JP2009516674A - デルモピノールとその誘導体の製造方法 - Google Patents
デルモピノールとその誘導体の製造方法 Download PDFInfo
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- JP2009516674A JP2009516674A JP2008540690A JP2008540690A JP2009516674A JP 2009516674 A JP2009516674 A JP 2009516674A JP 2008540690 A JP2008540690 A JP 2008540690A JP 2008540690 A JP2008540690 A JP 2008540690A JP 2009516674 A JP2009516674 A JP 2009516674A
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- QSFOWAYMMZCQNF-UHFFFAOYSA-N delmopinol Chemical compound CCCC(CCC)CCCC1COCCN1CCO QSFOWAYMMZCQNF-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 34
- 229960003854 delmopinol Drugs 0.000 title claims abstract description 25
- -1 4-propylheptyl Chemical group 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000012458 free base Substances 0.000 claims abstract description 3
- 239000012453 solvate Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 84
- 239000000126 substance Substances 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 150000002170 ethers Chemical class 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 239000011777 magnesium Substances 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- ZIJCSOPWDDXJLH-UHFFFAOYSA-N C(C)O[AlH]OCC.[Na] Chemical compound C(C)O[AlH]OCC.[Na] ZIJCSOPWDDXJLH-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 abstract description 25
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 abstract description 20
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000007818 Grignard reagent Substances 0.000 abstract 2
- 150000004795 grignard reagents Chemical class 0.000 abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 11
- NLQNYAFMZKEJEO-UHFFFAOYSA-N 4-(2-hydroxyethyl)morpholin-3-one Chemical compound OCCN1CCOCC1=O NLQNYAFMZKEJEO-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005580 one pot reaction Methods 0.000 description 6
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 235000019502 Orange oil Nutrition 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000010502 orange oil Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 0 *C1N(CCO)CCOC1 Chemical compound *C1N(CCO)CCOC1 0.000 description 3
- JYZUFTSYNSOVNI-UHFFFAOYSA-N 1-bromo-4-propylheptane Chemical compound CCCC(CCC)CCCBr JYZUFTSYNSOVNI-UHFFFAOYSA-N 0.000 description 3
- INJQDJRUXSSZRY-UHFFFAOYSA-N 2-(3-benzylmorpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1CC1=CC=CC=C1 INJQDJRUXSSZRY-UHFFFAOYSA-N 0.000 description 3
- VIJYGBOPLCWXPJ-UHFFFAOYSA-N 2-(3-heptylmorpholin-4-yl)ethanol Chemical compound CCCCCCCC1COCCN1CCO VIJYGBOPLCWXPJ-UHFFFAOYSA-N 0.000 description 3
- LYAPJRCDFPVZKB-UHFFFAOYSA-N 2-(3-propylmorpholin-4-yl)ethanol Chemical compound CCCC1COCCN1CCO LYAPJRCDFPVZKB-UHFFFAOYSA-N 0.000 description 3
- JFZBMJJFVBMZNC-UHFFFAOYSA-N 2-[3-(4-propylheptyl)morpholin-4-yl]ethanol;hydrochloride Chemical compound Cl.CCCC(CCC)CCCC1COCCN1CCO JFZBMJJFVBMZNC-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MPKNQUUKESZRHP-UHFFFAOYSA-N 2-(3-octylmorpholin-4-yl)ethanol Chemical compound CCCCCCCCC1COCCN1CCO MPKNQUUKESZRHP-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FUCKANLEEVIGBL-UHFFFAOYSA-N C1N(CCOC2)C2OC1 Chemical compound C1N(CCOC2)C2OC1 FUCKANLEEVIGBL-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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
- 239000011630 iodine Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- LSXKDWGTSHCFPP-UHFFFAOYSA-N 1-bromoheptane Chemical compound CCCCCCCBr LSXKDWGTSHCFPP-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- OUKZCLWTXYJXGZ-UHFFFAOYSA-N 1-butoxybutane;1,2-xylene Chemical group CC1=CC=CC=C1C.CCCCOCCCC OUKZCLWTXYJXGZ-UHFFFAOYSA-N 0.000 description 1
- PEROROPTZQXUFQ-UHFFFAOYSA-N 1-butoxybutane;toluene Chemical compound CC1=CC=CC=C1.CCCCOCCCC PEROROPTZQXUFQ-UHFFFAOYSA-N 0.000 description 1
- PDKQOCKNXAXHBH-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethanol sulfo hydrogen sulfate Chemical class S(=O)(=O)(O)OS(=O)(=O)O.C(COCCO)O PDKQOCKNXAXHBH-UHFFFAOYSA-N 0.000 description 1
- CRWNQZTZTZWPOF-UHFFFAOYSA-N 2-methyl-4-phenylpyridine Chemical compound C1=NC(C)=CC(C=2C=CC=CC=2)=C1 CRWNQZTZTZWPOF-UHFFFAOYSA-N 0.000 description 1
- WRNSAYACFKOUBH-UHFFFAOYSA-N 2-methyloxolane;1,2-xylene Chemical group CC1CCCO1.CC1=CC=CC=C1C WRNSAYACFKOUBH-UHFFFAOYSA-N 0.000 description 1
- FNAYLSDQHZLYQB-UHFFFAOYSA-N 2-methyloxolane;toluene Chemical compound CC1CCCO1.CC1=CC=CC=C1 FNAYLSDQHZLYQB-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZVWCWXUOSBDXEQ-UHFFFAOYSA-N 4-(bromomethyl)heptane Chemical compound CCCC(CBr)CCC ZVWCWXUOSBDXEQ-UHFFFAOYSA-N 0.000 description 1
- OURXRFYZEOUCRM-UHFFFAOYSA-N 4-hydroxymorpholine Chemical compound ON1CCOCC1 OURXRFYZEOUCRM-UHFFFAOYSA-N 0.000 description 1
- MWNGOSTXPPRZIS-UHFFFAOYSA-N BrCCBr.CCCCCC Chemical compound BrCCBr.CCCCCC MWNGOSTXPPRZIS-UHFFFAOYSA-N 0.000 description 1
- WMUZNBCXTKYDNV-UHFFFAOYSA-N CCCC(CCC)CC1N(CCO)CCOC1 Chemical compound CCCC(CCC)CC1N(CCO)CCOC1 WMUZNBCXTKYDNV-UHFFFAOYSA-N 0.000 description 1
- GVSXOJRMRUNWFR-UHFFFAOYSA-N CCCCC(CC)CC1N(CCO)CCOC1 Chemical compound CCCCC(CC)CC1N(CCO)CCOC1 GVSXOJRMRUNWFR-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PLZYVVWXSYGBAX-UHFFFAOYSA-M [Br-].CCCC(CCC)CCC[Mg+] Chemical compound [Br-].CCCC(CCC)CCC[Mg+] PLZYVVWXSYGBAX-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004969 haloethyl group Chemical group 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical class II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- ZKUUVVYMPUDTGJ-UHFFFAOYSA-N methyl 5-hydroxy-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C=C1[N+]([O-])=O ZKUUVVYMPUDTGJ-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
- WTOQPBCSJLJRTR-UHFFFAOYSA-N oxolane;1,2-xylene Chemical group C1CCOC1.CC1=CC=CC=C1C WTOQPBCSJLJRTR-UHFFFAOYSA-N 0.000 description 1
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 1
- UZFKWFJEEJVXOO-UHFFFAOYSA-N potassium 2-(2-hydroxyethylamino)ethanol 2-methylpropan-2-olate Chemical compound [K+].CC(C)(C)[O-].OCCNCCO UZFKWFJEEJVXOO-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Saccharide Compounds (AREA)
- Iron Core Of Rotating Electric Machines (AREA)
- Glass Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
手順II
カリウムtert−ブトキシド(176g、1.1当量)を1440mlのトルエンに添加した。この懸濁液を75℃まで加熱し、白色の固形物が完全に溶解するまで、30分間保持した。この温度で、ジエタノールアミン(150g、1当量)をゆっくりと添加した。濃い黄白色の懸濁液を、30分間、激しく撹拌したまま保持し、クロロ酢酸メチル(163g、1.05当量)をゆっくりと添加した。この溶液を、2時間、同じ温度で保持した。反応混合液を30℃で冷却し、ビトリド溶液(412g、2当量、トルエン中70%)を室温でゆっくりと添加した。この温度で、30分間、反応を維持した。該混合液を室温に保ちながら、50%の水酸化ナトリウム水溶液(360g、3.15当量)をゆっくりと添加した。該混合液を50℃まで温め、同じ温度において、トルエン(924ml)を用いて水層を分離、抽出した。両有機層をともに濃縮し、乾燥させた。オキサゾリジン(147g、80%)を、茶色味がかった油分として得た。
182mlのTHFおよび400mlのトルエンからなる混合液中に、32.6gのマグネシウム、0.5gのヨウ素および2.4mlのジブロモエタンを含む懸濁液に、200gの1−ブロモヘプタンを65℃で添加した。該反応混合液を、同じ温度で3時間、撹拌した。対応するグリニャール化合物の形成が完了した時点で、該混合液を室温で冷却し、500mlのトルエン中に158gのオキサゾリジン(II)を含有する溶液を1時間後に添加した。該混合液を30分間撹拌してから、795mlの5%HCl水溶液に添加した。有機層を静かに注ぎ出し、濃縮して乾燥させた。化合物(IC)は、オレンジ色の油分(179g)として得られた。MS(EI)、(m/z、%):229(M+.、1)、198(M−CH2OH、25)、130(M−C7H15、100)、112(M−C7H15−H2O、4)、100(M−73、30)、86(5 56(10)、41(8)。
41mlのTHF中に3.5gのマグネシウムと7.5gのヨウ素とを含有する懸濁液に、25gの1−ブロモオクタンを65℃でゆっくりと添加した。該反応混合液を、同じ温度で2時間撹拌した。対応するグリニャール化合物が調製された時点で、該混合液を5℃に冷却し、40mlのトルエン中に16.7gのオキサゾリジン(II)を含有する溶液を、1時間後に添加した。該混合液を、5℃で30分間撹拌し、該反応液を室温まで温めた。さらに該混合液を5%HCl水溶液に添加し、30分間撹拌した。有機層を静かに注ぎ出し、濃縮して乾燥させ、所望の化合物19gを茶色の油分として得た。MS(EI)、(m/z、%):243(M+.、5)、242(M−H、5)、212(M−CH2OH、50)、198(M−(CH2)2OH、8)、130(M−C8H17、100)、112(M−C8H17−H2O、8)、100(M−73、30)、86(8)、71(8)、56(9)、41(14)。
Claims (18)
- 前記化学式(III)のXが臭素であることを特徴とする、請求項1に記載の方法。
- 前記反応が、エーテル類(C4−C12)、該エーテル類と(C5−C8)脂肪族炭化水素との混合液、該エーテル類と(C6−C8)芳香族炭化水素との混合液、又はそれらの組み合わせから選択される溶媒中で行われることを特徴とする、先行請求項のいずれか1項に記載の方法。
- 前記還元反応が、水素化ビス(2−メトキシエトキシ)アルミニウムナトリウム、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、水素化ビスエトキシアルミニウムナトリウムから選択される還元剤を用いて行われることを特徴とする、請求項6に記載の方法。
- 前記還元剤が、水素化ビス(2−メトキシエトキシ)アルミニウムナトリウムであることを特徴とする、請求項7に記載の方法。
- 前記還元反応が、(C6−C8)芳香族炭化水素およびエーテル(C4−C12)から選択される溶媒中で行われることを特徴とする、請求項6〜8のいずれか1項に記載の方法。
- 前記塩基が、水素化ナトリウム、ナトリウムメトキシド、カリウムtert−ブトキシド、ナトリウムtert−ブトキシドから選択されることを特徴とする、請求項10に記載の方法。
- 前記化学式(VI)で表される化合物が、クロロ酢酸メチルであることを特徴とする、請求項10または11のいずれか1項に記載の方法。
- 単一の反応容器内で行われることを特徴とする、請求項6〜12のいずれか1項に記載の化学式(II)で表される化合物の製造方法。
- 前記Xが、臭素であることを特徴とする、請求項16に記載の化合物。
- デルモピノールの製造における、請求項15〜17のいずれか1項に記載の化合物の使用。
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GBGB0523435.6A GB0523435D0 (en) | 2005-11-17 | 2005-11-17 | Process |
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PCT/GB2006/004293 WO2007057681A1 (en) | 2005-11-17 | 2006-11-17 | Process for the preparation of delmopinol and derivatives thereof |
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JP2023508602A (ja) * | 2020-01-31 | 2023-03-02 | ユー ファースト サービシズ インコーポレイテッド | デルモピノール及びその塩の製造方法 |
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EP2827865B1 (en) | 2012-03-20 | 2018-12-12 | Merial, Inc. | Treatment of microbial infections |
IT201600130642A1 (it) | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | Processo per la produzione di 2(3 alchilmorfolino)-etan-1-olo |
IT201600130538A1 (it) * | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | Processo per la produzione del delmopinolo |
IT201600130729A1 (it) * | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | Processo per la produzione degli intermedi del delmopinolo |
IT201700076821A1 (it) | 2017-08-24 | 2019-02-24 | Lundbeck Pharmaceuticals Italy S P A | Nuovo sale del delmopinolo |
RU2696099C1 (ru) * | 2019-01-14 | 2019-07-31 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Хемоэнзиматический синтез производных 2,5-дикетоморфолина |
CN112047964A (zh) * | 2020-09-07 | 2020-12-08 | 宋喂 | 格氏试剂制备方法与应用 |
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JPH04500219A (ja) * | 1989-05-24 | 1992-01-16 | バイオサーフイス・フアーマ・アクチエボラーグ | 置換されたイソキサゾリジンおよびイソキサゾリン |
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JP2023508602A (ja) * | 2020-01-31 | 2023-03-02 | ユー ファースト サービシズ インコーポレイテッド | デルモピノール及びその塩の製造方法 |
JP7424685B2 (ja) | 2020-01-31 | 2024-01-30 | ユー ファースト サービシズ インコーポレイテッド | デルモピノール及びその塩の製造方法 |
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US20110092751A1 (en) | 2011-04-21 |
PL1948626T3 (pl) | 2009-08-31 |
AU2006314309A1 (en) | 2007-05-24 |
NZ568143A (en) | 2010-04-30 |
AU2006314309B2 (en) | 2009-12-24 |
MY143867A (en) | 2011-07-15 |
CN101309913A (zh) | 2008-11-19 |
BRPI0618675B1 (pt) | 2016-03-29 |
EP1948626B1 (en) | 2009-03-04 |
US8143463B2 (en) | 2012-03-27 |
ATE424390T1 (de) | 2009-03-15 |
CA2628921A1 (en) | 2007-05-24 |
GB0523435D0 (en) | 2005-12-28 |
WO2007057681A1 (en) | 2007-05-24 |
US7902357B2 (en) | 2011-03-08 |
DE602006005513D1 (de) | 2009-04-16 |
US20100222579A1 (en) | 2010-09-02 |
DK1948626T3 (da) | 2009-05-18 |
CA2628921C (en) | 2013-01-08 |
ES2321657T3 (es) | 2009-06-09 |
RU2008118067A (ru) | 2009-12-27 |
NO20082617L (no) | 2008-06-12 |
US20090137798A1 (en) | 2009-05-28 |
BRPI0618675A2 (pt) | 2011-09-06 |
CN101309913B (zh) | 2011-05-25 |
JP5202326B2 (ja) | 2013-06-05 |
RU2404169C2 (ru) | 2010-11-20 |
US7910730B2 (en) | 2011-03-22 |
CY1109049T1 (el) | 2014-07-02 |
EP1948626A1 (en) | 2008-07-30 |
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