Note: Descriptions are shown in the official language in which they were submitted.
~L2~
- 1 - 23189-5934
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~
-- 2 --
(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
TP 74
__
8~
-- 3
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.
TP 74
23189-5934
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~
23189-5934
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
TP 74
~;~4~Z~
- 6 -
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-
TP 74
~Z~2~3~
-- 7 --
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
TP 74
~Z~8~
- 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.
TP 74
~Z4~92~3~
- 10 -
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
TP 74
~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
30
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
TP 74
- 12 -
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~
- 13 -
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
TP 74
~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~
TP 74
~$9~
- 15 -
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,
TP 74
~Z49~84
- 16 -
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~
TP 74
___
~Z4928~
- 17 -
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
TP 74
9;2~3~
- 18 -
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).
TP 74
-
4 ~ ~ Q ~
- 19 -
(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
N02
~3
tFor the descript;on of the preparat;on according to the
invention, see above).
TP 74
