CA1249284A - Process for the preparation of 3-methyl-7-fluoro-5- nitrobenzothiophene - Google Patents
Process for the preparation of 3-methyl-7-fluoro-5- nitrobenzothiopheneInfo
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- CA1249284A CA1249284A CA000475083A CA475083A CA1249284A CA 1249284 A CA1249284 A CA 1249284A CA 000475083 A CA000475083 A CA 000475083A CA 475083 A CA475083 A CA 475083A CA 1249284 A CA1249284 A CA 1249284A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to a novel process for preparing 3-methyl-7-fluoro-5-nitrobenzothiophene of the formula I below and to novel intermediates used in the process. The process has the following reaction sequence (II) (III) (IV) 7-fluorisatin acid (VII) (VI) (V) (3-fluoro-2-chloro-5-nitrobenzoyl)- 3-fluoro-2-chloro-5-nitro-malonate benzoic acid (VIII) (IX) 3-fluoro-2-chloro-5 nitroacetophenone (2-acetyl-6-fluoro-4-nitro-phenyl-thio)acetic acid
The invention relates to a novel process for preparing 3-methyl-7-fluoro-5-nitrobenzothiophene of the formula I below and to novel intermediates used in the process. The process has the following reaction sequence (II) (III) (IV) 7-fluorisatin acid (VII) (VI) (V) (3-fluoro-2-chloro-5-nitrobenzoyl)- 3-fluoro-2-chloro-5-nitro-malonate benzoic acid (VIII) (IX) 3-fluoro-2-chloro-5 nitroacetophenone (2-acetyl-6-fluoro-4-nitro-phenyl-thio)acetic acid
Description
~L2~
The invention relates to a process for the preparation of 3-methyl-7-fluoro-5-nitrobenzothiophene and to intermediates used in the preparation and their preparation.
German Patent Application P 33 11 349.4 (published September 29, 1984) describes 7,8,9,10-tetrahydrothieno[3,2-e]-pyrido[4,3-b]-indoles, processes for their preparation and their use as medicaments. 3-Methyl-7-fluoro-5-nitrobenzothiophene is a key product in the synthesis of l-methyl-9-ethyl-4-fluoro-7,8,9,10-te-trahydrothieno[3,2-e]-pyrido[4,3-b]-indole.
The synthesis of 3-methyl-7-fluoro-5-nitrobenzothiophene in the patent application mentioned presents some difficulties, in particular in the prepara-tion of relatively large amounts of sub-stance. Thus, the reaction of 1,1-dimethyl-3-(3-methyl-5-nitroben-zothiophen-7-yl)-triazene with hydrofluoric acid to give 3-methyl-7-fluoro-5-nitrobenzothiophene requires the use of special appara-tuses. The diazotisation of the 3-methyl-5-nitro-7-amino-benzothio-phene requires the use of nitrosylsulphuric acid in concentrated sulphuric acid and thus leads to a considerable amount of inor~anic salts being obtained in the triazene formation; furthermore, puri-fication by column chromatography is necessary. Although the re-duction of 3-methyl-5,7-dinitrobenzothiophene with ammonium sulphi.de leads chiefly to the desired 3-methyl-5-nitro-7--amino-benzothiophene, in this case also purification by column chromatography is necessary.
The present invention describes a process for the prepa-ration o 3-methyl-7-fluoro-5-nitrobenzothiophene which bypasses the difficulties mentioned.
~;'i`` ~'`: -- 1 --- la - 23189-5934 The invention relates to a process for the preparation of 3-methyl-7-fluoro-5-nitrobenzothiophene, which is characterized in that a) 2-fluoroaniline (II) is converted into 7-fluoroisa-tin - la -, ~z~
(III) by known preparation processesO
b) 7-fluoro;satin (III) is nitrated and the product is then oxidised to 3-fluoro-5-nitroanthraniLic acid tIV), c) 3-fluoro-5-nitroanthranil;c acid ~IV) is dia20tised and the diazotisation product is reacted with hydrochLoric acid in the presence of copper-I chloride to g;ve 3-fluoro-
The invention relates to a process for the preparation of 3-methyl-7-fluoro-5-nitrobenzothiophene and to intermediates used in the preparation and their preparation.
German Patent Application P 33 11 349.4 (published September 29, 1984) describes 7,8,9,10-tetrahydrothieno[3,2-e]-pyrido[4,3-b]-indoles, processes for their preparation and their use as medicaments. 3-Methyl-7-fluoro-5-nitrobenzothiophene is a key product in the synthesis of l-methyl-9-ethyl-4-fluoro-7,8,9,10-te-trahydrothieno[3,2-e]-pyrido[4,3-b]-indole.
The synthesis of 3-methyl-7-fluoro-5-nitrobenzothiophene in the patent application mentioned presents some difficulties, in particular in the prepara-tion of relatively large amounts of sub-stance. Thus, the reaction of 1,1-dimethyl-3-(3-methyl-5-nitroben-zothiophen-7-yl)-triazene with hydrofluoric acid to give 3-methyl-7-fluoro-5-nitrobenzothiophene requires the use of special appara-tuses. The diazotisation of the 3-methyl-5-nitro-7-amino-benzothio-phene requires the use of nitrosylsulphuric acid in concentrated sulphuric acid and thus leads to a considerable amount of inor~anic salts being obtained in the triazene formation; furthermore, puri-fication by column chromatography is necessary. Although the re-duction of 3-methyl-5,7-dinitrobenzothiophene with ammonium sulphi.de leads chiefly to the desired 3-methyl-5-nitro-7--amino-benzothiophene, in this case also purification by column chromatography is necessary.
The present invention describes a process for the prepa-ration o 3-methyl-7-fluoro-5-nitrobenzothiophene which bypasses the difficulties mentioned.
~;'i`` ~'`: -- 1 --- la - 23189-5934 The invention relates to a process for the preparation of 3-methyl-7-fluoro-5-nitrobenzothiophene, which is characterized in that a) 2-fluoroaniline (II) is converted into 7-fluoroisa-tin - la -, ~z~
(III) by known preparation processesO
b) 7-fluoro;satin (III) is nitrated and the product is then oxidised to 3-fluoro-5-nitroanthraniLic acid tIV), c) 3-fluoro-5-nitroanthranil;c acid ~IV) is dia20tised and the diazotisation product is reacted with hydrochLoric acid in the presence of copper-I chloride to g;ve 3-fluoro-
2-chloro-5-nitrobenzoic acid (V)~
d) 3-fluoro-2-chloro-5-nitrobenzoic acid ~V) is reacted with th;onyl chloride to give the corresponding acid chloride tVI)~
e) 3-fluoro-2-chloro-5-nitrobenzoyl chloride (VI) is reacted with diethyl ethoxymagnesium-malonate to give diethyl (3-fluoro~Z-chloro-5-nitrobenzoyl)-mal~nate tVII), f~ diethyl (3-fluoro-2-chloro-5-nitroben~oyl)-malonate (VII) is reacted with propion;c acid in the presence of su~phuric acid to g;ve 3-fluoro-2-chloro-5-nitroacetophen-one (VIII), 9) 3-fluoro-2-chloro-5-nitroacetophenone (VIII) is con-verted into (2-acetyl-6-fluoro-4-nitrophenylthio)-acetic acid tIX) ~ith mercaptoacetic acid and h~ the acid (IX~ is cyclised to 3-methyl-7-fLuoro-5-nitrobenzothiophene (I).
For iLlustration of the process according to the invention, reference is made to the following equation.
1st sta~e:
F NH2I) a) CCl3 CHO, NH20~ ~ N ~ O
2nd stage ONO COOH
a) HN03 ~ (IV) N'~ ~ 3D l F ~ b) H22' NaOH ~ ~N~2 __ 8~
3rd sta~e N ~ COOH a) ~NO2 ~ ~ COOH
NH2 b) CuCl/HC1 ~ Cl ~ F
5th stage N~ ~ OOH N2 ~ -cH(co2Et)2 a) SOC12 ~ ~`Cl ~VII) `C1 F b ) EtOMgCH IC02Et ) 2 F
5th stage O
NO2 ~ ~C-cH(co2Et~2 ~2SO4NO2 ~ C-~H3 ~Cl C2H5COOH~ (VIII ) F F
6th stage O ..
N ~ ~ C~CH3 NO2 ~ C-CH3 HS-C~2-COOH ~ ~
Cl ~ 5 CH2 COOH
F F (IX) 7th stage o N~ ~ C-CH3 N2 ~ CH3 10 ~ C2 5 j~ ~ (I) F F
The compounds in steps (2) to (6) wh;ch have not h;therto been descr;bed are prepared by methods ~hich are kno~n per se; ho~lever, the combination of process steps ~1) to (7) represents a substant;al advance in the pre-paration of 3-methyl-7~fluoro-5-nitrobenzothiophene.
The compounds of the general formula (X) 2N ~ ( X ) ~\R 2 in which Rl denotes a carboxyl group or a halide thereof or an alkylcarbonyl group optionally substituted in the alkyl group by one or more alkoxycarbonyl groups and R2 represents halogen, an amino group or a thioalkyl-carboxyl group, in particular the compounds3-fluoro-5-nitroanthranilic acid (IV),
d) 3-fluoro-2-chloro-5-nitrobenzoic acid ~V) is reacted with th;onyl chloride to give the corresponding acid chloride tVI)~
e) 3-fluoro-2-chloro-5-nitrobenzoyl chloride (VI) is reacted with diethyl ethoxymagnesium-malonate to give diethyl (3-fluoro~Z-chloro-5-nitrobenzoyl)-mal~nate tVII), f~ diethyl (3-fluoro-2-chloro-5-nitroben~oyl)-malonate (VII) is reacted with propion;c acid in the presence of su~phuric acid to g;ve 3-fluoro-2-chloro-5-nitroacetophen-one (VIII), 9) 3-fluoro-2-chloro-5-nitroacetophenone (VIII) is con-verted into (2-acetyl-6-fluoro-4-nitrophenylthio)-acetic acid tIX) ~ith mercaptoacetic acid and h~ the acid (IX~ is cyclised to 3-methyl-7-fLuoro-5-nitrobenzothiophene (I).
For iLlustration of the process according to the invention, reference is made to the following equation.
1st sta~e:
F NH2I) a) CCl3 CHO, NH20~ ~ N ~ O
2nd stage ONO COOH
a) HN03 ~ (IV) N'~ ~ 3D l F ~ b) H22' NaOH ~ ~N~2 __ 8~
3rd sta~e N ~ COOH a) ~NO2 ~ ~ COOH
NH2 b) CuCl/HC1 ~ Cl ~ F
5th stage N~ ~ OOH N2 ~ -cH(co2Et)2 a) SOC12 ~ ~`Cl ~VII) `C1 F b ) EtOMgCH IC02Et ) 2 F
5th stage O
NO2 ~ ~C-cH(co2Et~2 ~2SO4NO2 ~ C-~H3 ~Cl C2H5COOH~ (VIII ) F F
6th stage O ..
N ~ ~ C~CH3 NO2 ~ C-CH3 HS-C~2-COOH ~ ~
Cl ~ 5 CH2 COOH
F F (IX) 7th stage o N~ ~ C-CH3 N2 ~ CH3 10 ~ C2 5 j~ ~ (I) F F
The compounds in steps (2) to (6) wh;ch have not h;therto been descr;bed are prepared by methods ~hich are kno~n per se; ho~lever, the combination of process steps ~1) to (7) represents a substant;al advance in the pre-paration of 3-methyl-7~fluoro-5-nitrobenzothiophene.
The compounds of the general formula (X) 2N ~ ( X ) ~\R 2 in which Rl denotes a carboxyl group or a halide thereof or an alkylcarbonyl group optionally substituted in the alkyl group by one or more alkoxycarbonyl groups and R2 represents halogen, an amino group or a thioalkyl-carboxyl group, in particular the compounds3-fluoro-5-nitroanthranilic acid (IV),
3-fluoro-2-chloro-5-nitrobenzoic acid (V), the halides thereof (for example VI)I diethyl (3-fluoro-2-chloro-5-nitrobenzoyl)-malonate (VII), 3-fluoro-2-chloro-5-nitroacetophenone (VIII) and (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid (IX) are new and, like their preparation processes, are the subject of the invention.
The individual synthesis steps for the intermediates used in the preparation process according to the invention are illustrated in more detail below.
1st stage: 7-Fluoroisatin(III) is known. It is prepared from 2-fluoroaniline (II), which is available in industrial amounts.
(Compare: S.J. Holt and P.W. Sadler, Proc. Roy. Soc. (London) 148 B, 481-494 (1958); and R.R. Smo]ders et al., Ing. Chim.
(Brussels) 1982, 64(303), 3-6).
2nd stage: 3-Fluoro-5-nitroanthranilic acid (IV). This compound is prepared in a manner which is known per se by nitration of 7-t - 4 -~z~
fluoroisatin andoxidation with hydrogen peroxide.
The nitration is preferably carried out with 100~ strength nitric acid in concentrated sulphuric acid.
IIowever, it is also possible to use other nitrating agents, such as alkali metal nitrates, mixed anhydrides of nitric acid or nitric acid esters or other sol-- 4a -~2~ 8D~
vents, such as glac;al acetic acid or chlorinated hydro-carbons. The reaction temperatures can be varied. In general, the reaction is carried out at temperatures bet-~een -20 and 40, preferably at 0~
(Compare: W.C. Sumpter and W.F. Jones, J. Amer. Chem.
Soc. 6~, 1802 (1943)).
3rd stage: 3-Fluoro-2-chloro-5-nitrobenzo;c acid (V).
This compound is prepared in a manner which is known per se by diazotisation of the corresponding anthranilic acid and reaction of the diazotisation product with hydro-chloric acid in the presence of copper-I chloride. The diazotisat;on is carried out with customary reagents, such as sodium nitrite, nitrosylsulphuric acid or alkyl-nitrites. Suitable solvents are concentrated sulphuric ~5 acid~ phosphoric acid~ hydrochloric acid or glacial acetic acid or mixtures thereof. Diazotisation with nitrosyl-sulphur;c acid in phosphoric acid/glacial acetic acid mix tures is preferred. The reaction temperatures here can be varied from -5 to 30. ~eplacement of the diazoniwm group by chlorine is carried out with aqueous hydrochloric acid in the presence of copper catalysts. Copper-I
chloride is the preferred catalyst.
~Compare: ~ouben-WeylO Volume V/3, page 846 et seq.
(1962)).
4th sta~: Diethyl ~3-fluoro-2-chloro-5-nitrobenzoyl)-malonate tVII).
This compound can be obtained in a manner which is known per se from the corresponding benzoic acidy via the acid chlor;de ~VI).
The acid chloride is formed by reaction with ;n-organic acid chlorides, such as thionyl chloride, phos-phorus-V chloride or phosphorus-III chloride. The reac-tion can be carr;ed out in solvents such as aromatic hydrocarbons or chlorinated hydrocarbons, or in excess chlorinating agents, at temperatures between 20 and 100. The reaction in thionyl chloride at the reflux ~;~4~Z~
temperature is preferred~
Aromatic hydrocarbons are suitable solvents for the reaction of the acid chloride w;th diethyl ethoxy-magnesium-malonate; toluene is part;cularly preferred.
(Compare: A.P.G. Kieboom, Synthesis 1975, 327; and S.R. Alpha~ J. Org. Chem. 38, 3136 (1973)~.
5th sta~: 3-Fluoro-2-chloro-5-nitroacetophenone ~III).
Th;s compound is prepared ;n a manner ~h;ch ;s known per se by reacting diethyl ~3-fluoro-2-chloro-5-nitrobenzoyl)-malonate with prop;onic ac;d and sulphuric ac;d. Acylatedmalonic esters can be converted ;nto methyl ketones by hydrolys;s and decarboxylat;on. Preferred react-;on con-d;t;ons here are ~arming ;n prop;onic acid in the presence of catalytic amounts of concentrated sulphuric ac;d until the evolution of COz has ended.
(Compare: N.~. Chapman et al., J. Chem. So~. (C) 1968, 518; and Houben-Weyl, VoLume VII/2, page 1338 et seq.
(1976)) 6th stage: t2-Acetyl-6-fluoro-4-n;tro-phenylthio)acet;c ac;d (IX).
This compound can be obta;ned ;n a manner ~hich is kno~n per se by reacting 3-fluoro-2-chloro~5-n;tro-acetophenone w;th mercaptoacet;c acid.
The reaction ;s carr;ed out in ~ater or water-m;sc;ble organic solvents (for example alcohols or lowerketones) ;n the presence of an alkal; (for example alkal;
metal b;carbonates, carbonates or hydrox;des or tert;ary am;nes). Sodium b;carbonate in aqueous ;sopropanol ;s preferably used. The react;on temperatures can be var;ed from 20 up to the boiling po;nt of the solvent used;
the temperature is preferably 45 to 50.
(Compare: A. R;cc; and N. Cagnol;, Ann. Ch;m. tRome) 45, 172 (1955); C. Angel;n;, Ann. Ch;m. ~Rome) 47, 705 ~1957);
and S. M;ddleton, Austr. J. Chem. 12, 218 (1959)).
7th stage: The cycl;sat;on of (2-acetyl-6-fluoro-4-nitro-phenylth;o)acet;c ac;d to 3-methyl-7-fluoro-5-n;trobenzo-~Z~2~3~
th;ophene ~I) is carr;ed out in the presence of carboxylic acids~ as condens;ng agents~ and, ;f appropriate, in the presence of inert organic solvents at temperatures bet~een 50 and 20D.
The use of propionic acid has proved particularly advant3geous~ The preferred reaction temperature here is in the range from 110 to 150.
(Compare: DE-OS ~German Published Specification) 3,03~,738).
The present invention may be illustrated in more detail by the following examples:
Example 1 N02~, COO~
r NH2 a) 3-Fluoro-5 nitroanthranilic acid tfrom 7-fluoroisatin) 33.0 g tO.2 mole) of 7-fluoroisatin are dissolved in 80 ml of concentrated sulphuric acid. 8.3 ml of 100%
strength nitric acid are added dropwise at 0 in the course of ZO minutes, ~ith cooling. The mixture is sub-sequently stirred at 0 for 30 minutes. It is then poured onto 400 9 of ice and rendered alkaline at 20 to 30 ~ith 45X strength sodium hydroxide solution. 30 ml of 30% strength hydrogen peroxide are added dropwise at 20 ;n the course of 10 minutes. The m;xture is subse-quently stirred for a further 30 minutes and the product Z5 is precipitated with concentrated hydrochloric acid up to pH 2. The product is filtered off with suction, ~ashed ~;th water until free from salts and dried at 50 in vacuo.
Yield: 34.5 9 = 86.3X of theory Melting point: 243 to 246 (decomposition) b) 3-Fluoro-5-nitroanthranilic acid (from N~ fluoro-phenyl)-2-hydroxyiminoacetamide, ~ithout isolation of ~Z~8~
the 7-fluoroisation) ~) N-(2-Fluorophenyl)-2-hydroxy-iminoacetamide NEI-C-S X=2~-gH
F
A m;xture of 400 mL of water, 110 9 of anhydrous sod;um sulphate and 10.7 9 ~0.154 mole) of hydroxylam;ne hydrochloride ;s ~armed to 85. A solution of 24.8 g (0.15 mole) of chloral hydrate, 15.~ 9 tO.14 mole) of 2-fluoroan;l;ne and 1Z ml of concentrated hydrochloric acid in 50 ml of water is added drop~ise at 85 in the course 1D of 60 minutes~ The mixture ;s subsequently stirred at 85 for 60 minutes and cooled to 30. It is extracted by stirr;ng with 200 ml of methylene chloride. The organic phase is separated off, 70 ml of water are added and the mixture is brought to pH 12 ~ith sodium hydroxide solution. After stirring for 30 minutes, the mixture is brought to pH 10.5 ~ith dilute hydrochlorir ac;d. The aqueous phase is cleanly separated off and the product is prec;pitated at 20 - 25 by addition of hydrochloric acid up to pH 7~ The product is filtered off ~ith suction, ~ashed ~ith ~ater and dried at 50 in vacuo.
Yield 15.5 9 ~ 60.8% of theory.
Melt;ng point: 113 - 115.
~) 3-Fluoro-5-nitroanthranilic acid 50 9 (0~274 mole) of N-(2-fluorophenyl)-2-hydroxy iminoacetamide are introduced into 150 ml of concentrated sulphuric acid at 80 - 85 ;n the course of 20 minutes.
Thereafter, the mixture i5 subsequently stirred at 80 -85 for a further 40 minutesA It is cooled to 0O
13 ml of 100X strength nitric acid are added dropwise at 0 ;n the course of 30 rn;nutes and the mixture ;s sub-sequently stirred at 0 for a further 30 minutesn It is poured onto ice and brought to pH 12 ~ith sodium hydroxide solution. After add;tion of 50 ml of 30X strength hydro-TP 7_ ~Z~8~
g gen peroxide~ the mixture is stirred at 20 for 30 m;nutes. Thereafter, the product ;s precipitated by addi-tion of hydrochloric acid up to pH 2, filtered off with suct;ony washed w;th water unt;l free from salts and dried at 50 in vacuo.
Yield: 31~8 9 = 58.0X of theory Melt;ng po;nt: 237 - 239 tdecomposition) Example 2 NO2 ~ COOH
~ Cl F
3-Fluoro-Z-chloro-5-nitrobenzo;c ac;d A suspension of 100.5 9 of 3-fluoro-5-nitroanthan-ilic acid (0.5 mole~ in 400 ml of 85% strength phosphoric acid and 200 ml of glacial acetic acid is diazotised at 0 ~ith a nitrosylsulphuric acid obtained from 35.2 9 of sod;um nitr;te (D.51 mole) and 250 ml of concentrated sulphuric acid~ The mixture is subsequently stirred at 0 for 2 hours~ The diazonium salt solut;on is st;rred ;nto a m;xture of 65 9 of copper-I chloride and 600 ml of concentrated hydrochloric ac;d at 20 to 25. The mixture is st;rred at 25 for a further 15 minutes, warmed briefly to 70 and then cooled to room temperature.
The prec;pitate is filtered off with suction and washed with water. The mother liquor is extracted w;th 1,000 ml of diisopropyl ether. The prec;pitate ;s dis-solved in the ether extract; the mixture is filtered overk;eselguhr. After the solvent has been distilled off in vacuo, the residue is recrystallised from 250 ml of toluene and the crystals are filtered off with suction and dried ;n vacuo at 50.
Yield: 69.4 9 = 62~4% of theory; melting point: 155-157.
~Z4~92~3~
Example 3 N02 ~ C C~(C02CH2CH3~2 ~J`
T Cl D;ethyl ~3-fluoro-2-chloro-5-nitrobenzoyl)malonate 40.0 9 tO.18 mole) of 3-fluoro-2-chloro-5-nitro-benzoic acid are warmed under reflux in 120 ml of thionylchloride with 1 ml of dimethylformamide until the evolu-tion of gas has ended (about 2 hours). The excess thionyl chloride is distilled off and the acid chloride formed is distilled in vacuo.
Yield: 40.0 9 ~ 93~0X of theory ~oiling point: 98 to lû1/0.1 mm Hg A solution of 40.0 9 (0.168 mole) of 3-fluoro-2-chloro-5-nitrobenzoyl chlor;de in 190 ml of absolute tolu-ene is added dropwise to a solution of 0.25 mole of diethyl ethoxymagnesium-malonate in 140 ml of absolute toluene at room temperature and the mixture is subsequently st;rred for 15 rninutPs and poured onto a mixture of 170 9 of ice and 30 ml of concentrated sulphur;c acid. The organ;c phase is separated off and ~ashed neutral with water and the toluene is distilled off in vacuo. The residue is made to crystallise by addition of 100 ml of petroleum ether (40/60). The crystals are filtered off with suction, washed with petroleum ether and dried in vacuo at room temperature.
Yield: 47.7 9 ~ 78.5% of theory Melting point: 59 ~92~3~
~ 11 --Example 4 o N2 `~1CH3 3-Fluoro-2-chloro-5-nitroacetophenone 47~7 ~ (0.132 mole) of diethyl (3-fluoro-2 chloro-5-nitrobenzoyl)malonate are ~armed at the boiling point under reflux for Z.0 hours ;n 55 ml of propionic acid, ~;th addition of 0.5 ml of concentrated sulphuric acid.
The propionic acid is then distilled off in vacuo up to an internal temperature of 100. The residue is dissolved in 100 ml of methylene chloride and the solution is washed neutral with ~ater and filtered over an Al203 layer.
The solvent is dist;lled off in vacuo and the residue ;s made to crystall;se by add;t;on of 100 ml of petroleum ether (40/60). The crystals are f;ltered off ~;th suc-tion9 r;nsed with petroleum ether and dr;ed in vacuo at Y;eld- 25.2 9 ~ 87.8X of theory, Melting point 67.
ExampLe 5 NO2~f ~CH3 ~
-r S-CR2-CH
F
~2-Acetyl-6-fluoro-4-n;tro-phenylth;o)acet;c ac;d 25.0 9 ~0.115 mole) of 3-fluoro-2-chloro-5-n;tro-acetophenone and 21.0 9 (0~25 mole) of sodium bicarbonate are suspended in a mixture of 90 ml of isopropanol and 30 ml of water. 11~1 9 ~0~12 mole) of freshly distilled mercaptoacetic acid are added dropwise at 45 to 50 in the course of 10 minutes and the mixture is subsequently stirred at this temperature for a further hour. After the mixture has been diluted wi~h 250 ml of ;ce-water~ the produc~ is precipitated by dropwise addi~ion of 20 ml of concentrated hydrochloric ac;d and is filtered off ~ith suction, ~ashed ~;th ~ater and dr;ed in vacuo at 50.
Yield: 29aO 9 ~ 92~3X of theory, Melt;ng po;nt: 110 to 1157 Example _ N2~ ~ J CH3 1U 3-Methyl-7-fluoro-5-n;trobenzothio hene P
10.0 9 (OAO366 mole) of ~2 acetyL-6-fluoro-4-nitro~phenylthio)acetic acid are ~armed under reflux ;n 40 ml of prop;onic acid until the evolution of C02 has ended (about 1.5 hours). The propionic ac;d is then dis-t;lled off ;n vacuo, the res;due ;s d;ssolved in 50 ml ofmethylene chloride and the solution is filtered over sil;ca gel. Thereafter, the solvent is d;stilled off ;n vacuo and the residue which remains is recrystallised from 40 ml of isopropanol. The product ;s f;ltered off ~ith suction, washed w;th ;sopropanol and dried in vacuo at 45.
Y;eld: 5.1 9 - 66.0X of theory, Melt;ng po;nt: 111.
The 3-methyl-7-fluoro-5-nitrobenzothiophene pre-pared accord;ng to the ;nvent;on is used for the prepara-tion of 7,8,9,10-tetrahydrothienoC302-e]pyr;do-C4,3-b~-;ndoles of the general formula (XI) (XI) ~P 74 28~
in ~h;ch R represents hydrogen or alkyl.
The new substituted 7,8,9,10-tetrahydrothieno~
~3,2-e~pyrido-C4~3-b~indole derivatives of ~he formula (XI), Yhich are not the subject of the present ;nvention~
exh;b;t a better act;on spectrum on the central nervous system, in particular also a better therapeutically useful in vivo activity, than the compounds known from the prior art and described ;n European Patent Spec;fication 12,347.
The compounds of the formula (XI) and the;r pharmaceut;cal use thus represent an enrichment of pharmacy.
The compounds of the formula ~XI) can be processed to pharmaceutical formulat;ons ~h;ch conta;n, ;n addit;on to non~toxic, ;nert, pharmaceutically suitable exc;p;ents, one or more of the compounds ~IX~ or their salts.
Such formulat;ons also include pharmaceut;cal formulations in dosage units. This means that the formu-lat;ons are in the form of individual parts, for example tablets, dragees, capsules, pills, suppos;tories and ampoules, of which the active compound content corresponds to a fraction or a mult;ple of an ;ndiv;dual dose. The dosage un;ts can conta;n, for exampleO 1~ 2, 3 or 4 ;ndi~
vidual doses or 1/2, 1/3 or 1/4 of an indiv;dual dose.
An individual dose preferably contains the amount of active compound ~h;ch is given in one administration and which usually corresponds to a whole, one half, one third or one quarter of a daily dose.
By non-toxic, inert, pharmaceut;cally su;table exc;pients there are to be understood solid~ sem;-sol;d or liquid diluents, fillers and formulat;on aux;liar;es of every k;nd.
Tablets, dragees, capsules, p;lls, granules~
suppos;tor;es, solut;ons, suspens;ons and emuls;ons may be ment;oned as preferred pharraceut;cal formulat;ons~
Tablets, dragees, capsules, p;lls and granules can contain the active compound or compounds alongside the ~L9~:8~
customary excipients, such as (a) fillers and extenders, for example starches, lactose~ sucrose, glucose, mannitol and silica, (b~ binders~ for example carboxymethylcellu-lose, aLg;nates, gelatine and polyv;nylpyrrolidone, (c) humectants, for example glycProl, (d) disintegrating agents, for example agar~agar~ calGium carbonate and sod;um b;carbonate, (e) solut;on retarders, for example paraffinO and (f) absorption accelerators, for example quaternary ammonium compounds, ~9) ~ett;ng agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaol;n and beton;te, and (;) lubr;cants, for example talcu, calcium stearate, magnesium stearate and sol;d polyethylene glycols, or m;xtures of the substances l;sted under (a) to (i).
The tablets, dragees, capsules, p;lls and granules can be provided ~;th the customary coat;ngs and shells, opt;onally conta;n;ng opal;s;ng agents, and can also be of such compos;t;on that they rel~ase the act;ve compound or compounds only, or preferentially~ in a certa;n part of the ;ntest;nal tract, optionally ;n a delayed manner, examples of embedding compos;tions ~hich can be used be;ng polymeric substances and ~axes.
The act;ve compound or compounds, optionally together ~ith one or more of the abovemen~ioned exc;pients, can also be in a microencapsulated form.
Suppositories can contain, in addit;on to the act;ve compound or compounds, the customary water-soluble or water-;nsoluble excipients, for example polyethylene glycols, fats, for exarple cacao fat~ and higher esters (for example C14-alcohol with C16-fatty acid), or mix-tures of these substances.
Solutions and emulsions can contain, ;n addition to the active compound or compounds, the customary exc;pients, such as solvents, solub;l;s;ng agen~s and emuls;f;ers, for example ~ater, ethyl alcohol, ;sopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol~
~$9~
benzyl benzoate, propylene glycol, 1,3-butylene glycol~
dimethylformamideD oils, in particular cottonseed oil, groundnut oil, maize germ o;l~ ol;ve o;l~ castor oil and sesame o;l, glycerol, glycerolformal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
For parenteral administration, the solutions and emulsions can also be in a sterile form wh;ch is ;sotonic with blood~
Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example ~ater, ethyl alcohol or pro-pylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar~agar and tragacanth, or mixtures of these substances.
The formulation forms mentioned can also contain colorants, preservatives and addit;ves which improve ~he odour and flavour~ for example peppermint oil and eucalyp-tus oil, and s~eeteners, for example saccharin.
The therapeutically active compounds should pre-ferably be present in ~he abovementioned pharmaceutical formulations in a concentration of about 0.1 to 9905X by ~eight, preferably about 0.5 to 95% by ~eight~ of the total m;xture.
The abovementioned pharmaceutical formulations can also contain other pharmaceutical active compounds, in addit;on to compounds of the formula (XI) andJor their salts.
The abovementioned pharmaceut;cal formulations are prepared in the customary manner by known methods, for example by mix;ng the active compound or compounds w;th the excipient or excip;ents.
The active compounds of the formula (XI~ or the pharmaceut;cal formulations can be adm;n;stered orally, ~Z49~84 parenterally and/or restally, preferabLy orally and paren-terally, in particular orally and ;ntravenously~
In general, it has proved advantageous to adm;nis-ter the active compound or compounds~ in the case of 5 parenteral (intravenous or intramuscular) administration, in amounts of about D.~1 to about 10, preferably 0.1 to 1, mg/kg of body weight every 2~ hours, and, in the case of oral administration~ in amounts of about 0.05 to about 100, preferably 0.1 to 10, mg/kg of body we;ght every 24 hours, optionally in the form of several individual administrations, in order to achieve the desired results.
An indiv;dual administration preferably contains the active compound or compounds in amounts of about 0001 to about 30, ;n part;cular ~.03 to 3, mg/kg of body weight~
~owever, it can be necessary to deviate from the dosages mentioned, and in particular to do so as a func-tion of the nature and body we;ght of the subject to be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament, and the time or interval over ~hich the administration takes place. Thus it can in some cases suffice to manage with less than the abovementioned amount of active compound~ ~hilst in other cases the abovemen-tioned amount of active compound must be exceeded. The particular optimum dosage required and the type of adminis-tration of the act;ve compounds can easily be determined by anyone skilled in the art on the basis of his expert kno~ledge D
The active compounds of the formula (XI) can also 3D be in the form of medicaments ~hich add;tionally contain other active compounds besides compounds of the formula (XI~. ~ctive compounds which may be mentioned as pre-ferred are: ~-receptor blockers, parasympatholytics~
anxiolytics, neuroleptics, hypnstics and tranquillizers.
The preparation of the compounds of the formula ~XI) may be illustrated by the foLlowing examples~
___ ~Z4928~
Example 7 ~3 ~2~3 S~
F J~L~
1-Methyl~9-ethyl-4-fluoro-7,8,9,10-tetrahydrothieno-C3 2-e] ridor4 3-blindole D PY _ O _. _ _ _ _ 0.1 mole of 3-methyl-7-fluoro-5~hydrazinobenzo-th;ophene hydrochloride and 0.11 mole of 1-ethylpiperidone are dissolved in 300 ml of ;sopropanol ;n the cold. The solut;on ;s brought to the boil;ng po;nt, and 100 ml of HCl-saturated isopropanol arr added, ~hile the solution ;s hot, in the course of 10 m;nutes. After the m;xture has been boiled for 1 hour, it is cooled to 0C and the crystals formed are filtered off ~ith suction. For puri-fication~ 300 ml of 10X strength sodium hydro~ide solutîon are added to the crude product, the base ;s taken up in methylene chLoride and the organic phase is washed with ~ater and dried over sodium suLphate. The mixture is filteredO the solvent is evaporated off and the base is obtained as crystals from isopropyl ether.
Y;eld: 75% of theory; melting point: 182 ~ 183C, after recrystallisation from ethyl acetate.
Lactate: 0.05 mole of base ;s dissolved in 700 ml of acetone9 and 15 g of L~+)-lactic acid are added. Colour-less crystals. Yield: 95% of theory; melting point:
203 - 205Cu 9;2~3~
Preparat;on of the starting substance 3-Methyl-7-fluoro-S-hydrazinobenzothiophene hydrochloride N~NH2 ~HCl C~3 0.1 mole of 3-methyl-7-fluoro-5-aminobenzothio-phene hydrochloride are suspended in 100 ml of water and 100 ml of concentrated hydrochloric acid, and a solution of 0~11 mole of sod;um nitrite in S0 ml of water is added dropwise at between -5C and 0C. The diazon;um salt solut;on is added dropw;se to a mixture, cooled to 0C~
of 0.21 mole of SnCl2.2H20 and 200 ml of concentrated hydrochlor;c acid~ After the mixture has been ~armed to room temperature, 60 ml of ;sopropanol are added. The crystal mass is filtered off with suction and recrystal-l;sed from ;sopropanol.
Y;eld: 88X of theory; melting point: 205 - 210C
(decomposit;on).
3-Methy,l-7-~luoro-5 ami benzothiophene hydrochloride Cl ~3 SProcess ~, 0.01 mole of 3-methyl-7-fluoro-5-nitrobenzothio-phene are hydrogenated in 300 ml of methanol in the pre-sence of 1 9 of palladium-on-charcoal at 25C, After the catalyst has been f;ltered off, the filtrate is con-centrated to about 100 ml, an ether-HCl solution is added and the hydrochloride is filtered off w;th suct;on.
Yield: 92X of theory; melting po;nt: 273 - 275C
(decomposition).
-
The individual synthesis steps for the intermediates used in the preparation process according to the invention are illustrated in more detail below.
1st stage: 7-Fluoroisatin(III) is known. It is prepared from 2-fluoroaniline (II), which is available in industrial amounts.
(Compare: S.J. Holt and P.W. Sadler, Proc. Roy. Soc. (London) 148 B, 481-494 (1958); and R.R. Smo]ders et al., Ing. Chim.
(Brussels) 1982, 64(303), 3-6).
2nd stage: 3-Fluoro-5-nitroanthranilic acid (IV). This compound is prepared in a manner which is known per se by nitration of 7-t - 4 -~z~
fluoroisatin andoxidation with hydrogen peroxide.
The nitration is preferably carried out with 100~ strength nitric acid in concentrated sulphuric acid.
IIowever, it is also possible to use other nitrating agents, such as alkali metal nitrates, mixed anhydrides of nitric acid or nitric acid esters or other sol-- 4a -~2~ 8D~
vents, such as glac;al acetic acid or chlorinated hydro-carbons. The reaction temperatures can be varied. In general, the reaction is carried out at temperatures bet-~een -20 and 40, preferably at 0~
(Compare: W.C. Sumpter and W.F. Jones, J. Amer. Chem.
Soc. 6~, 1802 (1943)).
3rd stage: 3-Fluoro-2-chloro-5-nitrobenzo;c acid (V).
This compound is prepared in a manner which is known per se by diazotisation of the corresponding anthranilic acid and reaction of the diazotisation product with hydro-chloric acid in the presence of copper-I chloride. The diazotisat;on is carried out with customary reagents, such as sodium nitrite, nitrosylsulphuric acid or alkyl-nitrites. Suitable solvents are concentrated sulphuric ~5 acid~ phosphoric acid~ hydrochloric acid or glacial acetic acid or mixtures thereof. Diazotisation with nitrosyl-sulphur;c acid in phosphoric acid/glacial acetic acid mix tures is preferred. The reaction temperatures here can be varied from -5 to 30. ~eplacement of the diazoniwm group by chlorine is carried out with aqueous hydrochloric acid in the presence of copper catalysts. Copper-I
chloride is the preferred catalyst.
~Compare: ~ouben-WeylO Volume V/3, page 846 et seq.
(1962)).
4th sta~: Diethyl ~3-fluoro-2-chloro-5-nitrobenzoyl)-malonate tVII).
This compound can be obtained in a manner which is known per se from the corresponding benzoic acidy via the acid chlor;de ~VI).
The acid chloride is formed by reaction with ;n-organic acid chlorides, such as thionyl chloride, phos-phorus-V chloride or phosphorus-III chloride. The reac-tion can be carr;ed out in solvents such as aromatic hydrocarbons or chlorinated hydrocarbons, or in excess chlorinating agents, at temperatures between 20 and 100. The reaction in thionyl chloride at the reflux ~;~4~Z~
temperature is preferred~
Aromatic hydrocarbons are suitable solvents for the reaction of the acid chloride w;th diethyl ethoxy-magnesium-malonate; toluene is part;cularly preferred.
(Compare: A.P.G. Kieboom, Synthesis 1975, 327; and S.R. Alpha~ J. Org. Chem. 38, 3136 (1973)~.
5th sta~: 3-Fluoro-2-chloro-5-nitroacetophenone ~III).
Th;s compound is prepared ;n a manner ~h;ch ;s known per se by reacting diethyl ~3-fluoro-2-chloro-5-nitrobenzoyl)-malonate with prop;onic ac;d and sulphuric ac;d. Acylatedmalonic esters can be converted ;nto methyl ketones by hydrolys;s and decarboxylat;on. Preferred react-;on con-d;t;ons here are ~arming ;n prop;onic acid in the presence of catalytic amounts of concentrated sulphuric ac;d until the evolution of COz has ended.
(Compare: N.~. Chapman et al., J. Chem. So~. (C) 1968, 518; and Houben-Weyl, VoLume VII/2, page 1338 et seq.
(1976)) 6th stage: t2-Acetyl-6-fluoro-4-n;tro-phenylthio)acet;c ac;d (IX).
This compound can be obta;ned ;n a manner ~hich is kno~n per se by reacting 3-fluoro-2-chloro~5-n;tro-acetophenone w;th mercaptoacet;c acid.
The reaction ;s carr;ed out in ~ater or water-m;sc;ble organic solvents (for example alcohols or lowerketones) ;n the presence of an alkal; (for example alkal;
metal b;carbonates, carbonates or hydrox;des or tert;ary am;nes). Sodium b;carbonate in aqueous ;sopropanol ;s preferably used. The react;on temperatures can be var;ed from 20 up to the boiling po;nt of the solvent used;
the temperature is preferably 45 to 50.
(Compare: A. R;cc; and N. Cagnol;, Ann. Ch;m. tRome) 45, 172 (1955); C. Angel;n;, Ann. Ch;m. ~Rome) 47, 705 ~1957);
and S. M;ddleton, Austr. J. Chem. 12, 218 (1959)).
7th stage: The cycl;sat;on of (2-acetyl-6-fluoro-4-nitro-phenylth;o)acet;c ac;d to 3-methyl-7-fluoro-5-n;trobenzo-~Z~2~3~
th;ophene ~I) is carr;ed out in the presence of carboxylic acids~ as condens;ng agents~ and, ;f appropriate, in the presence of inert organic solvents at temperatures bet~een 50 and 20D.
The use of propionic acid has proved particularly advant3geous~ The preferred reaction temperature here is in the range from 110 to 150.
(Compare: DE-OS ~German Published Specification) 3,03~,738).
The present invention may be illustrated in more detail by the following examples:
Example 1 N02~, COO~
r NH2 a) 3-Fluoro-5 nitroanthranilic acid tfrom 7-fluoroisatin) 33.0 g tO.2 mole) of 7-fluoroisatin are dissolved in 80 ml of concentrated sulphuric acid. 8.3 ml of 100%
strength nitric acid are added dropwise at 0 in the course of ZO minutes, ~ith cooling. The mixture is sub-sequently stirred at 0 for 30 minutes. It is then poured onto 400 9 of ice and rendered alkaline at 20 to 30 ~ith 45X strength sodium hydroxide solution. 30 ml of 30% strength hydrogen peroxide are added dropwise at 20 ;n the course of 10 minutes. The m;xture is subse-quently stirred for a further 30 minutes and the product Z5 is precipitated with concentrated hydrochloric acid up to pH 2. The product is filtered off with suction, ~ashed ~;th water until free from salts and dried at 50 in vacuo.
Yield: 34.5 9 = 86.3X of theory Melting point: 243 to 246 (decomposition) b) 3-Fluoro-5-nitroanthranilic acid (from N~ fluoro-phenyl)-2-hydroxyiminoacetamide, ~ithout isolation of ~Z~8~
the 7-fluoroisation) ~) N-(2-Fluorophenyl)-2-hydroxy-iminoacetamide NEI-C-S X=2~-gH
F
A m;xture of 400 mL of water, 110 9 of anhydrous sod;um sulphate and 10.7 9 ~0.154 mole) of hydroxylam;ne hydrochloride ;s ~armed to 85. A solution of 24.8 g (0.15 mole) of chloral hydrate, 15.~ 9 tO.14 mole) of 2-fluoroan;l;ne and 1Z ml of concentrated hydrochloric acid in 50 ml of water is added drop~ise at 85 in the course 1D of 60 minutes~ The mixture ;s subsequently stirred at 85 for 60 minutes and cooled to 30. It is extracted by stirr;ng with 200 ml of methylene chloride. The organic phase is separated off, 70 ml of water are added and the mixture is brought to pH 12 ~ith sodium hydroxide solution. After stirring for 30 minutes, the mixture is brought to pH 10.5 ~ith dilute hydrochlorir ac;d. The aqueous phase is cleanly separated off and the product is prec;pitated at 20 - 25 by addition of hydrochloric acid up to pH 7~ The product is filtered off ~ith suction, ~ashed ~ith ~ater and dried at 50 in vacuo.
Yield 15.5 9 ~ 60.8% of theory.
Melt;ng point: 113 - 115.
~) 3-Fluoro-5-nitroanthranilic acid 50 9 (0~274 mole) of N-(2-fluorophenyl)-2-hydroxy iminoacetamide are introduced into 150 ml of concentrated sulphuric acid at 80 - 85 ;n the course of 20 minutes.
Thereafter, the mixture i5 subsequently stirred at 80 -85 for a further 40 minutesA It is cooled to 0O
13 ml of 100X strength nitric acid are added dropwise at 0 ;n the course of 30 rn;nutes and the mixture ;s sub-sequently stirred at 0 for a further 30 minutesn It is poured onto ice and brought to pH 12 ~ith sodium hydroxide solution. After add;tion of 50 ml of 30X strength hydro-TP 7_ ~Z~8~
g gen peroxide~ the mixture is stirred at 20 for 30 m;nutes. Thereafter, the product ;s precipitated by addi-tion of hydrochloric acid up to pH 2, filtered off with suct;ony washed w;th water unt;l free from salts and dried at 50 in vacuo.
Yield: 31~8 9 = 58.0X of theory Melt;ng po;nt: 237 - 239 tdecomposition) Example 2 NO2 ~ COOH
~ Cl F
3-Fluoro-Z-chloro-5-nitrobenzo;c ac;d A suspension of 100.5 9 of 3-fluoro-5-nitroanthan-ilic acid (0.5 mole~ in 400 ml of 85% strength phosphoric acid and 200 ml of glacial acetic acid is diazotised at 0 ~ith a nitrosylsulphuric acid obtained from 35.2 9 of sod;um nitr;te (D.51 mole) and 250 ml of concentrated sulphuric acid~ The mixture is subsequently stirred at 0 for 2 hours~ The diazonium salt solut;on is st;rred ;nto a m;xture of 65 9 of copper-I chloride and 600 ml of concentrated hydrochloric ac;d at 20 to 25. The mixture is st;rred at 25 for a further 15 minutes, warmed briefly to 70 and then cooled to room temperature.
The prec;pitate is filtered off with suction and washed with water. The mother liquor is extracted w;th 1,000 ml of diisopropyl ether. The prec;pitate ;s dis-solved in the ether extract; the mixture is filtered overk;eselguhr. After the solvent has been distilled off in vacuo, the residue is recrystallised from 250 ml of toluene and the crystals are filtered off with suction and dried ;n vacuo at 50.
Yield: 69.4 9 = 62~4% of theory; melting point: 155-157.
~Z4~92~3~
Example 3 N02 ~ C C~(C02CH2CH3~2 ~J`
T Cl D;ethyl ~3-fluoro-2-chloro-5-nitrobenzoyl)malonate 40.0 9 tO.18 mole) of 3-fluoro-2-chloro-5-nitro-benzoic acid are warmed under reflux in 120 ml of thionylchloride with 1 ml of dimethylformamide until the evolu-tion of gas has ended (about 2 hours). The excess thionyl chloride is distilled off and the acid chloride formed is distilled in vacuo.
Yield: 40.0 9 ~ 93~0X of theory ~oiling point: 98 to lû1/0.1 mm Hg A solution of 40.0 9 (0.168 mole) of 3-fluoro-2-chloro-5-nitrobenzoyl chlor;de in 190 ml of absolute tolu-ene is added dropwise to a solution of 0.25 mole of diethyl ethoxymagnesium-malonate in 140 ml of absolute toluene at room temperature and the mixture is subsequently st;rred for 15 rninutPs and poured onto a mixture of 170 9 of ice and 30 ml of concentrated sulphur;c acid. The organ;c phase is separated off and ~ashed neutral with water and the toluene is distilled off in vacuo. The residue is made to crystallise by addition of 100 ml of petroleum ether (40/60). The crystals are filtered off with suction, washed with petroleum ether and dried in vacuo at room temperature.
Yield: 47.7 9 ~ 78.5% of theory Melting point: 59 ~92~3~
~ 11 --Example 4 o N2 `~1CH3 3-Fluoro-2-chloro-5-nitroacetophenone 47~7 ~ (0.132 mole) of diethyl (3-fluoro-2 chloro-5-nitrobenzoyl)malonate are ~armed at the boiling point under reflux for Z.0 hours ;n 55 ml of propionic acid, ~;th addition of 0.5 ml of concentrated sulphuric acid.
The propionic acid is then distilled off in vacuo up to an internal temperature of 100. The residue is dissolved in 100 ml of methylene chloride and the solution is washed neutral with ~ater and filtered over an Al203 layer.
The solvent is dist;lled off in vacuo and the residue ;s made to crystall;se by add;t;on of 100 ml of petroleum ether (40/60). The crystals are f;ltered off ~;th suc-tion9 r;nsed with petroleum ether and dr;ed in vacuo at Y;eld- 25.2 9 ~ 87.8X of theory, Melting point 67.
ExampLe 5 NO2~f ~CH3 ~
-r S-CR2-CH
F
~2-Acetyl-6-fluoro-4-n;tro-phenylth;o)acet;c ac;d 25.0 9 ~0.115 mole) of 3-fluoro-2-chloro-5-n;tro-acetophenone and 21.0 9 (0~25 mole) of sodium bicarbonate are suspended in a mixture of 90 ml of isopropanol and 30 ml of water. 11~1 9 ~0~12 mole) of freshly distilled mercaptoacetic acid are added dropwise at 45 to 50 in the course of 10 minutes and the mixture is subsequently stirred at this temperature for a further hour. After the mixture has been diluted wi~h 250 ml of ;ce-water~ the produc~ is precipitated by dropwise addi~ion of 20 ml of concentrated hydrochloric ac;d and is filtered off ~ith suction, ~ashed ~;th ~ater and dr;ed in vacuo at 50.
Yield: 29aO 9 ~ 92~3X of theory, Melt;ng po;nt: 110 to 1157 Example _ N2~ ~ J CH3 1U 3-Methyl-7-fluoro-5-n;trobenzothio hene P
10.0 9 (OAO366 mole) of ~2 acetyL-6-fluoro-4-nitro~phenylthio)acetic acid are ~armed under reflux ;n 40 ml of prop;onic acid until the evolution of C02 has ended (about 1.5 hours). The propionic ac;d is then dis-t;lled off ;n vacuo, the res;due ;s d;ssolved in 50 ml ofmethylene chloride and the solution is filtered over sil;ca gel. Thereafter, the solvent is d;stilled off ;n vacuo and the residue which remains is recrystallised from 40 ml of isopropanol. The product ;s f;ltered off ~ith suction, washed w;th ;sopropanol and dried in vacuo at 45.
Y;eld: 5.1 9 - 66.0X of theory, Melt;ng po;nt: 111.
The 3-methyl-7-fluoro-5-nitrobenzothiophene pre-pared accord;ng to the ;nvent;on is used for the prepara-tion of 7,8,9,10-tetrahydrothienoC302-e]pyr;do-C4,3-b~-;ndoles of the general formula (XI) (XI) ~P 74 28~
in ~h;ch R represents hydrogen or alkyl.
The new substituted 7,8,9,10-tetrahydrothieno~
~3,2-e~pyrido-C4~3-b~indole derivatives of ~he formula (XI), Yhich are not the subject of the present ;nvention~
exh;b;t a better act;on spectrum on the central nervous system, in particular also a better therapeutically useful in vivo activity, than the compounds known from the prior art and described ;n European Patent Spec;fication 12,347.
The compounds of the formula (XI) and the;r pharmaceut;cal use thus represent an enrichment of pharmacy.
The compounds of the formula ~XI) can be processed to pharmaceutical formulat;ons ~h;ch conta;n, ;n addit;on to non~toxic, ;nert, pharmaceutically suitable exc;p;ents, one or more of the compounds ~IX~ or their salts.
Such formulat;ons also include pharmaceut;cal formulations in dosage units. This means that the formu-lat;ons are in the form of individual parts, for example tablets, dragees, capsules, pills, suppos;tories and ampoules, of which the active compound content corresponds to a fraction or a mult;ple of an ;ndiv;dual dose. The dosage un;ts can conta;n, for exampleO 1~ 2, 3 or 4 ;ndi~
vidual doses or 1/2, 1/3 or 1/4 of an indiv;dual dose.
An individual dose preferably contains the amount of active compound ~h;ch is given in one administration and which usually corresponds to a whole, one half, one third or one quarter of a daily dose.
By non-toxic, inert, pharmaceut;cally su;table exc;pients there are to be understood solid~ sem;-sol;d or liquid diluents, fillers and formulat;on aux;liar;es of every k;nd.
Tablets, dragees, capsules, p;lls, granules~
suppos;tor;es, solut;ons, suspens;ons and emuls;ons may be ment;oned as preferred pharraceut;cal formulat;ons~
Tablets, dragees, capsules, p;lls and granules can contain the active compound or compounds alongside the ~L9~:8~
customary excipients, such as (a) fillers and extenders, for example starches, lactose~ sucrose, glucose, mannitol and silica, (b~ binders~ for example carboxymethylcellu-lose, aLg;nates, gelatine and polyv;nylpyrrolidone, (c) humectants, for example glycProl, (d) disintegrating agents, for example agar~agar~ calGium carbonate and sod;um b;carbonate, (e) solut;on retarders, for example paraffinO and (f) absorption accelerators, for example quaternary ammonium compounds, ~9) ~ett;ng agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaol;n and beton;te, and (;) lubr;cants, for example talcu, calcium stearate, magnesium stearate and sol;d polyethylene glycols, or m;xtures of the substances l;sted under (a) to (i).
The tablets, dragees, capsules, p;lls and granules can be provided ~;th the customary coat;ngs and shells, opt;onally conta;n;ng opal;s;ng agents, and can also be of such compos;t;on that they rel~ase the act;ve compound or compounds only, or preferentially~ in a certa;n part of the ;ntest;nal tract, optionally ;n a delayed manner, examples of embedding compos;tions ~hich can be used be;ng polymeric substances and ~axes.
The act;ve compound or compounds, optionally together ~ith one or more of the abovemen~ioned exc;pients, can also be in a microencapsulated form.
Suppositories can contain, in addit;on to the act;ve compound or compounds, the customary water-soluble or water-;nsoluble excipients, for example polyethylene glycols, fats, for exarple cacao fat~ and higher esters (for example C14-alcohol with C16-fatty acid), or mix-tures of these substances.
Solutions and emulsions can contain, ;n addition to the active compound or compounds, the customary exc;pients, such as solvents, solub;l;s;ng agen~s and emuls;f;ers, for example ~ater, ethyl alcohol, ;sopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol~
~$9~
benzyl benzoate, propylene glycol, 1,3-butylene glycol~
dimethylformamideD oils, in particular cottonseed oil, groundnut oil, maize germ o;l~ ol;ve o;l~ castor oil and sesame o;l, glycerol, glycerolformal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
For parenteral administration, the solutions and emulsions can also be in a sterile form wh;ch is ;sotonic with blood~
Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example ~ater, ethyl alcohol or pro-pylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar~agar and tragacanth, or mixtures of these substances.
The formulation forms mentioned can also contain colorants, preservatives and addit;ves which improve ~he odour and flavour~ for example peppermint oil and eucalyp-tus oil, and s~eeteners, for example saccharin.
The therapeutically active compounds should pre-ferably be present in ~he abovementioned pharmaceutical formulations in a concentration of about 0.1 to 9905X by ~eight, preferably about 0.5 to 95% by ~eight~ of the total m;xture.
The abovementioned pharmaceutical formulations can also contain other pharmaceutical active compounds, in addit;on to compounds of the formula (XI) andJor their salts.
The abovementioned pharmaceut;cal formulations are prepared in the customary manner by known methods, for example by mix;ng the active compound or compounds w;th the excipient or excip;ents.
The active compounds of the formula (XI~ or the pharmaceut;cal formulations can be adm;n;stered orally, ~Z49~84 parenterally and/or restally, preferabLy orally and paren-terally, in particular orally and ;ntravenously~
In general, it has proved advantageous to adm;nis-ter the active compound or compounds~ in the case of 5 parenteral (intravenous or intramuscular) administration, in amounts of about D.~1 to about 10, preferably 0.1 to 1, mg/kg of body weight every 2~ hours, and, in the case of oral administration~ in amounts of about 0.05 to about 100, preferably 0.1 to 10, mg/kg of body we;ght every 24 hours, optionally in the form of several individual administrations, in order to achieve the desired results.
An indiv;dual administration preferably contains the active compound or compounds in amounts of about 0001 to about 30, ;n part;cular ~.03 to 3, mg/kg of body weight~
~owever, it can be necessary to deviate from the dosages mentioned, and in particular to do so as a func-tion of the nature and body we;ght of the subject to be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament, and the time or interval over ~hich the administration takes place. Thus it can in some cases suffice to manage with less than the abovementioned amount of active compound~ ~hilst in other cases the abovemen-tioned amount of active compound must be exceeded. The particular optimum dosage required and the type of adminis-tration of the act;ve compounds can easily be determined by anyone skilled in the art on the basis of his expert kno~ledge D
The active compounds of the formula (XI) can also 3D be in the form of medicaments ~hich add;tionally contain other active compounds besides compounds of the formula (XI~. ~ctive compounds which may be mentioned as pre-ferred are: ~-receptor blockers, parasympatholytics~
anxiolytics, neuroleptics, hypnstics and tranquillizers.
The preparation of the compounds of the formula ~XI) may be illustrated by the foLlowing examples~
___ ~Z4928~
Example 7 ~3 ~2~3 S~
F J~L~
1-Methyl~9-ethyl-4-fluoro-7,8,9,10-tetrahydrothieno-C3 2-e] ridor4 3-blindole D PY _ O _. _ _ _ _ 0.1 mole of 3-methyl-7-fluoro-5~hydrazinobenzo-th;ophene hydrochloride and 0.11 mole of 1-ethylpiperidone are dissolved in 300 ml of ;sopropanol ;n the cold. The solut;on ;s brought to the boil;ng po;nt, and 100 ml of HCl-saturated isopropanol arr added, ~hile the solution ;s hot, in the course of 10 m;nutes. After the m;xture has been boiled for 1 hour, it is cooled to 0C and the crystals formed are filtered off ~ith suction. For puri-fication~ 300 ml of 10X strength sodium hydro~ide solutîon are added to the crude product, the base ;s taken up in methylene chLoride and the organic phase is washed with ~ater and dried over sodium suLphate. The mixture is filteredO the solvent is evaporated off and the base is obtained as crystals from isopropyl ether.
Y;eld: 75% of theory; melting point: 182 ~ 183C, after recrystallisation from ethyl acetate.
Lactate: 0.05 mole of base ;s dissolved in 700 ml of acetone9 and 15 g of L~+)-lactic acid are added. Colour-less crystals. Yield: 95% of theory; melting point:
203 - 205Cu 9;2~3~
Preparat;on of the starting substance 3-Methyl-7-fluoro-S-hydrazinobenzothiophene hydrochloride N~NH2 ~HCl C~3 0.1 mole of 3-methyl-7-fluoro-5-aminobenzothio-phene hydrochloride are suspended in 100 ml of water and 100 ml of concentrated hydrochloric acid, and a solution of 0~11 mole of sod;um nitrite in S0 ml of water is added dropwise at between -5C and 0C. The diazon;um salt solut;on is added dropw;se to a mixture, cooled to 0C~
of 0.21 mole of SnCl2.2H20 and 200 ml of concentrated hydrochlor;c acid~ After the mixture has been ~armed to room temperature, 60 ml of ;sopropanol are added. The crystal mass is filtered off with suction and recrystal-l;sed from ;sopropanol.
Y;eld: 88X of theory; melting point: 205 - 210C
(decomposit;on).
3-Methy,l-7-~luoro-5 ami benzothiophene hydrochloride Cl ~3 SProcess ~, 0.01 mole of 3-methyl-7-fluoro-5-nitrobenzothio-phene are hydrogenated in 300 ml of methanol in the pre-sence of 1 9 of palladium-on-charcoal at 25C, After the catalyst has been f;ltered off, the filtrate is con-centrated to about 100 ml, an ether-HCl solution is added and the hydrochloride is filtered off w;th suct;on.
Yield: 92X of theory; melting po;nt: 273 - 275C
(decomposition).
-
4 ~ ~ Q ~
(Process b) 0.09 mole of 3 methyl-7 fluoro-5-nitrobenzothio-phene are heated to the boil;ng po;nt in 220 ml of methanol together with 2 9 of palladium on-charcoal.
0.35 mole of hydraz;ne hydrate ;s then added dropwise in the course of 30 m;nutes. After the m;xture has been boiled for 2 hours, it is filtered~ the filtrate is con-centrated, the residue ;s dissolved in ether and the solu-tion is washed ~ith water. The hydrochloride is precipi-tated from the ether solution.
Yield: 97% of theory; melting point: 273 - 275C
(decompos;tion).
3-Meth~l-7-fluoro-5-nitrobenzothiophene F
~3 tFor the descript;on of the preparat;on according to the invention, see above).
(Process b) 0.09 mole of 3 methyl-7 fluoro-5-nitrobenzothio-phene are heated to the boil;ng po;nt in 220 ml of methanol together with 2 9 of palladium on-charcoal.
0.35 mole of hydraz;ne hydrate ;s then added dropwise in the course of 30 m;nutes. After the m;xture has been boiled for 2 hours, it is filtered~ the filtrate is con-centrated, the residue ;s dissolved in ether and the solu-tion is washed ~ith water. The hydrochloride is precipi-tated from the ether solution.
Yield: 97% of theory; melting point: 273 - 275C
(decompos;tion).
3-Meth~l-7-fluoro-5-nitrobenzothiophene F
~3 tFor the descript;on of the preparat;on according to the invention, see above).
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 3-methyl-7-fluoro-5-nitrobenzothiophene of formula (I) (I) which process comprises cyclising (2-acetyl-6-fluoro-4-nitrophenylthio) acetic acid.
2. A process as claimed in claim 1 wherein the (2-acetyl-6-fluoro-4-nitrophenylthio) acetic acid is prepared by reacting 3-fluoro-2-chloro-5-nitro-acetophenone with mercaptoacetic acid.
3. A process as claimed in claim 2 wherein the 3-fluoro-2-chloro-5-nitroacetophenone is prepared by reacting diethyl(3-fluoro-2-chloro-5-nitrobenzoyl)-malonate with propionic acid in the presence of sulphuric acid.
4. A process as claimed in claim 3 wherein the diethyl(3-fluoro-2-chloro-5-nitrobenzoyl)-malonate is prepared by reacting 3-fluoro-2-chloro-5-nitro-benzoyl chloride with diethyl ethoxymagnesium-malonate.
5. A process as claimed in claim 4 wherein the 3-fluoro-2-chloro-5-nitrobenzoyl chloride is prepared by reacting 3-fluoro-2-chloro-5-nitrobenzoic acid with thionyl chloride.
6. A process as claimed in claim 5 wherein the 3-fluoro-2-chloro-5-nitrobenzoic acid is prepared by diazotising 3-fluoro-5-nitroanthranilic acid and reacting the diazotisation product with hydrochloric acid in the presence of copper-I chloride.
7. A process as claimed in claim 6 wherein the 3-fluoro-5-nitroanthranilic acid is prepared by nitrating 7-fluoroisatin and then oxidizing the product.
8. A compound of the general formula (X) (X) in which R1 represents a carboxyl group or a halide thereof or an alkylcarbonyl group which is optionally substituted in the alkyl group by one or more alkoxycarbonyl groups and R2 represents halogen, an amino group or a thioalkyl-carboxyl group.
9. The compound 3-fluoro-5-nitroanthranilic acid.
10. The compound 3-fluoro-2-chloro-5-nitrobenzoic acid.
11. The compound 3-fluoro-2-chloro-5-nitrobenzoic acid chloride.
12. The compound diethyl (3-fluoro-2-chloro-5-nitrobenzoyl)-malonate.
13. The compound 3-fluoro-2-chloro-5-nitroacetophenone.
14. The compound (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3406997.6 | 1984-02-27 | ||
| DE19843406997 DE3406997A1 (en) | 1984-02-27 | 1984-02-27 | Process for the preparation of 3-methyl-7-fluoro-5-nitro- benzothiophene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1249284A true CA1249284A (en) | 1989-01-24 |
Family
ID=6228903
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000475083A Expired CA1249284A (en) | 1984-02-27 | 1985-02-25 | Process for the preparation of 3-methyl-7-fluoro-5- nitrobenzothiophene |
Country Status (9)
| Country | Link |
|---|---|
| KR (1) | KR850006398A (en) |
| CA (1) | CA1249284A (en) |
| DE (1) | DE3406997A1 (en) |
| DK (1) | DK87285A (en) |
| ES (1) | ES8609301A1 (en) |
| FI (1) | FI850758L (en) |
| GR (1) | GR850475B (en) |
| NO (1) | NO850561L (en) |
| PT (1) | PT80006B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA921101B (en) * | 1991-02-14 | 1993-04-05 | Brocades Pharma Bv | Use of tetra: Hydro-thieno-pyrido-indole derivatives for the prepartion of a medicine for the treatment of skin disorders. |
-
1984
- 1984-02-27 DE DE19843406997 patent/DE3406997A1/en not_active Withdrawn
-
1985
- 1985-02-13 NO NO850561A patent/NO850561L/en unknown
- 1985-02-22 GR GR850475A patent/GR850475B/el unknown
- 1985-02-25 CA CA000475083A patent/CA1249284A/en not_active Expired
- 1985-02-25 PT PT80006A patent/PT80006B/en unknown
- 1985-02-25 FI FI850758A patent/FI850758L/en not_active Application Discontinuation
- 1985-02-25 KR KR1019850001166A patent/KR850006398A/en not_active Application Discontinuation
- 1985-02-25 ES ES540669A patent/ES8609301A1/en not_active Expired
- 1985-02-26 DK DK87285A patent/DK87285A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE3406997A1 (en) | 1985-08-29 |
| FI850758L (en) | 1985-08-28 |
| ES8609301A1 (en) | 1986-08-01 |
| PT80006B (en) | 1986-11-12 |
| DK87285D0 (en) | 1985-02-26 |
| ES540669A0 (en) | 1986-08-01 |
| KR850006398A (en) | 1985-10-05 |
| NO850561L (en) | 1985-08-28 |
| FI850758A0 (en) | 1985-02-25 |
| DK87285A (en) | 1985-08-28 |
| PT80006A (en) | 1985-03-01 |
| GR850475B (en) | 1985-06-25 |
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