CN87104206A - M-nitro benzoic acid derivative and manufacture method thereof - Google Patents
M-nitro benzoic acid derivative and manufacture method thereof Download PDFInfo
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- CN87104206A CN87104206A CN198787104206A CN87104206A CN87104206A CN 87104206 A CN87104206 A CN 87104206A CN 198787104206 A CN198787104206 A CN 198787104206A CN 87104206 A CN87104206 A CN 87104206A CN 87104206 A CN87104206 A CN 87104206A
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- Prior art keywords
- benzoic acid
- nitro benzoic
- compound
- salt
- represented
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Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical class OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 206010003210 Arteriosclerosis Diseases 0.000 abstract description 6
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 6
- 239000008280 blood Substances 0.000 abstract description 6
- 150000002632 lipids Chemical class 0.000 abstract description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- AXLYJLKKPUICKV-UHFFFAOYSA-N methyl 3-nitrobenzoate Chemical class COC(=O)C1=CC=CC([N+]([O-])=O)=C1 AXLYJLKKPUICKV-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- -1 isobutyl- Chemical group 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010060891 General symptom Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- MUADFEZFSKAZLT-UHFFFAOYSA-M sodium;3-nitrobenzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC([N+]([O-])=O)=C1 MUADFEZFSKAZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UEOQGGDCTJBMII-UHFFFAOYSA-M C(C)OC([O-])=O.[Cl+] Chemical class C(C)OC([O-])=O.[Cl+] UEOQGGDCTJBMII-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- KIGXMYYGQYMICF-UHFFFAOYSA-N Diphenylphosphine Acid Chemical compound C=1C=CC=CC=1P(=O)(CCCCC(=O)O)C1=CC=CC=C1 KIGXMYYGQYMICF-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ZSGNESWZWFRGKW-UHFFFAOYSA-N [Cl].OC(O)=O Chemical compound [Cl].OC(O)=O ZSGNESWZWFRGKW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000004459 forage Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment 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
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of by general formula [I]:
Salt that is allowed on represented M-nitro benzoic acid derivative and the pharmacology thereof and their manufacture method.The salt that is allowed on this novel M-nitro benzoic acid derivative and the pharmacology thereof can reduce lipid in the blood, and is very useful aspect treatment and preventing hyperlipidemia and arteriosclerosis.
Description
The present invention relates to reduce lipid in the blood, to treatment hyperlipidaemia and arteriosclerosis useful and by the salt that is allowed on represented novel M-nitro benzoic acid derivative of following general formula [I] and the physiology thereof.
X represents that halogen, R represent hydrogen or alkyl in the formula.
As the therapeutical agent of hyperlipidaemia, arteriosclerosis, the past is to adopt various pharmaceuticals always, does not still still have validity of appearing at and security aspect so far and makes the satisfied medicine of people.On the other hand, as with the existing HB-699[A-cta Endocrinol.100 of The compounds of this invention similar compounds, Suppl.247,26(1982)].
This material uses as antidiabetic, and the material that can show pharmacological action involved in the present invention is not as yet by known to the people.
The present inventor is to be that purpose is studied repeatedly with the compound that obtains having novel texture, have than the more excellent effect of lipid depressant in the known blood of past.
Have the compound that reduces lipid effect in the blood in order to develop, the present inventor has carried out deep repeatedly research with regard to the myriad of compounds with novel texture, found that by the represented compound of general formula [I] to be suitable for this purpose, thereby has finished the present invention.
Compound involved in the present invention be document not the record novel cpd, be characterised in that on its chemical structure that the M-nitro benzoic acid amino-ethyl is to combine with M-nitro benzoic acid by Sauerstoffatom.
In general formula [I], be preferably the material that carbon number is 1～7 straight or branched by the represented alkyl of R, for example can enumerate methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-, tert-butyl, just-amyl group, isopentyl, just-hexyl, isohexyl, n-heptyl, different heptyl etc.Especially, carbon number is that 1～4 material is better.
The halogen represented by X can adopt fluorine, chlorine, bromine, iodine.
When R is hydrogen, also can directly use in the free mode, but also can employing itself disclosed method used with the form of the salt that allowed on the pharmacology.As this salt, can exemplify out sodium salt and calcium salt etc.
As compound involved in the present invention, the compound of in the embodiment that the method for making of mentioning is related of back, having put down in writing, also can exemplify out following compound, but these to be parts for the illustration The compounds of this invention disclose, and compound of the present invention is not limited by these.
The 4-[2-(3-chlorobenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
The 4-[2-(2-chlorobenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
The 4-[2-(3-chlorobenzamide) oxyethyl group] M-nitro benzoic acid
The 4-[2-(2-chlorobenzamide) oxyethyl group] the M-nitro benzoic acid sodium salt
The 4-[2-(3-fluorobenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
The 4-[2-(3-fluorobenzamide) oxyethyl group] M-nitro benzoic acid
The 4-[2-(3-brombenzamide) oxyethyl group] M-nitro benzoic acid
The 4-[2-(3-brombenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
The 4-[2-(2-brombenzamide) oxyethyl group] M-nitro benzoic acid
The 3-[2-(2-chlorobenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
The 3-[2-(3-fluorobenzamide) oxyethyl group] M-nitro benzoic acid
The 3-[2-(2-brombenzamide) oxyethyl group] ethyl benzoate
The 2-[2-(3-chlorobenzamide) oxyethyl group] M-nitro benzoic acid
The 2-[2-(2-fluorobenzamide) oxyethyl group] ethyl benzoate
The 2-[2-(3-brombenzamide) oxyethyl group] M-nitro benzoic acid
The compounds of this invention [I] all belongs to the novel cpd that document is not put down in writing, and for example can make by method shown below.
[X, R are as hereinbefore in the formula]
That is, make compound [III] and carbonic acid [II] thereby or its reactive derivatives react and produce [I].This amyl group reaction can the known method of employing itself be carried out.For example, can adopt with condensing agent and make directly bonded method or can adopt the reactive derivatives that makes [II] for example hydracid, imidazolidine or mixing acid anhydride etc. carry out the method for appropriate reaction of [II] and [III].
When adopting hydracid (for example chloric acid, bromic acid etc.), reaction is normally in appropriate solvent (for example solvent, water or their mixture etc. of hydrocarbon series such as the solvent of halocarbon hydrogen series such as the solvent of ether series such as ether, tetrahydrofuran (THF), diox, methyl chloride, chloroform, benzene,toluene,xylene) and carry out under-20～30 ℃ temperature in the presence of alkali (for example third stage organic basess such as mineral alkalis such as salt of wormwood, sodium hydroxide, potassium hydroxide, pyridine, triethylamine etc.).It is 1～1.2 mole during normally relative 1 mole compound of the usage quantity of hydracid [III].
When using the mixing acid anhydride, at first make compound [II] and for example chlorine carbonic ether (as chlorine carbonic acid methyl alcohol, chlorine carbonic acid ethanol, chlorine charcoal acid isopropylcarbinol) in the presence of alkali (as organic basess such as pyridine, triethylamines) and in appropriate solvent, preferably in the solution of halocarbon hydrogen series such as methyl chloride, chloroform, under-20 °～20 ℃ temperature, react, be modulated into mixing acid anhydride solution, compound (III) is reacted with-10～30 ℃ temperature.The consumption of mixing acid anhydride during with 1 mole compound (III) 1～1.2 mole be advisable.
Using condensing agent directly to carry out under the situation of condensation, reaction is usually at appropriate solvent (for example solvent, acetonitrile, the N of ether series such as the solvent of halocarbon such as methyl chloride, chloroform hydrogen series, tetrahydrofuran (THF), diox, the non-protonic solvent of dinethylformamide etc.) adopt condensing agent (for example N, N '-dicyclohexylcarbodiimide, diphenylphosphine acid amide etc.) under-10 ℃～room temperature, to carry out in.The consumption of compound (II) during with 1 mole compound (VI) 1～1.2 mole be advisable.
In The compounds of this invention [I], R is that the compound of hydrogen can add water decomposition manufacturing by ester (R=low alkyl group) execution that aforesaid method is made.It is this that to add water decomposition reaction be to carry out under the temperature of room temperature to 80 ℃ in aqueous alcohol (as methyl alcohol, ethanol etc.) in the presence of the mineral acids such as hydrochloric acid, sulfuric acid.The usage quantity of acid is measured relative 1 mole of ester (R=low alkyl group) usually and is 0.1～10 mole, is preferably 0.2～3 mole.
This add water decomposition reaction also can in the presence of salt of wormwood, sodium hydroxide, the potassium hydroxide etc. in methyl alcohol, ethanol or its mixing solutions usually in 0～150 ℃, preferably carry out under 20～100 ℃ the temperature.The usage quantity of alkali is 1～5 mole during with 1 mole of ester (R=low alkyl group) is advisable, and is preferably 2～3 moles.
In compound of the present invention, R is that the compound of alkyl also can be made carbonic acid (R=hydrogen) the execution esterification made from aforesaid method by employing itself disclosed method.This esterification can be utilized itself known esterification process, for example diazomethane, alcohol and sour (for example hydrochloric acid, sulfuric acid, tosic acid etc.), and perhaps thionyl chloride and alcohol etc. carry out.
At the compound that obtains with aforesaid method (I) under the situation of free carbonic acid (R=H), the salt of the alkali that can adopt usual method to generate on the pharmacology to be allowed.
For example under the occasion of an alkali metal salt, be placed on the acid (R=low alkyl group) of making in the alcohol or adopt sodium hydroxide or potassium hydroxide etc. to obtain in the aqueous alcohol by adding water decomposition with above-mentioned same method with aforesaid method.Perhaps in carbonic acid (R=H), preferably in the solvent of alcohol series, obtain corresponding potassium metal-salt by adding normal sodium hydroxide or potassium hydroxide.
So purpose compound [I] that obtains or its salt by adopting common separation and purification means, for example extract, concentrate, means separation and purifications from reaction mixture such as chromatography, tlc come out in the neutralization, filtration, recrystallize, post.
The used starting compound of the present invention is known compound, and it can be made by known method (spy opens clear 50-123671 communique), but also can be by method manufacturing shown below.
(R is same as described above in the formula)
That is, compound [IV] is placed on by in the represented alcohol of ROH, uses the amine of 1～5 times of mole to reflux.Compound [IV] though be new compound, can be by following either party's manufactured.
[R as hereinbefore in the formula]
The reaction of A method adopts the peptide imide potassium of equivalent mole to carry out in 50～100 ℃ normally in appropriate solvent (for example acetonitrile, N, dinethylformamide).
The reaction of B method normally in the presence of suitable de-acidying agent (for example Anhydrous potassium carbonate, sodium methylate, sodium ethylate etc.) and in appropriate solvent (for example, during the occasion of Anhydrous potassium carbonate is N, dinethylformamide, acetonitrile etc., during the occasion of sodium methylate is methyl alcohol etc., and the occasion of sodium ethylate is an ethanol etc.) in adopt the Para Hydroxy Benzoic Acid (or ester) of equivalent mole under 40～100 ℃, to carry out.
The compound (II) that constitutes another raw material is a compound known, perhaps can make by known method.
The salt that is allowed on compound of the present invention and the pharmacology thereof has the effect of intensive lipid lowering, and toxicity is extremely low, therefore can be widely used in the treatment of hyperlipidaemia and arteriosclerosis.
The result that below will show pharmacological testing, these test cards are understood the availability of representational compound in the The compounds of this invention.
(1) to the effect of big white mouse that cholesterol load is arranged
Male Vista (Http Ren ス one) to three weeks of back of being born is that big white mouse has carried out having carried out group's branch after preparation in 7 days is raised with normal synthetic foodstuff.Make it freely to absorb the high-cholesterol diet that contains 0.1% tested medicine then and reach 3 days, make it to go on a hunger strike one day and take a blood sample again afterwards, thereby measured the total cholesterol value (TC) of gained serum.Make a group group in contrast who has eaten the high-cholesterol diet of not adding medicament again, and make a group of having eaten normal synthetic foodstuff as normal group.Calculated the rising inhibiting rate of the serum TC of tested medicine according to following formula:
TC rising inhibiting rate=((control group)-(experiment group))/((control group)-(normal group)) * 100
Its result is by shown in the table 1
Table 1
* means the obvious errors of 1% risk.
The serum TC reduction effect of The compounds of this invention is very clear.
(2) to the serum TC effect of falling of normal red hair monkey
Test method(s): is the age that 2～6 years old male red hair monkey (body weight is 3.0～8.0 kilograms) is used for experiment.At the amount feeding solid type feed (east yeast corporate system) of experimental session with 1 day 1 time 150 gram.The experiment group is an a group with 2～6.By the test medicine is 0.5% CMC suspension liquid (experiment numbers 1 and 2) or 0.5% MC suspension liquid (experiment numbers 3), with 30,100 or 300 milligrams/kilogram dosages 10 days (experiment numbers 3) or dropped into from mouth by the rubber probe in (experiment numbers 1 and 2) in 14 days.Blood sampling be before a week of dispensing, before the dispensing at once and 4,7,10,14,21,28 days of beginning of dispensing after the lower limb great saphenous vein carries out, and measured serum TC.Calculated the velocity of variation of serum TC by following formula.
The velocity of variation of serum TC=((by the TC after the reagent input)-(being dropped into preceding TC))/((being dropped into preceding TC)) by reagent by reagent
(week before the TC before the so-called tested medicine input is meant and drops into drop into before at once mean value)
Its result is as shown in table 2.
Table 2
The serum TC effect of falling of The compounds of this invention is very clear
(3) acute toxicity
(a) test method(s) on mouse:
The ddy that makes birth 6 weeks of back is the back medication of going on a hunger strike that male mice was done 24 hours.From mouth, drop into the physiological water suspension liquid of 0.5% Walsroder MC 20000S contain tested medicine, carry out common forage feed then, and to whether general symptom occurring and dead example has been carried out the observation in 2 weeks.
Consequently, all embodiment compounds all belong to hypotoxicity, do not find dead example with the input amount of 2 gram/kilograms.
(b) test method(s) on big white mouse:
Make that the male white rat in 5 weeks is an a group with four after the birth of SD system, from mouth, offer medicine, whether occur the observation that general symptom and dead example carried out for 2 weeks then.
Its result, the compound of enforcement 4 is not all found any unusual with 5 gram/kilogram dosages.
Compound of the present invention is thrown as medicine and the time, can directly throw The compounds of this invention and the animal body that comprises human body, perhaps for example to throw to the animal body that comprises human body as medical component in 0.1%～99.5% nontoxicity that preferably is comprised in pharmaceutically to be allowed with 0.5～90% amount and the not active carrier.
As carrier can use solid-state, semi-solid state or liquid thinner filling agent and other prescription usefulness auxiliary agent more than one.The best throwing with form with unit of the dispensing of medical component carried out.The mode that drop in medical component of the present invention can drop into from mouth, organize, (applying through subcutaneous) or per rectum input is dropped in the part is carried out.Certainly should offer medicine with the formulation that is fit to these input methods.For example from mouth, drop into to best.
Preferably to after factors such as the state of having considered patients such as age, body weight, dosing way, sick character and degree, adjust as the consumption of arteriosclerosis Remedies, but be 100 milligrams～3 gram/sky/people effective ingredient amount of the present invention every day used as the grownup, preferably is generally 500 milligrams～1 gram/sky/people's scope.It is also much of that according to circumstances to be less than this amount sometimes, also must be higher than this scope sometimes.In addition, preferably three separately dispensings every day.
Thereby below put down in writing the reference example and the embodiment that relate to the The compounds of this invention manufacturing the present invention has been made more specific description.
Reference example 1
(1) ethyl N-[2-(4-methoxycarbonyl phenoxy group)] phthalic diamide
126.52 gram 4-(2-bromo oxyethyl groups) M-nitro benzoic acid methyl esters and the sylvite of 99.5 gram phthalic diamides are dissolved in 660 milliliters N, in the dinethylformamide, 78～80 ℃ of stirrings 2 hours down.Then reaction solution being injected frozen water extracts with chloroform.As chloroform layer being done after twice washing then with anhydrous magnesium sulfate drying again and made concentrating under reduced pressure, then residue begins to carry out crystallization.Then in residue, add ether and then filtration, thereby crystallization (yield the is 94%) fusing point that obtains 149.23 grams is 129～130.5 ℃.
(2) M-nitro benzoic acid methyl esters 4-(2-amino ethoxy)
The N-[2-(4-methoxycarbonyl phenoxy groups that obtain with quadrat method with (1) of 158.86 grams) ethyl] hydrazine hydrate of phthalic diamide and 73.33 grams are dissolved in 1.5 liters the methyl alcohol and do backflow in 1 hour.Disgorging and filtrate made concentrating under reduced pressure after filtration.Clean 2 times with the chloroform extraction residue and with saturated aqueous common salt then.Then with the anhydrous magnesium sulfate drying organic layer and make concentrating under reduced pressure.Just in residue, add-hexane carries out crystallization and filters, and then obtained 85.74 crystallizations (yield is 90%) that restrain.
Fusing point is 53～55.5 ℃
Embodiment 1
The 4-[2-(4-chlorobenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
19.5 gram 4-(2-amino ethoxies) M-nitro benzoic acid methyl esters and 13.8 restrains Anhydrous potassium carbonates and is incorporated in 200 milliliters of chloroforms and makes cooling and stirring.Under 10～20 ℃ interior temperature, splash into the right-chloro-benzoyl chloride of 17.5 grams.Do 3 hours stirring after dripping.Washed reaction liquid.With anhydrous magnesium sulfate chloroform layer is carried out drying and makes concentrating under reduced pressure then.With just-hexane makes residue carry out crystallization.With acetic acid second vinegar-just-hexane recrystallize being implemented in crystallization again, is 125～127 ℃ crystallization (yield is 76%) thereby obtain melting point.
The ultimate analysis value is (as C
17H
16Cl NO
4)
Calculated value (%) C:61.18 H:4.83 N:4.20
Measured value (%) C:61.34 H:4.8 N:4.24
Embodiment 2
4-[2-(4-bromobenzene methane amide) oxyethyl group] the M-nitro benzoic acid methyl esters
6 right-bromine M-nitro benzoic acids of gram and 3.35 gram triethylamines are dissolved in 80 milliliters of chloroforms, under 0～5 ℃, make cooling and stirring and splash into 3.26 gram chlorine ethyl-carbonates.Splash into the back and under this temperature, do 30 minutes stirring, add 5.86 gram 4-(2-amino ethoxies then) M-nitro benzoic acid methyl esters and remake 7 hours stirring.Then clean this reaction solution with the unsaturated carbonate aqueous solutions of potassium then with 10% hydrochloric acid.The washing back is with anhydrous magnesium sulfate drying and make concentrating under reduced pressure.With just-hexane carried out just having obtained after the crystallization crystallizations of 8.5 grams to residue.With vinyl acetic monomer this is carried out recrystallize more at last.The gained amount is 6.4 grams.Fusing point is 134～136 ℃
The ultimate analysis value is (as C
17H
16Br NO
4)
Calculated value (%) C:53.99 H:4.26 N:3.70
Measured value (%) C:53.98 H:4.04 N:3.72
Embodiment 3
The 4-[2-(4-fluorobenzamide) oxyethyl group] the M-nitro benzoic acid methyl esters
19.5 gram 4-(2-amino ethoxies) M-nitro benzoic acid methyl esters and 14 restrains right-fluorine M-nitro benzoic acid and is dissolved in 300 milliliters of N, in the dinethylformamide, at room temperature with 20.6 gram N, stir on N-dicyclohexyl carbodiimide limit then, the limit adds, but needs to add slightly on a small quantity.After stirring in 8 hours, with the N that is produced, the N-dicyclohexylurea (DCU) removes by filter, and filtrate is injected frozen water, extracts with vinyl acetic monomer.Then with the unsaturated carbonate aqueous solutions of potassium organic layer is cleaned washing more again with 10% hydrochloric acid earlier.With anhydrous magnesium sulfate drying and make concentrating under reduced pressure.Just in residue, add-thereby hexane carries out the crystallizations that crystallization obtains 25.4 grams.With vinyl acetic monomer-hexane this being made just to obtain behind the recrystallize fusing point is 105～107 ℃ crystallization 21.3 grams (yield is 67%).
Ultimate analysis value (%) is (as C
17H
16FNO
4)
Calculated value (%) C:64.35 H:5.08 N:4.41
Measured value (%) C:64.41 H:5.14 N:4.47
Embodiment 4
The 4-[2-(4-chlorobenzamide) oxyethyl group] M-nitro benzoic acid
10.0 gram 4-[2-(4-chlorobenzamides) oxyethyl group] M-nitro benzoic acid methyl esters heating for dissolving is in 100 milliliters ethanol.2.4 gram dissolution of sodium hydroxide in 20 ml waters, are joined then and make 2 hours reflux in the above-mentioned ethanolic soln.Reaction solution is made behind the concentrating under reduced pressure to add 100 milliliters water again and neutralized with 10% hydrochloric acid in residue, wash after the crystallization that leaching is separated out, then drying.Carrying out crystallization at last from ethanol again, is 219～220 ℃ crystallization 8.4 grams (yield is 87%) thereby obtained fusing point.
The ultimate analysis value is (as C
16H
14Cl NO
4)
Calculated value (%) C:60.11 H:4.41 N:4.38
Measured value (%) C:60.23 H:4.28 N:4.32
Embodiment 5
The 4-[2-(4-chlorobenzamide) oxyethyl group] the M-nitro benzoic acid sodium salt
3.19 gram 4-[2-(4-chlorobenzamides) oxyethyl group] M-nitro benzoic acid is dissolved in 50 milliliters the methyl alcohol.Then restrain dissolution of sodium hydroxide to 0.40 in 5 ml waters again, it is added carry out concentrating under reduced pressure in the above-mentioned methanol solution then, thereby residue carries out crystallization.2.30 crystallizations that restrain have just been obtained after making its recrystallize with methyl alcohol then.Fusing point is more than 300 ℃.
IR
kBr max（cm
-1）：1640，1605
The ultimate analysis value is (as C
16H
13Cl NO
4Na 1/2 H
2O)
Calculated value (%) C:54.79 H:4.02 N:3.99
Measured value (%) C:54.83 H:4.15 N:4.01
Done with the same operation of embodiment 1～5 after obtained following compound.
Embodiment 6
The 4-[2-(4-brombenzamide) oxyethyl group] M-nitro benzoic acid
Fusing point is 233～235 ℃.
The ultimate analysis value is (as C
16H
14Br NO
4)
Calculated value (%) C:52.77 H:3.86 N:3.85
Measured value (%) C:52.82 H:3.80 N:3.84
Embodiment 7
The 4-[2-(4-fluorobenzamide) oxyethyl group] M-nitro benzoic acid
Fusing point is 196～198 ℃
The ultimate analysis value is (as C
16H
14FNO
3)
Calculated value (%) C:63.36 H:4.65 N:4.62
Measured value (%) C:63.14 H:4.84 N:4.67
Embodiment 8
The 4-[2-(4-chlorobenzamide) oxyethyl group] ethyl benzoate
Fusing point is 136～137 ℃
The ultimate analysis value is (as C
18H
18Cl NO
4)
Calculated value (%) C:62.16 H:5.22 N:4.03
Measured value (%) C:62.15 H:5.15 N:4.04
Embodiment 9
The 4-[2-(4-fluorobenzamide) oxyethyl group] ethyl benzoate
Fusing point is 111～112 ℃
The ultimate analysis value is (as C
18H
18FNO
4)
Calculated value (%) C:65.25 H:5.48 N:4.23
Measured value (%) C:65.30 H:5.68 N:4.19
Can be clear that from above result, The compounds of this invention [I] be on the document not the record new compound, when being applied to the human or animal, shown very strong lipid lowering effect, and have only significantly low toxicity, so be of great use as the high hyperlipidaemia of TC in the blood, TG value and the curative of arteriosclerosis.
Claims (3)
1, a kind of by the salt that is allowed on represented M-nitro benzoic acid derivative of following general formula [I] and the pharmacology thereof.
X represents halogen in the formula, and R represents hydrogen or alkyl.
2, a kind of by general formula [I] promptly
The manufacture method of the salt that is allowed on M-nitro benzoic acid derivative that (X, R are as hereinbefore) is represented and the pharmacology thereof is characterized in that: make general formula [III] promptly
Compound that (R represents hydrogen or alkyl in the formula) is represented and general formula [II] are promptly
The derivative that the carbonic acid that (X represents halogen in the formula) is represented or its reaction generate reacts.
3, a kind of by general formula [I]:
The manufacture method of the salt that is allowed on M-nitro benzoic acid derivative that (X, R are as hereinbefore) is represented and the pharmacology thereof is characterized in that making general formula [V]:
(X represents halogen in the formula) represented compound with by general formula [VI]
(R represents hydrogen or alkyl in the formula), represented compound reacted.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP136407/86 | 1986-06-11 | ||
| JP61136407A JPH0625092B2 (en) | 1986-06-11 | 1986-06-11 | Benzoic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN87104206A true CN87104206A (en) | 1987-12-23 |
Family
ID=15174441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN198787104206A Pending CN87104206A (en) | 1986-06-11 | 1987-06-11 | M-nitro benzoic acid derivative and manufacture method thereof |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPH0625092B2 (en) |
| KR (1) | KR880000384A (en) |
| CN (1) | CN87104206A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI759595B (en) * | 2018-05-11 | 2022-04-01 | 日商東京威力科創股份有限公司 | Substrate processing system and substrate processing method |
-
1986
- 1986-06-11 JP JP61136407A patent/JPH0625092B2/en not_active Expired - Lifetime
-
1987
- 1987-06-11 CN CN198787104206A patent/CN87104206A/en active Pending
- 1987-06-11 KR KR870005905A patent/KR880000384A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| KR880000384A (en) | 1988-03-25 |
| JPH0625092B2 (en) | 1994-04-06 |
| JPS62292754A (en) | 1987-12-19 |
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