ZA200506499B - Synthesis of 2-cholormethyl-6-methylbenzoic acid esters - Google Patents
Synthesis of 2-cholormethyl-6-methylbenzoic acid esters Download PDFInfo
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- ZA200506499B ZA200506499B ZA200506499A ZA200506499A ZA200506499B ZA 200506499 B ZA200506499 B ZA 200506499B ZA 200506499 A ZA200506499 A ZA 200506499A ZA 200506499 A ZA200506499 A ZA 200506499A ZA 200506499 B ZA200506499 B ZA 200506499B
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- South Africa
- Prior art keywords
- alkyl
- formula
- aryl
- compounds
- cycloalkyl
- Prior art date
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- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 3
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 3
- -1 Y is -(CH2)3- Chemical group 0.000 claims description 3
- 239000000556 agonist Substances 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
- 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
- 239000007795 chemical reaction product Substances 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
- 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 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
- 150000002367 halogens Chemical group 0.000 description 7
- 239000012074 organic phase Substances 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 Chemical compound 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
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 4
- 150000001805 chlorine compounds Chemical class 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 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
- 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 238000003860 storage Methods 0.000 description 3
- 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 238000005660 chlorination reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000002497 iodine compounds Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- UDNSKBMNXZVXKW-UHFFFAOYSA-N methyl 2-(bromomethyl)-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1CBr UDNSKBMNXZVXKW-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000005191 phase separation Methods 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
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 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
- 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
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- NLJDACYMGBJSBU-UHFFFAOYSA-N 2-(chloromethyl)-6-methylbenzoic acid Chemical class CC1=CC=CC(CCl)=C1C(O)=O NLJDACYMGBJSBU-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
- UMBGNXDCYYVVOL-UHFFFAOYSA-N 3-[(2-phenyl-1,3-oxazol-4-yl)methoxy]propan-1-ol Chemical compound OCCCOCC1=COC(C=2C=CC=CC=2)=N1 UMBGNXDCYYVVOL-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- 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
- 238000004140 cleaning Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 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
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 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
- 238000000746 purification Methods 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
- 238000007142 ring opening reaction Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 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
- 238000005944 trans-halogenation reaction 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (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)
Description
; 2004/085377 PCT/EP2004/002579
Synthesis of 2-chloromethyl-6-methylbenzoic acid esters 2-Haloalkylbenzoic acid derivatives are used as building blocks for the synthesis of active pharmaceutical ingredients. For various reasons, it is desirable for the use to have storage-stable compounds which can additionally be prepared and purified in a simple manner. These reasons include, for example, the ensuring of a constant quality, the avoidance of frequent checks on the materials to record the product quality, the avoidance of the necessity of cold storage and/or cold transport, easy transfer to production plants and also simple cleaning of used vessels. 2-Bromomethyl-6-methylbenzoic esters (A1 and A2) are known, for example, from WO 00/64888 (R = iBu (A1)) and WO 00/64876 (R = Me (A2)). These compounds are not storage-stable at room temperature, since they cyclize spontaneously to the lactone (B) and in the process, as is well known, release mutagenic alkyl bromides as a by-product.
JO JOH A
CO-0OiBu CO-OCH, 0 Oo (A1) (A2) (B)
The use of these thermally labile substances on the industrial scale is therefore associated with occupational hygiene risks, difficulties and additional costs.
Among other uses, the 2-bromomethyl-6-methylbenzoic esters are of interest as starting materials for the preparation of PPAR agonists, as described, for example, in WO 00/64888, WO 00/64876 and WO 03/020269. Particular mention should be made here of the compounds of the formula (C):
A
J 2
R' 0)
R"
A
O~,-©
COR
(C) where
R is H, C4-Cq2-alkyl, C3-Cg-cycloalkyl, Cg-C12-aryl, C1-C4-alkyl-Cg-C12- aryl or Cs-Cqp-heteroaryl, where, in alkyl and cycloalkyl, one or more
CH2 groups may be replaced by —O- and alkyl, cycloalkyl and aryl may be substituted by halogen,
Y is —(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl;
R’ is H, F, Br, CF3, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl, phenyl;
R" is H, (C1-Cg)alkyl, (C1-C3)-alkylphenyl, (Cs-Cg)-cycloalkyl, phenyl,
CFs.
Preference is given to the compounds of formula (C) in which the phenyl ring is substituted by R’ in the m- or p-position. it is thus an object of the invention to find more stable compounds than (A1) and (A2) which do not have the above-outlined disadvantages. In addition, the compounds which can occur in a purity which is not yet sufficient when they are prepared even from a crude product should, in contrast to the compounds of the formulae (A1) and (A2), be purifiable.
This is achieved by the compounds of the formula (I) described below.
The present invention provides the compounds of formula (|)
COR a 3 where
R is H, C4-Cqz-alkyl, C3-Cg-cycloalkyl, Cg-Cq2-aryl, C1-Cs-alkyl-
Ce-C12-aryl or C5-C1p-heteroaryl, and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -O-, and alkyl, cycloalkyl and aryl may be substituted by halogen.
Preference is given to the compounds of the formula (I) in which
R is C1-Cg alkyl, C3-Cg-cycloalkyl or C1-C4-alkyl-Cg-C12-aryl, each of which may optionally be substituted by halogen and in which one or two CH2 groups may be replaced by -O-.
Particular preference is given to the compounds of the formula (I) in which
R is C1-Cg alkyl or C4-Cgs-alkyl-Cg-Cq2-aryl, each of which may optionally be substituted by halogen and in which one CH2 group may be replaced by -O-.
Very particular preference is given to the compounds of the formula (I) in which
R is methyl, ethyl, propyl, i-propyl, t-butyl, phenyl, 2-methoxyethyl or benzyl.
Alkyl may be branched or unbranched. Halogen is Cl, Br, |, preferably CI. In this context, heteroaryl refers to 5- to 10 membered aromatic rings which contain from one to four identical or different heteroatoms from the group of
N, O, S, for example pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, triazine, tetrazine, preference is given to: pyrrole, imidazole, oxazole, thiazole and pyridine.
The present invention also provides a process for preparing the compounds of the formula (1)
a 4
JO
COR
(1) where
R is H, Cq-Cqz-alkyl, C3-Cg-cycloalkyl, Cg-Cq2-aryl, C1-C4-alkyl-
Ce-C12-aryl or C5-Cqp-heteroaryl, and, in alkyl or cycloalkyl, one or more CH2 groups may be replaced by -O-, and alkyl, cycloalkyl and aryl may be substituted by halogen, which comprises reacting dimethylbenzoic esters of the formula (11)
CO,R (in where R is as defined above with a chlorinating reagent, for example sulfuryl chloride, N-chloro- succinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (NDDH) or trichloro- isocyanuric acid [Org Process Research & Development 2002,6,384-393], in an inert solvent, for example CCl4, chlorobenzene, or without solvents above 40°C and subsequently optionally purifying.
Preference is given to carrying out the reaction at 60-90°C, while chlorination on the aromatic ring is observed at lower temperatures than 40°C. The purification is preferably distillative or by a silica gel filtration.
The chlorine compounds of the formula (I) are only obtainable very inefficiently, if at all, by a ring-opening chlorination of the lactones (B), since the lactone structure is very stable. in addition, the 2-chioromethylbenzoic a 5 acid derivatives can surprisingly be distilled, can be isolated by this method in excellent chemical purity and do not react spontaneously in the course of storage to give the lactones.
A conversion of the chlorine compounds of the formula (1) to more reactive bromine or iodine compounds may likewise be advantageous, in order to increase the reactivity of this molecular building block in the further synthesis (for example to give PPAR agonists (C)). However, these compounds then have the “technical” disadvantages mentioned in the introduction. The conversion of the chlorine into the bromine or iodine compound is effected with alkali metal halides in inert solvents, preferably with sodium bromide or iodide in acetone under reflux. Alternatively, the transhalogenation and the further synthesis can also be carried out as a one-pot method with catalytical or stoichiometric amounts of alkyl halide, based on the chlorine compound used.
The present invention further provides a process for preparing the compounds of the formula (C)
R! oO
R"
DE
OL,-©
COR
C
(C) in which
R is H, C4-Cq2-alkyl, C3-Cg-cycloalkyl, Cg-C12-aryl, C1-C4-alkyl-Cg-
Cq2-aryl or Cs-C1p-heteroaryl and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by —O- and alkyl, cycloakyl and aryl may be substituted by halogen,
Y is -(CH2)3-, 1,3-phenylene, 1,3-cyciohexanediyl,
R’ is H, F, Br, CF3, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl, phenyl;
R” is H, (C4-Cg)-alkyl, (C1-C3)-alkylphenyl, (Cs-Cg)-cycloalkyl, phenyl,
CFs;
zc 6 which comprises reacting compounds of the formula (C1)
R' 0
R" \
N
HO. 0 (C1) where Y, R’ and R” are each as defined above with compounds of the formula (1)
Ql.
CO,R ( where R is as defined above in toluene, NMP or other aprotic solvents, in the presence of a suitable base, preferably with potassium tert-butoxide, at from -78 to +50°C, preferably at from -30 to +20°C, and subsequently working up extractively and optionally crystallizing the end product.
The compounds of the formula (I) are notable for high stability compared to the corresponding bromine compounds. When the stability of methyl 2-bromomethyl-6-methylbenzoate is compared to that of the analogous chlorine compound, the following result is obtained: methyl 2-chloromethyl- 6-methylbenzoate can be distilled without decomposition at 66-77°C/0.1 mbar, and only a bottom temperature of above 120°C leads to significant lactone formation. At room temperature, it can be stored stably over several months. The storage stability of methyl 2-bromomethyl-6-methylbenzoate differs distinctly from this. At room temperature, the content of the bromine
: 7 2005/086499 compound reduces sharply within a few days, within one week from 92.6 to 81.0%, within 2 weeks to 67.8% and within 2 months to 7.8%. At the same time, the lactone content rises from 1.9% via 13.9% after 1 week and 89.5% in 2 months.
The following examples are cited without restriction to them:
Example 1:
Synthesis of methyl 2-chloromethyl-6-methylbenzoate 11.9 g of methyl 2,6-dimethylbenzoate are initially charged in 50 ml of chlorobenzene admixed at room temperature with 8.2 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60-90°C for 2 h. Afterwards, the mixture is admixed with 80 ml of saturated NaHCO3 solution. After the phase separation, the organic phase is washed with 100 ml of 10%
Na2SO03 solution, the organic phase is dried over magnesium sulfate and the chlorobenzene is distilled off in vacuo. 15.5 g of colorless liquid are obtained. The product is distilled under high vacuum (0.1 mbar, 66-77°C).
Yield: 10.2g (71% of theory; 95.2 area%).
Example 2:
Synthesis of isopropyl 2-chloromethyl-6-methylbenzoate 19.2 g of isopropyl 2,6-dimethylbenzoate are initially charged in 100 ml of carbon tetrachloride admixed at room temperature with 13.3g of
N-chlorosuccinimide and 200 mg of AIBN. The mixture is heated to reflux for 3 h. After the mixture has been cooled, it is filtered with suction and the succinimide is washed with 20 ml of carbon tetrachloride. The filtrates are combined and carbon tetrachloride is distilled off in vacuo. 21.8 g of color- less liquid are obtained. The product is distilled under high vacuum (0.05 mbar, 94-97°C). Yield: 13.9 g (61% of theory; 93.6 area%).
Example 3:
Synthesis of 2-methoxyethyl 2-chloromethyl-6-methylbenzoate 10.4 g of 2-methoxyethyl 2,6-dimethylbenzoate are admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60-90°C for 1-2 h. Afterwards, the mixture is admixed with 20 ml of water, the phases are separated and the organic phase is dried over magnesium sulfate. The product is distilled under high vacuum (0.02 mbar, 95-103°C). Yield: 6.4 g (66% of theory; 91.8 area%).
Example 4:
Synthesis of benzyl 2-chloromethyl-6-methylbenzoate 12.0 g of benzyl 2,6-dimethylbenzoate are initially charged in 50 ml of carbon tetrachloride admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at reflux for 4-5 h.
Afterwards, it is admixed with 40 ml of saturated NaHCO3 solution. After the phase separation, the organic phase is washed with 50 mi of 10% sodium sulfite solution and the organic phase is dried over magnesium sulfate. The product-containing solution is filtered through silica gel and washed again with 20 ml of carbon tetrachloride. After distilling off the solvent in vacuo, the product obtained is a bright yellow oil. Yield: 8.0 g (73% of theory; 88.4 area%).
Example 5: 2-Methyl-6-[3-(2-phenyloxazol-4-ylmethoxy)propoxymethyllbenzoic acid 4.8 g of methyl 2-chloromethyl-6-methylbenzoate are dissolved at room temperature in 250 ml of acetone and admixed with 35 g of sodium iodide.
The mixture is heated to reflux for 6 h. Subsequently, the solvent is removed at 0°C in vacuo. The residue is analyzed by means of LC-MS (87.7 area% of methyl 2-iodomethyl-6-methylbenzoate) and dissolved in 20 mi of toluene. The solution is added dropwise at -20°C within 10 min to a mixture of 5.0 g of 3-(2-phenyloxazol-4-ylmethoxy)propan-1-ol, 4.8 g of potassium tert-butoxide and 30 ml of toluene. Afterwards, the mixture is stirred at -20°C for 6 h and diluted with 100 ml of water, and the aqueous phase is removed. The organic phase is admixed with 40 ml of NMP and 10 ml of 32% sodium hydroxide solution and heated to reflux for 8 h on a water separator. Subsequently, the mixture is admixed with 100 ml of water and extracted twice with 25 ml of MTB ether each time. The aqueous phase is acidified with 5 ml of acetic acid and extracted twice with 50 ml of ethyl acetate each time. After the phases have been separated, the organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. After the crystallization from diisopropyl! ether, 4.2 g of 2-methyl-6- [3-(2-phenyloxazol-4-ylmethoxy)propoxymethyllbenzoic acid (50% of theory, 99.2 HPLC area%) are obtained.
Claims (8)
1. A compound of the formula (I) JO CO,R (1) where R is H, C4-Cq2-alkyl, C3-Cg-cycloalkyl, Cg-C12-aryl, C1-C4- alkyl-Cg-C+2-aryl or Cs-Cqg-heteroaryl, and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by -O-, and alkyl, cycloalkyl and aryl may be substituted by halogen.
2. A compound of the formula (I) as claimed in claim 1 in which : R is C1-Cg alkyl, C3-Cg-cycloalkyl or C4-Cs-alkyl-Cg-C12-aryl, each of which may optionally be substituted by halogen and in which one or two CH groups may be replaced by -O-.
3. A compound of the formula (1) as claimed in claim 1 or 2 in which R is C1-Cg alkyl or C1-C4-alkyl-Cg-C42-aryl, each of which may optionally be substituted by halogen and in which one CH» group may be replaced by -O-.
4, A compound of the formula (I) as claimed in claims 1 to 3 in which R is methyl, ethyl, propyl, i-propyl, t-butyl, phenyl, 2-methoxy- ethyl or benzyl.
5. A process for preparing the compounds of the formula (I) as claimed in claims 1 to 4, which comprises reacting dimethylbenzoic esters of the formula (11)
CO,R (i where R is as defined above with a chlorinating reagent in an inert solvent or without solvents above 40°C and subsequently optionally purifying.
6. A process for preparing the compounds of the formula (C) rR 0) R" bs OLy-© COR (C) in which R is H, C4-Cq2-alkyl, C3-Cg-cycloalkyl, Cg-Cq2-aryl, C4-C4- alkyl-Cg-C12-aryl or Cs-C1p-heteroaryl and, in alkyl and cycloalkyl, one or more CH2 groups may be replaced by —-O- and alkyl, cycloakyl and aryl may be substituted by halogen, Y is -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl, R' is H, F, Br, CF3, (C1-Cg)-alkyl, O-(C4-Cg)-alkyl, phenyl; R” is H, (C1-Cg)alkyl, (C1-C3)-alkylphenyl, (Cs-Cg)-cycloalkyl, phenyl, CF3; which comprises reacting compounds of the formula (C1)
oo 11 - 2005/064889 R' 0] R" ba HOO (C1) where Y, R' and R"” are each as defined above with compounds of the formula (I) JO COR where R is as defined above in toluene, NMP or other aprotic solvents, in the presence of a suitable base, at -78 to +50°C, and subsequently working up extractively and optionally crystallizing the end product.
7. The process for preparing the compounds of the formula (C) as claimed in claim 6, wherein the phenyl ring is substituted by R’ in the m- or p-position.
8. The use of the compounds of the formula (I) as claimed in claims 1 to 4 for preparing PPAR agonists of the general formula (C).
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TW200502213A (en) | 2005-01-16 |
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