外加酐类,特别是三氟醋酐,在适当的有机溶剂中,特别是卤化烃(例如二氯甲烷或氯仿),或烃类(例如苯,甲苯,二甲苯或己烷),或醚类中(例如乙醚,二噁烷或四氢呋喃)或在上述溶剂混合物中,例如由S.L.Huans,K.Omura和D.Swern在Synthesis1980,297页中所介绍的。
使用通常的还原剂可使(Ⅴ)还原为(Ⅱb)。金属氢化物和复合金属氢化物对此都是特别适合的,如硼烷基锂〔Lithium boranate),硼氢化锂,硼氢化钠,硼烷,铝氢化钠,铝氢化锂或氢化锡对此都是特别适合的。硼氢化锂类,如三乙基硼氢化锂或三(1-甲基-丙基)硼氢化锂,或硼氢化钠都是特别优选的。
适宜的溶剂是在用氢化物还原时所使用的通常的惰性有机溶剂。最好的是醚类,例如乙醚和四氢呋喃。还原反应是用与已知方法相似的方法完成的(W.Friedrichsen in Houben-Weyl′s“Methoden der organischen Chemie(“Methods of Organic Chemistry)卷Ⅷ/1b,第145页及以后;H.C.Brown,S.Krish-namurthy,Chem.Commun.1972,868页;和A.Hajos in Houbez-Weyl′s“Methoden der organischen Chemie(“Methods of Organic Chemistry)卷Ⅳ/Id,第267页及以后.〕。
化合物(Ⅱa)还可用与其它已知方法相似的方法进行差向异构化,例如,由O.Mitsuuobu在Synthesis1981,第1页和后面所介绍的方法。
例如,若使用(±)-4(R),(5R)-5-甲酰基-1-甲基-4-苯基四氢吡咯-2-酮作为起始物质,则反应可以用下式表示:
假若使用易起反应的格氏化合物(在Ⅳ中X代表MgCl或MgBr)作为有机金属试剂,则形成的化合物Ⅱa全部具有7-R-构型,这些化合物在上述条件下能被差向异构化。无论是7-R-,还是7-S-构型的化合物以及它们的异构体,异构体混合物,外消旋体或光学对映体都能按照本发明的方法被羟基化得到化合物Ⅰ。
式Ⅳ的有机金属化合物是已知的,或者可按已知方法制备〔K.Nutzel,在Houben-Weyl的“Methoden der Organischen Chemit”(“Methods of Organic Chemistry”)卷ⅩⅢ/2a中第47页及以后〕
通式(Ⅲ)的醛是新的,可按以下方程式制备:
(R1和R3如上所述,R4和R5可相同或不同,代表C1-C4-烷基)。
按照本方程式,式(Ⅳ)化合物在步骤a中与式(Ⅶ)化合物起反应,
若合适,在碱存在下,例如钠、氢化钠、氨基钠、丁基锂或二异丙氨基锂,在适当的溶剂中进行反应,例如乙醚,四氢呋喃、二甲基甲酰胺或六甲基磷酰胺,温度为-20℃到+80℃,最好从0℃到+40℃。二甲基甲酰胺是特别合适的溶剂。已证明此处使用氢化钠作为碱是有好处的。用通常专家所熟悉的方法完成反应并制出产品。
R1-y (Ⅶ)
其中R1如上所述
Y代表卤素,最好为溴或碘,重氮基或下式的基:
在步骤b中,通式Ⅷ的化合物(由Ⅵ制得)用类似于P.Pachaly在Chem,Ber.卷104(2),412-39页(1971)中所描述的方法进行水解和脱羧,由此所形成的(C(4)-C(5)-顺式或反式)异构体混合物(Ⅸ),如果合适,用通常已知的层析方法或用重结晶方法进行分离。随后的反应用异构体混合物或者用单独的顺式或反式异构体来完成。更可取的是先分离混合物Ⅸ,然后用单独的异构体来完成反应,最好用C(4)-C(5)-顺式-构型的异构体。
式Ⅸ化合物到式Ⅹ化合物的还原反应(步骤C)是用与已经叙述的化合物(Ⅴ)到化合物(Ⅱb)的还原反应同样的方法和同样的条件下实现的。
式Ⅹ化合物到式Ⅲ化合物的氧化反应(步骤d)是用与已经叙述的式(Ⅱa)化合物到式(Ⅴ)化合物的氧化反应同样的方法和同样的条件下实现的。
式Ⅵ的起始化合物可从文献中知道,或用文献中已知的方法制备〔C.H.Cocolas,W.H.Hartung,J.Am.Chem.Soc,79卷,5203页(1957);和F.Zymalkowski,P.Pachaly,Chem.Ber.100卷,1137页(1967)〕。
下式是想用来说明通过所有可能的中间体化合物(Ⅱ)-(Ⅹ),最终合成化合物(Ⅰ)的全过程:
例1.(±)5,5-二乙氧基羧基-4-苯基吡咯烷-2-酮
在室温和氮气下将400毫升无水乙醇中有18克钠(0.8克原子)的溶液滴加到432克(2摩尔)乙酰胺基丙二酸二乙酯在1.6升绝对乙醇中的悬浮液中。缓慢加入564克肉桂酸乙酯(3.2摩尔),然后将混合物加热回流24小时。
为了进行加工,让混合物降至室温,加入2.5升氯仿,用醋酸将混合物中和。用水彻底洗涤混合物(洗五次,每次用水500毫升),用硫酸镁干燥,在旋转蒸发器上浓缩。将油状残余物溶解于少量丙酮中,加入己烷直至出现结晶,然后再加入一些己烷直到在滴加处观察不到更多的混浊出现。抽滤得到398克(54%)标题化合物,熔点97-99℃。母液层析(甲苯/醋酸乙酯)又可得到85克(14%)标题化合物,总产率413克(68%)。
红外光谱(KBr):ν=1770(酯),1700(酰胺)核磁共振1H-NMR(300MHz,CDCl3):δ=0.84和1.28(在每个三重峰(t)时,J=7.5Hz;6H,CH2CH3);ABX信号:δA=2.63,δB=2.96(JAB=17.3Hz,JAX=6Hz,JBX=9Hz;2H,C(3)-H);3.66和3.71(在所有多重峰(m),2H,顺-CH2CH3);4.28(重多峰(m),2H,反-CH2CH3);4.39(双重峰(dd),JAX=6Hz,JBX=9Hz,1H,C(4)-H);6.95(宽峰(br),1H,NH);和7.39(宽峰(br),5H,C6H5)。例2:(±)5,5-二乙氧基羰基-1-甲基-4-苯基-吡咯烷-2-酮
在室温和氮气下将500毫升无水二甲基甲酰胺中有100克(0.33摩尔)5,5-二乙氧基羰基-4-苯基吡咯烷-2-酮的溶液滴加到9.64克(0.36摩尔)氢化钠在200毫升无水二甲基甲酰胺的悬浮液中。随后将混合物在室温下搅拌直到不再有气体放出,然后加入50毫升无水二甲基甲酰胺中有93.7克(0.66摩尔)碘甲烷的溶液,然后在室温下搅拌直到所有的原料都已起反应(约1小时,用薄层层析查)。将反应混合物倒入2升缓冲溶液(pH=7)中,用乙醚抽提五次,每次用量600毫升。
将有机提取液进行干燥(用MgSO4),在真空下除去溶剂,得到105克(99.6%)标题化合物(根据1H-NMR谱,纯度95%),该化合物直接用于下一步反应。将样品在球形管中蒸馏(沸点0.5∶240℃)以备分析用,
Rf:0.36(甲苯/乙酸乙酯:2/1),IR(膜):γ=1735(酯),1700(酰胺)
1H-NMR(500MHz,CDCl3):δ=0.9和1.33(在每一种t,J=7.5Hz;6H,CH2CH3);ABX信号:δA=2.66,δB=3.0(JAB=18Hz,JAX=6Hz,JBX=8.3Hz;2H,C(3)-H);3.06(S;3H,N-CH);3.62和3.79(在每一种m,2H,顺-CH2-CH3);4.31(m,3H,反-CH2-CH3);和C(4)-H);和7.26(m,5H,C6H5)。例3:(±)-4(R*),5(R*)-〔Ⅰ).和4(R*),5(S*)-5-乙氧基羰基-1-甲基-4-苯基吡咯烷-2-酮〔Ⅱ)。
将49.5克(0.156摩尔)氢氧化钡八水合物放入483毫升蒸馏水中,在70℃加热直到溶液接近清亮。加入724毫升乙醇中有100克(0.313摩尔)(±)5,5-二乙氧基羰基-1-甲基-4-苯基-吡咯烷-2-酮的溶液
(澄清液),随后将混合物在70℃下搅拌20分钟直到原料完全起反应(约20分钟,用薄层层析检查)。将混合物冷却并酸化至pH=1-2,同时用冰冷却,在真空中除去乙醇(浴温30-40℃)。将固体物抽滤出来,水相中加入氯化钠,用醋酸乙酯抽提三次,每次用200毫升。干燥并除去溶剂后得到的残渣与上面所得到的固体物合并,将混合物放在保干器中在高真空下用P4O10干燥24小时。然后将固体物放在油浴上加热到170℃,同时进行充分搅拌,直到不再有气体放出(5-10分钟)。冷却并进行快速色谱分离(环己烷/醋酸乙酯=1/1,最后用醋酸乙酯)得到39.3克(50.7%)顺式产物Ⅰ,其Rf=0.10,和19.6克(25.3%)反式产物Ⅱ,其Rf=0.20(每种情况都是在环己烷/乙酸乙酯1/1中)。IR(KBr):γ=1736,1690cm-1。
1H-NMR(200MHz,CDCl3)〔1〕:δ=0.83(t,J=7.5Hz;3H,CH2CH3);ABX信号:δA=2.67,δB=29.5(JAB=17.5Hz,JAX=9Hz,JBX=10Hz;2H,C(3)-H),2.87(S,3H,N-CH3),3.75(m,2H,CH2CH3);3.91(q,J=9-10Hz,1H,C(4)-H),4.36(d,J=9Hz,1H,C(5)-H),7.28(m,5H,C6H5)。〔Ⅱ〕:δ=1.30,(t,J=7.5Hz,3H,CH2CH3);ABX信号:δA=2.54,δB=2.82(JAB=18.5Hz,JAX=5Hz,JBX=9Hz;2H,C(3)-H);3.80(S,3H,N-CH3),3.53(ddd,j=9Hz,j=5Hz,j=4Hz,1HC(4)-H)4.07(d.j=4Hz,1H,C(5)-H),4.27(m,2H,CH2-CH3)7.3(m,5H,C6H5)。
例4(±)4(R*),5(R*)-5-羟甲基-1-甲基-4-苯基吡咯烷-2-酮。
将0.317摩尔LiB(Et)3H(做成在316.9ml四氢呋喃中的1摩尔溶液)在氮气和-15到-20℃条件下滴加到含39.2克(0.159摩尔)(±)4(R*),5(R*)-5-乙氧基羰基-1-甲基-4-苯基吡咯烷-2-酮的390毫升无水四氢呋喃的溶液中。
然后将反应混合物在0℃搅拌1小时,再倒到约200毫升冰冷的2N盐酸中,用乙酸乙酯抽提两次,每次用200毫升。水相用氯化钠饱和并再用乙酸乙酯抽提两次,每次200毫升。用少量水洗涤收集的有机提取液,以MgSO4干燥并在旋转蒸发器上浓缩。残渣用少量乙醚使呈结晶,再用戊烷沉淀产物直到在滴加处不再观察到混浊。抽滤后进行干燥,得到29.1克(89.2%)标题化合物,熔点93-95℃。
IR(KBr):ν=3324,1687cm-1
1H-NMR(3000MH2,CDCL3):δ=ABM系统的AB-部分,δA=2.59,δB=2.97(在每一种情况中,dd,j=15Hz,JAM=7.5Hz,jBM=9Hz,2H,C(3)-H);2.97(S,3H,N-CH3)ABM系统的AB部分,δA=3.36,δB=3.62(在每一种情况中,dd,jAB=11.2Hz,jAM=jBM=3Hz,2H,C(7)-H);3.72-3.85(m,2H,C(4)-H,C(5)-H);7.32(m,5H,C6H5)。
例5:(±)4(R*),5(R*)-5-甲酰基-1-甲基-4-苯基吡咯烷-2-酮
将56毫升无水二氯乙烷中有29.7毫升三氟醋酐的溶液在N2气氛和-60℃下,用10分钟时间滴加到140毫升无水二氯甲烷有19.9毫升(0.28摩尔)无水二甲基亚砜的溶液中。混合物在此温度下搅拌15分钟,再滴加250毫升二氯甲烷中有28.8克(0.140摩尔)(±)4(R*),5(R*)-5-羟基-甲基-1-甲基-4-苯基吡咯烷-2-酮的溶液,并使温度不超过-60℃。随后将混合物在-60℃搅拌90分钟,短时间温热到-30℃(5-10分钟)后再冷却到-60℃。在此温度下缓慢加入56毫升绝对三乙胺并将混合物在-60℃下搅拌30分钟,然后再温热到室温。加入600毫升水,分层后将水相用二氯甲烷抽提三次,每次用250毫升。收集的有机提取液用水洗涤两次,每次用300毫升,以硫酸镁干燥并浓缩。得到28.3克(100%)标题化合物,Rf=0.25(乙酸乙酯)(91%纯,根据1H-NMR谱分析)。干燥以后(24小时,高真空),如此得到的粗产物可直接进一步反应。
IR(CHCl3):ν=1734,1689cm-1
1H-NMR(300MHz,CDCl3):δ2.79(dd,j=5.3Hz,J=9.7Hz,2H,C(3)-H);2.91(S,3H,N-CH3);4.02(q,j=9.7Hz,1H,C(4)-H);4.30(dd,j=1Hz,J=9.7Hz,1H,C(5)-H;)7.3(m,5H,C6H5),9.17(d,j=1Hz,1H,CHO)。
例6:(±)4(R*),5(R*)7(R*)-5-α-羟苄基-1-甲基-4-苯基-吡咯烷-2-酮
将44毫升无水四氢呋喃中有24.8克(16.7ml,0.156摩尔)溴苯的溶液在N2气下滴加到3.84克镁屑中,于是四氢呋喃慢慢沸腾。然后再加入100毫升纯四氢呋喃,将混合物在沸点温度下回流加热直至所有的镁都被溶解(1-2小时)。
混合物冷却到0℃,在强力搅拌下滴加250毫升无水四氢呋喃中有24.7克(0.12摩尔)(±)4(R),5(R)-5-甲酰基-1-甲基-4-苯基吡咯烷-2-酮的溶液,并使温度不超过5℃。如果需要,为了更好搅拌需再加入些无水四氢呋喃。然后将反应混合物在0-5℃下再搅拌1小时,倒在350毫升0.5NHCl-水上,用乙酸乙酯抽提4次,每次用300毫升,再用二氯甲烷抽提两次,每次300毫升。将所收集的醋酸乙酯和二氯乙烷提取液用水洗涤(分开洗!)两次,每次200毫升,合并并以硫酸镁干燥。除去溶剂(在真空中)后所留下的残渣用100毫升乙醚研制直到出现结晶。然后缓慢加入500毫升戊烷,让混合物在冰箱中静置过夜。抽滤出固体物得到25克(74.3%)标题化合物,熔点:210-212℃。
为了分析,将产品以丙酮重结晶(熔点:214-5℃)。
IR(KBr)ν=3362(br),1654cm-1。
1H-NMR(300MHz,d6-DMSO):δ=2.21(S,3H,NCH3);2.24(dd,ABM系统的A部分,JAB=15.7Hz,JAM=9.4Hz,1H,顺-C(3)-H;3.05(dd,ABM系统的B部分,JBM=12.7Hz,1H,反-C(3)-H;3.80(dt,ABM系统的M-部分,JAM=8.5Hz,JAB=12.7Hz,J4.5=8.5Hz,1H,C(4)-H);4.15(dd,J=8.5Hz,J=1Hz,1H,C(5)-H);4.26(dd,J=6Hz,J=1Hz,1H,C(7)-H);5.35(d,J=6Hz,1H,OH);7.15-7.5(m,10H,C6H5)。
例7:(±)4(R*),5(R*)-5-苯甲酰基-1-甲基-4-苯基吡咯烷-2-酮
在-60℃和氮气流下将34毫升无水二氯甲烷中有18毫升三氟醋酐的溶液用10分钟的时间滴加到87毫升无水二氯甲烷中有12.24毫升(0.171摩尔)无水二甲基亚砜的溶液中。随后将此混合物在此温度下搅拌15分钟,再滴加约700毫升无水二氯甲烷中有24克(0.085摩尔)的(±)4(R*),5(R*),7(R*)-5-α-羟苄基-1-甲基-4-苯基吡咯烷-2-酮的溶液,使温度不超过-60℃。随后将混合物在-60℃搅拌90分钟,短时间温热到-30℃(9-10分钟)后再冷却到-60℃。在此温度下缓慢加入34.2毫升三乙胺,再将混合物在-60℃搅拌20分钟,再温热到室温。加入370毫升水,待分层后用二氯甲烷把水相抽提三次,每次用250毫升。合并的有机提取液用水洗两次,每次300毫升,以硫酸镁干燥,再在旋转蒸发器上浓缩。在旋转蒸发器内的残渣用乙醚蒸发两次,每次用200毫升。得到呈固态的23.5克(100%)标题化合物,熔点:115-116℃。根据1H-NMR谱分析此产物是纯的可直接进一步反应。
为了分析,将样品在硅胶上用醋酸乙酯进行层析(Rf=0.25),熔点:121-2℃。
TR(KBr):ν=1695,1682cm-1
1H-NMR(300MHz,CDCl3)δ=2.78和2.91(ABM光谱的AB部分,JAB=16.5Hz,JAM=JBM8.3Hz,2H,C(3)-H);2.88(S,3H,N-CH3);4.02(q,J=8.3Hz,1H,C(4)-H);5.42(d,J=8.3Hz,1H,C(5)-H);7.0,7.21,7.59和7.50(在每一种情况中,m,10H,C6H5)。
例8:(±)4(R*),5(R*),7(S*)-5-α-羟苄基-1-甲基-4-苯基吡咯烷-2-酮
将83毫摩尔的LiB(Et)3H(83毫升的1摩尔四氢呋喃溶液)在-15℃到-20℃和在氮气流下滴加到含23克(82.3毫摩尔)(±)4(R),5(R)-5-苯甲酰-1-甲基-4-苯基吡咯烷-2-酮中的200到270毫升的无水四氢呋喃溶液。随后将反应混合物在0℃下搅拌1小时,再倒入100毫升冰冷的1NHCl中,再用醋酸乙酯抽提两次,每次用200毫升。水相用氯化钠饱和,用乙酸乙酯再抽提两次,每次200毫升。合并后的有机抽提液用MgSO4干燥,在旋转蒸发器上浓缩。将残渣溶解
在二氯甲烷中,用水洗两次,每次100毫升。有机相以MgSO4干燥,在旋转蒸发器上浓缩。残渣用100毫升乙醚处理使成结晶,然后在搅拌下缓慢加入戊烷直到在滴加处不再观察到混浊。用抽滤过滤出沉淀并进行干燥。得到16.6克(72%)的标题化合物,熔点:189-195℃。
根据1H-NMR分析,产物有95%纯,可直接进一步反应。
为了分析,将产物从丙酮中重结晶(熔点:197-8℃)。IR(KBr):ν=3251,1692cm-1
1H-NMR(300MHz,DMSO):δ=1.97和2.05(ABM信号,JAB=13.5Hz,JAM=8.2Hz,JAM=13.Hz,2H,C(3)-H);2.91(S,3H,N-CH3);3.82(dt,JAM=J4.5=8.2Hz,JBM=13Hz,1H,C(4)-H);4.27(dd,J=8.2Hz,J=1.5Hz,1H,C(5)-H);4.65(dd,J=1.5Hz,J=3.5Hz,1H,C(7)-H);5.34(d,J=3.5Hz,1H,OH);6.70,7.11和7.25(在每种情况中,m,10H,C6H5)。
例9:
(±)3(S*),4(R*),5(R*),7(S)-3-羟基-5-α-羟苄基-1-甲基-4-苯基吡咯烷-2-酮(黄皮胺)
将烧瓶事先放在真空中彻底加热并用纯氮气流冲洗,然后向烧瓶中注入490毫升无水四氢呋喃中有17.7克(62.8毫摩尔)的(±)4(R*),5(R*),7(S*)-5-α-羟苄基-1-甲基-4-苯基吡咯烷-2-酮的溶液及130毫升无水六甲基磷酰胺,使溶液冷却到-70℃。在此温度下滴加180毫升无水四氢呋喃/己烷中有0.152摩尔二异丙胺基/锂的溶液(在-20℃到0℃下,由22.1毫升二异丙胺在80毫升四氢呋喃中的溶液,再加入103毫升1.5Nn-丁基-锂在己烷中的溶液来制备)。
随后将混合物保持在-70℃至-60℃的条件下搅拌1小时,加入5.3毫升新蒸馏的三甲基亚磷酸酯(溶于少量无水四氢呋喃中),以50-100毫升/分钟的速率通过干燥氧(经H2SO4和P4O10干燥)。根据薄层层析检查(SiO2;醋酸乙酯/甲醇:2/1;Rf=0.3(标题化合物),Rf=0.37(起始化合物)用磷钼酸喷雾剂显色),一旦产物/起始物之比值不再改变时(2-3小时),立即将混合物倒入600毫升0.5NHCl中,同时用冰冷却,如果合适,酸化到pH3到4。
分开两相,水相用酸醋乙酯抽提四次,每次300毫升。将合并的有机提取液用水洗三次,每次300毫升,MgSO4干燥并在旋转蒸发器上浓缩。将残渣收在50-100毫升乙醚中,搅拌混合物直到开始结晶,边搅拌边慢慢加入戊烷,直到在滴加处不再观察到混浊。让混合物在冰箱中放置过夜,吸滤。得到约17克粗固体物,除标题化合物以外,内含约35-40%的起始物质。为了纯制,将产物在甲醇中重结晶两次。这样得到的标题化合物纯度约为95%。在氧化铝(中性)上进行层析毫无丢失并全部回收纯的起始物。为此,将粗产品吸收到硅胶上(在加热下使溶于甲醇,加入五倍重量的硅胶,在旋转蒸发仪上浓缩,再用酸醋乙酯在旋转蒸发仪上蒸发数次直到无甲醇的产物干成粉末状)。将吸收物放入装有Al2O3(中性,50倍重量)的柱内,先用酸醋乙酯洗脱起始物质(快速层析,用薄层层析和分析性高效液谱检查)。然后用酸醋乙酯/甲醇混合物洗脱标题化合物(40/1,20/1,再用10/1)。得到8.6克(46.1%)标题化合物,熔点:236-7.5℃(真正的黄皮胺:236-7℃),纯度约98%(根据1H-NMR,含有约2%的起始物质)。有可能回收5克纯的起始物。
IR(KBr):ν=3402,3321,1689cm-1
1H-NMR(300MHz,DMSO):δ=3.01(S,3H,N-CH3);3.50(dd,J=8Hz,J=10.5Hz,1H,c(4)-H);3.82(dd,J=10Hz,J=7Hz,1H,C(3)-H);4.30(dd,J=8Hz,J=2Hz,1H,C(5)-H);4.65(dd,J=2Hz,J=3Hz,1H,C(7)-H);5.39(d,J=7Hz,1H,C(3)-OH);5.45(d,J=3Hz,1H,C(7)-OH);6.61-6.64(m,2H,芳香H)和7.03-7.28(m,8H,芳香H)。
例10:
(±)3(S*),4(R*),5(R*),7(R)-3-羟基-5-α-羟苄基-1-甲基-4-苯基吡咯烷-2-酮(7-表-黄皮胺)。
当用乙醚/戊烷沉淀以后,由2克(0.71摩尔)4(R),5(R),7(R)-5-α-羟苄基-1-甲基-4-苯基吡咯烷-2-酮,得到1.8克固体物,在硅胶上用环己烷/酸醋乙酯=1/2进行层析(“快速”层析)。得到0.94克(45%)纯的标题化合物,熔点:200-1℃。有可能回收
0.7克的起始物质。
IR(KBr):ν=3435,3363,1660cm-1。
1H-NMR(300MHz,DMSO)δ=2.18(S,3H,N-CH3),3.54(dd,J=8Hz,J=10Hz,1H,C(4)-H),4.12(d,J=8Hz,1H,1H,C(5)-H),4.25(d,J=6Hz,1H,C(7)-H),4.93(dd,J=10Hz,J=7.5Hz,1H,C(3)-H),5.43(d,J=6Hz,1H,C(3)-OH),5.47(d,J=7.5Hz,1H,C(7)-OH)和7.18-7.55(m,10H,芳香H)。
例11:
(±)4(R*),5(R*),7(R*)-5-(1-羟基-1-对-氯苯基)甲基-1-甲基-4-苯基吡咯烷-2-酮
操作方法相似于例6,所不同的是格氏试剂是在超声浴中制备的。使用了15.12克(0.079毫摩尔)的4-氯溴苯和12.19克(0.06摩尔)例5的标题化合物。按照相似于例6的操作处理以后,将残渣收入少量热的乙酸乙酯中,使慢慢冷却同时用玻璃棒研磨(最后保存在冰浴中)。让反应产物静置12小时,然后抽气过滤出来。得到11.53克(理论量的60.9%)标题化合物,熔点:201℃(乙醚/戊烷)。
1H-NMR(200MHz,CDCl3):δ=2.44(S,3H,NCH3);2.40(dd,ABM系统的A-部分,JAB=15Hz,JAM=9.5Hz,1H,顺式-C(3)-H;3.15(dd,ABM系统的B-部分,JBM=12.5Hz,1H,反式-C(3)-H);3.78(dt,ABM系统的M部分,JAM=9.5Hz,JBM=12.5Hz,J4.5=7.5Hz,1H,C(4)-H);3.83(d,J=6Hz,1H,OH);3.97(dd,J=7.5Hz,J=1Hz,1H,C(5)-H);4.39(dd,J=6Hz,J=1Hz,1H,C(7)-H);7.12-7.38(m,9H,芳香H)。
例12:
(±)4(R*),5(R*),7(R*),-5-(1-羟基-1-间-氟苯基)-甲基-1-甲基-4-苯基吡咯烷-2-酮
操作方法相似于例11。使用了13.83克(0.079摩尔)3-氟代溴苯和12.19克(0.06摩尔)例5的标题化合物。得到11.73克(理论值的70.9%)的标题化合物,熔点:213℃(乙醚/戊烷)。
1H-NMR(200MHz,CDCL3/DMSO):δ=2.45(S,1H,N-CH3);2.40(dd,ABM系统的A-部分,JAB=15Hz,JAM=9.5Hz,1H,顺式-C(3)-H);3.20(dd,ABM系统的B部分,JBM=12.5Hz,1H,反式-C(3)-H);3.8(dt,ABM系统的M部分,JAM=9.5Hz,JBM=12.5Hz,J4.5=7.5Hz,1H,C(4)-H);4.03(dd,J=7.5Hz,J=1Hz,1H,C(5)-H);4.36(dd,J=6Hz,J=1Hz,1H,C(7)-H);5.03(d,J=6Hz,1H,OH);6.8-7.1和7.17-7.4(在每种情况中,m,9H,芳香H)。
例13:
(±)4(R*),5(R*),7(R*)-5-(1-羟基-1-间-氯苯基)甲基-1-甲基-4-苯基吡咯烷-2-酮
操作方法相似于例11。使用了15.12克(0.079摩尔)3-溴代氯苯和12.19克(0.06摩尔)例5的标题化合物。得到12.2克(理论量的64.4%)标题化合物,熔点:220℃。
1H-NMR(200MHz,CDCl3/DMSO):δ=2.43(S,3H,NCH3);2.38(dd,ABM系统的A-部分,JAB=15Hz,JAM=9.5Hz,1H,顺式-C(3)-H);3.18(dd,ABM系统的B-部分,JBM=12.5Hz,1H,反式-C(3)-H);3.81(dt,ABM系统的M部分,JAM=9.5Hz,JBM=12.5Hz,J=4.5=7.5Hz,1H,C(-4)-H);4.05(dd,J=7.5Hz,J=1Hz,1H,C(5)-H);4.32(dd,J=6Hz,J=1Hz,1H,C(7)-H);5.32(d,J=6Hz,1H,OH);7.12-7.45(m,1H,芳香H)。
例14
(±)4(R*),5(R*),7(R*)-5-(1-羟基-1-(2,6-二氯苯基)〕-甲基-1-甲基-4-苯基吡咯烷-2-酮
操作方法相似于例11。使用了17.85克(0.079摩尔)的2,6-二氯代溴苯和12.91克(0.06摩尔)例
5的标题化合物。得到4.7克(理论量的22.3%)标题化合物,熔点:156℃。
1H-NMR(200MHz,CDCL3)δ=2.53(dd,ABM系统的A-部分,JAB=17.5Hz,JAM=9.5Hz,1H,顺式-C(3)-H);2.92(S,3H,N-CH3);3.08(dd,ABM系统的B-部分,JBM=11Hz,1H,反式-C(3)-H);3.50(d,J=9Hz,1H,OH);3.08(dt,ABM系统的M-部分,J=4.5=7.5Hz,1H,C(4)-H);4.49(dd,J=7.5Hz,J=5Hz,1H,C(5)-H);5.16(dd,J=9Hz,J=5Hz,1H,C(7)-H);6.9-7.35(m,8H,芳香H)。
例15:
(±)4(R*),5(R*),7(R*)-5-(1-羟基-1-对-氟苯基)甲基-1-甲基-4-苯基吡咯烷-2-酮。
操作方法相似于11。使用了13.83克(0.079摩尔)4-氟代溴苯和12.19克(0.06摩尔)例5的标题化合物。得到10.19克(理论值的61.6%)标题化合物,熔点:211-213℃,Rf(醋酸乙酯)=0.45。
1H-NMR(300MHz,CDCl3):δ=2.47(S,3H,NCH3),2.49(dd,ABM系统的A-部分,JAB=15.7Hz,JAM=8.2Hz,1H,顺式-C(3)-H);2.55(宽峰,1H,OH);3.20(dd,ABM系统的B-部分,JBM=13Hz,1H,反式-C(3)-H);3.82(dt,ABM系统的M-部分,J=4.5=7.5Hz,1H,C(4)-H);4.01(dd,J=7.5Hz,J=1Hz,1H;C(5)-H);4.48(d,J=1Hz,1H,C(7)-H);6.95,7.15,7.28和7.35(在每种情况中m,9H,芳香H)。
例16:
(±)4(R*),5(R*),-5-(对-氯代苯甲酰基)-1-甲基-4-苯基吡咯烷-2-酮。
操作方法相似于例7。使用了7.9克(0.025摩尔)例11的标题化合物。得到5.72克(理论值的73.1%)标题化合物,可进一步加工而不需纯化。
1H-NMR(200MHz,CDCl3):δ=2.93(q,ABM信号的AB-部分,JAB=17.5Hz,JAM,JBM=9.5Hz,2H,C(3)-H);4.03(q,ABM信号的M-部分,JAM=JBM=J4.5=9.5Hz,1H,
C(4)-H);5.39(d,J=9.5Hz,1H,C(5)-H);7.04(S,5H,C6H5);AB信号(δA=7.2,δA=7.46,J=Ab=9.5Hz,4H,C6H4Cl)。
例17
(±)4(R*),5(R*),-5-间-氟代苯甲酰基)-1-甲基-4-苯基吡咯烷-2-酮
操作方法相似于例7。使用了7.48克(0.025摩尔)例12的标题化合物。得到6.36克(理论值的85.6%)标题化合物,可进一步加工而不需纯化。
1H-NMR(200MHz,CDCl3):δ=2.92(q,ABM信号的AB部分,JAB=17.5Hz,JAM=JBM=9.5Hz,2H,(C(3)-H);4.01(q,ABM信号的M-部分,JAM=JAM=J4.5=9.5Hz,1H,C(4)-H);5.39(d,J=9.5Hz,1H,C(4)-H);7.03(S,5H,C6H5);7.5-7.35(m,4H,C6H4F)。
例18
(±)4(R*),5(R*),-5-对-氟代苯甲酰基-1-甲基-4-苯基吡咯烷-2-酮。
操作方法相似于例7。使用了7.28克(0.016摩尔)例15的标题化合物。得到5.78克(理论值的80%)标题化合物,可进一步加工而不需纯化。
1H-NMR(200MHz,CDCl3):δ=ABM信号(δA=2.72,δB=2.89,JAB=16Hz,JAM=9.5Hz,2H,(C(3)-H);2.88(S,3H,NCH3);3.98(q,ABM信号的-部分,JBM=J4.5=9.5Hz,1H,C(4)-H);5.34(d,J=9.5Hz,1H,C(5)-H);6.87和7.5(在每种情况中,m,4H,C6H4F);7.0(S,5H,C6H5)。
例19
(±)4(R*),5(R*),7(S*)-5-(1-羟基-1-间-氟代苯基)甲基-1-甲基-4-苯基吡咯烷-2-酮。
将例17标题化合物5.95克(0.02摩尔)溶于98毫升无水甲醇中,使与0.77克(0.02摩尔)硼氢化钠混合并加热到60℃直到在TJC上不再呈现起始物(2-3小时)。把产物倒入200毫升磷酸盐缓冲液(pH=4)中,将反应产物抽滤出来并用水充分淋洗。在高真空中干燥以后,得到4.92克(理论值的82.2%)标题化合物。可直接用于进一步反应。
1H-NMR(200MHz,CDCl3/DMSO):δ=2.18和2.38(ABM信号,JAB=16Hz,JAM=9Hz,JBM=12.5Hz,2H,C(3)-H);3.04(S,3H,N-CH3);3.82(dt,ABM信号的M-部分,J4.5=9Hz,1H,C(4)-H);4.24(dd,J=9Hz,J=2Hz,1H,C(5)-H);4.77(dd,J=2Hz,J=4Hz,1H,C(7)-H);5.19(d,J=4Hz,1H,OH);6.37(d,J=10Hz,1H,由C6H4F中);6.55(d,J=7.5Hz,1H,由C6H4F中);6.75,7.07,和7.18(在每种情况中,m,C6H5和C6H4F)。
例20:
(±)4(R*),5(R*),7(S*)-5-(1-羟基-1-间-氟代苯基)甲基-1-甲基-4-苯基吡咯烷-2-酮。
操作方法相似于例19。用5.17克(0.0164摩尔)(±)4(R*),5(R*),-5-(3-氯)苯甲酰基-1-甲基-4-苯基吡咯烷-2-酮(制备方法同例7)。得到4.79克(理论值的92.4%)标题化合物。
1H-NMR(200MHz,CDCl3/DMSO):δ=2.15和2.45(ABM信号的A和B部分,JAB=16Hz,JAM=9Hz,JBM=12.5Hz,2H,C(3)-H);3.04(S,3H,N-CH3);3.81(dt,J4.5=8Hz,1H,C(4)-H);4.26(dd,J=8Hz,J=2.5Hz,1H,C(5)-H);4.75(dd,J=2.5Hz,J=4.5Hz,1H,C(7)-H);6.56(S,1H,C(2)-C6H4Cl),6.70,7.5和7.15(在各种情况下,m,8H,C6H5和C6H4Cl)。
例21
(±)4(R*),5(R*),7(S*)-5-(1-羟基-1-对-氟代苯基甲基-1-甲基-4-苯基吡咯烷-2-酮。
操作方法相似于例19。用5.45克(0.02摩尔)例16的标题化合物。得到5.47克(理论值的99%)本标题化合物。
1H-NMR(200MHz,CDCl3/DMSO):δ=2.15(d,J=10Hz,2H,C(3)-H);3.06(S,3H,N-CH3);3.82(q,宽峰,J=10Hz,1H,C(4)-H;4.26(dd,J=8Hz,J=2.5Hz,1H,C(5)-H);4.72(dd,J=2.5Hz,J=4.5Hz,1H,C(7)-H);5.25(d,J=4.5Hz,1H,OH);6.64(d,J=9Hz,2H,C6H4Cl的AB信号);7.04(d,J=9Hz,2H,C6H4Cl的AB信号);7.06和7.20(每种情况中,m,H5,C6H5)。
例22:
(±)3(S*),4(R*),5(S*),7(S*)-3-1-羟基-5-(1-羟基-1-间-氟代苯基)甲基-1-甲基-4-苯基吡咯烷-2-酮。
操作方法相似于例9。用2克(0.0067摩尔)例19的标题化合物。层析后(见例19)得到0.61克(理论值的31%)纯的标题化合物。熔点:254-7℃。
保留时间:6.07分钟(HPLC,Hibar预装柱250-4,Lichrosorb si60(5微米),洗脱剂∶醋酸乙酯/甲醇=20/1;1毫升/分)。有可能回收0.7克(35%)
1H-NMR(200MHz,CDCl3/DMSO):δ=3.16(S,3H,N-CH3);3.64(dd,J=10.5Hz,J=7.5Hz,1H,C(4)-H);4.13(dd,J=5.5Hz,J=10.5Hz,1H,C(3)-H);4.26(dd,J=7.5Hz,J=1Hz,1H,C(5)-H);4.83(dd,J=1Hz,J=4Hz,1H,C(7)-H);5.23(d,J=5.5Hz,1H,C(3)-OH,可与D2O交换);5.38(d,J=4Hz,1H,C(7)-OH,可与D2O交换);6.40(d,J=10Hz,1H,从C6H4F中);6.58(d,J=7.5Hz,1H,从C6H4F中);6.80和7.13(每种情况下,m,7H,C6H5和从C6H4F中)。
例23:
(±)3(S*),4(R*),5(S*),7(S)-3-羟基-5-〔1-羟基-1-对-氯苯基)甲基〕-1-甲基-4-苯基吡咯烷-2-酮
操作方法相似于例9。用2.0克(0.0063摩尔)例21的标题化合物。得到0.71克(理论值的31%)纯的本标题化合物。保留时间为6.34分钟(条件见例22)熔
点254-7℃。可以回收0.3克未起反应的原料。
1H-NMR(300MHz,CDCl3/DMSO):δ=3.11(S,3H,N-CH3);3.58(dd,J=7.5Hz,J=10.5Hz,1H,C(4)-H);3.90(dd,J=10.5Hz,J=5.5Hz,1H,C(3)-H);4.20(dd,J=7.5Hz,J=2Hz,1H,C(5)-H);4.50(dd,J=5.5Hz,1H,C(3)-OH,可与D2O交换);4.70(t,J=2Hz,1H,C(7)-H);4.80(d,J=2Hz,1H,C(7)-OH,可与D2O交换);6.58和6.98(AB信号,J=8.3Hz,4H,C6H4Cl);7.13(m,5H,C6H5)。
Claims (8)
2、按权利要求1的方法,其中使用氧气作为氧化剂。
3、按权利要求1的方法,其中使用亚磷酸酯作为助剂。
4、按权利要求1的方法,其中是在三甲基亚磷酸酯存在下,在四氢呋喃或六甲基磷酰胺或这些溶剂的混合物中用氧气进行氧化反应。
5、按权利要求1的方法,其中式(Ⅱ)的原料化合物(其不同异构体,异构体混合物,外消旋体或光学对映体形式)是通过式(Ⅲ)的醛与式(Ⅳ)所示的化合物反应而制备的,反应在惰性溶剂中进行,所得产物在7位碳原子处是差向异构化的,
(Ⅲ)
其中R1和R3定义如权利要求1所述,
其中R2定义如权利要求1所述,X代表MgBr或MgCl;或
将式(Ⅲ)化合物与式(Ⅳ)化合物反应,首先生成7-R-构型的式(Ⅱa)化合物,随后如果需要,再进一步差向异构化,即通过氧化作用,形成式(Ⅴ)中间体化合物:
(Ⅱa)
其中R1、R2和R3定义同上,
其中R1,R2和R3定义同上,再将式(Ⅴ)化合物还原,得到7-s-构型的式(Ⅱb)化合物:
式中R1、R2、R3同上所述。
8、按权利要求7的方法,其中式(Ⅸ)化合物是通过下述步骤制备的:
a)令式(Ⅺ)化合物与式(Ⅻ)化合物反应,得到式(Ⅷ)化合物,
其中R1,R3定义同权利要求7,R4和R5可相同或不同,表示C1-4烷基,Y代表卤素;
b)将式(ⅥⅡ)化合物水解脱羧。
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Application Number | Priority Date | Filing Date | Title |
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DE3537074 | 1985-10-18 | ||
DEP3537074.2 | 1985-10-18 | ||
DEP3632589.9 | 1986-09-25 | ||
DE19863632589 DE3632589A1 (de) | 1985-10-18 | 1986-09-25 | Verfahren zur herstellung von (gamma)-butyrolactamen |
Publications (2)
Publication Number | Publication Date |
---|---|
CN86106592A CN86106592A (zh) | 1987-06-03 |
CN1019486B true CN1019486B (zh) | 1992-12-16 |
Family
ID=25837071
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86106592A Expired CN1019486B (zh) | 1985-10-18 | 1986-10-18 | r-丁内酰胺的制备方法 |
Country Status (11)
Country | Link |
---|---|
US (2) | US4731455A (zh) |
EP (1) | EP0222163B1 (zh) |
JP (2) | JPH0794431B2 (zh) |
KR (1) | KR870003980A (zh) |
CN (1) | CN1019486B (zh) |
CA (1) | CA1279650C (zh) |
DE (2) | DE3632589A1 (zh) |
DK (1) | DK498286A (zh) |
ES (1) | ES2009757B3 (zh) |
HU (1) | HU198450B (zh) |
IL (1) | IL80305A (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3616989A1 (de) * | 1986-05-21 | 1987-11-26 | Bayer Ag | Enantiomerenreine 4,5-disubstituierte (gamma)-butyrolactame, verfahren zu ihrer herstellung und ihre verwendung |
DE3717394A1 (de) * | 1987-05-23 | 1988-12-01 | Basf Ag | 3-phenyl-2-styryl-pyrrolidine, ihre herstellung und verwendung |
DE3717395A1 (de) * | 1987-05-23 | 1988-12-08 | Basf Ag | 5-phenyl-1,2,3a,4,5,9b-hexahydro-3h-benz(e) indole, ihre herstellung und verwendung als arzneimittel |
EG18833A (en) * | 1988-12-09 | 1994-11-30 | Kumiai Chemical Industry Co | Cyclic amide compounds and herbicides |
DE3927370A1 (de) * | 1989-08-19 | 1991-02-21 | Bayer Ag | Verfahren zur herstellung von clausenamid und neoclausenamid und deren derivate |
WO2002026706A2 (en) * | 2000-09-29 | 2002-04-04 | Bayer Pharmaceuticals Corporation | 17-beta-hydroxysteroid dehydrogenase-ii inhibitors |
US6787564B2 (en) * | 2002-03-26 | 2004-09-07 | Institute Of Materia Medica, Chinese Academy Of Medical Sciences | Optically active clausenamides, process of the preparation thereof, pharmaceutical composition containing the same and their medical use |
JP6059510B2 (ja) * | 2012-11-05 | 2017-01-11 | 花王株式会社 | セラミド産生促進剤 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT374457B (de) * | 1977-08-18 | 1984-04-25 | Hoechst Ag | Verfahren zur herstellung von neuen benzolsulfonamidderivaten |
CH646149A5 (de) * | 1981-02-05 | 1984-11-15 | Hoffmann La Roche | Pyrrolidin-derivat. |
US4454327A (en) * | 1982-05-24 | 1984-06-12 | Warner-Lambert Company | 5-Oxo-2,2-pyrrolidinedipropanoic acid and ester derivatives thereof |
DE3346623A1 (de) * | 1983-12-14 | 1985-07-04 | Bayer Ag, 5090 Leverkusen | N-glycosylierte harnstoffe, carbamate und thiocarbamate, verfahren zu ihrer herstellung sowie ihre verwendung |
DE3508025A1 (de) * | 1985-03-07 | 1986-09-11 | Bayer Ag, 5090 Leverkusen | Substituierte o-sulfonyl-glycosylamide, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
JPS61245606A (ja) * | 1985-04-23 | 1986-10-31 | Alps Electric Co Ltd | マイクロ波発振器 |
-
1986
- 1986-09-25 DE DE19863632589 patent/DE3632589A1/de not_active Withdrawn
- 1986-10-01 US US06/914,210 patent/US4731455A/en not_active Expired - Lifetime
- 1986-10-08 DE DE8686113938T patent/DE3664464D1/de not_active Expired
- 1986-10-08 ES ES86113938T patent/ES2009757B3/es not_active Expired
- 1986-10-08 EP EP86113938A patent/EP0222163B1/de not_active Expired
- 1986-10-15 IL IL80305A patent/IL80305A/xx unknown
- 1986-10-16 CA CA000520592A patent/CA1279650C/en not_active Expired - Lifetime
- 1986-10-17 DK DK498286A patent/DK498286A/da not_active Application Discontinuation
- 1986-10-17 KR KR1019860008707A patent/KR870003980A/ko not_active Application Discontinuation
- 1986-10-17 JP JP61245607A patent/JPH0794431B2/ja not_active Expired - Lifetime
- 1986-10-17 HU HU864333A patent/HU198450B/hu not_active IP Right Cessation
- 1986-10-18 CN CN86106592A patent/CN1019486B/zh not_active Expired
-
1987
- 1987-08-27 US US07/089,897 patent/US4803285A/en not_active Expired - Lifetime
-
1995
- 1995-04-04 JP JP7103136A patent/JP2520582B2/ja not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
CA1279650C (en) | 1991-01-29 |
EP0222163A1 (de) | 1987-05-20 |
US4803285A (en) | 1989-02-07 |
JPH0794431B2 (ja) | 1995-10-11 |
JP2520582B2 (ja) | 1996-07-31 |
IL80305A (en) | 1990-04-29 |
HU198450B (en) | 1989-10-30 |
IL80305A0 (en) | 1987-01-30 |
EP0222163B1 (de) | 1989-07-19 |
JPS62187451A (ja) | 1987-08-15 |
HUT46661A (en) | 1988-11-28 |
DE3664464D1 (en) | 1989-08-24 |
DE3632589A1 (de) | 1987-04-23 |
KR870003980A (ko) | 1987-05-06 |
DK498286D0 (da) | 1986-10-17 |
US4731455A (en) | 1988-03-15 |
CN86106592A (zh) | 1987-06-03 |
DK498286A (da) | 1987-04-19 |
JPH0853413A (ja) | 1996-02-27 |
ES2009757B3 (es) | 1989-10-16 |
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