NO157418B - NEW BENZOTIAZINE DERIVATIVE SUITABLE FOR USE IN PIROXICAM PREPARATION. - Google Patents
NEW BENZOTIAZINE DERIVATIVE SUITABLE FOR USE IN PIROXICAM PREPARATION. Download PDFInfo
- Publication number
- NO157418B NO157418B NO872669A NO872669A NO157418B NO 157418 B NO157418 B NO 157418B NO 872669 A NO872669 A NO 872669A NO 872669 A NO872669 A NO 872669A NO 157418 B NO157418 B NO 157418B
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- Prior art keywords
- piroxicam
- methoxyethyl
- ester
- reaction
- methyl
- Prior art date
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- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 title description 24
- 229960002702 piroxicam Drugs 0.000 title description 22
- 238000002360 preparation method Methods 0.000 title description 3
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical class C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 claims 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- -1 compound 2-methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide Chemical class 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- SVLBINWLZIVRJX-UHFFFAOYSA-N 2-methoxyethyl 2-chloroacetate Chemical compound COCCOC(=O)CCl SVLBINWLZIVRJX-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEBOMJVUVHOAGO-UHFFFAOYSA-N 2-methoxyethyl 4-hydroxy-1,1-dioxo-2h-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)NC(C(=O)OCCOC)=C(O)C2=C1 HEBOMJVUVHOAGO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005915 ammonolysis reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- VJGMQUWZFATDFA-UHFFFAOYSA-N 2-methoxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)N(C)C(C(=O)OCCOC)=C(O)C2=C1 VJGMQUWZFATDFA-UHFFFAOYSA-N 0.000 description 2
- CPIFFCMMBZLKDK-UHFFFAOYSA-N 2-methyl-1,1-dioxo-3h-1$l^{6},2-benzothiazin-4-one Chemical class C1=CC=C2S(=O)(=O)N(C)CC(=O)C2=C1 CPIFFCMMBZLKDK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- IFTPCUVCJPGKFN-UHFFFAOYSA-N 2-[4-(2-methoxyethyl)-1,1,3-trioxo-1,2-benzothiazol-2-yl]acetic acid Chemical compound COCCC1=CC=CC2=C1C(=O)N(CC(O)=O)S2(=O)=O IFTPCUVCJPGKFN-UHFFFAOYSA-N 0.000 description 1
- CUIGSPBMMQWNLR-UHFFFAOYSA-N 2-isocyanatopyridine Chemical compound O=C=NC1=CC=CC=N1 CUIGSPBMMQWNLR-UHFFFAOYSA-N 0.000 description 1
- ASQUQUOEFDHYGP-UHFFFAOYSA-N 2-methoxyethanolate Chemical compound COCC[O-] ASQUQUOEFDHYGP-UHFFFAOYSA-N 0.000 description 1
- BYHUHMDBGLBLTI-UHFFFAOYSA-N 4-hydroxy-2-(2-methoxyethyl)-1,1-dioxo-1lambda6,2-benzothiazine-3-carboxamide Chemical compound C1=CC=C2S(=O)(=O)N(CCOC)C(C(N)=O)=C(O)C2=C1 BYHUHMDBGLBLTI-UHFFFAOYSA-N 0.000 description 1
- RQRCJRUUPFZABV-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,2-benzothiazine-3-carboxylic acid Chemical compound C1=CC=C2C(O)=C(C(O)=O)N(C)SC2=C1 RQRCJRUUPFZABV-UHFFFAOYSA-N 0.000 description 1
- CEZONZYUIJKSND-UHFFFAOYSA-N 4-hydroxy-2-methyl-n-phenyl-1,2-benzothiazine-3-carboxamide Chemical class CN1SC2=CC=CC=C2C(O)=C1C(=O)NC1=CC=CC=C1 CEZONZYUIJKSND-UHFFFAOYSA-N 0.000 description 1
- JGXDTHDXNCUXBJ-UHFFFAOYSA-N 4-hydroxy-n-pyridin-2-yl-2h-1,2-benzothiazine-3-carboxamide Chemical compound N1SC2=CC=CC=C2C(O)=C1C(=O)NC1=CC=CC=N1 JGXDTHDXNCUXBJ-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- QWTNANUGXZEPFQ-UHFFFAOYSA-N ethyl 4-hydroxy-2-methyl-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)N(C)C(C(=O)OCC)=C(O)C2=C1 QWTNANUGXZEPFQ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012907 medicinal substance Substances 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 239000002362 mulch Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical class O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- UIICPZFWHBJNIG-UHFFFAOYSA-N sodium;2-methoxyethanolate Chemical compound [Na+].COCC[O-] UIICPZFWHBJNIG-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Denne oppfinnelse angår den nye forbindelse 2-metoksyetyl-4-hydroksy-2-metyl-2H-l,2-benzotiazin-3-karboksylat-l,1-dioksyd This invention relates to the new compound 2-methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide
en ester som er av stor verdi ved syntese av piroxicam (4-hydroksy-2-metyl-N-2-pyridyl-2 H-l,2-benzotiazin-3-karboksamid-1,1-dioksyd) et antiinflammatorisk middel som er velkjent som et verdifullt medisinsk stoff. Tidligere har acyl-radikalet i forbindelser av denne type noen ganger vært skrevet som an ester of great value in the synthesis of piroxicam (4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) an anti-inflammatory agent well known as a valuable medicinal substance. In the past, the acyl radical in compounds of this type has sometimes been written as
og slike forbindelser betegnes alternativt som 3,4-dihydro-2-metyl-4-okso-2H-l,2-benzotiazin-l,1-dioksyd-derivater. and such compounds are alternatively referred to as 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide derivatives.
Det vil være klart at disse er likeverdige tautomere former It will be clear that these are equivalent tautomeric forms
av samme forbindelse. Foreliggende oppfinnelse omfatter begge tautomere former selv om bare en av dem er tegnet av praktiske grunner. of the same connection. The present invention includes both tautomeric forms even if only one of them is drawn for practical reasons.
Piroxicam ble opprinnelig beskrevet av Lombardino Piroxicam was originally described by Lombardino
(US-patent 3.591.584). En fremgangsmåte for syntese av (US Patent 3,591,584). A method for the synthesis of
piroxicam som er beskrevet der, er å omsette en 3-karboksylsyre-ester med 2-aminopyridin. Esteren er spesielt angitt som en (C1~C12) alkylester eller fenyl- (C^-C-j) -alkylester. Den spesielle ester som er beskrevet er metylesteren, nemlig piroxicam described there is to react a 3-carboxylic acid ester with 2-aminopyridine. The ester is specifically indicated as a (C 1 -C 12 ) alkyl ester or phenyl-(C 1 -C 12 ) alkyl ester. The particular ester described is the methyl ester, viz
[se også Lombardino et al., J. Med. Chem. 14, s. 1171-1175 [see also Lombardino et al., J. Med. Chem. 14, pp. 1171-1175
(1971)]. En ulempe ved denne ellers nyttige fremgangsmåte for fremstilling av piroxicam er at et sterkt farvet biprodukt dannes i varierende mengder. Dette sterkt farvede biprodukt, som bare kan fjernes ved flere omkrystalliseringer med tap av hovedproduktet, gjør at piroxicam-sluttproduktet får en uakseptabel, sterkt gul farve, selv når det er til stede i meget små mengder (f.eks. 0,5-1%). Dette biprodukt er isolert og bestemt til å ha den følgende struktur: (1971)]. A disadvantage of this otherwise useful method for producing piroxicam is that a strongly colored by-product is formed in varying amounts. This strongly colored by-product, which can only be removed by several recrystallizations with loss of the main product, gives the final piroxicam product an unacceptable strong yellow color, even when present in very small amounts (e.g. 0.5-1 %). This by-product has been isolated and determined to have the following structure:
Det er vist at (IV) i virkeligheten dannes som et biprodukt ved omsetningen og er ikke avledet fra en forurensning i forløperen. Hvordan denne forbindelse virkelig dannes i reaksjonsblandingen er ikke fullstendig forstått, selv om metoder som går ut på hurtig fjernelse av metanol-biproduktet eftersom det dannes i reaksjonsblandingen synes å redusere hyppigheten av piroxicam-porsjoner med uakseptabel farve. Disse metoder er imidlertid ikke helt pålitelige, og det har vært et mål å finne frem til en ester som er lett tilgjengelig ved syntese og som ikke for-årsaker dannelse av en eter så som (IV) som et brysomt biprodukt It has been shown that (IV) is in fact formed as a by-product of the reaction and is not derived from a contaminant in the precursor. How this compound actually forms in the reaction mixture is not fully understood, although methods that involve rapid removal of the methanol byproduct as it forms in the reaction mixture appear to reduce the frequency of piroxicam portions with unacceptable color. However, these methods are not completely reliable, and it has been a goal to find an ester that is easily accessible by synthesis and that does not cause the formation of an ether such as (IV) as a troublesome by-product
under omdannelsen til piroxicam. during the conversion to piroxicam.
Alternative synteser av piroxicam som er beskrevet i litteraturen, omfatter omsetning av 3,4-dihydro-2-metyl-4-okso-2H-l,2-benzotiazin-l,1-dioksyd med 2-pyridyl-isocyanat Alternative syntheses of piroxicam described in the literature include reaction of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide with 2-pyridyl isocyanate
(Lombardino, US-patent 3.591.584), transamidering av 4-hydroksy-2-metyl-2H-l,2-benzotiazin-3-karboksanilider med 2-amino-pyridin (Lombardino, US-patent 3.891.637), ringslutning av (Lombardino, US Patent 3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilides with 2-amino-pyridine (Lombardino, US Patent 3,891,637), ring closure of
(Lombardino, US-patent 3.853.862), kobling av et 4-( C^- C^)-alkoksy-2-metyl-2H-l,2-benzotiazin-3-karboksylsyre-l,1-dioksyd med 2-aminopyridin fulgt av hydrolyse av enol-eter-bindingen (Lombardino, US Patent 3,853,862), coupling of a 4-(C 1 -C 4 )-Alkoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide with 2- aminopyridine followed by hydrolysis of the enol-ether bond
(Lombardino, US-patent 3.892.740), kobling av 4-hydroksy-2-metyl-2H-l,2-benzotiazin-3-karboksylsyre via syrekloridet, med 2-amino-pyridin (Hammen, US-patent 4.100.347) og metylering av et 4-hydroksy-N-2-pyridyl-2H-l,2-benzotiazin-3-karboksamid (kanadisk patent 1.069.894). (Lombardino, US Patent 3,892,740), coupling of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid via the acid chloride, with 2-amino-pyridine (Hammen, US Patent 4,100,347 ) and methylation of a 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide (Canadian Patent 1,069,894).
En annen ester som er beslektet med metoksyetylesteren ifølge foreliggende oppfinnelse og som er spesielt beskrevet i litteraturen, er etyl-4-hydroksy-2-metyl-2H-l,2-benzotiazin-3-karboksylat-l,1-dioksyd (Rasmussen, US-patent 3.501.466, se også Zinnes et al., US-patent 3.816.628). Another ester which is related to the methoxyethyl ester according to the present invention and which is particularly described in the literature, is ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (Rasmussen, US Patent 3,501,466, see also Zinnes et al., US Patent 3,816,628).
2-metoksyetylesteren (I) er syntetisert. Ved den kjente fremgangsmåte for omdannelse av en tilsvarende 3-karboksylsyre-ester til piroxicam, har denne ester vært anvendt istedenfor den tidligere kjente metylester (III). Anvendelse av den nye ester (I) har den overraskende fordel at det således fremstilte piroxicam ikke inneholder noen påviselig mengde av det ventede, sterkt farvede eter-biprodukt [4-(2-metoksyetoksy)-2-metyl-N-2-pyridyl-2H-l,2-benzotiazin-3-karboksamid] med formelen The 2-methoxyethyl ester (I) has been synthesized. In the known method for converting a corresponding 3-carboxylic acid ester into piroxicam, this ester has been used instead of the previously known methyl ester (III). Use of the new ester (I) has the surprising advantage that the thus produced piroxicam contains no detectable amount of the expected, strongly colored ether by-product [4-(2-methoxyethoxy)-2-methyl-N-2-pyridyl- 2H-1,2-benzothiazine-3-carboxamide] with the formula
analogt med eteren (IV). analogous to the ether (IV).
Den ønskede 2-metoksyetylester (I) fremstilles lett fra sakkarin-2-acetat-esteren [2-metoksyetyl-3-okso-2H-l,2-benzisotiazolin-2-acetat-l,1-dioksyd, formel (VI)] ved det følgende reaksjonsforløp: The desired 2-methoxyethyl ester (I) is easily prepared from the saccharin-2-acetate ester [2-methoxyethyl-3-oxo-2H-1,2-benzisothiazoline-2-acetate-1,1-dioxide, formula (VI)] by the following reaction sequence:
Omleiringen utføres ved behandling av sakkarin-2-eddiksyreester-mellomproduktet med et alkoksyd, fortrinnsvis et 2-metoksy-etoksyd så som natrium-2-metoksyetoksyd for å unngå komplika-sjonen med transforestring, i et polart, organisk oppløsnings-middel så som dimetylsulfoksyd eller dimetylformamid. Metylering oppnås ved hjelp av et metyleringsmiddel så som dimetylsulfat eller et metylhalogenid, hensiktsmessig metyljodid, i et reaksjonsinert oppløsningsmiddel så som et lavere keton, en lavere alkanol, formamid, dimetylformamid eller dimetylsulfoksyd. The rearrangement is carried out by treating the saccharin-2-acetic acid ester intermediate with an alkoxide, preferably a 2-methoxyethoxide such as sodium 2-methoxyethoxide to avoid the complication of transesterification, in a polar organic solvent such as dimethylsulfoxide or dimethylformamide. Methylation is achieved by means of a methylating agent such as dimethyl sulfate or a methyl halide, conveniently methyl iodide, in a reaction-inert solvent such as a lower ketone, a lower alkanol, formamide, dimethylformamide or dimethylsulfoxide.
Sakkarin-2-eddiksyreesteren som anvendes som utgangs-materiale ved det ovenfor beskrevne reaksjonsforløp, fremstilles fra sakkarin og 2-metoksyetyl-kloracetat analogt med fremgangsmåten for fremstilling av den tilsvarende metylester [Chemische Berichte 30, s. 1267 (1897)], eller, mindre direkte, ved hydrolyse av nevnte metylester til den tilsvarende sakkarin-eddiksyre og kobling, så som via syrekloridet, med 2-metoksyetanol. The saccharin-2-acetic acid ester, which is used as starting material in the reaction process described above, is prepared from saccharin and 2-methoxyethyl chloroacetate analogously to the method for the preparation of the corresponding methyl ester [Chemische Berichte 30, p. 1267 (1897)], or, less directly, by hydrolysis of said methyl ester to the corresponding saccharin-acetic acid and coupling, such as via the acid chloride, with 2-methoxyethanol.
Omsetningen av metoksyesteren (I) med 2-aminopyridin for The reaction of the methoxy ester (I) with 2-aminopyridine for
å danne piroxicam to form piroxicam
utføres vanligvis ved å omsette de to komponenter i et reaksjonsinert oppløsningsmiddel ved 115-175°C inntil omsetningen er tilnærmet fullstendig, f.eks. i en periode på ca. en halv til flere timer, idet 2-metoksyetanol-biprodukt fortrinnsvis fjernes ved med-destillasjon med oppløsningsmidlet under omsetningen. is usually carried out by reacting the two components in a reaction-inert solvent at 115-175°C until the reaction is almost complete, e.g. for a period of approx. half to several hours, the 2-methoxyethanol by-product being preferably removed by co-distillation with the solvent during the reaction.
Selv om det bare er nødvendig at disse to reaksjonskomponenter er til stede i tilnærmet ekvimolare mengder for at reaksjonen skal skje, er et lite overskudd av den ene eller annen (og fortrinnsvis den mer lett tilgjengelige aminbase-reaksjons-komponent) ikke skadelig og kan til og med tjene til å Although it is only necessary that these two reaction components be present in approximately equimolar amounts for the reaction to occur, a small excess of one or the other (and preferably the more readily available amine base reaction component) is not harmful and can and with serve to
forskyve ammonolyse-reaksjonen til fullførelse. Foretrukne reaksjonsinerte organiske oppløsninsmidler for anvendelse ved delay the ammonolysis reaction to completion. Preferred reaction-inert organic solvents for use with
ammonolyse-reaksjonen, omfatter slike lavere N,N-dialkyl-alkanamider som dimetylformamid, dimetylacetamid og lignende, så vel som slike aromatiske hydrokarbonoppløsningsmidler som benzen, toluen, xylen og lignende. I ethvert tilfelle er det funnet å være gunstig og vanligvis hensiktsmessig å avdestil-lere det flyktige alkohol-biprodukt eftersom det dannes ved omsetningen og derved forskyve ammonolyse-likevekten til fullførelse på denne måte. I dette tilfelle er det mest foretrukne oppløsningsmiddel xylen, eftersom 2-metoksyetanol-biprodukt lett fjernes som en lavtkokende azeotrop. Mengden av xylen kan opprettholdes ved tilsetning av mer xylen under destillasjonen. Efter fjernelse av alkoholen og fullførelse av omsetningen utvinnes hensiktsmessig det resulterende piroxicam ved avkjøling og enkel filtrering av det krystal-liserte produkt. Eventuelt omkrystalliseres piroxicam fra dimetylacetamid/aceton/vann. the ammonolysis reaction, includes such lower N,N-dialkylalkanamides as dimethylformamide, dimethylacetamide and the like, as well as such aromatic hydrocarbon solvents as benzene, toluene, xylene and the like. In any case, it has been found to be beneficial and usually expedient to distill off the volatile alcohol by-product since it is formed during the reaction and thereby shift the ammonolysis equilibrium to completion in this way. In this case, the most preferred solvent is xylene, since the 2-methoxyethanol byproduct is easily removed as a low-boiling azeotrope. The amount of xylene can be maintained by adding more xylene during the distillation. After removal of the alcohol and completion of the reaction, the resulting piroxicam is expediently recovered by cooling and simple filtration of the crystallized product. Optionally, piroxicam is recrystallized from dimethylacetamide/acetone/water.
Under anvendelse av det nye mellomprodukt ifølge foreliggende oppfinnelse er det mulig å oppnå utbytter som er like gode som de som oppnåes i henhold til US-patent 3 591 584 (norsk patent 129 746) uten at det dannes noen forurensende eter eller noen gulfarve. Tilstedeværelsen av eter-forurens-ningen kan påvises ved væskekromatografi, eftersom den har en lengre retensjonstid enn rent piroxicam. Foreliggende oppfinnelse medfører også fordeler i forhold til fremgangsmåten beskrevet i US-patent 3 892 740 (norsk ansøkning 75 3250) eftersom det nye mellomprodukt ifølge foreliggende oppfinnelse kan kobles med 2-aminopyridin for å danne piroxicam uten at det er nødvendig å anvende koblingsmidler. Using the new intermediate product according to the present invention, it is possible to obtain yields that are as good as those obtained according to US patent 3,591,584 (Norwegian patent 129,746) without any contaminating ether or any yellow color being formed. The presence of the ether contaminant can be detected by liquid chromatography, since it has a longer retention time than pure piroxicam. The present invention also entails advantages in relation to the method described in US patent 3 892 740 (Norwegian application 75 3250) since the new intermediate product according to the present invention can be coupled with 2-aminopyridine to form piroxicam without the need to use coupling agents.
Det følgende eksempel illustrerer fremstilling av forbindelsen (I) ifølge oppfinnelsen: The following example illustrates the preparation of the compound (I) according to the invention:
Eksempel Example
a) 2- metoksyetyl- 2- kloracetat a) 2-Methoxyethyl-2-chloroacetate
Mens temperaturen ble holdt på -5 til 5°C ble 2-klor-acetylklorid (11,2 g, 0,10 mol) i 15 ml metylenklorid satt dråpevis i løpet av 1 time til en kald oppløsning av pyridin (8,0 g, 0,11 mol) og 2-metoksyetanol (7,6 g, 0,10 mol) i 35 ml metylenklorid. Reaksjonsblandingen ble omrørt i ytterligere 1 time ved 0°C, oppvarmet til romtemperatur og ekstrahert med to 50 ml porsjoner vann. De to vandige ekstrakter ble samlet og tilbakevasket med 50 ml kloroform. Det opprinnelige organiske lag og kloroform-tilbakevaskingsvæskene ble samlet og vasket med 50 ml av en 5% kobbersulfat-oppløsning. While maintaining the temperature at -5 to 5°C, 2-chloroacetyl chloride (11.2 g, 0.10 mol) in 15 mL of methylene chloride was added dropwise over 1 hour to a cold solution of pyridine (8.0 g , 0.11 mol) and 2-methoxyethanol (7.6 g, 0.10 mol) in 35 mL methylene chloride. The reaction mixture was stirred for a further 1 hour at 0°C, warmed to room temperature and extracted with two 50 ml portions of water. The two aqueous extracts were combined and backwashed with 50 ml of chloroform. The original organic layer and the chloroform backwashes were collected and washed with 50 mL of a 5% copper sulfate solution.
5% kobbersulfat-vaskevæsken ble tilbakevasket med 25 ml kloroform og kombinert påny med den organiske fase. Endelig ble den organiske fase vasket med 50 ml saltoppløsning, behandlet med aktivt kull og vannfritt magnesiumsulfat, filtrert, konsentrert til en olje og destillert for å gi 2-metoksyetyl-2-kloracetat (14,1 g, k.p. 80-82°C). The 5% copper sulfate wash was backwashed with 25 mL of chloroform and recombined with the organic phase. Finally, the organic phase was washed with 50 mL of brine, treated with activated charcoal and anhydrous magnesium sulfate, filtered, concentrated to an oil and distilled to give 2-methoxyethyl-2-chloroacetate (14.1 g, b.p. 80-82°C) .
b) 2- metoksyetyl- 3- okso- 2H- l, 2- benzisotiazolin- 2- acetat-1, 1- dioksyd ( 2- metoksetyl- sakkarin- 2- acetat ) ( VI) b) 2-Methoxyethyl-3-oxo-2H-1,2-benzisothiazoline-2-acetate-1,1-dioxide (2-methoxyethyl-saccharin-2-acetate) (VI)
Natrium-sakkarin (18 g, 0,088 mol) og 2-metoksyetyl-2-kloracetat (13,4 g, 0,088 mol) ble blandet i 40 ml dimetylformamid og oppvarmet ved 120°C i 4 timer. Reaksjonsblandingen ble avkjølt til 25°C, hellet i 100 ml vann, granulert ved 5-lo°C Sodium saccharin (18 g, 0.088 mol) and 2-methoxyethyl-2-chloroacetate (13.4 g, 0.088 mol) were mixed in 40 ml of dimethylformamide and heated at 120°C for 4 hours. The reaction mixture was cooled to 25°C, poured into 100 ml of water, granulated at 5-10°C
i 0,5 time, filtrert med vannvasking og lufttørret for å gi 2-metoksyetyl-sakkarin-2-acetat [23,2 g, 90%, sm.p. 91-92°C, for 0.5 h, filtered with water washing and air dried to give 2-methoxyethyl-saccharin-2-acetate [23.2 g, 90%, m.p. 91-92°C,
m/e 299; IR (KBr) 2985 cm"<1>]. m/e 299; IR (KBr) 2985 cm"<1>].
c) 2- metoksyetyl- 4- hydroksy- 2H- l, 2- benzotiazin- 3- karboksamid-1, 1- dioksyd c) 2- methoxyethyl- 4- hydroxy- 2H- 1, 2- benzothiazine- 3- carboxamide-1, 1- dioxide
Under tørr nitrogenatmosfære ble 2-metoksyetanol (72,9 ml, 0,924 mol) innført i en flammetørret kolbe under omrøring. Natrium-perler (10,6 g, 0,463 mol; pentanvasket og noe flat-klemte med pinsett) ble tilsatt porsjonsvis i løpet av 2 timer mens reaksjonsblandingens temperatur ble holdt i området 25-45°C. Efter ytterligere 1 times omrøring ble ytterligere 10 ml 2-metoksyetanol tilsatt, og reaksjonsblandingen ble oppvarmet til 57°C. Under a dry nitrogen atmosphere, 2-methoxyethanol (72.9 mL, 0.924 mol) was introduced into a flame-dried flask with stirring. Sodium beads (10.6 g, 0.463 mol; pentane-washed and somewhat flattened with tweezers) were added portionwise over 2 hours while the temperature of the reaction mixture was maintained in the range of 25-45°C. After a further 1 hour of stirring, a further 10 ml of 2-methoxyethanol was added, and the reaction mixture was heated to 57°C.
Ved svak avkjøling stivnet reaksjonsblandingen. Reaksjonsblandingen ble fortynnet med 75 ml tørr dimetylsulfoksyd og en eneste gjenværende partikkel av natriummetall ble fjernet mekanisk. 2-metoksyetyl-sakkarin-2-acetat (50 g, 0,167 mol) i.70 ml varm, tørr dimetylsulfoksyd ble tilsatt dråpevis i Upon slight cooling, the reaction mixture solidified. The reaction mixture was diluted with 75 ml of dry dimethylsulfoxide and a single remaining particle of sodium metal was removed mechanically. 2-Methoxyethyl-saccharin-2-acetate (50 g, 0.167 mol) in 70 mL of warm, dry dimethylsulfoxide was added dropwise in
løpet av 20 minutter. Reaksjonsblandingen ble omrørt i 1 time ved omgivelsestemperatur, satt til en blanding av konsentrert saltsyre (276 ml) og vann (1,84 1), mens temperaturen i blandingen ble holdt ved 20-25°C ved hjelp av et is-vann-bad og regulering av tilsetningshastigheten. Oppslemningen ble granulert ved 6-8°C i 1 time, filtrert med koldt vann og tørret i luft for å gi 2-metoksyetyl-4-hydroksy-2H-l,2-benzotiazin-3-karboksylat-l,1-dioksyd [32,8 g, 66%, sm.p. 120-122°C, IR (KBr) 3448, 3226 cm"<1>]. within 20 minutes. The reaction mixture was stirred for 1 hour at ambient temperature, added to a mixture of concentrated hydrochloric acid (276 mL) and water (1.84 L), while the temperature of the mixture was maintained at 20-25°C using an ice-water bath and regulation of the rate of addition. The slurry was granulated at 6-8°C for 1 hour, filtered with cold water and dried in air to give 2-methoxyethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide [ 32.8 g, 66%, m.p. 120-122°C, IR (KBr) 3448, 3226 cm"<1>].
d) 2- metoksyetyl- 4- hydroksy- 2- metyl- 2H- l, 2- benzotiazin- 3-karboksylat- 1, 1- dioksyd ( I) d) 2- methoxyethyl- 4- hydroxy- 2- methyl- 2H- 1, 2- benzothiazine- 3-carboxylate- 1, 1- dioxide ( I)
2-metoksyetyl-4-hydroksy-2H-l,2-benzotiazin-3-karboksylat-1.1- dioksyd (31,0 g, 0,1035 mol) ble blandet med 230 ml aceton og avkjølt til 10°C. Metyljodid (21,9 g, 0,155 mol) ble tilsatt, fulgt av dråpevis tilsetning i løpet av 10 minutter av natrium-hydroksyd (103,5 ml av IN). Kjølebadet ble fjernet, og reaksjonsblandingen fikk oppvarmes langsomt til romtemperatur (ca. 45 minutter), og ble derefter oppvarmet ved 35°C i 2 timer og til slutt ved 39-40°C i 16 timer. Reaksjonsblandingen ble avkjølt til romtemperatur, fortynnet med 200 ml aceton, behandlet med aktivt kull, filtrert og konsentrert i vakuum ved 0-5°C til ca. 50 ml. Den resulterende oppslemning ble filtrert, og faste stoffer ble vasket med is-vann og derefter tørret i vakuum for å gi 2-metoksyetyl-4-hydroksy-2-metyl-2H-1.2- benzotiazin-3-karboksylat-l,1-dioksyd [29,26 g, 90%, 2-Methoxyethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (31.0 g, 0.1035 mol) was mixed with 230 mL of acetone and cooled to 10°C. Methyl iodide (21.9 g, 0.155 mol) was added, followed by the dropwise addition over 10 min of sodium hydroxide (103.5 mL of IN). The cooling bath was removed and the reaction mixture was allowed to warm slowly to room temperature (about 45 minutes), and was then heated at 35°C for 2 hours and finally at 39-40°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with 200 ml of acetone, treated with activated carbon, filtered and concentrated in vacuo at 0-5°C to approx. 50 ml. The resulting slurry was filtered and the solids were washed with ice-water and then dried in vacuo to give 2-methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide [29.26 g, 90%,
sm.p. 106-107,5°C; m/e 313; IR (KBr) 3345, 2941, 1684, 1351, sm.p. 106-107.5°C; m/e 313; IR (KBr) 3345, 2941, 1684, 1351,
1053 cm"<1>]. 1053 cm"<1>].
Forbindelsen med formel (I) fremstilt ifølge eksemplet The compound of formula (I) prepared according to the example
kan omdannes til 4-hydroksy-2-metyl-N-2-pyridyl-2H-l,2-benzotiazin-3-karboksamid-l,1-dioksyd (piroxicam) (II), can be converted to 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam) (II),
som følger: 2-metoksyetyl-4-hydroksy-2H-l,2-benzotiazin-3-karboksylat-1,1-dioksyd (28 g, 0,089 mol) og 2-amino-pyridin (9,26 g, as follows: 2-methoxyethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (28 g, 0.089 mol) and 2-amino-pyridine (9.26 g,
0,098 mol) ble blandet med 500 ml xylen i en 1 liters kolbe 0.098 mol) was mixed with 500 ml of xylene in a 1 liter flask
utstyrt med en tilsetningstrakt og en variabel tilbakeløps-kjøler. Den omrørte reaksjonsblanding ble oppvarmet til tilbakeløpstemperatur, og xylenet ble avdestillert i en mengde på ca..100 ml/time mens volumet i kolben ble holdt nesten konstant ved tilsetning av ny xylen. Efter 6 timer steg temperaturen på toppen, som hadde vært forholdsvis konstant ved 134°C, til 142°C, og tiibakeløpet avtok. Reaksjonsblandingen ble derefter avkjølt i et isbad, og de utfelte faste stoffer ble gjenvunnet ved filtrering med heksan for overføring og vasking og tørret ved 45°C i vakuum for å gi piroxicam (28,5 g, 96%, sm.p. 167-174°C). Dette produkt ble undersøkt ved væskekromatografi med stor nøyaktighet under anvendelse av 60:40 0,1M Na2HP04 regulert til pH 7,5 med sitronsyre:metanol på "Micro-Bonda pak C^g" (varemerke for Waters Associates for en standard HPLC kolonne pakking bestående av siloksy-substituert kiselsyre belagt på mikroglassperler). Under de anvendte betingelser har piroxicam en retensjonstid på equipped with an addition funnel and a variable return cooler. The stirred reaction mixture was heated to reflux temperature, and the xylene was distilled off in a quantity of about 100 ml/hour while the volume in the flask was kept almost constant by the addition of new xylene. After 6 hours, the temperature at the top, which had been relatively constant at 134°C, rose to 142°C, and the ten-back race slowed down. The reaction mixture was then cooled in an ice bath, and the precipitated solids were recovered by filtration with hexane for transfer and washing and dried at 45°C in vacuo to give piroxicam (28.5 g, 96%, m.p. 167- 174°C). This product was examined by high precision liquid chromatography using 60:40 0.1M Na2HP04 adjusted to pH 7.5 with citric acid:methanol on "Micro-Bonda pak C^g" (trademark of Waters Associates for a standard HPLC column packing consisting of siloxy-substituted silicic acid coated on microglass beads). Under the conditions used, piroxicam has a retention time of
ca. 6 minutter, mens den potensielle forurensning 0 4-metoksy-etylpiroxicam, har en retensjonstid på 16,5 minutter. Intet av den potensielle forurensning ble påvist i produktet ifølge eksemplet. about. 6 minutes, while the potential contaminant 0 4-methoxy-ethylpiroxicam has a retention time of 16.5 minutes. None of the potential contamination was detected in the product according to the example.
For omkrystallisering ble det ovenfor fremstilte piroxicam (25 g) tatt opp i 190 ml dimetylacetamid ved 70-75°C, behandlet med 1,26 g aktivt kull ved 75-80°C og filtrert gjennom diatomé-jord med 55 ml varm dimetylacetamid for overføring og vasking. En blanding av 173 ml aceton og 173 ml vann ble avkjølt til 5-10°C. Det kull-behandlede filtrat ble satt langsomt i løpet av 10-15 minutter til det avkjølte, vandige aceton, og de resulterende krystaller ble granulert ved 0-5°C i 5 minutter. Omkrystallisert piroxicam ble utvunnet ved filtrering med For recrystallization, the above-prepared piroxicam (25 g) was taken up in 190 ml of dimethylacetamide at 70-75°C, treated with 1.26 g of activated carbon at 75-80°C and filtered through diatomaceous earth with 55 ml of hot dimethylacetamide for transfer and washing. A mixture of 173 ml of acetone and 173 ml of water was cooled to 5-10°C. The charcoal-treated filtrate was added slowly over 10-15 minutes to the cooled aqueous acetone, and the resulting crystals were granulated at 0-5°C for 5 minutes. Recrystallized piroxicam was recovered by filtration with
154 ml kald metanol for overføring og vasking. Utbytte: 18,75 g, 75%; IR (nujol-muld) identisk med autentisk piroxicam. 154 ml of cold methanol for transfer and washing. Yield: 18.75 g, 75%; IR (nujol mulch) identical to authentic piroxicam.
Claims (1)
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NO872669A NO157418C (en) | 1980-09-29 | 1987-06-25 | NEW BENZOTIAZINE DERIVATIVE SUITABLE FOR USE IN PIROXICAM PREPARATION. |
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US06/191,716 US4289879A (en) | 1980-09-29 | 1980-09-29 | Synthetic method and intermediate for piroxicam |
NO813290A NO158061C (en) | 1980-09-29 | 1981-09-28 | PROCEDURE FOR PREPARING 4-HYDROXY-2-METHYL-N-2-PYRIDYL-2H-1,2-BENZOTIAZINE-3-CARBOXAMIDE-1,1-DIOXYD (PIROXICAM). |
NO872669A NO157418C (en) | 1980-09-29 | 1987-06-25 | NEW BENZOTIAZINE DERIVATIVE SUITABLE FOR USE IN PIROXICAM PREPARATION. |
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