PL67917B1

PL67917B1 -

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Publication number: PL67917B1
Authority: PL; Poland
Prior art keywords: acid; formula; chlorobenzoyl; acylated; base
Prior art date: 1967-10-12

Application number

PL122989A

Other languages

English (en)

Polish (pl)

Original Assignee

Merck And Co

Filing date

1967-10-12

Publication date

1972-12-30

1967-10-12 Application filed by Merck And Co filed Critical Merck And Co

1972-12-30 Publication of PL67917B1 publication Critical patent/PL67917B1/pl

Links

239000002253 acid Chemical group 0.000 claims description 26
238000000034 method Methods 0.000 claims description 22
JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 claims description 20
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
239000002585 base Substances 0.000 claims description 14
-1 p-chlorobenzoyl halide Chemical class 0.000 claims description 14
RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 claims description 10
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
150000001875 compounds Chemical class 0.000 claims description 10
229940040102 levulinic acid Drugs 0.000 claims description 10
150000004031 phenylhydrazines Chemical class 0.000 claims description 9
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 6
239000001632 sodium acetate Substances 0.000 claims description 6
235000017281 sodium acetate Nutrition 0.000 claims description 6
150000002148 esters Chemical class 0.000 claims description 5
238000002360 preparation method Methods 0.000 claims description 5
150000003839 salts Chemical group 0.000 claims description 5
230000002378 acidificating effect Effects 0.000 claims description 4
150000001540 azides Chemical class 0.000 claims description 4
150000007530 organic bases Chemical group 0.000 claims description 4
150000008064 anhydrides Chemical class 0.000 claims description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
QDAPWMKWLVMBBU-UHFFFAOYSA-N 2-[1-(4-chlorobenzoyl)-2-methylindol-3-yl]acetic acid Chemical class CC1=C(CC(O)=O)C2=CC=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 QDAPWMKWLVMBBU-UHFFFAOYSA-N 0.000 claims 1
PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical group [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 claims 1
229910052783 alkali metal Inorganic materials 0.000 claims 1
150000001340 alkali metals Chemical class 0.000 claims 1
229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims 1
125000001174 sulfone group Chemical group 0.000 claims 1
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
239000011541 reaction mixture Substances 0.000 description 22
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
239000000203 mixture Substances 0.000 description 20
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
230000010933 acylation Effects 0.000 description 17
238000005917 acylation reaction Methods 0.000 description 17
239000000243 solution Substances 0.000 description 15
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
229940067157 phenylhydrazine Drugs 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
239000002904 solvent Substances 0.000 description 11
238000003756 stirring Methods 0.000 description 11
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
150000007857 hydrazones Chemical class 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
229910000147 aluminium phosphate Inorganic materials 0.000 description 7
229910052757 nitrogen Inorganic materials 0.000 description 7
HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 7
239000000047 product Substances 0.000 description 7
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
238000009833 condensation Methods 0.000 description 6
230000005494 condensation Effects 0.000 description 6
239000003960 organic solvent Substances 0.000 description 5
238000007363 ring formation reaction Methods 0.000 description 5
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
238000006243 chemical reaction Methods 0.000 description 4
CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
238000002844 melting Methods 0.000 description 4
230000008018 melting Effects 0.000 description 4
ZNSBPFFOQMIZIO-UHFFFAOYSA-N phenyl N-aminosulfamate Chemical class NNS(=O)(=O)OC1=CC=CC=C1 ZNSBPFFOQMIZIO-UHFFFAOYSA-N 0.000 description 4
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
150000001299 aldehydes Chemical class 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
238000001816 cooling Methods 0.000 description 3
239000000284 extract Substances 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
239000010410 layer Substances 0.000 description 3
150000007522 mineralic acids Chemical class 0.000 description 3
NNPXCKWGJZVCKD-UHFFFAOYSA-M sodium;n-amino-n-(4-methoxyphenyl)sulfamate Chemical compound [Na+].COC1=CC=C(N(N)S([O-])(=O)=O)C=C1 NNPXCKWGJZVCKD-UHFFFAOYSA-M 0.000 description 3
239000000725 suspension Substances 0.000 description 3
MWUSAETYTBNPDG-UHFFFAOYSA-N (4-chlorobenzoyl) 4-chlorobenzoate Chemical compound C1=CC(Cl)=CC=C1C(=O)OC(=O)C1=CC=C(Cl)C=C1 MWUSAETYTBNPDG-UHFFFAOYSA-N 0.000 description 2
FQHCPFMTXFJZJS-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine;hydrochloride Chemical compound Cl.COC1=CC=C(NN)C=C1 FQHCPFMTXFJZJS-UHFFFAOYSA-N 0.000 description 2
ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
235000011114 ammonium hydroxide Nutrition 0.000 description 2
229940121363 anti-inflammatory agent Drugs 0.000 description 2
239000002260 anti-inflammatory agent Substances 0.000 description 2
239000012736 aqueous medium Substances 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
239000012043 crude product Substances 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
239000012065 filter cake Substances 0.000 description 2
SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical class C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 2
150000002475 indoles Chemical class 0.000 description 2
150000007529 inorganic bases Chemical class 0.000 description 2
229910052500 inorganic mineral Inorganic materials 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
150000002576 ketones Chemical class 0.000 description 2
239000011707 mineral Substances 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
239000012044 organic layer Substances 0.000 description 2
239000002244 precipitate Substances 0.000 description 2
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
238000010992 reflux Methods 0.000 description 2
239000000758 substrate Substances 0.000 description 2
239000012485 toluene extract Substances 0.000 description 2
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
OZPSGURLNSOOAG-UHFFFAOYSA-N 2-(5-methoxy-1h-indol-3-yl)propanoic acid Chemical compound COC1=CC=C2NC=C(C(C)C(O)=O)C2=C1 OZPSGURLNSOOAG-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
IURNVVIQOMTXSM-UHFFFAOYSA-N 4-chloro-n-(4-methoxyphenyl)benzohydrazide Chemical compound C1=CC(OC)=CC=C1N(N)C(=O)C1=CC=C(Cl)C=C1 IURNVVIQOMTXSM-UHFFFAOYSA-N 0.000 description 1
125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
URUDZLDUJCDPDC-UHFFFAOYSA-N 4-hydrazinyl-N,N-dimethylaniline dihydrochloride Chemical compound Cl.Cl.CN(C1=CC=C(C=C1)NN)C URUDZLDUJCDPDC-UHFFFAOYSA-N 0.000 description 1
OIJUIOFPGITTDF-UHFFFAOYSA-N COC1=CC=C(C=C1)NN.[Na] Chemical compound COC1=CC=C(C=C1)NN.[Na] OIJUIOFPGITTDF-UHFFFAOYSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
206010063560 Excessive granulation tissue Diseases 0.000 description 1
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
238000003436 Schotten-Baumann reaction Methods 0.000 description 1
239000003377 acid catalyst Substances 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
ZMJZYXKPJWGDGR-UHFFFAOYSA-N aminosulfamic acid Chemical compound NNS(O)(=O)=O ZMJZYXKPJWGDGR-UHFFFAOYSA-N 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
239000003849 aromatic solvent Substances 0.000 description 1
230000002917 arthritic effect Effects 0.000 description 1
JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
230000000903 blocking effect Effects 0.000 description 1
238000009835 boiling Methods 0.000 description 1
239000006227 byproduct Substances 0.000 description 1
239000002775 capsule Substances 0.000 description 1
239000003610 charcoal Substances 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
239000007859 condensation product Substances 0.000 description 1
238000006482 condensation reaction Methods 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000012467 final product Substances 0.000 description 1
239000012458 free base Substances 0.000 description 1
210000001126 granulation tissue Anatomy 0.000 description 1
JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
150000002429 hydrazines Chemical class 0.000 description 1
230000003301 hydrolyzing effect Effects 0.000 description 1
239000005457 ice water Substances 0.000 description 1
239000012535 impurity Substances 0.000 description 1
230000001939 inductive effect Effects 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
238000002955 isolation Methods 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
229910052808 lithium carbonate Inorganic materials 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
239000012071 phase Substances 0.000 description 1
229910052698 phosphorus Inorganic materials 0.000 description 1
239000011574 phosphorus Substances 0.000 description 1
XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
230000007017 scission Effects 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000007858 starting material Substances 0.000 description 1
125000000542 sulfonic acid group Chemical group 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
BHAROVLESINHSM-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1.CC1=CC=CC=C1 BHAROVLESINHSM-UHFFFAOYSA-N 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
239000008096 xylene Substances 0.000 description 1

PL122989A 1967-10-12 PL67917B1 (esLanguage)