CN1162595A - 4-氧代咪唑啉盐的制备方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 18
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical class O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- -1 for example Substances 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract 2
- 229940123413 Angiotensin II antagonist Drugs 0.000 abstract 1
- 239000013543 active substance Substances 0.000 abstract 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 abstract 1
- 150000001450 anions Chemical class 0.000 abstract 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 229950001902 dimevamide Drugs 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000151 deposition Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- RMIGTEGRHJUHHM-UHFFFAOYSA-N propan-1-ol;hydrochloride Chemical compound Cl.CCCO RMIGTEGRHJUHHM-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- JCLSEQJEXYHVTC-UHFFFAOYSA-N 2-amino-2-methylbutanenitrile Chemical compound CCC(C)(N)C#N JCLSEQJEXYHVTC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000005219 aminonitrile group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical class [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 description 1
- 238000004834 15N NMR spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZXIXBPGNGUZOBB-UHFFFAOYSA-N 2-amino-2-phenylpropanenitrile Chemical compound N#CC(N)(C)C1=CC=CC=C1 ZXIXBPGNGUZOBB-UHFFFAOYSA-N 0.000 description 1
- NVAOLENBKNECGF-UHFFFAOYSA-N 2-phenylpropanenitrile Chemical compound N#CC(C)C1=CC=CC=C1 NVAOLENBKNECGF-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FGKYTJCFTGGDSL-UHFFFAOYSA-N C(CCC)C1=C(C(=O)O)C=CC(C1C(=O)O)(C)CC Chemical compound C(CCC)C1=C(C(=O)O)C=CC(C1C(=O)O)(C)CC FGKYTJCFTGGDSL-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 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
- LMSNZLCSZWZZGU-UHFFFAOYSA-N butan-1-ol;hydrochloride Chemical compound Cl.CCCCO LMSNZLCSZWZZGU-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- WXALHTONIYRUCO-UHFFFAOYSA-N peroxycyanic acid Chemical compound OOC#N WXALHTONIYRUCO-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/70—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及下式4-氧代咪唑啉盐的制备方法：其中R1和R2各自是C1-10烷基、C2-10链烯基、C3-7环烷基或任意取代的芳基、芳烷基、芳杂基或芳杂基烷基，或R1和R2与相连的碳原子结合在一起形成三-到七元饱和或不饱和的碳环或杂环，R3是C1-10烷基、C2-10链烯基、C3-7环烷基或任意取代的芳基、芳烷基或芳杂基、A-是强酸的阴离子，通过低级醇和强酸的存在下，在非水溶剂中环化α-酰基氨基腈而制得。该化合物是药物活性物质，如血管紧张肽Ⅱ拮抗剂的中间体。
Description
本发明涉及下式：4-氧代咪唑啉盐的制备方法：
其中R1和R2各自是C1-10烷基、C2-10链烯基、C3-7环烷基或任意取代的芳基、芳烷基、芳杂基或芳杂基烷基，或R1和R2与相连的碳原子结合在一起形成三-到七元饱和或不饱和的碳环或杂环，R3是C1-10烷基、C2-10链烯基、C3-7环烷基或任意取代的芳基、芳烷基或芳杂基，
A-是强酸的阴离子。
上述和下述的C1-10烷基被理解成有1到10个碳原子的直链和支链的伯、仲和叔烃基。相应的是，C2-10烷基被理解成在任何位置上有一个或多个双键的直链和支链的伯、仲和叔烃基。芳基被理解成单环或多环的芳基，特别是苯基和萘基。芳烷基被理解成被芳基取代的低级烷基，特别是苄基和苯乙基。芳杂基被理解成诸如呋喃基或噻吩基(苯硫基)的特殊基团，相应的是，芳杂基烷基被理解成诸如糠基(呋喃基甲基)或噻吩基甲基(苯硫基甲基)的基团。芳基、芳烷基、芳杂基或芳杂基烷基可任意地带有一个或多个取代基，例如带有C1-4烷基、C1-4烷氧基或卤素。
该类化合物或基于这些盐的2-咪唑啉-4-酮(1H-咪唑-5(4H)-酮)在药物活性物，如血管紧张肽II拮抗剂(WO-A91/14679，US-A5424450)的合成中是重要的中间体。迄今为止它们可这样制备：例如通过将α-氨基腈酰化为相应的酰氨基腈(＝α-酰基氨基腈，也称为“脂族Reissert化合物”)，将腈基团水解成氨基甲酰基，接着碱催化环化所得的酰氨基酰胺(US-A 5424450，流程3)。酰化和水解的次序也可互换(WO-A 91/14679，25-26页)。这些方法的一个缺点是需要在酸性和碱性反应条件之间改变，这要求每次中和，导致形成大量相应的废物盐。
本发明的目的是提供产生较少废物的简单的方法。
该目的可用权利要求1所述的方法得到。
现已令人惊奇地发现，在非水溶剂中，在低级醇和式HA的强酸存在下，其中A或阴离子A-定义如上，4-氧代咪唑啉盐(I)可直接从下式的α-酰基氨基腈一步得到，无需分离中间体，无需中和步骤。
其中R1、R2和R3的定义同上。
可用已知的方法，如将相应的羰基化合物R1-C(＝O)-R2与羟基氰酸和氨水进行Strecker反应，接着用酰氯R3COCl酰化所得的α-氨基腈可制得α-酰基氨基腈(II)。
无机酸和有机酸，如磺酸，都适合用作强酸HA。
较好的是使用选自氢卤酸、硫酸、甲酸、三氟乙酸和甲磺酸的酸。最好的是盐酸。
酸的用量对于每摩尔起始物质为1-2当量，较好的是1.1-1.5当量。
作为非水溶剂，较好的是使用选自芳烃，如苯、甲苯或二甲苯的溶剂或选自卤代烃，如二氯甲烷的溶剂。
特别好的技术方案是其中低级醇同时作为非水溶剂。甲醇、乙醇、丙醇、丁醇和异丙醇都可达到这样的目的。
本发明的方法较好地用来制备螺环化合物4-氧代咪唑啉盐(I)，其中R1和R2与相连的碳原子结合在一起形成环戊烷或环己烷环。
较好的也可制备4-氧代咪唑啉盐(I)，其中R3是C1-6烷基。
反应温度有利的是0-120℃，较好的是20-100℃。
当然，将4-氧代咪唑啉盐(I)用碱转化为咪唑啉-4-酮也在本发明的范围里。
下列实施例阐述了本发明方法的实施，并非用于限定。
实施例1
2-丁基-1，3-二氮杂螺[4，4]壬-2-烯-4-酮单氢氯化物
(I，R1+R2＝-(CH2)4-，R3＝正丁基)
将9.39克(39毫摩尔)新鲜制备的盐酸乙醇溶液(15.15wt％)加入6.80克(30毫摩尔)在28克无水乙醇中的N-(1-氰基环戊基)戊酰胺内(通过Strecker合成从环戊酮中制得1-氨基环戊腈，用戊酰氯酰化，含量85.7％)。在氮气下将混合物加热到50℃，在该温度下搅拌3.1小时。然后冷却到1℃，在该温度下静置1小时。过滤沉淀出的产物，用10毫升冰冷却乙醇洗涤，在40℃/24毫巴下干燥。
得率：4.05克(58％)无色晶体，含量98.3％(HPLC)。
实施例2
2-丁基-1，3-二氮杂螺[4，4]壬-2-烯-4-酮单氢氯化物
(I，R1+R2＝-(CH2)4-，R3＝正丁基)
在氮气下，70℃时15分钟内将6.88克(30毫摩尔)N-(1-氰基环戊基)戊酰胺溶液(含量84.7wt％)滴加入9.84克(45毫摩尔)16.7％盐酸丙醇溶液和11.71克无水丙醇的混合物内，有固体析出。再将混合物在70℃下搅拌1.7小时，冷却到1℃，在该温度下静置1小时。然后过滤沉淀出的产物，用10毫升冰冷却丙醇洗涤，在40℃/24毫巴下干燥。
得率：5.74克(79％)，含量95.4％(滴定分析)。
IR(KBr)：ν＝1779；1642；1517cm-1.
1H NMR(DMSO-d6)：δ＝13.64(s，2H)；2.80(m，2H)；1.7-2.0(m，10H)；
1.34(m，2H)；0.91(t，J＝7.3Jz，3H)。
15N NMR(DMSO-d6)：5＝-211.8；-219.6(标准：N-乙酰苯胺)。
实施例3
2-丁基-1，3-二氮杂螺[4，4]壬-2-烯-4-酮单氢氯化物
(I，R1+R2＝-(CH2)4-，R3＝正丁基)
在氮气和室温下，将6.88克(30毫摩尔)N-(1-氰基环戊基)戊酰胺溶液(含量84.7wt％)，27.3克无水异丙醇和9.92克(39毫摩尔)新鲜制备的14.33％盐酸异丙醇溶液搅拌44小时。将混合物冷却到1℃，在该温度下静置1/2小时。然后过滤沉淀出的产物，用10毫升冰冷却异丙醇洗涤，在40℃/24毫巴下干燥。
得率：3.04克(44％)，含量99.7％(HPLC)。
实施例4
2-丁基-1，3-二氮杂螺[4，4]壬-2-烯-4-酮单氢氯化物
(I，R1+R2＝-(CH2)4-，R3＝正丁基)
在氮气下，将6.88克(30毫摩尔)N-(1-氰基环戊基)戊酰胺溶液(含量84.7wt％)，16.66克无水丁醇和10.06克(39毫摩尔)新鲜制备的14.13％盐酸丁醇溶液搅拌加热到回流温度(预热油浴)，内部温度一达到约100℃就有产物析出。(115℃)回流2.9小时后将混合物冷却到1℃，在该温度下静置1小时。然后过滤沉淀出的产物，用10毫升冰冷却丁醇洗涤，在40℃/24毫巴下干燥。
得率：4.93克(66％)，含量92.7％(HPLC)。
实施例5
2-氨基-2-甲基丁腈
将40.0克(800毫摩尔)氰化钠溶于78毫升水。在室温和氮气下，将所述的氰化钠溶液加入47.5克(880毫摩尔)氯化铵在70毫升浓氨水溶液(0.92摩尔NH3)和118毫升水的混合物中的溶液。接着在20-25℃(水浴)下滴加入51.8克(714毫摩尔)丁酮和76毫升甲醇(经分子筛干燥)的混合物。让反应混合物在室温下搅拌约2小时，然后加热到60℃，在该温度下保持约1小时。冷却后，反应混合物用200毫升二氯甲烷萃取一次，然后用100毫升二氯甲烷萃取两次。合并的有机相经20克硫酸钠干燥，过滤，用二氯甲烷稀释成700克溶液。所得的溶液可直接用于酰化，无需进一步的精制。
得率：94％(GC)。
实施例6
N-(1-氰基-1-甲基丙基)戊酰胺
(II，R1＝乙基，R2＝甲基，R3＝正丁基)
在室温和氮气下将39.6克(389毫摩尔)三乙胺加入到350克2-氨基-2-甲基丁腈的二氯甲烷溶液(实施例5制得，最多357毫摩尔)。然后在10-25℃(冷却)下于1小时内滴加入戊酰氯，有固体析出(三乙基氯化铵)。当加料完成后，将反应混合物在室温下再搅拌2小时。然后加入100毫升水，分离各相。有机相用100毫升1N盐酸洗涤，然后用100毫升水洗涤，经20克硫酸钠干燥，最后在水喷射真空下浓缩。
得率：50.2克油，含量(GC)86％(相应于理论值66％)。
IR(膜)：ν＝3305；2230；1656；1535cm-1.
1H NMR(DMSO-d6)：δ＝8.13(s，1H)；2.14(t，J＝7.3Hz，2H)；
1.8(m，2H)；1.52(s，3H)；1.4-1.5(m，2H)；1.29(m，2H)；
1.29(m，2H)；0.98(t，J＝7.3Hz，3H)；0.88(t，J＝7.2Hz，3H)。
实施例7
2-丁基-4-乙基-4-甲基-1H-咪唑-5(4H)-酮氢氯化物
(I，R1＝乙基，R2＝甲基，R3＝正丁基，A-＝Cl-)
在氮气下将在25.6克16.7％盐酸丙醇溶液(117毫摩尔HCl)和53.8克丙醇(经分子筛干燥)混合物中的实施例6制备的19.05克(90毫摩尔)N-(1-氰基-1-甲基丙基)戊酰胺在30℃下搅拌6.5小时。所得的澄清黄色溶液放在冰箱中过夜。过滤已析出的晶体，用10毫升冰冷却的丙醇洗涤，在40℃/24毫巴下干燥。
得率：5.38克(27％)白色晶体，含量(HPLC)99.5％。
IR(KBr)：ν＝1779；1638；1519cm-1.
1H NMR(DMSO-d6)：δ＝13.71(s，1H)；2.87(m，2H)；1.7-1.8(m，4H)；
1.43(s，3H)；1.37(m，2H)；0.92(t，J＝7.4Hz，3H)；
0.83(t，J＝7.3Hz，3H)。
15N NMR(DMSO-d6)：δ＝-215.4；-217.7。
实施例8
2-氨基-2-苯基丙腈
在氮气下将40.0克(800毫摩尔)氰化钠和47.5克(880毫摩尔)氯化铵悬浮于196毫升甲醇。然后在室温下于15分钟内滴加入87.5克(714毫摩尔)乙酰苯和76毫升甲醇(经分子筛干燥)混合物。让反应混合物在室温下再搅拌1小时，然后加热到40℃，在该温度下保持5.5小时，再在22℃下搅拌2天。所得的有机橙色悬液通过玻璃料过滤，在真空和最高35℃下将滤液浓缩到1/4体积，再过滤。该滤液(约100克)用乙醚稀释到400克，再过滤一次。然后在70分钟内向所得的澄清桔红色溶液中加入11.4克(1.1当量)盐酸，析出亮色固体。让混合物在冰箱中静置过夜，从沉淀中倒出上清液。沉淀物用50毫升乙醚洗涤，并溶于100毫升水。用氢氧化钠浓溶液将该水溶液(pH≈2.5)调节到pH8.7，然后用3×100毫升乙醚萃取。合并的醚萃取物用20克硫酸钠干燥，然后真空蒸发。将残留物悬浮于两次15毫升甲苯，然后再真空浓缩至于。
得率：56.2克，含量(1H NMR)83％(基于乙酰苯，相应于45％的理论值)。
IR(NaCl)：ν＝3378；3313；2224cm-1.
1H NMR(CDCl3)：δ＝7.63-7.68(m，2H)；
7.30-7.43(m，3H)；2.08(s，2H)；1.74(s，3H)。
实施例9
N-(1-氰基-1-苯乙基)戊酰胺
(II，R1＝苯基，R2＝甲基，R3＝正丁基)
在氮气、12-23℃下，于55分钟内向55.8克2-氨基-2-苯基丙腈(实施例8制得，约0.34摩尔)和38.1克(375毫摩尔)三乙胺在280克二氯甲烷中的物质内滴加入46.1克(375毫摩尔)戊酰氯，有固体(三乙基氯化铵)析出。当加料完成后，再让反应混合物在室温下搅拌2小时。然后加入100毫升水，分离各相。有机相用100毫升1N盐酸和100毫升水洗涤，用20克硫酸钠干燥，最后在水喷射真空下与50℃下浓缩。为了纯化40.0克残留物(米色固体总量为84.1克)，用230毫升沸腾的乙酸乙酯/环己烷(70∶30)重结晶，冷却到室温，经过玻璃料过滤，用50毫升环己烷洗涤，在40℃/30毫巴下干燥。
得率：31.71克白色晶体(基于氨基腈，相应于84％的理论值，外推到粗产品的总量：66.7克)。
IR(KBr)：ν＝2228；1657；1539cm-1.
1H NMR(DMSO-d6)：δ＝7.3-7.4(m，5H)；7.03(s，1H)；2.15(t，J＝7.6Hz，2H)；
1.77(s，3H)；1.55(m，2H)；1-30(m，2H)；
0.89(t，J＝7.3Hz，3H)。
实施例10
2-丁基-4-甲基-4-苯基-1H-咪唑-5(4H)-酮氢氯化物
(I，R1＝苯基，R2＝甲基，R3＝正丁基，A-＝Cl-)
在氮气下将8.49克(30毫摩尔)实施例9制得的N-(1-氰基-1-苯乙基)戊酰胺在9.2克15.5％盐酸丙醇溶液(30毫摩尔HCl)和33.3克丙醇(经分子筛干燥)混合物中的物质加热到50℃，在该温度下搅拌3.25小时。然后将所得的澄清黄色溶液在室温下静置过夜，接着在50℃/16毫巴下蒸发至干。将残留物(17.76克)在室温下悬浮于30毫升丙酮达1.25小时。悬浮液通过玻璃料过滤，滤饼用10毫升丙酮洗涤，在40℃/24毫巴下干燥。
得率：5.47克白色固体，含量(滴定分析)98％(基于氨基腈，相应于67％的理论值)。
IR(KBr)：ν＝1787；1633；1517cm-1.
1H NMR(DMSO-d6)：δ＝14.0(s，2H)；7.3-7.6(m，5H)；
2.99(t，J＝7.5Hz，2H)；1.7-2.0(m，2H)；1.85(s，3H)；
1.38(m，2H)；0.93(t，J＝7.5Hz，3H)。
15N NMR(DMSO-d6)：δ＝-213.5；-220.0。
Claims (7)
1.一种制备下式4-氧代咪唑啉盐的方法：
其中R1和R2各自是C1-10烷基、C2-10链烯基、C3-7环烷基或任意取代的芳基、芳烷基、芳杂基或芳杂基烷基，或R1和R2与相连的碳原子结合在一起形成三-到七元饱和或不饱和的碳环或杂环，R3是C1-10烷基、C2-10链烯基、C3-7环烷基或任意取代的芳基、芳烷基或芳杂基，
A-是强酸的阴离子，
其特征在于，该方法包括下式的α-酰基氨基腈在非水溶剂中环化
其中R1、R2和R3的定义同上，在低级醇和式HA的强酸存在下，其中A定义如上。
2.根据权利要求1所述的方法，其特征在于用作强酸HA的酸选自氢卤酸、硫酸、甲酸、甲磺酸和三氟乙酸。
3.根据权利要求2所述的方法，其特征在于盐酸用作强酸HA。
4.根据权利要求1-3之一所述的方法，其特征在于选自芳烃或卤代烃的溶剂被用作非水溶剂。
5.根据权利要求1-3之一所述的方法，其特征在于甲醇、乙醇、丙醇、丁醇或异丙醇被用作低级醇和非水溶剂。
6.根据权利要求1-5之一所述的方法，其特征在于用作α-酰基氨基腈(II)的化合物中，R1和R2与相连的碳原子一起形成环戊烷或环己烷环。
7.根据权利要求1-6之一所述的方法，其特征在于用作α-酰基氨基腈(II)的化合物中，R3是C1-6烷基。
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| HU218680B (hu) * | 1997-07-25 | 2000-10-30 | Sanofi-Synthelabo | Eljárás 1,3-diaza-spiro[4,4]non-1-én-4-on-származékok előállítására és 1-ciano-1-(acil-amino)-ciklopentán intermedierek |
| JP2002507611A (ja) * | 1998-03-25 | 2002-03-12 | ブリストル−マイヤーズ スクイブ カンパニー | イミダゾロン食欲抑制薬：ｉｉ．フェニル誘導体 |
| EP0945441A3 (de) * | 1998-03-27 | 2002-07-17 | Degussa AG | Verfahren zur Herstellung von cyclischen 4-Oxoamidinen |
| US5910595A (en) * | 1998-06-26 | 1999-06-08 | Salsbury Chemicals, Inc. | Process for preparing oximidazoles |
| JP4505329B2 (ja) * | 2002-09-04 | 2010-07-21 | メルク フロスト カナダ リミテツド | カテプシンシステインプロテアーゼ阻害薬 |
| US9126998B2 (en) | 2012-11-05 | 2015-09-08 | Bayer Pharma AG | Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use |
| US9624214B2 (en) | 2012-11-05 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use |
| US8796305B2 (en) | 2012-11-05 | 2014-08-05 | Bayer Pharma Aktiengesellschaft | Carboxy-substituted imidazo[1,2-a]pyridinecarboxamides and their use |
| US8778964B2 (en) | 2012-11-05 | 2014-07-15 | Bayer Pharma Aktiengesellschaft | Hydroxy-substituted imidazo[1,2-a]-pyridinecarboxamides and their use |
| CA2914100A1 (en) | 2013-06-04 | 2014-12-11 | Bayer Pharma Aktiengesellschaft | 3-aryl-substituted imidazo[1,2-a]pyridines and the use thereof |
| US9422285B2 (en) | 2013-08-08 | 2016-08-23 | Bayer Pharma Aktiengesellschaft | Substituted pyrazolo[1,5-A]-pyridine-3-carboxamides and use thereof |
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| CA2969265A1 (en) | 2014-12-02 | 2016-06-09 | Bayer Pharma Aktiengesellschaft | Substituted pyrazolo[1,5-a]pyridines and imidazo[1,2-a]pyrazines and their use |
| CA2969268A1 (en) | 2014-12-02 | 2016-06-09 | Bayer Pharma Aktiengesellschaft | Heteroaryl-substituted imidazo[1,2-a]pyridines and their use |
| CN107567446A (zh) | 2015-02-05 | 2018-01-09 | 拜耳制药股份公司 | 取代的吡唑并[1,5‑a]吡啶‑3‑甲酰胺及其用途 |
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- 1997-02-06 KR KR1019970003797A patent/KR100490220B1/ko not_active IP Right Cessation
- 1997-02-07 EP EP97102004A patent/EP0789019B1/de not_active Expired - Lifetime
- 1997-02-07 PT PT97102004T patent/PT789019E/pt unknown
- 1997-02-07 CZ CZ1997386A patent/CZ291500B6/cs not_active IP Right Cessation
- 1997-02-07 DK DK97102004T patent/DK0789019T3/da active
- 1997-02-07 HU HU9700380A patent/HU225694B1/hu not_active IP Right Cessation
- 1997-02-07 DE DE59703745T patent/DE59703745D1/de not_active Expired - Lifetime
- 1997-02-07 ES ES97102004T patent/ES2158385T3/es not_active Expired - Lifetime
- 1997-02-07 AT AT97102004T patent/ATE202090T1/de active
- 1997-02-07 NO NO970581A patent/NO306674B1/no not_active IP Right Cessation
- 1997-02-07 PL PL318370A patent/PL191419B1/pl not_active IP Right Cessation
-
2001
- 2001-09-06 GR GR20010401412T patent/GR3036558T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU9700380D0 (en) | 1997-03-28 |
| JP4224629B2 (ja) | 2009-02-18 |
| PL191419B1 (pl) | 2006-05-31 |
| HUP9700380A3 (en) | 1998-04-28 |
| NO970581L (no) | 1997-08-11 |
| PT789019E (pt) | 2001-11-30 |
| HUP9700380A2 (en) | 1997-10-28 |
| PL318370A1 (en) | 1997-08-18 |
| CZ291500B6 (cs) | 2003-03-12 |
| NO970581D0 (no) | 1997-02-07 |
| CA2196263C (en) | 2004-10-26 |
| KR970061874A (ko) | 1997-09-12 |
| HU225694B1 (en) | 2007-06-28 |
| NO306674B1 (no) | 1999-12-06 |
| DE59703745D1 (de) | 2001-07-19 |
| EP0789019A1 (de) | 1997-08-13 |
| TW407152B (en) | 2000-10-01 |
| JPH09227527A (ja) | 1997-09-02 |
| SK282845B6 (sk) | 2002-12-03 |
| DK0789019T3 (da) | 2001-09-03 |
| CN1071747C (zh) | 2001-09-26 |
| ATE202090T1 (de) | 2001-06-15 |
| US5698704A (en) | 1997-12-16 |
| CZ38697A3 (en) | 1997-08-13 |
| GR3036558T3 (en) | 2001-12-31 |
| KR100490220B1 (ko) | 2005-09-08 |
| SK16097A3 (en) | 1997-09-10 |
| ES2158385T3 (es) | 2001-09-01 |
| EP0789019B1 (de) | 2001-06-13 |
| CA2196263A1 (en) | 1997-08-10 |
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