GB2137987A - Process for the Preparation of 3,4-Dihydro-2-Substituted-2H-1,2-Benzothiazine-Carboxylic Acid 1,1-Dioxide Derivatives - Google Patents
Process for the Preparation of 3,4-Dihydro-2-Substituted-2H-1,2-Benzothiazine-Carboxylic Acid 1,1-Dioxide Derivatives Download PDFInfo
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- GB2137987A GB2137987A GB08405872A GB8405872A GB2137987A GB 2137987 A GB2137987 A GB 2137987A GB 08405872 A GB08405872 A GB 08405872A GB 8405872 A GB8405872 A GB 8405872A GB 2137987 A GB2137987 A GB 2137987A
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- -1 3,4-Dihydro-2-Substituted-2H-1,2-Benzothiazine-Carboxylic Acid 1,1-Dioxide Chemical class 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 150000003254 radicals Chemical class 0.000 claims abstract description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 5
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
- 150000002431 hydrogen Chemical group 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 10
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- DRKNPHHSFRLJSL-UHFFFAOYSA-N 2-methyl-1,1,4-trioxo-3h-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound C1=CC=C2S(=O)(=O)N(C)C(C(O)=O)C(=O)C2=C1 DRKNPHHSFRLJSL-UHFFFAOYSA-N 0.000 description 4
- 238000006114 decarboxylation reaction Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000001095 magnesium carbonate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 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 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FXVZHDXESSYZIB-UHFFFAOYSA-N 1,1,4-trioxo-2,3-dihydro-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical class C1=CC=C2C(=O)C(C(=O)O)NS(=O)(=O)C2=C1 FXVZHDXESSYZIB-UHFFFAOYSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- CPIFFCMMBZLKDK-UHFFFAOYSA-N 2-methyl-1,1-dioxo-3h-1$l^{6},2-benzothiazin-4-one Chemical compound C1=CC=C2S(=O)(=O)N(C)CC(=O)C2=C1 CPIFFCMMBZLKDK-UHFFFAOYSA-N 0.000 description 1
- GGPCERYTJXDGOH-UHFFFAOYSA-N 2-methyl-1,1-dioxo-4h-1$l^{6},2-benzothiazin-3-one Chemical compound C1=CC=C2S(=O)(=O)N(C)C(=O)CC2=C1 GGPCERYTJXDGOH-UHFFFAOYSA-N 0.000 description 1
- FIPBGFYKXKDTFW-UHFFFAOYSA-N 2-methyl-4-oxo-3h-1,2-benzothiazine-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(O)=O)N(C)SC2=C1 FIPBGFYKXKDTFW-UHFFFAOYSA-N 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- FKPXGNGUVSHWQQ-UHFFFAOYSA-N 5-methyl-1,2-oxazol-3-amine Chemical compound CC1=CC(N)=NO1 FKPXGNGUVSHWQQ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 235000011160 magnesium carbonates Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A compound <IMAGE> in which R1 is C1-3 alkyl and R2 is hydrogen, halogen, nitro, trifluoromethyl, C1-5 alkyl, C1-3 alkoxy, phenyl or phenyl-C1-3 alkyl, is obtained by reaction of a compound <IMAGE> with a compound R5-O-Mg-O-COOR5 in which R5 is C1-3 alkyl, to give a compound <IMAGE> in which R1 and R2 have the same meanings as above, which is hydrolysed in the presence of an acid to give (I) or (II). A compound <IMAGE> in which R1 and R2 have the meanings given above and R3 is hydrogen, C1-3 alkyl, C1-3 alkoxy, phenyl, phenyl- C1-3 alkyl, 2-pyridyl, 2-thiazolyl or 5-methyl-3-isoxazolyl, is obtained by reaction of a compound (I) or (II) with compounds R4-X and R3NH2, in which R4 is a tri-C1-3-alkylacetyl radical, benzenesulphonyl or methyl- substituted benzenesulphonyl and X is a halogen atom, to give a compound <IMAGE> which is then hydrolysed in the presence of an alkali.
Description
SPECIFICATION
Process for the Preparation of 3,4-Dihydro-2-substituted-2H-1 ,2-benzothiazine-carboxylic Acid 1,1-Dioxide Derivatives
The present invention is concerned with a process for the preparation of 3,4-dihydro-2-substituted4-(or 3)-oxo-2H-benzothiazine-3(or 4)-carboxylic acid l,l-dioxide derivatives, which are valuable intermediates for the preparation of non-steroidal anti-inflammatory agents.More particularly, the present invention is concerned with a process for the preparation of the above-mentioned carboxylic acid compounds by reacting appropriately substituted 3,4-dihydro-2-substituted-4(or 3)-oxo-2H-1 2- benzothiazine 1,1-oxide compounds with alkyl magnesium carbonates and then hydrolysing the intermediates obtained in the presence of acids and to the use of the products obtained as intermediates for the preparation of N-substituted-4(or 3)-hydroxy-2-substituted-2H- 1 2- benzothiazine-3(or 4)-carboxamide 1,1-dioxides.
The instability of P-keto carboxylic acid represented by the following general formulae (I) and (II) which is evidenced by their tendency to undergo decarboxylation and, therefore, to give a lower yield of the desired compounds resulting therefrom, is well known. Thus, U.S. Patent Specification No.
3,892,740 describes the preparation of 3,4-dihydro-4-oxo-2H- 1 ,2-benzothiazine-3-carboxylic acid 1 ,1 -dioxides by hydrolysis of the corresponding ester but these carboxylic acids decarboxylate rapidly.
The observed instability is due to their p-keto structure.
U.S. Patent Specification No. 4,100,347 discloses that the decarboxylation can be avoided by hydrolysing, in the presence of hydroxyl ions, an alkyl ester or aralkyl ester of 3,4-dihydro-2-methyl-4oxo-1 ,2-benzothiazine-3-carboxylic acid 1,1-dioxide to give the corresponding 3 ,4-dihydro-2-methyl4-oxo-2H-1 ,2-benzothiazine-3-carboxylic acid 1 ,1-dioxide.
It is an object of the present invention to provide a process for the preparation of 3,4-dihydro-2substituted-4(or 3)-oxo-2H-1 ,2-benzothiazine-3(or 4)-carboxylic acid 1 ,1 -dioxides.
It is a further object of the present invention to provide a process for the preparation of Nsubstituted 4(or 3)-hydroxy-2-substituted-2H- 1 ,2-benzothiazine-3 (or 4)-carboxamide 1 1-dioxides.
Thus, according to the present invention, there is provided a process for the preparation of a compound of the general formula (I) or (Il):-
in which R1 is an alkyl radical containing up to 3 carbon atoms and R2 is a hydrogen or halogen atom, a nitro or trifluoromethyl radical, a lower alkyl radical containing up to. 5 carbon atoms, an alkoxy radical cdntaining up to 3 carbon atoms, a phenyl radical, a phenyl-alkyl radical containing up to 3 carbon atoms in alkyl moiety, wherein compound of the general formula (III) or (IV):--
in which R1 and R2 have the same meanings as above, is reacted with a compound of the general formula;(Vll)::- R5-0-Mg-0-C00R5 (Vll)
in which R5 is an alkyl radical containing up to 3 carbon atoms, to give a compound of the general formula (VIII) or (IX):-
in which R1 and R2 have the same meanings as above, which is hydrolysed in the presence of an acid to give a compound of the general formula (I) or (II).
The compounds of general formulae (I) and (II) prepared by this process are obtained in high yield and in high purity.
The acid compounds (I) and (II) thus obtained are valuable intermediates for synthesising nonsteroidal anti-inflammatory agents, such as compounds having the general formulae (V) and (VI):-
wherein R1 and R2 have the same meanings as above and R3 is a hydrogen atom, an alkyl radical containing up to 3 carbon atoms, an alkoxy radical containing up to 3 carbon atoms, a phenyl radical, a phenylalkyl radical containing up to 3 carbon atoms in alkyl moiety or a 2-pyridyl, 2-thiazolyl or 5 methyl-3-isoxazolyl radical.
Thus, the present invention also provides a process for the preparation of a compound of the general formula (V) or (VI):-
in which R1 and R2 have the meanings given above and R3 is a hydrogen atom, an alkyl radical containing up to 3 carbon atoms, an alkoxy radical containing up to 3 carbon atoms, a phenyl radical, a phenylalkyl radical containing up to 3 carbon atoms in alkyl moiety or a 2-pyridyl, 2-thiazolyl or 5methyl-3-isoxazolyl radical, wherein a compound of general formula (I) or (II) is reacted with a compound of the general formula R4-X or B3-NH2, in which R3 has the same meaning as above, B4is a trialkylacetyl radical, the alkyl moieties of which contain up to 3 carbon atoms, or a benzenesulphonyl or methyl-substituted benzenesulphonyl radical and Xis a halogen atom, to give a compound of the formula (X) or (Xl):-
in which R1, R2, R3 and R4 have the same meanings as above, which is then hydrolysed in the presence of an alkali.
The processes described in the prior art use, as starting materials, alkyl 3,4-dihydro-2-methyl-4oxo-2H-1 ,2-benzothiazine-3-carboxylate 1 ,1 -dioxides, which are hydrolysed under alkaline conditions, as shown by the following equation:
wherein R is a lower alkyl radical, the yields obtained being low.
In contradistinction thereto, the present invention uses, as starting materials, 3,4-dihydro-2substituted-4(or 3)-oxo-2H-1 ,2-benzothiazine 1 1-dioxides of general formulae (III) and (IV), the desired compounds of general formulae (I) and (II) being obtained quantitatively in a simple manner.
The processes according to the present invention for the preparation of the compounds of general formulae (I) and (II) can be illustrated by the following equations:
Process 1
Process 2
wherein R1, R2, R5 have the above-given meanings.
Examples of alkyl radicals represented by R, and R5 include methyl and ethyi radicals and R2 is preferably a hydrogen atom. The most preferred compounds of general formulae (I) and (II) are those in which R, is a methyl radical and R2 is a hydrogen atom.
These reactions are usually carried out in a conventional organic solvent, such as N,Ndimethylformamide, dimethyl sulphoxide or the like, which does not adversely influence the reaction.
The reaction temperature is not critical, the reaction usually being carried out with warming or heating, the preferred reaction temperature being from 50 to 1 500 C. It is preferable to carry out the reaction at about the melting temperature of the compounds of general formula (III) or (IV), having regard to the effect of the R2-substituent.
The reaction of the compounds of general formulae (III) or (IV) with the compounds of general formula (VII) is usually complete within 1 to 5 hours.
The compounds of general formula (VII) are usually used in amounts of 1 to 10 equivalents and preferably in amounts of 4 to 7 equivalents.
Preferably, a compound of general formula (III) or (IV) and a compound of general formula (VII) are suspended in an inert solvent. After the reaction is complete, the reaction mixture is poured into chilled hydrochloric acid.
By pouring the reaction mixture obtained in the first step of process 1 or 2 into chilled hydrochloric acid solution, a compound of general formula (I) or (II) is obtained.
It is preferable to carry out the neutralisation procedure in the presence of an appropriate organic solvent in order to avoid decarboxylation of the compound obtained of general formula (I) or (II). An aprotic solvent, such as hexane, an ether, such as dimethyl ether or diethyl ether, ethyl acetate, dichloromethane or the like can be used for this purpose.
It is preferable to carry out the neutralisation with the addition of ice chips and, after separating off the organic layer, the organic solvent is evaporated in vacuo to give a compound of general formula (I) or (II) in a pure state and in almost quantitative yield.
The compounds obtained of general formulae (I) or (II) can be used as intermediates for the preparation of the above-mentioned N-substituted-4(or 3)-hydroxy-2-substituted-2 H- 1 ,2- benzothiazine-3(or 4)-carboxamide 1,1-dioxides, which are effective as anti-inflammatory agents.
According to the prior art, the yield obtained of these compounds is very low.
The present invention uses a niixed anhydride method in order to avoid decarboxylation by acylating the intermediate compound (I) or (II) with an at least 2 molar amount of the acylating agent, the keto group in the 4(or 3)-position of the compound (I) or (II) being protected and, at the same time, by adding and reacting with an appropriate amine (B3-NH2), amidation occurs.
The compound obtained is hydrolysed in the presence of an alkali and is then neutralised with a mineral acid, such as hydrochloric acid, sulphuric acid or the like, to give a compound of general formula (V) or (VI).
These reactions can be illustrated by the following equations:
Process 3
Process 4
wherein R1, R2 and R3 have the same meanings as above and R4 is a trialkylacetyl radical containing up to 3 carbon atoms in alkyl moieties or a benzene-sulphonyl or methyl-substituted benzene-sulphonyl radical and X is a halogen atom.
Examples of R4 include trimethylacetyl, benzenesulphonyl and p-toluenesulphonyl radicals.
The compounds of general formulae (I), (II), (V) and (VI) exist as mixtures of keto and enol tautomers. It is to be understood that both tautomers of these compounds are within the scope of the present invention. For convenience, only one of the tautomers is illustrated.
A process for the preparation of the compound of general formulae (III) or (IV) is disclosed in J.
Org. Chem., 31, 162/1966; and J. Med. Chem., 14, 973/1971
The following Examples are given for the purpose of illustrating the present invention: EXAMPLE 1
Preparation of 3,4-Dihydro-2-methyl-4-oxo-2H-1 ,2-benzothiazine-3-cal"boxylic Acid 1 ,1-Dioxide Into a four-necked flask equipped with a reflux condenser, stirrer, thermometer and calcium chloride drying tube, there were placed 6.34 g (0.03 mole) 3,4-dihydro-2-methyl-4-oxo-1 ,2- benzothiazine 1,1-dioxide, 19.5 g (0.15 mole) methyl magnesium carbonate and 150 ml N,N-dimethyl formamide. The mixture was stirred at 140 to 1 500C for 2 hours. The resulting solution was poured quickly into a mixture of 200 ml concentrated hydrochloric acid, 200 g of ice chips and 500 ml diethyl ether.After stirring the mixture for 10 minutes, the diethyl ether layer was separated and the separated diethyl ether solution was evaporated in vacuo. The precipitated pale yellow crystals were filtered off and recrystallised from dilute methanol to give 7.21 g ofthe title compound in the form of white crystals: yield: 94% of theory.
IR (KBr): 3583 cm-1 (enolic OH), 3000--2 500 (acid OH),
1600 cm-1 (C=0), 1340, 1170 cm-l (SO2).
EXAMPLE 2
Preparation of 3-Hydroxy-2-methyl-2-H- 1 ,2-benzothiazine-4-carboxa ni lide 1 ,1-Dioxide Into a four-necked flask equipped with a reflux condenser, stirrer, thermometer and calcium chloride drying tube, there were placed 1.06 g (0.005 mole) 3,4-dihydro-2-methyl-3-oxo-2H-1 ,2- benzothiazine 1,1-dioxide, 2.6 g (0.02 mole) methyl magnesium carbonate in 20 ml N,N-dimethyl formamide. The mixture was stirred at 90 to 1000C for 3 hours. The resulting solution was.poured quickly into a mixture of 30 ml concentrated hydrochloric acid, 70 g of ice chips and'200 ml diethyl ether.After stirring the mixture for 10 minutes, the diethyl ether layer was separated and evaporated in vacuo to give 1.25 g 3,4-dihydro-2-methyl-3-oco-2H-1,2-benzothiazine-4-carboxylic acid 1,1-dioxide.
The compound obtained was dissolved in 20 ml benzene and 1.3 ml thionyl chloride and 0.4 ml N,Ndimethylformamide were added to the solution. The mixture was stirred in a water-bath for 3 hours and the resulting pale yellow precipitate was separated off by filtration and washed with a small amount of benzene. The precipitate was dissolved in 10 ml N,N-dimethylformamide and 1.02 g aniline was added thereto. The mixture was stirred at ambient temperature for 3 hours. To the resulting mixture was added twice the volume of ice to give a precipitate. The precipitate obtained was filtered off and recrystallised to give 0.85 g of the title compound; yield: 51.2% of theory; m.p. 155-1 560C.
The title compound was identified by elemental analysis, IR and NMR spectrum.
EXAMPLE 3
Preparation of N-(2-pyridyl)-4-hydroxy-2-methyl-2H- 1 ,2-benzothiazine-3-carboxamide 1,1-Dioxide Into a four necked flask equipped with a reflux condenser, stirrer, thermometer and calcium chloride drying tube, were placed 1.29 g (0.005 mole) 3,4-dihydro-2-methyl-4-oxo-2H-1 ,2- benzothiazine-3-carboxylic acid-l,l-dioxide, 2.0 ml thionyl chloride, 15 ml benzene and 0.4 ml N,Ndimethylformamide and the mixture was stirred in a water-bath for 3 hours. The precipitate formed was filtered off and washed with a small volume of benzene. The pricipitate obtained was dissolved in 10 ml N,N-dimethylformamide and 1.2 g 2-aminopyridine was added thereto. The solution reacted exothermally and turned to a pale yellow colour.The mixture was stirred for 3 hours and twice its volume of ice-water was added thereto. The precipitate formed was filtered off, washed with water and dried to give 0.89 g of the title compound; yield: 52% of theory; m.p. 1 99--2000C.
EXAMPLE 4
Preparation of N-(2-pyridyl)-4-hydroxy-2-methyl-2H- 1 ,2-benzothiazine-3-carboxa mide- 1,1-dioxide 1.29 g (0.005 mole) 3,4-dihydro-2-methyl-4-oxo-2H-1 ,2-benzothiazine-3-carboxylic acid 1,1dioxide and 20 ml triethylamine were dissolved in 15 ml tetrahydrofuran and the mixture was cooled to -1 50C. 1.3 ml pivaloyl chloride was added slowly to the stirred mixture, whereafter 1.0 g 2aminopyridine was added, while stirring. The temperature of the mixture was slowly raised to ambient temperatuve and stirred for 5 hours. Twice its volume of ice-water was added to the mixture to form a precipitate. The precipitate formed was dissolved in 50 ml sodium hydroxide solution containing 1.0 g sodium hydroxide.After complete hydrolysation, the solution was neutralised with concentrated hydrochloric acid to form a precipitate. The precipitate obtained was filtered off and recrystallised from acetonitrile to give 0.97 g of the title compound; yield: 58% of theory; m.p. 198-201 OC.
The title compound was identified by elemental analysis, IR and NMR spectrum.
Similar results were obtained when benzenesulphonyl chloride orp-toluenesulphonyl chloride was used instead of pivaloyl chloride.
EXAMPLE 5 Preparation of N-(2-thiazolyl)-4-hydroxy-2-methyl-2 H- 1 ,2-benzothiazine-3-carboxamide-1 ,1 -dioxide 0.82 g of the title compound was obtained in substantially the same manner as in Example 4 from 1.29 g (0.005 mole) 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1dioxide and 1.10 g 2-aminothiazole instead of 2-aminopyridine; yield: 54% of theory; m.p. 250- 2520C.
The title compound was identified by elemental analysis, IR and NMR spectrum.
EXAMPLE 6 Preparation of N-(5-methyl-3-isoxazolyl)-4-hydroxy-2-methyl-2H- 1 ,2-benzothiazine-3-carboxamide- 1,1-dioxide 0.80 g of the title compound was obtained in substantially the same manner as in Example 4 from 1.29 g (0.005 mole) 3.4-dihydro-2-methyl-4-oxo-2H-1 ,2-benzothiazine-3-carboxylic acid-i ,1 - dioxide and 1.10 g 3-amino-5-methylisoxazole instead of 2-aminopyridine; yield: 48% of theory; m.p.
254-2560C.
The title compound was identified by elemental analysis, IR and NMR spectrum.
Claims (6)
1. A process for the preparation of a compound of the general formula (I) or (Il):-
in which R, is an alkyl radical containing up to 3 carbon atoms and R2 is a hydrogen or halogen atom, a nitro or trifluoromethyl radical, a lower alkyl radical containing up to 5 carbon atoms, an alkoxy radical containing up to 3 carbon atoms, a phenyl radical, a phenyl-alkyl radical containing up to 3 carbon atoms in alkyl moiety, wherein a compound of the general formula (III) or (IV):--
in which R1 and R2 have the same meanings as above, is reacted with a compound of the general formula (VII)::- B5-0-Mg-0CO0B5 (Vll) in which R5 is an alkyl radical containing up to 3 carbon atoms, to give a compound of the general formula (VIII) or (IX):-
in which R, and R2 have the same meanings as above, which is hydrolysed in the presence of an acid to give a compound of the general formula (I) or (II).
2. A process according to claim 1 for the preparation of compounds of general formulae (I) and (II), substantially as hereinbefore described and exemplified.
3. Compounds of the general formulae (I) and (II) whenever prepared by the process according to claim 1 or 2.
4. A process for the preparation of a compound of the general formula (V) or (VI):-
in which R, and R2 have the meanings given in claim 1 and R3 is a hydrogen atom, an alkyl radical containing up to 3 carbon atoms, an alkoxy radical containing up to 3 carbon atoms, a phenyl radical, a phenyl-alkyl radical containing up to 3 carbon atoms in alkyl moiety or a 2-pyridyl, 2-thiazolyl or 5methyl-3-isoxazolyl radical, wherein a compound of general formula (I) or (II) is reacted with a compound of the general formula B4-X or B3-NH2, in which R3 has the same meaning as above, R4 is a trialkylacetyl radical, the alkyl moieties of which contain up to 3 carbon atoms, or a benzenesulphonyl or methyl-substituted benzenesulphonyl radical and X is a halogen atom, to give a compound of the general formula (X) or (Xl):-
in which R,, R2, R3 and R4 have the same meanings as above, which is then hydrolysed in the presence of an alkali.
5. A process according to claim 4 for the preparation of compounds of general formulae (V) and (VI), substantially as hereinbefore described and exemplified.
6. Compounds of general formulae (V) and (VI), whenever prepared by the process according to claim 4 or 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019830001019A KR850001037B1 (en) | 1983-03-15 | 1983-03-15 | Process for 3,4-dihydro-2-substituted-2h-1,2-benzothiazine-carboxylic acid 1,1-dioxide derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8405872D0 GB8405872D0 (en) | 1984-04-11 |
| GB2137987A true GB2137987A (en) | 1984-10-17 |
| GB2137987B GB2137987B (en) | 1986-10-01 |
Family
ID=19228456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08405872A Expired GB2137987B (en) | 1983-03-15 | 1984-03-06 | Process for the preparation of 3,4-dihydro-2-substituted-2h-1,2-benzothiazine-carboxylic acid 1,1-dioxide derivatives |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS6034958A (en) |
| KR (1) | KR850001037B1 (en) |
| BE (1) | BE899161A (en) |
| GB (1) | GB2137987B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5874429A (en) * | 1993-12-24 | 1999-02-23 | Suntory Limited | Benzothiazine derivative |
| US6001827A (en) * | 1993-12-24 | 1999-12-14 | Suntory Limited | Benzothiazine derivative |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5409780A (en) * | 1992-02-13 | 1995-04-25 | Chemtrak, Inc. | Aniline analogs for hydrogen peroxide detection |
-
1983
- 1983-03-15 KR KR1019830001019A patent/KR850001037B1/en not_active IP Right Cessation
-
1984
- 1984-03-06 GB GB08405872A patent/GB2137987B/en not_active Expired
- 1984-03-09 JP JP59046372A patent/JPS6034958A/en active Pending
- 1984-03-15 BE BE212566A patent/BE899161A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5874429A (en) * | 1993-12-24 | 1999-02-23 | Suntory Limited | Benzothiazine derivative |
| US6001827A (en) * | 1993-12-24 | 1999-12-14 | Suntory Limited | Benzothiazine derivative |
| US6316442B1 (en) | 1993-12-24 | 2001-11-13 | Suntory Limited | Benzothiazine derivative |
| US6664251B2 (en) | 1993-12-24 | 2003-12-16 | Daiichi Suntory Pharma Co., Ltd. | Benzothiazine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| KR850001037B1 (en) | 1985-07-19 |
| JPS6034958A (en) | 1985-02-22 |
| GB2137987B (en) | 1986-10-01 |
| BE899161A (en) | 1984-07-02 |
| GB8405872D0 (en) | 1984-04-11 |
| KR840004093A (en) | 1984-10-06 |
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| PG | Patent granted |