CN100378065C - 2-氯甲基-6-甲基苯甲酸酯的合成 - Google Patents
2-氯甲基-6-甲基苯甲酸酯的合成 Download PDFInfo
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- CN100378065C CN100378065C CNB2004800062464A CN200480006246A CN100378065C CN 100378065 C CN100378065 C CN 100378065C CN B2004800062464 A CNB2004800062464 A CN B2004800062464A CN 200480006246 A CN200480006246 A CN 200480006246A CN 100378065 C CN100378065 C CN 100378065C
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- phenyl
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- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title abstract description 10
- 150000002148 esters Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- -1 dimethylbenzoic acid ester Chemical class 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229940126033 PPAR agonist Drugs 0.000 claims 1
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 10
- 125000003118 aryl group Chemical group 0.000 abstract description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 abstract description 3
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 abstract description 3
- 239000000556 agonist Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000002877 alkyl aryl group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical group 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 7
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000002596 lactones Chemical class 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 150000001805 chlorine compounds Chemical class 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- UDNSKBMNXZVXKW-UHFFFAOYSA-N methyl 2-(bromomethyl)-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1CBr UDNSKBMNXZVXKW-UHFFFAOYSA-N 0.000 description 3
- HYKRJRNYWUORKO-UHFFFAOYSA-N methyl 2-(chloromethyl)-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1CCl HYKRJRNYWUORKO-UHFFFAOYSA-N 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- AIJFHFWXQDMLEP-UHFFFAOYSA-N 2-(bromomethyl)-6-methylbenzoic acid Chemical compound CC1=CC=CC(CBr)=C1C(O)=O AIJFHFWXQDMLEP-UHFFFAOYSA-N 0.000 description 2
- WLHOBCUVPMOXAT-UHFFFAOYSA-N 2-methyl-6-[3-[(2-phenyl-1,3-oxazol-4-yl)methoxy]propoxymethyl]benzoic acid Chemical compound CC1=CC=CC(COCCCOCC=2N=C(OC=2)C=2C=CC=CC=2)=C1C(O)=O WLHOBCUVPMOXAT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000002497 iodine compounds Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- NLJDACYMGBJSBU-UHFFFAOYSA-N 2-(chloromethyl)-6-methylbenzoic acid Chemical compound CC1=CC=CC(CCl)=C1C(O)=O NLJDACYMGBJSBU-UHFFFAOYSA-N 0.000 description 1
- YTEUDCIEJDRJTM-UHFFFAOYSA-N 2-(chloromethyl)benzoic acid Chemical class OC(=O)C1=CC=CC=C1CCl YTEUDCIEJDRJTM-UHFFFAOYSA-N 0.000 description 1
- ZCDHOYWPVVXKKH-UHFFFAOYSA-N 2-methoxyethyl 2,6-dimethylbenzoate Chemical compound COCCOC(=O)C1=C(C)C=CC=C1C ZCDHOYWPVVXKKH-UHFFFAOYSA-N 0.000 description 1
- ZYTLRMHXJVMJHS-UHFFFAOYSA-N 2-methoxyethyl 2-(chloromethyl)-6-methylbenzoate Chemical compound COCCOC(=O)C1=C(C)C=CC=C1CCl ZYTLRMHXJVMJHS-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- QDBMHIWOESYODH-UHFFFAOYSA-N benzyl 2,6-dimethylbenzoate Chemical compound CC1=CC=CC(C)=C1C(=O)OCC1=CC=CC=C1 QDBMHIWOESYODH-UHFFFAOYSA-N 0.000 description 1
- HCXHKYDDZUNTJM-UHFFFAOYSA-N benzyl 2-(chloromethyl)-6-methylbenzoate Chemical compound CC1=CC=CC(CCl)=C1C(=O)OCC1=CC=CC=C1 HCXHKYDDZUNTJM-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XJMULMWDHLJUKP-UHFFFAOYSA-N methyl 2,6-dimethylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1C XJMULMWDHLJUKP-UHFFFAOYSA-N 0.000 description 1
- HZSYTSUXSGUPKV-UHFFFAOYSA-N methyl 2-(iodomethyl)-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1CI HZSYTSUXSGUPKV-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- OUMJAQDLGCZJJI-UHFFFAOYSA-N propan-2-yl 2,6-dimethylbenzoate Chemical compound CC(C)OC(=O)C1=C(C)C=CC=C1C OUMJAQDLGCZJJI-UHFFFAOYSA-N 0.000 description 1
- OJBLIYMGYFRQRT-UHFFFAOYSA-N propan-2-yl 2-(chloromethyl)-6-methylbenzoate Chemical compound CC(C)OC(=O)C1=C(C)C=CC=C1CCl OJBLIYMGYFRQRT-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及制备式(I)化合物的方法,其中R表示 H、任选被卤素取代的烷基、环烷基、芳基、烷基-芳基或杂芳基,并且在烷基和环烷基中至少一个CH2基团可以被O替换。所述式(I)化合物在合成PPAR激动剂中是有价值的中间体。
Description
2-卤代烷基苯甲酸衍生物用作活性药物成分合成的结构单元。出于多种原因,可以预期用于具有储存稳定性的化合物,它们可以以简单方式另外制备和纯化。这些原因例如包括保证稳定的品质、缺乏对材料进行频繁检查以记录产品品质、缺乏冷藏储存和/或冷藏运输的必要条件、生产工厂的易迁移性以及所用容器的简单清洁。
2-溴甲基-6-甲基苯甲酸酯(A1和A2)是已知的,例如从WO 00/64888(R=iBu(A1))和WO 00/64876(R=Me(A2))中已知。这些化合物在室温下不具有储存稳定性,因为它们自发环化形成内酯(B),并且在该过程中,如众所周知的那样,产生致突变的副产物烷基溴。
因此,这些热不稳定的物质在工业规模的应用伴随有职业卫生的风险、困难以及额外的费用。
除了其它用途,2-溴甲基-6-甲基苯甲酸酯作为制备PPAR激动剂的原料是令人感兴趣的,例如如WO 00/64888、WO 00/64876和WO 03/020269中所述。这里应当特别提及的是式(C)化合物:
其中,
R是H、C1-C12-烷基、C3-C8-环烷基、C6-C12-芳基、C1-C4-烷基-C6-C12-芳基或C5-C10-杂芳基,其中在烷基和环烷基中,一个或多个CH2-基团可被-O替换,烷基、环烷基和芳基可被卤素取代,
Y是-(CH2)3-、1,3-亚苯基、1,3-环己烷二基;
R′是H、F、Br、CF3、(C1-C6)-烷基、O-(C1-C6)-烷基、苯基;
R″是H、(C1-C6)-烷基、(C1-C3)-烷基苯基、(C5-C6)-环烷基、苯基、CF3。
优选其中苯环在间位或对位被R′取代的式(C)化合物。
因此,本发明的目的是发现一种没有上述缺点的比(A1)和(A2)更稳定的化合物。另外,甚至当由粗品来制备所述化合物所得的纯度是不足够的时,与式(A1)和(A2)化合物相比,它们应当是可以被纯化的。
这可以通过下述式(I)化合物来实现。
本发明提供了式(I)化合物
其中,
R是H、C1-C12-烷基、C3-C8-环烷基、C6-C12-芳基、C1-C4-烷基-C6-C12-芳基或C5-C10-杂芳基,并且在烷基和环烷基中,一个或多个CH2-基团可以被-O-替换,并且烷基、环烷基和芳基可以被卤素取代。
优选如下定义的式(I)化合物:其中,
R是C1-C8烷基、C3-C6-环烷基或C1-C4-烷基-C6-C12-芳基,它们中的每个可任选被卤素取代且其中一个或两个CH2-基团可以被-O-替换。
特别优选如下定义的式(I)化合物:其中,
R是C1-C6烷基或C1-C4-烷基-C6-C12-芳基,它们中的每个可任选被卤素取代且其中一个CH2-基团可以被-O-替换。
非常特别优选如下定义的式(I)化合物:其中,
R是甲基、乙基、丙基、异丙基、叔丁基、苯基、2-甲氧基乙基或苄基。
烷基可以是支链或直链的。卤素是Cl、Br、I,优选是Cl。在本文中,杂芳基指含有1至4个选自N、O、S的相同或不同杂原子的5-至10-元芳香环,例如吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、呋喃、噻吩、唑、异唑、噻唑、异噻唑、三唑、四唑、三嗪、四嗪,优选是吡咯、咪唑、唑、噻唑和吡啶。
本发明还提供了制备式(I)化合物的方法,
其中,
R是H、C1-C12-烷基、C3-C8-环烷基、C6-C12-芳基、C1-C4-烷基-C6-C12-芳基或C5-C10-杂芳基,并且在烷基和环烷基中,一个或多个CH2-基团可以被-O-替换,且烷基、环烷基和芳基可以被卤素取代,
该方法包括:
使式(II)二甲基苯甲酸酯
其中R如上定义,
与氯化剂如磺酰氯、N-氯琥珀酰亚胺(NCS)、1,3-二氯-5,5-二甲基乙内酰胺(NDDH)或三氯异氰尿酸[Org Process Research & Development 2002,6,384-393]在惰性溶剂如CCl4、氯苯或者在没有溶剂存在下于高于40℃的温度下反应,然后任选纯化。
优选于60-90℃进行反应,虽然在低于40℃的温度下观察到芳香环氯化。纯化优选经蒸馏或经硅胶过滤进行。
如果式(I)氯化合物完全通过内酯(B)的开环氯化,则式(I)氯化合物仅仅是没有效率地获得,因为内酯结构非常稳定。另外,2-氯甲基苯甲酸衍生物出人意料地可以蒸馏,可以通过该方法以极好的化学纯度进行分离,并且在储存过程中不会自发反应形成内酯。
为了增加该分子结构单元在进一步合成(例如给出PPAR激动剂(C))中的反应活性,式(I)氯化合物向更反应活性的溴或碘化合物的转化同样是有利的。然而,这些化合物具有在介绍中所提及的“技术”缺陷。氯向溴或碘化合物的转化在惰性溶剂中用碱金属卤化物进行,优选在回流丙酮中用溴化钠或碘化钠进行。或者,卤素转移作用和进一步的合成还可以以单罐法用催化量或化学计算量的烷基卤(基于所用的氯化合物)来进行。
本发明还提供了制备式(C)化合物的方法,
其中,
R是H、C1-C12-烷基、C3-C8-环烷基、C6-C12-芳基、C1-C4-烷基-C6-C12-芳基或C5-C10-杂芳基,其中在烷基和环烷基中,一个或多个CH2基团可以被-O-替换,并且烷基、环烷基和芳基可以被卤素取代,
Y是-(CH2)3-、1,3-亚苯基、1,3-环己烷二基;
R′是H、F、Br、CF3、(C1-C6-烷基、O-(C1-C6)-烷基、苯基;
R″是H、(C1-C6)-烷基、(C1-C3)-烷基-苯基、(C5-C6)-环烷基、苯基、CF3;
该方法包括使式(C1)化合物
其中Y、R′和R″各自如上定义,
与式(I)化合物于-78至+50℃、优选-30至+20℃的温度下在甲苯、1-甲基-吡咯烷-2-酮(NMP)或其它质子惰性溶剂中和在适宜碱、优选叔丁醇钾的存在下反应,
其中R如上定义,
接着进行萃取处理以及任选将终产物结晶。
式(I)化合物由于与相应的溴化合物相比具有高稳定性因而是引人注意的。当比较2-溴甲基-6-甲基苯甲酸甲酯与类似的氯化合物的稳定性时,可以得出下述结论:2-氯甲基-6-甲基苯甲酸甲酯可以在66-77℃/0.1mbar下蒸馏而没有分解,而仅高于120℃的底层温度即显著导致内酯形成。在室温下,它可以温度储存数个月以上。2-溴甲基-6-甲基苯甲酸甲酯的储藏稳定性与之明显不同。在室温下,溴化合物的含量在几天之内迅速下降,在一周之内由92.6%下降至81.0%,在两周之内下降至67.8%,在两个月之内下降至7.8%。同时内酯含量在一周后由1.9%升至13.9%,在两个月内升至89.5%。
非限制性地引用下述实施例:
实施例1:2-氯甲基-6-甲基苯甲酸甲酯的合成
首先将11.9g2,6-二甲基苯甲酸甲酯加入在室温下与8.2g磺酰氯和40mg AIBN混合的50ml氯苯中。混合物于60-90℃搅拌2小时,然后将混合物与80ml饱和NaHCO3溶液混合。相分离后,有机相用100ml10%的Na2SO3溶液洗涤,有机相经硫酸镁干燥,真空蒸除氯苯。获得15.5g无色液体。高真空蒸馏产物(0.1mbar,66-77℃)。产量:10.2g(理论值的71%;95.2面积%)。
实施例2:2-氯甲基-6-甲基苯甲酸异丙酯的合成
首先将19.2g2,6-二甲基苯甲酸异丙酯加入在室温下与13.3gN-氯琥珀酰亚胺和200mgAIBN混合的100ml四氯化碳中。混合物于回流加热3小时。在混合物冷却后,将其抽滤并将琥珀酰亚胺用20ml四氯化碳洗涤。合并滤液并真空蒸除四氯化碳。获得21.8g无色液体。高真空蒸馏产物(0.05mbar,94-97℃)。产量:13.9g(理论值的61%;93.62面积%)。
实施例3:2-氯甲基-6-甲基苯甲酸-2-甲氧基-乙酯的合成
于室温将10.4g2,6-二甲基苯甲酸-2-甲氧基-乙酯与5.4g磺酰氯和40mgAIBN混合。混合物于60-90℃搅拌1-2小时。然后将混合物与20ml水混合,相分离,有机相经硫酸镁干燥。高真空蒸馏产物(0.02mbar,95-103℃)。产量:6.4g(理论值的66%;91.8面积%)。
实施例4:2-氯甲基-6-甲基苯甲酸苄酯的合成
首先将12.0g2,6-二甲基苯甲酸苄酯加入在室温下与5.4g磺酰氯和40mgAIBN混合的50ml四氯化碳中。混合物于回流搅拌4-5小时。然后将混合物与40ml饱和NaHCO3溶液混合。相分离后,有机相用50ml10%亚硫酸钠溶液洗涤,有机相经硫酸镁干燥。将含有产物的溶液经硅胶过滤,并再次用20ml四氯化碳洗涤。真空蒸除溶剂后,所得产物为亮黄色油状物。产量:8.0g(理论值的73%;88.4面积%)。
实施例5:2-甲基-6-[3-(2-苯基-唑-4-基甲氧基)-丙氧基甲基]-苯甲酸
于室温将4.8g2-氯甲基-6-甲基苯甲酸甲酯溶于250ml丙酮中,与35g碘化钠混合。混合物于回流加热6小时。然后于0℃真空除去溶剂。残余物经LC-MS分析(2-碘甲基-6-甲基苯甲酸甲酯的87.7面积%)并溶于20ml甲苯中。于-20℃历经10分钟将该溶液滴加至5.0g3-(2-苯基唑-4-基甲氧基)-丙-1-醇、4.8g叔丁醇钾和30ml甲苯的混合物中。然后,混合物于-20℃搅拌6小时,用100ml水稀释,弃去水相。有机相与40mlNMP和10ml32%氢氧化钠溶液混合,在水分离器上于回流加热8小时。然后,将混合物与100ml水混合并用MTB-醚萃取两次,每次25ml。水相用5ml乙酸酸化,用乙酸乙酯萃取两次,每次50ml。相分离后,有机相经硫酸镁干燥,真空除去溶剂。在二异丙醚中结晶后,获得4.2g2-甲基-6-[3-(2-苯基-唑-4-基甲氧基)-丙氧基甲基]-苯甲酸(理论值的50%,99.2HPLC面积%)。
Claims (6)
2.权利要求1所要求的式(I)化合物,其中:
R 是甲基、乙基、丙基、异丙基、叔丁基、2-甲氧基乙基或苄基。
4.制备式(C)化合物的方法,
其中,
R 是H、C1-C6-烷基或C1-C4-烷基-C6-C12-芳基,其中一个CH2基团可以被-O-替换,
Y 是-(CH2)3-、1,3-亚苯基、1,3-环己烷二基;
R′是H、F、Br、CF3、(C1-C6)-烷基、O-(C1-C6)-烷基、苯基;
R″是H、(C1-C6)-烷基、(C1-C3)-烷基-苯基、(C5-C6)-环烷基、苯基、CF3;
该方法包括使式(C1)化合物
其中Y、R′和R″各自如上定义,
与式(I)化合物于-78至+50℃的温度下在甲苯、1-甲基-吡咯烷-2-酮或其它质子惰性溶剂中和在适宜碱的存在下反应,
其中R如上定义,
接着进行萃取处理以及任选将终产物结晶。
5.权利要求4中所要求的制备式(C)化合物的方法,其中苯环被R′在间位或对位取代。
6.权利要求1或2所要求的式(I)化合物在制备具有通式(C)的PPAR激动剂中的用途。
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