CA1267653A - THIOPHENE RING-SUBTITUTED .alpha.-(ALKYLAMINOPROPIONYL)- THIOPHENE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents
THIOPHENE RING-SUBTITUTED .alpha.-(ALKYLAMINOPROPIONYL)- THIOPHENE DERIVATIVES AND PROCESS FOR THEIR PRODUCTIONInfo
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Abstract
ABSTRACT OF THE DISCLOSURE:
The invention relates to thiophene ring-substitutsd .alpha.-(alkylaminopropionyl)-thiophene derivatives having the general formula (I):
The invention relates to thiophene ring-substitutsd .alpha.-(alkylaminopropionyl)-thiophene derivatives having the general formula (I):
Description
7~
The present invention relates to thiophene ring-substituted d-(alkylaminopropionyl)-thiophene derivativ~s of the general formula (I):
X ~ C-CH-CHS
S NHR
(I) wherein X is a group different from hydrogen selected between : methyl or chlorine an~ R is an alkyl -linear or branched chain-~: grouF having ~ to 4 carbon atoms, and the nontoxic addition salts thereof, as well as to a process tor preparing these compounds and to pharmaceutical compositions containing these compounds.
~; The preterred addition salts are the hydrochlorides.
~, The compounds ot the present invention may be prepared according to the following schema:
X ~ C-CH-CH3 + H~N-R --~ X t~ ~-CH-CH3 S Br S NHR
(II) (III) (I) ~Y~
~7~
Bromine displacement in the compounds of formula (II), wherein X is as defined above for (I), by the amines of formula (III), wherein R is as defined above for (I), occurs in an iner-t medium, preferably acetonitrile, and at a maximal temperature of 50C, followed by vacuum evaporation of solvent, removal and evaporation to dryness of extracts.
From the residue thus obtained, corresponding to the compounds of formula (I), it is possib:Le to form their pharmaceutically acceptable salts, preferably hydro-chlorides, by treating respective acids ln an inert solvent;aliphatic-chlorinated hydrocarbons are preferred, specially methylene chloride, or ether, specially diethyl ether, and then the formed precipitate is separated by filtration.
Neutralization of respective salts allows to obtain the compounds of this invention as free bases.
a-(Bromopropionyl)-thiphene precursors of general formula (II) are obtained by conventional methods in Organic Chemistry; the reaction of propionyl-thiophenes with bromine in a medium composed by an aliphatic-chlorinated hydro-carbon, for example, methylene chloride, chloroform orcarbon tetrachloride, are preferred. In turn, propionyl-thiophenes are susceptible to be obtained either by acylation of respective thiophenes with a derivative of propionic acid, preferably propionyl chloride, under suitable conditions of Friedel-Crafts' reaction, or by reacting lithium derivatives of respective thiophenes with propionitrile. When X is chlorine, starting compounds such as commercially-available chlorothiophenes or dichlorothio-phenes are, if possible, used, and substituent X=Cl may be introduced into the synthesis se~uence on intermediate steps depending on the desired position. Sulphuryl chloride is preferred as a chlorinating agent. When X is methyl, respective methylthiophenes are, if possible, also used.
The preparation of a-~bromopropionyl)-thiophene precursors ~, ~L~6~53 , . .
of formula (II) is hereinafter illustrated.
5 ~3 ~ ~C-C~H5 ~
10 Cl ~ CI_~2Hs 9r~_~ Cl ~ ~-~H-CH3 (II, X= 4-Cl; chain position= 2) .:
C1~3 ~lCOE2H5 ~ 1 S C14Sn ~S~ C-C2H5 ~r~
C1~32 C- C~-CH3 Br (II, X= 5-Cl; chain position= 2) O
Cl ~ Cl ClCOC2H5 C ~ Cl C13Al ~L~6~
D O
Cl~_c2~5 Cl~ br 3 (II, X= 5-Cl; chain position= 3) CH3 ~3 ClCOC2H5 CH3 ~C--C2H5 a ? ,, 10 CH3 ~53~C~cH~cH3 ~II ', X'= 5-CH3, chain pOSitiDn= 2) C H 3~3 N - b u t y l l i th i um ~3~ C C 2 H 5 2
The present invention relates to thiophene ring-substituted d-(alkylaminopropionyl)-thiophene derivativ~s of the general formula (I):
X ~ C-CH-CHS
S NHR
(I) wherein X is a group different from hydrogen selected between : methyl or chlorine an~ R is an alkyl -linear or branched chain-~: grouF having ~ to 4 carbon atoms, and the nontoxic addition salts thereof, as well as to a process tor preparing these compounds and to pharmaceutical compositions containing these compounds.
~; The preterred addition salts are the hydrochlorides.
~, The compounds ot the present invention may be prepared according to the following schema:
X ~ C-CH-CH3 + H~N-R --~ X t~ ~-CH-CH3 S Br S NHR
(II) (III) (I) ~Y~
~7~
Bromine displacement in the compounds of formula (II), wherein X is as defined above for (I), by the amines of formula (III), wherein R is as defined above for (I), occurs in an iner-t medium, preferably acetonitrile, and at a maximal temperature of 50C, followed by vacuum evaporation of solvent, removal and evaporation to dryness of extracts.
From the residue thus obtained, corresponding to the compounds of formula (I), it is possib:Le to form their pharmaceutically acceptable salts, preferably hydro-chlorides, by treating respective acids ln an inert solvent;aliphatic-chlorinated hydrocarbons are preferred, specially methylene chloride, or ether, specially diethyl ether, and then the formed precipitate is separated by filtration.
Neutralization of respective salts allows to obtain the compounds of this invention as free bases.
a-(Bromopropionyl)-thiphene precursors of general formula (II) are obtained by conventional methods in Organic Chemistry; the reaction of propionyl-thiophenes with bromine in a medium composed by an aliphatic-chlorinated hydro-carbon, for example, methylene chloride, chloroform orcarbon tetrachloride, are preferred. In turn, propionyl-thiophenes are susceptible to be obtained either by acylation of respective thiophenes with a derivative of propionic acid, preferably propionyl chloride, under suitable conditions of Friedel-Crafts' reaction, or by reacting lithium derivatives of respective thiophenes with propionitrile. When X is chlorine, starting compounds such as commercially-available chlorothiophenes or dichlorothio-phenes are, if possible, used, and substituent X=Cl may be introduced into the synthesis se~uence on intermediate steps depending on the desired position. Sulphuryl chloride is preferred as a chlorinating agent. When X is methyl, respective methylthiophenes are, if possible, also used.
The preparation of a-~bromopropionyl)-thiophene precursors ~, ~L~6~53 , . .
of formula (II) is hereinafter illustrated.
5 ~3 ~ ~C-C~H5 ~
10 Cl ~ CI_~2Hs 9r~_~ Cl ~ ~-~H-CH3 (II, X= 4-Cl; chain position= 2) .:
C1~3 ~lCOE2H5 ~ 1 S C14Sn ~S~ C-C2H5 ~r~
C1~32 C- C~-CH3 Br (II, X= 5-Cl; chain position= 2) O
Cl ~ Cl ClCOC2H5 C ~ Cl C13Al ~L~6~
D O
Cl~_c2~5 Cl~ br 3 (II, X= 5-Cl; chain position= 3) CH3 ~3 ClCOC2H5 CH3 ~C--C2H5 a ? ,, 10 CH3 ~53~C~cH~cH3 ~II ', X'= 5-CH3, chain pOSitiDn= 2) C H 3~3 N - b u t y l l i th i um ~3~ C C 2 H 5 2
2. HCl CH3 ~C-CH-C~13 (II ', X'= 4-CH3, chzin ~osition= 2) ~r r3r N-~utyllithium CHD {~i N2~4 ~H3~S 2. HCl 3o f~-C2H5 ~C-~H-CH 5 CH3~ S ~ ~H3 S
( I I ', X ' = 2-CH3, chain position= 4) ~ 3 -4-The compounds ot the present invention have an ettective antidepressant activity as evidenced by R.D. Porsolt (Immobi-lity behsvioural despair test in mice: Arch~Int.Pharmacodyn., ~9, ~7-336, i977)~ which di~fer from the thiophene ring non-substituted d-(alkylaminopropionyl)-thiophenes, as dis-closed in French Patent No 3414M and ~ritish Patent No.~ 150, because these known compounds have anorexic activity devoided of central excitatory action or cardiovascular action, and neuroleptic, tranquillizing and anzlgesic action rsspectivelyO
Consequently, tha presence ot an X group difterent from hydro-gen, selected between methyl or chlorine, in the compounds of ~ormula (I) leads to compounds having a very effective anti-depressant action. Thus, the compounds of this invention are useful as a medicament for treating depressions The compounds ot the present invention mixed with pharma-ceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, coated tablets, syruos, solutions, etc., by injectable route and by rectal route at daily doses ranging from ~.5 to 250 mg/kg.
By way of a non-limitative illustration within the essence of the invention, some examples are described hereinbelow referring to the possible way to obtain (I) by following the steps ot the disclosed pro~ess.
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EXAMPLE 1: 2-Propionylthiophene 400 g of thiophene and 437.33 g of propionyl chloride in 2850 ml of anhydrous benzene are introduced into ,~ 5 a 6-liter flask fitted up with a mechanical stirrer. Then the mixture is cooled at 0-5C in ice-salt bath and by keeping this temperature, 1343.7 g of tin tetrachloride in 570 ml of anhydrous benzene are added (approximate addition time: 2 hours). Cooling bath is removed and the mixture is lO stirred for 20 hours at room temperature, then it is poured onto 3.8 kg of ice and 1 liter of water and vigorously stirred for 1 hour. The aqueous phase is decanted and extracted with 1.5 liters of ethyl ether; the organic extracts are washed with water to neutralization and 15 filtered off. After evaporation of solvent and vaccum distillation of the residue, 560 g (yield: 85%) of a colourless liquid are obtained. Boiling point: 77-79/
0.7-0.8 tors, n20= 1.5530, GLC: 100% and analysis correct.
;~ IR Spectrum (film), cm : 3090, 3000-2880, 1660, 1410, 1220, 1050, 900, 845, 715.
H-NMR ~Cl4C), ppm: 1.16 (t, 3H, J= 7Hz; CH3-), f 2.83 (q, 2H, J= 7Hz; -CH2-), 7.03 (dd, lH, J3 4= 3.75Hz, 4-5 ; Tiophene)~ 7-50 (dd, lH, J4 5= 4.75Hz
( I I ', X ' = 2-CH3, chain position= 4) ~ 3 -4-The compounds ot the present invention have an ettective antidepressant activity as evidenced by R.D. Porsolt (Immobi-lity behsvioural despair test in mice: Arch~Int.Pharmacodyn., ~9, ~7-336, i977)~ which di~fer from the thiophene ring non-substituted d-(alkylaminopropionyl)-thiophenes, as dis-closed in French Patent No 3414M and ~ritish Patent No.~ 150, because these known compounds have anorexic activity devoided of central excitatory action or cardiovascular action, and neuroleptic, tranquillizing and anzlgesic action rsspectivelyO
Consequently, tha presence ot an X group difterent from hydro-gen, selected between methyl or chlorine, in the compounds of ~ormula (I) leads to compounds having a very effective anti-depressant action. Thus, the compounds of this invention are useful as a medicament for treating depressions The compounds ot the present invention mixed with pharma-ceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, coated tablets, syruos, solutions, etc., by injectable route and by rectal route at daily doses ranging from ~.5 to 250 mg/kg.
By way of a non-limitative illustration within the essence of the invention, some examples are described hereinbelow referring to the possible way to obtain (I) by following the steps ot the disclosed pro~ess.
~". v,~
". "
~ i7~
EXAMPLE 1: 2-Propionylthiophene 400 g of thiophene and 437.33 g of propionyl chloride in 2850 ml of anhydrous benzene are introduced into ,~ 5 a 6-liter flask fitted up with a mechanical stirrer. Then the mixture is cooled at 0-5C in ice-salt bath and by keeping this temperature, 1343.7 g of tin tetrachloride in 570 ml of anhydrous benzene are added (approximate addition time: 2 hours). Cooling bath is removed and the mixture is lO stirred for 20 hours at room temperature, then it is poured onto 3.8 kg of ice and 1 liter of water and vigorously stirred for 1 hour. The aqueous phase is decanted and extracted with 1.5 liters of ethyl ether; the organic extracts are washed with water to neutralization and 15 filtered off. After evaporation of solvent and vaccum distillation of the residue, 560 g (yield: 85%) of a colourless liquid are obtained. Boiling point: 77-79/
0.7-0.8 tors, n20= 1.5530, GLC: 100% and analysis correct.
;~ IR Spectrum (film), cm : 3090, 3000-2880, 1660, 1410, 1220, 1050, 900, 845, 715.
H-NMR ~Cl4C), ppm: 1.16 (t, 3H, J= 7Hz; CH3-), f 2.83 (q, 2H, J= 7Hz; -CH2-), 7.03 (dd, lH, J3 4= 3.75Hz, 4-5 ; Tiophene)~ 7-50 (dd, lH, J4 5= 4.75Hz
3 5 ; Thiophene) and 7-59 (dd, lH, J3 = 3 75Hz J3 5= lHz; HThiophene) EXAMPLE 2 : 4-Chloro-2-propionylthiophene To a suspension of 400.02 g of aluminium chloride in 200 ml of dry chloroform under cooling at 10-20C, 280.4 g of 2-propionyl-thiophene are added under vigorous stirring. The mixture is then brought to 25-30C and 350.92 g of newly distilled sulfuryl chloride are slowly added (3.5 hours), then heated in water bath at 40-42C for 7i~
~Zi7~3 1 hour and left to stand overnight at room temperature.
Thexeafter, it is slowly poured onto 2.8 kg of ice under stirring, the aqueous phase is extracted with 1.2 and 0.5 liters of methylene chloride and the organic extracts are jointly washed with water (three times), sodium bicarbonate saturated solution, and water again to neutralization.
After evaporation of solvent, the residue (370.5 g) under rectifying column (Lo= 19 cm) with Raschig rings gives 216.6 g and recrystallizes from hexane (350 ml) to yield 157.4 g (45%) of a white solid with m.p. 58-60C, G~C: 98%.
IR Spectrum (KBr), cm : 3080, 3000-2880, 1665, 1400, 1220, 1190, 910.
H-NMR Spectrum (C14C), ppm: 1.16 (t, 3H, J= 7Hz;
CH3-), 2-81 (~, 2H, J= 7Hz; -CH2-), 7.29 (d, lH, J= 1.4Hz;
HThiophene) and 7.43 (d, lH, J= 1.4Hz; HThiop ~XAMPLE 3: ~-Bromo-4-chloro-2-propionylthiophene To a solution of 60 g of 4-chloro-2-propionylthiophene in 280 ml of dry methylene chloride under stirring and cooled at 0-5C, the equimolecular amount of bromo (54.9 g) dissolved in 135 ml of dry methylene chloride is slowly added; as the reaction starts, decolorization of bromo occurs immediately while adding the reaction mixture.
After completing the addition, the bath is removed, stirring for further 30 minutes is performed, the methylene chloride is evaporated under vaccum and the liquid residue is used without further purification.
IR Spectrum (film), cm 1 3100, 1665, 1400, 1230, 1155, 980, 910, 840.
1H-NMR Spectrum (Cl3C), ppm: 1.84 (_, 3H, J=
6.6Hz; CH3-), 4.93 tq, lH, J= 6.6Hz; -CH' ), 7.36 (d, lH, ; Thiophene) and 7.59 (d, lH, J= 1.25Hz;
HThiPhene ) ~, ~LZ676~
XAMPI,E 4: 2-t~-(tert-butylaminopropionyl)]-4-chlorothio-phene hydrochloride To 87.69 g of ~-bromo 4-chloro-2-propionylthio-phene in 100 ml of acetonitrile, 60.7 9 of tert-butylamine in 100 ml of acetonitrile are slowly added without exceeding 32 C (water bath regulation~. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature. The solvent is evaporated at vacuum (below 35 C), taken in methylene chloride (300 ml) and water (300 ml); the aqueous phase is removed with methylene ~; chloride, the organic extracts are washed four times with 200 ml of water, dried and evaporated to dryness. The residue (80.7 g) is dissolved in 600 ml of dry methylene chloride, cooled with ice-salt bath at 0C and a dry HCl (g) stream is slowly spread. The precipitated hydrochloride is filtered off, washed twice with dry methylene chloride and dried at vaccum to give 52.7 g of white solid ~m.p. 245-250 C) which, after recrystallizing from ethanol, yields ; 20 28 g ~30%) of the hydrochloride (m.p. 250-255C); analysis correct.
IR Spectrum tKBr), cm 1 3420; 3100-2400, 1675, 1545, 1400, 1240, 1205, 1125, 895, 795.
H-NMR Spec*rum (CD OD), ppm: 1.39 (s, 9H;
-C(CH3)3, 1.67 (d, 3H, J= 7Hz; CH3-), 5.14 (~, lH, J= 7Hz;
-CH_ ), 7.97 (d, lH, J= 1-75HZ; HThiophene) Neutralization of the hydrochloride allows to isolate respective base, m.p. 79-81C (he~ane) and analysis correct.
EXAMPLE 5: 5-Chloro-2-propionylthiophene To a solution of 77.44 g of 2-chlorothiophene and 60.42 g of propionyl chloride in 390 ml of anhydrous benzene '65~
under cooling at 0-5C (ice-salt bath), 184.56 g of tin tetrachloride in 78 ml of anhydrous benzene are dropwise added for about 1 hour and at the above temperature while separating a redish solid. Then it is stirred for 20 hours at room temperature, poured onto 520 g of ice and 130 g of water under stirring and 15 minutes later the phases are decanted: the aqueous phase is extracted with 250 ml of ethyl ether and the organic extracts are washed (3 times) with sodium chloride saturated soIution. The crude product (105.3 g) is rectified by Vigreaux Column (Lo= 11 cm~ thus obtaining 75.80 g (yield: 65%) of a white solid, m.p.
47-49 C, LGC: 100% and analysis correct.
IR Spectrum (KBr), cm 1 3080, 3000-2860, 1650, 1410, 1210, 1010, 880, 780.
H-NMR Spectrum (Cl4C), ppm: 1.14 (t, 3~-1, J-7.6Hz; CH3-), 2.75 (g, 2H, J- 7.6Hz; -CH2-), 6.85 (d, lH, J=
4Hz; HThiophene) and 7-37 (d, lH, J= 4Hz HThiO h )~
EXAMPLE 6: ~-Bromo-5-chloro-2-propionylthiophene To a solution of 112.37 g of 5-chloro-2-propionylthiophene in 500 ml of dry methylene chloride under stirring and cooling at 0-5C, 102.83 g of bromine in 250 ml of methylene chloride are added. Processing as described in Ex. 3, 167.8 g of a liquid residue corresponding to the ~-brome derivative are obtained which is pure enough to be used in the following synthesis step.
IR Spectrum (fiml), cm 1 3100, 3010-2880, 1660, 1420, 1240, 1010, 890, 800, 740.
lH-NMR (C14C) Spectrum, ppm: 1.81 (d, 3H, J=
6.6Hz; CH3-), 4.90 (~, lH, J= 6.6Hz, -CH- ), 6.91 (_, lH, J=
4Hz; HThiophene) and 7-55 (d, lH, J= 4Hz; HThioph ne).
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_ 9 _ EXAMPLE 7: 2-[~-(tert-butylaminopropionyl)]-5-chlorothio-phene hydrochloride To 81.50 g of a-bromo-5-chloro-2-propionylthio-phene in 100 ml of acetonitrile, 56.76 g of tert-butylamine in 100 ml of acetonitrlle are slowly added without exceeding 32C. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature. Processing as described in Ex. 4, 75.7 g of a crude product are isolated and respective hydrochloride in dry methylene chloride (700 ml) with HCl (g) is formed. The insolubilized hydrochloride (65.4 g, m.p. 246-248C) is recrystallized from ethanol thus obtaining 44.4 g (yield: 49~) of a white solid, m.p. 255-257C and analysis correct.
IR Spectrum ~KBr), cm : 3440, 3110-2500, 1660, - 1550, 1410, 1245, 1010, 880.
H-NMR Spectrum (CD30D~, ppm: 1.37 (_, 9H;
-C~CH3)3), 1.66 (d, 3H, J= 7Hz; -CH3), 5.14 (~, lH, J= 7Hz;
-CH= ), 7.24 (d, lH, J= 4.25Hz: HThiophene) - 20 J= 4.25Hz; HThiophene) Neutralization of the hydrochloride allows to isolate respective base, m.p. 72-75C (hexane) and analysis correct.
~XA~PL~ 8: 2,5-Dichloro-3-propionylthiophene To a solution of 65.1 g of 2,5-dichlorothiophene ' and 77.79 g of propionyl chloride in 325 ml of nitroethane, 63.5 g of aluminium chloride are slowly added in nitrogen atmosphere for about 20 minutes, thus causing the temperature of the mixture rise up to 37C. Then, the mixture is stirred for 4 hrs, poured on to 500 g of ice and removed twice with 250 ml of ethyl ether. The organic = extracts are consecutively washed with 3N hydrochloric acid !., ~6~
~150 ml), water (2xlO0 ml), 3N sodium hydroxide (3~600 ml) and saturated sodium chloride solution till neu-tralization.
After drying and evaporating the solvent, the solid residue (68.9 g) is distilled and 58.00 g (yield: 65%) of a white solid are obtained; b.p. 96-105C/1.2 tors, m.p. 63-66C and analysis correct.
IR Spectrum (KBr), cm 1 3120, 3080, 3000-2860, 1680, 1660, 1430, 1370, 1190, 1175, 1015, 800.
H-NMR Spectrum (Cl4C), ppm: 1~12 It, 3H, J= 7Hz;
CH3-), 2.83 (~, 2H, J= 7Hz; -CH2-) and 7.15 (s, lH;
Thiophene EXAMPLE 9 2-Chloro-4-propionylthiophene To a suspension of 53.28 g o~ 2,5-dichloro-4-propionylthiophene in 57 ml of glacial acetic acid and 181 ml of water, 33.31 g of zinc dust (2 equivalents) are added in the course of 5 minutes and thus the temperature rapidly rises up to 72C; then it is cooled in water bath till reaching 55 C within 10 minutes. 250 ml of ethyl ether are added, the insoluble solid is filtered off and the aqueous phase is removed with ether again; the extracts are washed with water, saturated ClN4 solution and dried with potassium carbonate. The residue (43.48 g), which is obtained after evaporating the solvent, recrystallizes from n-pentane to yield 28.9 g (65%) of a white solid, m.p. 50-53 C, LGC: 100~ and analysis correct.
IR Spectrum ~KBr), cm : 3100, 3000-2800, 1665, 1435, 1180, 1000, 780.
H-NMR Spectrum (Cl4C), ppm: 1.13 ~t, 3H, J= 7Hz;
CH3-), 2.75 (~, 2H, J= 7Hz; -CH2-), 7.28 ~d, lH, J= 1.5Hz;
HThiophene), and 7.68 ~d, lH, J= 1.5Hz; HThiophene)~
~26~53 EXAMPLE lO: ~-Bromo-2-chloro-4-propionylthiophene To a solution of 30.92 g o-f 2-chloro-4-propionylthiophene in 140 ml of dry methylene chloride under stirring and heating at 0-5C, 28.29 g of bromine in 70 ml of methylene chloride are added. Processing as described in Ex. 3, 44~9 g of a coloured liquid are obtained with analysis correct.
IR Spectrum (film), cm 1 3100, 3000-2900, 1680, 1425, 1210, 1150, 1005, 845.
H-NMR Spectrum (C14C), ppm: 1.80 (t, 3H, a=
7.0Hz; CH3-), 4.85 (q, lH, J= 7.0Hz; -CH-), 7.35 (_, lH, J=
l.SHz; HThiophene) and 7.87 ( , lH, J= 1.5Hz; HThio he 5 EXAMPLE 11: 4-Ca-(tert-butylaminopropionyl)3-2-chlorothio-phene To 44.50 g of a-brom o-2-chloro-4-propionylthiophene in 55 ml of acetonitrile, 31 g of tert-butylamine in 55 ml of acetonitrile are slowly added withoutexceeding 32C. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature.
Processing as described in Ex. 4, 42.4 g of a dark liquid are isolated and respective hydrochloride in methylene Z5 chloride (400 ml) at 0C with HCl (g) is formed. The insolubilized product (37.10 g) is recrystallized from ethanol to yield 38.5 g (40~) of a white solid, m.p. 257-259C (d) and analysis correct.
IR Spectrum (KBr), cm 1 3450, 3100-24Q0, 1675, 1545, 1230i 1200, 1175, 1000, 830.
H-NMR Spectrum (CD30D), ppm: 1.40 (s, 9H, -C(CH3)3), 1,62 (d, 3H, J= 7.0Hz; CH3-), 5.10 (q, lH, J=
7Hz; -CH-), 7.52 (d, lH, J= 1.5Hz; HThiophene) (_, lH, J= 1-5HZ; ~Thiophene) -` ~2S~7'~5~
EXAMPLE 12: 2-Propionyl-5-methylthiophene To a solution of 53.S0 g of 2-methylthiophene ~nd 50.43 g of propionyl chloride in 300 ml of anhydrous benzene under cooling at 0-5C in an ice-salt bath, 141.97 g of tin tetrachloride in 60 ml of anhydrous benzene are dropwise added for about 1 hour at the above temperature. Then it is stirred for 22 hours at room temperature to give a dark red mixture which is poured onto 400 g o~ ice and 100 g of water under vigorous stirring; after 1 hour, the aqueous phase is removed with 200 ml of ethyl ether and the organic extracts are washed three times with sodium chloride saturated solution. The crude product (76 g), which solidifies by standing, is distilled at vacuum and 68.24 g (81%) are obtained, b.p. 85-95C/0.5-0.6 tors and m.p. 32-34C.
IR Spectrum (KBr), cm 1 3100-2880, 1660~, 1455, 1230, 1050, 890, 790.
lH-NMR (Cl3CD), ppm: 1.18 ~t, 3H, J=8Hz; CH3-), 2.50 (d, 3H, J= lHz; CH3- thiophene), 2.83 (~, 2H, J= 8Hz;
-CH2-), 6,75 (dd, lH, J= lHz and~J'=-3.75Hz; H-thiophene) and 7.50 (d, lH, J= 3.75Hz, H-thiophene~.
:
EXAMPL~ 13: a-Bromo-2-propionyl-5-methylthiophene To a solution of 34.12 of 2-propionyl-5-methylthiophene in 180 ml of dry methylene chloride under stirring and cooling at 0-5C, 35.35 g of bromine in 90 ml of methylene chloride are gently added. After completing the addition, the bath is removed, stirred for further 30 minutes, the methylene chloride is evaporated at vacuum and the residue (53.27 g, 100%) is used for the following operation without further purification.
IR Spectrum (film), cm 1 3100-2900, 1665, 1450, 1245, 885.
~Z~'~`653 lH-NMR (C14C), ppm: 1.81 (d, 3H, J= 7Hz; CH3-)~
2.52 (s, 3H; CH3-thiophene), 4.95 ~, lH, J= 7Hz; -CH ), 6.75 (dd, lH, J= lHz, J'= 3.75Hz; H-thiophene) and 7.55 (d, lH, J= 3.75Hz; H-thiophene).
EXAMPLE 14: 2-L~-(tert-butylaminopropionyl)~-5-methylthio-phene hydrochloride To 44.5 g of ~-bromo-2-propionyl-5-methylthiophene in 60 ml of acetonitriIe, 36.57 g of tert-butylamine are gently added without exceeding 30C (water bath adjustment).
The solvent is evaporated at vacuum (below 35C), taken in 100 ml of methylene chloride and 100 ml of water, and the aqueous phase is removed again with 75 ml of the solvent;
the organic extracts are washed with water, dried and evaporated. The crude material (42.0 g) is dissolved in 400 ml of dry ethyl ether, and by cooling in water-ice bath a dry HCl (g) stream is spread; the precipitated hydrochloride is filtered off, washed with ether and dried at vacuum to 2Q give 35 g of a whitish solid which, after recrystallizing from ethanol, yieIds 19.7 g (40~) of a white solid corresponding to the hydrochloride (m.p. 262-263C).
IR Spectrum (KRr), cm 1 3100-2400, 1655, 1550, 1445, 1250, 1205, 1055, 880, 825.
H-NMR (d6-DMSO~, ppm: 1.35 (s, 9H; -C(CH3)3), 1.64 (d, 3H, J= 7Hz; CH3-), 2.58 (s, 3H; CH3-thiophene), 5.13 (g, lH, J= 7Hz; -CH = ), 7.05 (d, lH, J= 4Hz; H-thiophene) and 8.28 (d, lH, J= 4Hz; H-thiophene).
EXAMP~E 15: 2-C~ so-propylaminopropionyl)~-5-methylthio-phene hydrochloride From 53.27 g of ~-bromo-2-propionyl-5-methyl-thiophene in 65 ml of acetonitrile and 34.0 g of _~ ~Z~ 53 isopropylamine, and processing as described in Ex. 14, 41.3 of crude material are isolated and respective hydrochloride (11.2 g) is recrystallized from ethanol to give 6.5 g (15%) of a white solid, m.p. 230-233C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1645, 1550, 1445, 12SQ, 1065, 860, 830.
H-NMR (d6-DMSO), ppm: 1.30 (_, 6H, J= 7Hz;
CH(CH3)2), 1.54 (d, 3H, J= 7Hz; CH3-), 2.55 (s, 3H; CH3-10 thiophene), 3.25 (m, lH, J- 7Hz; C_(CH3)2), 5.05 (g, lH, J=
7Hz; CO-CH-), 7.05 (d, lH, J= 4Hz; H-thiophene) and 8.20 (d, lH, J= 4Hz; H-thiophene).
EXAMPLE 16: 2-C~-(sec-butylaminopropionyl)]-5-methylthio-lS phene hydrochloride From 24.16 g of a-bromo-2-propionyl-5-methylthio-phene in 30 ml of acetonitrile and 20 g of sec-butylamine, and processing as described in Ex. 14, 36 g of crude material are isolated, and respective hydrochloride in ethyl ether t26.3 g) is recrystalllzed from acetonitrile to give 8.35 g (35~) of a white solid, m.p. 191-194C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1650, 1550, 25 1440, 1240, 1060, 825.
H-NMR (D2O), ppm: 0.98 (t, 3H, J= 7Hz; CH3-), 1.32 (d, 3H, J= 6.5Hz; CH3-CH-NH), 1.67 (_ + wide band, 5H, J= 7Hz; CH3- and -CH2-), 2.59 (s, 3H; CH3-thiophene), 3.22 (m, lH; CH-NH), 5.06 (m, lH; CH-CH3), 7.06 (d, lH, J=
30 4Hz; H-thiophene) and 7.96 (d, lH, J= 4Hz; H-thiophene).
EXAMPLE 17: 2-Propionyl-4-methylthiophene To a solution of 44.92 g of 3-methylthiophene in i3 250 ml of dry ethyl ether under nitrogen atmosphere and cooled with water bath, 286 ml of n-butyllithium 1.6M
solution in hexane are added Eor about 1 hour. Then, the mixture is refluxed for 2 hours and cooled, and in the course of 30 minutes at -60C 25.21 g of propionitrile in 115 ml of ethyL ether are added under stirring for 4 hours, and allowed to stand overnight under cooling. Then, the imine is hydroly2ed by slow addition of 230 ml of 2N
hydrochloric acid and subsequent distillation of the ethyl ether by heating at 55C in oil bath. Distillation is stopped and the hydrochloric solution is refluxed for 1 hour. Then, it is cooled, removed twice with 150 ml of ethyl ether and the extracts are washed with water and dried. After evaporation of solvent, the residue weighs 54 g and contains a mixture of 2,4-isomer 75~ and 2,3-isomer 25%. By distillation, an early richer fraction in 2,3-isomer and 40.4 g are collected at 80-35C/0.5-O.a tors (yield: 57~) containing 81% of 2-propionyl-4-methylthio-phene (LGC).
IR Spectrum (film), cm 1 3100-2800, 1660, 1420, 1230, 1205, 1150, 885, 860, 800.
H-NMR(CDCl3), ppm: 1.20 (t, 3H, J= 7.25Hz; CH3-), 2.27 (s, 3H, CH3-thiophene), 2.86 (g, 2H, J= 7.25Hz; -CH2-), 7.20 (s, lH; H-thiophene) and 7.48 (s, lH; H-thiophene).
EXAMPLE 18: ~-Bromo-2-propionyl-4-methylthiophene From 39.22 g of 2-propionyl-4-methylthiophene (81~) in 200 ml of methylene chloride and 40.64 g of bromine in the same solvent, and processing as described in Ex. 13, 59.8 g ~100~) of a-bromoderivative are obtained, which is used without further purification.
IR Spectrum (film), cm 1 3100-2900, 1665, 1420, 1240, 1145, 1060, 980, 770.
~1 ~
H-NMR (CDC13), ppm: 1.87 (d, 3H, J= 7Hz; CH3-), 2.30 (s, 3H; CH3-thiophene), 5.10 (q, lH, J= 7Hz; -CHBr ), 7.27 ~s, lH; H-thiophene) and 7.63 (s, lH; H-thiophene).
EXAMPLE 19: 2-C~-(tert-butylaminopropionyl)~-4-methylthio-phene hydrochloride From 59.61 g of a-bromo-2-propionyl-4-methylthio-phene, as described in Ex. 14, in 75 ml of acetonitrile and 46.85 g of tert-butylamine, and processing as described in Ex. 3, 51,2 g of crude material are iso~ated, and respective hydrochloride in ethyl ether (43.2 g) is recrystallized in ethanol to give 17.8 g (30%), m.p. 255-258C ~d) and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1665, 1550, 1455, 1250i 1120, 870, 800.
H-NMR (D2O), ppm; 1.37 ~s, 9H; -C(CH3)3), 1-68 (d, 3H, J= 7.0Hz; CH3-), 2.34 (s, 3H; CH3-thiophene), 5.05 (g~ lH, J= 7.0Hz), 7.76 (s, 1~; H-thiophene) and 8.04 (s, lH; ~-thiophene).
EXA~PLE 20: 2-~ so-propylaminopropionyl)~-4-methylthio-phene hydrochlor1de From 32.72 g of a-bromo-2-propionyl-4-methylthiophene in 40 ml of acetonitrile and 20.7 g of iso-propylamine, and processing as described in Ex. 14, 26.93 g oE crude material are isolated, and respective hydrochloride in ethyl ether (13.5 g) is recrystallized in ethanol to give 30 7.0 g (25%), m.p. 230-234C (d), deprived from 2,3-isomer and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1675, 1445, 1420, 1320, 1230, 1150, 770.
H-NMR (D2O), ppm: 1.39 (d, 6H, J= 6.5Hz;
~267~i5~
-CH(CH3)2), 1~70 (d, 3H, J= 7Hz; CH3-), 2.33 (s, 3H; CH3-thiophene), 3.50 (_, lH, J= 6.5Hz; -CH(CH3)2)/ 5.08 (~ lH, J= 7Hz; -CO-CH-), 7.71 (s, lH; H-thiophene) and 7.98 (s, lH;
H-thiophene).
EXAMPLE 21: 4-Bromo-2-methylthiophene 100 g of 4-bromothiophene-2-aldehyde, 193 g of 100~ hydrazine hydrate and 520 ml of ethylene glycol are introduced into a three-necked flask (1-liter capacity) fitted up with a mechanical stirrer and a distillation device. The mixture is heated at 160C in oil bath which allows to distill the water and the excess of hydrazine;
from the distillate the lower phase is separated and introduced into the reactor again.
After completing distillation (6 hours approxi-mately), the mixture is cooled, 117.5 g of potassium hydroxide (exothermic reaction} are added and then carefully treated till reflux by keeping for 15 minutes. Then, it is allowed to stand overnight and distributed with ethyl ether (250 ml) and water (250 ml); the aqueous phase is removed twice with ether and the organic extracts a~e washed with 6N
hydrochloric acid and water till neutralization. The crude material is distilled at vacuum and 66.1 g ~71.5~), b.p. 66-73C/12-5 tors are obtained as colourless liquid.
IR Spectrum (film), cm : 3120, 3000-2850, 1530, 1330, 1190i 810, 720.
H-NMR (CDC13), ppm: 2.44 ~s, 3H; CH3-), 6.66 (m, lH; H-thiophene} and 6.95 (d, lH, J, 1.5Hz; H-thiophene).
EXAMPLB 22: 2-Methyl-4-propionylthiophene In a three-necked flask ~l-liter capacity) fitted up with a mechanical stirrer and nitrogen atmosphere, a solution of n-butyllithium is prepared by adding 57.45 g of 1-bromo-butane in 50 ml of dry ethyl ether to 4.90 g of lithium in 400 ml of ethyl ether. It is cooled at -70C
(ethanol/CO2 solid) and 38.04 g of 4-bromo-2-methylthiophene in 200 ml of ethyl ether are added along 45 minutes; it is kept for 2 hours at -70C in order to secure the formation of the lithium salt. Then, at the same temperature, 11.82 g of propionitrile in 50 ml of ethyl ether are added and allowed to stand under stirring for 4 hours and overnight at low temperature. At -15C, 110 ml of 2N hydrochloric acid are added, the bath is withdrawn and the ether is distilled under pressure; when distillation temperature reaches 100C, the mixture is refluxed for 1 hour, cooled and the insolubilized oil is removed twice with 200 ml of ethyl ether, then washed with water till neutralization and dried.
~y distillation of the residue, 12.8 g (40%) o a colourless liquid are obtained, b.p. 85-100C/1.5 tors.
IR Spectrum (film), cm 1 3120, 3020-2880, 1680, 1466, 1210, 1145, 860.
1H-NMR (CDC13), ppm: 1.17 (t, 3H, J= 7Hz; CH3-), 2.46 (s, 3H; CH3-thiophene), 2.82 l~, 2H, J= 7Hz; -CH2-J, 7.18 (m, lH; H-thiophene) and 7.75 (_, lH, J= 1.5Hz; H-thiophene).
EXAMPLE 23: a-Bromo-2-methyl-4-propionylthiophene F~om 12.75 g of 2-methyl-4-propionylthiophene in 65 ml of methylene chloride and 13.22 g of bromine in 35 ml of the same solvent, as described in Ex. 13, 19.4 g (100%) of ~-bromo-derivative are obtained and subsequently used without further purification.
IR Spectrum (film), cm 1 3110, 2980, 2930-2860, 1670, 1440, 1220,1130, 850.
H-NMR (CDC13), ppm: 1.81 (d, 3H, J= 7Hz; CH3-), ~`r 7~
-- lg --2.45 (s, 3H; CH3-thiophene), 5.03 (~, lH, J= 7Hz; _CH-), 7.22 (d, lH, J= 1.5Hz; H-thiophene) and 7.92 (d, lH, J=
1.5Hz; H-thiophene).
EXAMPLE 24: 4-ra-(tert-butylaminopropionyl)]-2-methylthio-phene hydrochloride From 19.3 g of the ~-bromoderiva-tive described in Ex. 23, in 25 ml of acetonitrile and 15.4 g of tert-butylamine, and processing as described in Ex. 14, 13.2 g of crude material are isolated, and respective hydrochloride in ethyl ether (8.0 g) is recrystallized in ethanol to give 4.1 g (22%), m.p. 241.8-242.4C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3200-2400, 1670, 1550, 1450, 1230, 1200, 1120, 1010, 840.
H-NMR (d6-DMSO), ppm: 1.29 (s, 9H; -C(CH3)3), 1.58 (d, 3H, J= 7Hz; CH3-), 2.48 (d, 3H, J= 0.5Hz; CH3-thiophene), 5.10 ( ~ lH, J= 7Hz; CH-), 7.36 (m, lH; H-thiophene) and 8.8 (d, lH, J= 1.5Hz; H-thiophene).
_XAMP~E 25: 4-~a-(lso-propylaminopropionyl)]-2-methylthi phene hydrochloride To 22.27 g o~ the ~-bromoderivative described in Ex. 23, in 30 ml of acetonitrile and 141.1 g of iso-butylamine, and processing as described in Ex. 14, 16 g of crude material are isolated, and respective hydrochloride is ethyl ether (13 g) is recrystallized in ethanol to give
~Zi7~3 1 hour and left to stand overnight at room temperature.
Thexeafter, it is slowly poured onto 2.8 kg of ice under stirring, the aqueous phase is extracted with 1.2 and 0.5 liters of methylene chloride and the organic extracts are jointly washed with water (three times), sodium bicarbonate saturated solution, and water again to neutralization.
After evaporation of solvent, the residue (370.5 g) under rectifying column (Lo= 19 cm) with Raschig rings gives 216.6 g and recrystallizes from hexane (350 ml) to yield 157.4 g (45%) of a white solid with m.p. 58-60C, G~C: 98%.
IR Spectrum (KBr), cm : 3080, 3000-2880, 1665, 1400, 1220, 1190, 910.
H-NMR Spectrum (C14C), ppm: 1.16 (t, 3H, J= 7Hz;
CH3-), 2-81 (~, 2H, J= 7Hz; -CH2-), 7.29 (d, lH, J= 1.4Hz;
HThiophene) and 7.43 (d, lH, J= 1.4Hz; HThiop ~XAMPLE 3: ~-Bromo-4-chloro-2-propionylthiophene To a solution of 60 g of 4-chloro-2-propionylthiophene in 280 ml of dry methylene chloride under stirring and cooled at 0-5C, the equimolecular amount of bromo (54.9 g) dissolved in 135 ml of dry methylene chloride is slowly added; as the reaction starts, decolorization of bromo occurs immediately while adding the reaction mixture.
After completing the addition, the bath is removed, stirring for further 30 minutes is performed, the methylene chloride is evaporated under vaccum and the liquid residue is used without further purification.
IR Spectrum (film), cm 1 3100, 1665, 1400, 1230, 1155, 980, 910, 840.
1H-NMR Spectrum (Cl3C), ppm: 1.84 (_, 3H, J=
6.6Hz; CH3-), 4.93 tq, lH, J= 6.6Hz; -CH' ), 7.36 (d, lH, ; Thiophene) and 7.59 (d, lH, J= 1.25Hz;
HThiPhene ) ~, ~LZ676~
XAMPI,E 4: 2-t~-(tert-butylaminopropionyl)]-4-chlorothio-phene hydrochloride To 87.69 g of ~-bromo 4-chloro-2-propionylthio-phene in 100 ml of acetonitrile, 60.7 9 of tert-butylamine in 100 ml of acetonitrile are slowly added without exceeding 32 C (water bath regulation~. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature. The solvent is evaporated at vacuum (below 35 C), taken in methylene chloride (300 ml) and water (300 ml); the aqueous phase is removed with methylene ~; chloride, the organic extracts are washed four times with 200 ml of water, dried and evaporated to dryness. The residue (80.7 g) is dissolved in 600 ml of dry methylene chloride, cooled with ice-salt bath at 0C and a dry HCl (g) stream is slowly spread. The precipitated hydrochloride is filtered off, washed twice with dry methylene chloride and dried at vaccum to give 52.7 g of white solid ~m.p. 245-250 C) which, after recrystallizing from ethanol, yields ; 20 28 g ~30%) of the hydrochloride (m.p. 250-255C); analysis correct.
IR Spectrum tKBr), cm 1 3420; 3100-2400, 1675, 1545, 1400, 1240, 1205, 1125, 895, 795.
H-NMR Spec*rum (CD OD), ppm: 1.39 (s, 9H;
-C(CH3)3, 1.67 (d, 3H, J= 7Hz; CH3-), 5.14 (~, lH, J= 7Hz;
-CH_ ), 7.97 (d, lH, J= 1-75HZ; HThiophene) Neutralization of the hydrochloride allows to isolate respective base, m.p. 79-81C (he~ane) and analysis correct.
EXAMPLE 5: 5-Chloro-2-propionylthiophene To a solution of 77.44 g of 2-chlorothiophene and 60.42 g of propionyl chloride in 390 ml of anhydrous benzene '65~
under cooling at 0-5C (ice-salt bath), 184.56 g of tin tetrachloride in 78 ml of anhydrous benzene are dropwise added for about 1 hour and at the above temperature while separating a redish solid. Then it is stirred for 20 hours at room temperature, poured onto 520 g of ice and 130 g of water under stirring and 15 minutes later the phases are decanted: the aqueous phase is extracted with 250 ml of ethyl ether and the organic extracts are washed (3 times) with sodium chloride saturated soIution. The crude product (105.3 g) is rectified by Vigreaux Column (Lo= 11 cm~ thus obtaining 75.80 g (yield: 65%) of a white solid, m.p.
47-49 C, LGC: 100% and analysis correct.
IR Spectrum (KBr), cm 1 3080, 3000-2860, 1650, 1410, 1210, 1010, 880, 780.
H-NMR Spectrum (Cl4C), ppm: 1.14 (t, 3~-1, J-7.6Hz; CH3-), 2.75 (g, 2H, J- 7.6Hz; -CH2-), 6.85 (d, lH, J=
4Hz; HThiophene) and 7-37 (d, lH, J= 4Hz HThiO h )~
EXAMPLE 6: ~-Bromo-5-chloro-2-propionylthiophene To a solution of 112.37 g of 5-chloro-2-propionylthiophene in 500 ml of dry methylene chloride under stirring and cooling at 0-5C, 102.83 g of bromine in 250 ml of methylene chloride are added. Processing as described in Ex. 3, 167.8 g of a liquid residue corresponding to the ~-brome derivative are obtained which is pure enough to be used in the following synthesis step.
IR Spectrum (fiml), cm 1 3100, 3010-2880, 1660, 1420, 1240, 1010, 890, 800, 740.
lH-NMR (C14C) Spectrum, ppm: 1.81 (d, 3H, J=
6.6Hz; CH3-), 4.90 (~, lH, J= 6.6Hz, -CH- ), 6.91 (_, lH, J=
4Hz; HThiophene) and 7-55 (d, lH, J= 4Hz; HThioph ne).
~,L ` ~
~;~6~
_ 9 _ EXAMPLE 7: 2-[~-(tert-butylaminopropionyl)]-5-chlorothio-phene hydrochloride To 81.50 g of a-bromo-5-chloro-2-propionylthio-phene in 100 ml of acetonitrile, 56.76 g of tert-butylamine in 100 ml of acetonitrlle are slowly added without exceeding 32C. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature. Processing as described in Ex. 4, 75.7 g of a crude product are isolated and respective hydrochloride in dry methylene chloride (700 ml) with HCl (g) is formed. The insolubilized hydrochloride (65.4 g, m.p. 246-248C) is recrystallized from ethanol thus obtaining 44.4 g (yield: 49~) of a white solid, m.p. 255-257C and analysis correct.
IR Spectrum ~KBr), cm : 3440, 3110-2500, 1660, - 1550, 1410, 1245, 1010, 880.
H-NMR Spectrum (CD30D~, ppm: 1.37 (_, 9H;
-C~CH3)3), 1.66 (d, 3H, J= 7Hz; -CH3), 5.14 (~, lH, J= 7Hz;
-CH= ), 7.24 (d, lH, J= 4.25Hz: HThiophene) - 20 J= 4.25Hz; HThiophene) Neutralization of the hydrochloride allows to isolate respective base, m.p. 72-75C (hexane) and analysis correct.
~XA~PL~ 8: 2,5-Dichloro-3-propionylthiophene To a solution of 65.1 g of 2,5-dichlorothiophene ' and 77.79 g of propionyl chloride in 325 ml of nitroethane, 63.5 g of aluminium chloride are slowly added in nitrogen atmosphere for about 20 minutes, thus causing the temperature of the mixture rise up to 37C. Then, the mixture is stirred for 4 hrs, poured on to 500 g of ice and removed twice with 250 ml of ethyl ether. The organic = extracts are consecutively washed with 3N hydrochloric acid !., ~6~
~150 ml), water (2xlO0 ml), 3N sodium hydroxide (3~600 ml) and saturated sodium chloride solution till neu-tralization.
After drying and evaporating the solvent, the solid residue (68.9 g) is distilled and 58.00 g (yield: 65%) of a white solid are obtained; b.p. 96-105C/1.2 tors, m.p. 63-66C and analysis correct.
IR Spectrum (KBr), cm 1 3120, 3080, 3000-2860, 1680, 1660, 1430, 1370, 1190, 1175, 1015, 800.
H-NMR Spectrum (Cl4C), ppm: 1~12 It, 3H, J= 7Hz;
CH3-), 2.83 (~, 2H, J= 7Hz; -CH2-) and 7.15 (s, lH;
Thiophene EXAMPLE 9 2-Chloro-4-propionylthiophene To a suspension of 53.28 g o~ 2,5-dichloro-4-propionylthiophene in 57 ml of glacial acetic acid and 181 ml of water, 33.31 g of zinc dust (2 equivalents) are added in the course of 5 minutes and thus the temperature rapidly rises up to 72C; then it is cooled in water bath till reaching 55 C within 10 minutes. 250 ml of ethyl ether are added, the insoluble solid is filtered off and the aqueous phase is removed with ether again; the extracts are washed with water, saturated ClN4 solution and dried with potassium carbonate. The residue (43.48 g), which is obtained after evaporating the solvent, recrystallizes from n-pentane to yield 28.9 g (65%) of a white solid, m.p. 50-53 C, LGC: 100~ and analysis correct.
IR Spectrum ~KBr), cm : 3100, 3000-2800, 1665, 1435, 1180, 1000, 780.
H-NMR Spectrum (Cl4C), ppm: 1.13 ~t, 3H, J= 7Hz;
CH3-), 2.75 (~, 2H, J= 7Hz; -CH2-), 7.28 ~d, lH, J= 1.5Hz;
HThiophene), and 7.68 ~d, lH, J= 1.5Hz; HThiophene)~
~26~53 EXAMPLE lO: ~-Bromo-2-chloro-4-propionylthiophene To a solution of 30.92 g o-f 2-chloro-4-propionylthiophene in 140 ml of dry methylene chloride under stirring and heating at 0-5C, 28.29 g of bromine in 70 ml of methylene chloride are added. Processing as described in Ex. 3, 44~9 g of a coloured liquid are obtained with analysis correct.
IR Spectrum (film), cm 1 3100, 3000-2900, 1680, 1425, 1210, 1150, 1005, 845.
H-NMR Spectrum (C14C), ppm: 1.80 (t, 3H, a=
7.0Hz; CH3-), 4.85 (q, lH, J= 7.0Hz; -CH-), 7.35 (_, lH, J=
l.SHz; HThiophene) and 7.87 ( , lH, J= 1.5Hz; HThio he 5 EXAMPLE 11: 4-Ca-(tert-butylaminopropionyl)3-2-chlorothio-phene To 44.50 g of a-brom o-2-chloro-4-propionylthiophene in 55 ml of acetonitrile, 31 g of tert-butylamine in 55 ml of acetonitrile are slowly added withoutexceeding 32C. As the exothermia diminishes, the mixture is left under stirring for 20 hours at room temperature.
Processing as described in Ex. 4, 42.4 g of a dark liquid are isolated and respective hydrochloride in methylene Z5 chloride (400 ml) at 0C with HCl (g) is formed. The insolubilized product (37.10 g) is recrystallized from ethanol to yield 38.5 g (40~) of a white solid, m.p. 257-259C (d) and analysis correct.
IR Spectrum (KBr), cm 1 3450, 3100-24Q0, 1675, 1545, 1230i 1200, 1175, 1000, 830.
H-NMR Spectrum (CD30D), ppm: 1.40 (s, 9H, -C(CH3)3), 1,62 (d, 3H, J= 7.0Hz; CH3-), 5.10 (q, lH, J=
7Hz; -CH-), 7.52 (d, lH, J= 1.5Hz; HThiophene) (_, lH, J= 1-5HZ; ~Thiophene) -` ~2S~7'~5~
EXAMPLE 12: 2-Propionyl-5-methylthiophene To a solution of 53.S0 g of 2-methylthiophene ~nd 50.43 g of propionyl chloride in 300 ml of anhydrous benzene under cooling at 0-5C in an ice-salt bath, 141.97 g of tin tetrachloride in 60 ml of anhydrous benzene are dropwise added for about 1 hour at the above temperature. Then it is stirred for 22 hours at room temperature to give a dark red mixture which is poured onto 400 g o~ ice and 100 g of water under vigorous stirring; after 1 hour, the aqueous phase is removed with 200 ml of ethyl ether and the organic extracts are washed three times with sodium chloride saturated solution. The crude product (76 g), which solidifies by standing, is distilled at vacuum and 68.24 g (81%) are obtained, b.p. 85-95C/0.5-0.6 tors and m.p. 32-34C.
IR Spectrum (KBr), cm 1 3100-2880, 1660~, 1455, 1230, 1050, 890, 790.
lH-NMR (Cl3CD), ppm: 1.18 ~t, 3H, J=8Hz; CH3-), 2.50 (d, 3H, J= lHz; CH3- thiophene), 2.83 (~, 2H, J= 8Hz;
-CH2-), 6,75 (dd, lH, J= lHz and~J'=-3.75Hz; H-thiophene) and 7.50 (d, lH, J= 3.75Hz, H-thiophene~.
:
EXAMPL~ 13: a-Bromo-2-propionyl-5-methylthiophene To a solution of 34.12 of 2-propionyl-5-methylthiophene in 180 ml of dry methylene chloride under stirring and cooling at 0-5C, 35.35 g of bromine in 90 ml of methylene chloride are gently added. After completing the addition, the bath is removed, stirred for further 30 minutes, the methylene chloride is evaporated at vacuum and the residue (53.27 g, 100%) is used for the following operation without further purification.
IR Spectrum (film), cm 1 3100-2900, 1665, 1450, 1245, 885.
~Z~'~`653 lH-NMR (C14C), ppm: 1.81 (d, 3H, J= 7Hz; CH3-)~
2.52 (s, 3H; CH3-thiophene), 4.95 ~, lH, J= 7Hz; -CH ), 6.75 (dd, lH, J= lHz, J'= 3.75Hz; H-thiophene) and 7.55 (d, lH, J= 3.75Hz; H-thiophene).
EXAMPLE 14: 2-L~-(tert-butylaminopropionyl)~-5-methylthio-phene hydrochloride To 44.5 g of ~-bromo-2-propionyl-5-methylthiophene in 60 ml of acetonitriIe, 36.57 g of tert-butylamine are gently added without exceeding 30C (water bath adjustment).
The solvent is evaporated at vacuum (below 35C), taken in 100 ml of methylene chloride and 100 ml of water, and the aqueous phase is removed again with 75 ml of the solvent;
the organic extracts are washed with water, dried and evaporated. The crude material (42.0 g) is dissolved in 400 ml of dry ethyl ether, and by cooling in water-ice bath a dry HCl (g) stream is spread; the precipitated hydrochloride is filtered off, washed with ether and dried at vacuum to 2Q give 35 g of a whitish solid which, after recrystallizing from ethanol, yieIds 19.7 g (40~) of a white solid corresponding to the hydrochloride (m.p. 262-263C).
IR Spectrum (KRr), cm 1 3100-2400, 1655, 1550, 1445, 1250, 1205, 1055, 880, 825.
H-NMR (d6-DMSO~, ppm: 1.35 (s, 9H; -C(CH3)3), 1.64 (d, 3H, J= 7Hz; CH3-), 2.58 (s, 3H; CH3-thiophene), 5.13 (g, lH, J= 7Hz; -CH = ), 7.05 (d, lH, J= 4Hz; H-thiophene) and 8.28 (d, lH, J= 4Hz; H-thiophene).
EXAMP~E 15: 2-C~ so-propylaminopropionyl)~-5-methylthio-phene hydrochloride From 53.27 g of ~-bromo-2-propionyl-5-methyl-thiophene in 65 ml of acetonitrile and 34.0 g of _~ ~Z~ 53 isopropylamine, and processing as described in Ex. 14, 41.3 of crude material are isolated and respective hydrochloride (11.2 g) is recrystallized from ethanol to give 6.5 g (15%) of a white solid, m.p. 230-233C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1645, 1550, 1445, 12SQ, 1065, 860, 830.
H-NMR (d6-DMSO), ppm: 1.30 (_, 6H, J= 7Hz;
CH(CH3)2), 1.54 (d, 3H, J= 7Hz; CH3-), 2.55 (s, 3H; CH3-10 thiophene), 3.25 (m, lH, J- 7Hz; C_(CH3)2), 5.05 (g, lH, J=
7Hz; CO-CH-), 7.05 (d, lH, J= 4Hz; H-thiophene) and 8.20 (d, lH, J= 4Hz; H-thiophene).
EXAMPLE 16: 2-C~-(sec-butylaminopropionyl)]-5-methylthio-lS phene hydrochloride From 24.16 g of a-bromo-2-propionyl-5-methylthio-phene in 30 ml of acetonitrile and 20 g of sec-butylamine, and processing as described in Ex. 14, 36 g of crude material are isolated, and respective hydrochloride in ethyl ether t26.3 g) is recrystalllzed from acetonitrile to give 8.35 g (35~) of a white solid, m.p. 191-194C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1650, 1550, 25 1440, 1240, 1060, 825.
H-NMR (D2O), ppm: 0.98 (t, 3H, J= 7Hz; CH3-), 1.32 (d, 3H, J= 6.5Hz; CH3-CH-NH), 1.67 (_ + wide band, 5H, J= 7Hz; CH3- and -CH2-), 2.59 (s, 3H; CH3-thiophene), 3.22 (m, lH; CH-NH), 5.06 (m, lH; CH-CH3), 7.06 (d, lH, J=
30 4Hz; H-thiophene) and 7.96 (d, lH, J= 4Hz; H-thiophene).
EXAMPLE 17: 2-Propionyl-4-methylthiophene To a solution of 44.92 g of 3-methylthiophene in i3 250 ml of dry ethyl ether under nitrogen atmosphere and cooled with water bath, 286 ml of n-butyllithium 1.6M
solution in hexane are added Eor about 1 hour. Then, the mixture is refluxed for 2 hours and cooled, and in the course of 30 minutes at -60C 25.21 g of propionitrile in 115 ml of ethyL ether are added under stirring for 4 hours, and allowed to stand overnight under cooling. Then, the imine is hydroly2ed by slow addition of 230 ml of 2N
hydrochloric acid and subsequent distillation of the ethyl ether by heating at 55C in oil bath. Distillation is stopped and the hydrochloric solution is refluxed for 1 hour. Then, it is cooled, removed twice with 150 ml of ethyl ether and the extracts are washed with water and dried. After evaporation of solvent, the residue weighs 54 g and contains a mixture of 2,4-isomer 75~ and 2,3-isomer 25%. By distillation, an early richer fraction in 2,3-isomer and 40.4 g are collected at 80-35C/0.5-O.a tors (yield: 57~) containing 81% of 2-propionyl-4-methylthio-phene (LGC).
IR Spectrum (film), cm 1 3100-2800, 1660, 1420, 1230, 1205, 1150, 885, 860, 800.
H-NMR(CDCl3), ppm: 1.20 (t, 3H, J= 7.25Hz; CH3-), 2.27 (s, 3H, CH3-thiophene), 2.86 (g, 2H, J= 7.25Hz; -CH2-), 7.20 (s, lH; H-thiophene) and 7.48 (s, lH; H-thiophene).
EXAMPLE 18: ~-Bromo-2-propionyl-4-methylthiophene From 39.22 g of 2-propionyl-4-methylthiophene (81~) in 200 ml of methylene chloride and 40.64 g of bromine in the same solvent, and processing as described in Ex. 13, 59.8 g ~100~) of a-bromoderivative are obtained, which is used without further purification.
IR Spectrum (film), cm 1 3100-2900, 1665, 1420, 1240, 1145, 1060, 980, 770.
~1 ~
H-NMR (CDC13), ppm: 1.87 (d, 3H, J= 7Hz; CH3-), 2.30 (s, 3H; CH3-thiophene), 5.10 (q, lH, J= 7Hz; -CHBr ), 7.27 ~s, lH; H-thiophene) and 7.63 (s, lH; H-thiophene).
EXAMPLE 19: 2-C~-(tert-butylaminopropionyl)~-4-methylthio-phene hydrochloride From 59.61 g of a-bromo-2-propionyl-4-methylthio-phene, as described in Ex. 14, in 75 ml of acetonitrile and 46.85 g of tert-butylamine, and processing as described in Ex. 3, 51,2 g of crude material are iso~ated, and respective hydrochloride in ethyl ether (43.2 g) is recrystallized in ethanol to give 17.8 g (30%), m.p. 255-258C ~d) and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1665, 1550, 1455, 1250i 1120, 870, 800.
H-NMR (D2O), ppm; 1.37 ~s, 9H; -C(CH3)3), 1-68 (d, 3H, J= 7.0Hz; CH3-), 2.34 (s, 3H; CH3-thiophene), 5.05 (g~ lH, J= 7.0Hz), 7.76 (s, 1~; H-thiophene) and 8.04 (s, lH; ~-thiophene).
EXA~PLE 20: 2-~ so-propylaminopropionyl)~-4-methylthio-phene hydrochlor1de From 32.72 g of a-bromo-2-propionyl-4-methylthiophene in 40 ml of acetonitrile and 20.7 g of iso-propylamine, and processing as described in Ex. 14, 26.93 g oE crude material are isolated, and respective hydrochloride in ethyl ether (13.5 g) is recrystallized in ethanol to give 30 7.0 g (25%), m.p. 230-234C (d), deprived from 2,3-isomer and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1675, 1445, 1420, 1320, 1230, 1150, 770.
H-NMR (D2O), ppm: 1.39 (d, 6H, J= 6.5Hz;
~267~i5~
-CH(CH3)2), 1~70 (d, 3H, J= 7Hz; CH3-), 2.33 (s, 3H; CH3-thiophene), 3.50 (_, lH, J= 6.5Hz; -CH(CH3)2)/ 5.08 (~ lH, J= 7Hz; -CO-CH-), 7.71 (s, lH; H-thiophene) and 7.98 (s, lH;
H-thiophene).
EXAMPLE 21: 4-Bromo-2-methylthiophene 100 g of 4-bromothiophene-2-aldehyde, 193 g of 100~ hydrazine hydrate and 520 ml of ethylene glycol are introduced into a three-necked flask (1-liter capacity) fitted up with a mechanical stirrer and a distillation device. The mixture is heated at 160C in oil bath which allows to distill the water and the excess of hydrazine;
from the distillate the lower phase is separated and introduced into the reactor again.
After completing distillation (6 hours approxi-mately), the mixture is cooled, 117.5 g of potassium hydroxide (exothermic reaction} are added and then carefully treated till reflux by keeping for 15 minutes. Then, it is allowed to stand overnight and distributed with ethyl ether (250 ml) and water (250 ml); the aqueous phase is removed twice with ether and the organic extracts a~e washed with 6N
hydrochloric acid and water till neutralization. The crude material is distilled at vacuum and 66.1 g ~71.5~), b.p. 66-73C/12-5 tors are obtained as colourless liquid.
IR Spectrum (film), cm : 3120, 3000-2850, 1530, 1330, 1190i 810, 720.
H-NMR (CDC13), ppm: 2.44 ~s, 3H; CH3-), 6.66 (m, lH; H-thiophene} and 6.95 (d, lH, J, 1.5Hz; H-thiophene).
EXAMPLB 22: 2-Methyl-4-propionylthiophene In a three-necked flask ~l-liter capacity) fitted up with a mechanical stirrer and nitrogen atmosphere, a solution of n-butyllithium is prepared by adding 57.45 g of 1-bromo-butane in 50 ml of dry ethyl ether to 4.90 g of lithium in 400 ml of ethyl ether. It is cooled at -70C
(ethanol/CO2 solid) and 38.04 g of 4-bromo-2-methylthiophene in 200 ml of ethyl ether are added along 45 minutes; it is kept for 2 hours at -70C in order to secure the formation of the lithium salt. Then, at the same temperature, 11.82 g of propionitrile in 50 ml of ethyl ether are added and allowed to stand under stirring for 4 hours and overnight at low temperature. At -15C, 110 ml of 2N hydrochloric acid are added, the bath is withdrawn and the ether is distilled under pressure; when distillation temperature reaches 100C, the mixture is refluxed for 1 hour, cooled and the insolubilized oil is removed twice with 200 ml of ethyl ether, then washed with water till neutralization and dried.
~y distillation of the residue, 12.8 g (40%) o a colourless liquid are obtained, b.p. 85-100C/1.5 tors.
IR Spectrum (film), cm 1 3120, 3020-2880, 1680, 1466, 1210, 1145, 860.
1H-NMR (CDC13), ppm: 1.17 (t, 3H, J= 7Hz; CH3-), 2.46 (s, 3H; CH3-thiophene), 2.82 l~, 2H, J= 7Hz; -CH2-J, 7.18 (m, lH; H-thiophene) and 7.75 (_, lH, J= 1.5Hz; H-thiophene).
EXAMPLE 23: a-Bromo-2-methyl-4-propionylthiophene F~om 12.75 g of 2-methyl-4-propionylthiophene in 65 ml of methylene chloride and 13.22 g of bromine in 35 ml of the same solvent, as described in Ex. 13, 19.4 g (100%) of ~-bromo-derivative are obtained and subsequently used without further purification.
IR Spectrum (film), cm 1 3110, 2980, 2930-2860, 1670, 1440, 1220,1130, 850.
H-NMR (CDC13), ppm: 1.81 (d, 3H, J= 7Hz; CH3-), ~`r 7~
-- lg --2.45 (s, 3H; CH3-thiophene), 5.03 (~, lH, J= 7Hz; _CH-), 7.22 (d, lH, J= 1.5Hz; H-thiophene) and 7.92 (d, lH, J=
1.5Hz; H-thiophene).
EXAMPLE 24: 4-ra-(tert-butylaminopropionyl)]-2-methylthio-phene hydrochloride From 19.3 g of the ~-bromoderiva-tive described in Ex. 23, in 25 ml of acetonitrile and 15.4 g of tert-butylamine, and processing as described in Ex. 14, 13.2 g of crude material are isolated, and respective hydrochloride in ethyl ether (8.0 g) is recrystallized in ethanol to give 4.1 g (22%), m.p. 241.8-242.4C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3200-2400, 1670, 1550, 1450, 1230, 1200, 1120, 1010, 840.
H-NMR (d6-DMSO), ppm: 1.29 (s, 9H; -C(CH3)3), 1.58 (d, 3H, J= 7Hz; CH3-), 2.48 (d, 3H, J= 0.5Hz; CH3-thiophene), 5.10 ( ~ lH, J= 7Hz; CH-), 7.36 (m, lH; H-thiophene) and 8.8 (d, lH, J= 1.5Hz; H-thiophene).
_XAMP~E 25: 4-~a-(lso-propylaminopropionyl)]-2-methylthi phene hydrochloride To 22.27 g o~ the ~-bromoderivative described in Ex. 23, in 30 ml of acetonitrile and 141.1 g of iso-butylamine, and processing as described in Ex. 14, 16 g of crude material are isolated, and respective hydrochloride is ethyl ether (13 g) is recrystallized in ethanol to give
4.5 g (21%), in m.p. 231.5-233.5C and elemental analysis correct.
IR Spectrum (KBr), cm l 3140-2400, 1665, 1500, 1460, 1210, 1100, 1010, 840, 745.
H-NMR (D2O), ppm: 1.37 (d, 6H, J= 6.5Hz;
-CH(CH3)2), 1.64 (d, 3H, J= 7Hz; CH3), 2.50 (s, 3H; CH3-`~"
~L~V
thiophene), 3.48 ~m, lH, J= 6.5Hz; -CH(CH312), 5.02 (q, lH, J= 7Hz; - CO-CH~ ), 7.31 ~d, lH, J= 1.5Hz; H-thiophene~ and 8.37 (d, lH, J= 1.5Hz; H-thiophene)~
EXAMPLE 26: 2-C~-(iso-propylaminopropionyl)]-4-chlorothio-phene hydrochloride To 63.8 g of a-bromo-4-chloro-2-propionylthiophene obtained according to Example 3 in 70 ml of acetonitrile, 37.2 g of iso-propylamine are gently added without exceeding 32C. When the exothermia stops, the mixture is left under stirring for 20 hours at room temperature. The solvent is evaporated at vacuum (below 35C), taken in methylene chloride (150 ml) and water (150 ml); the aqueous phase is removed with methylene chloride, and the organic extracts are washed with water, dried and evaporated to dryness. The crude material (51 g) is dissolved in 400 ml of dry ethyl ether, and by cooling in a water-ice bath a HCl (g) stream is spread; the insolubilized hydrochloride is filtered off, washed with ether and dried at vacuum to give 17.04 g of a white-yellowish solid whose recrystallization in ethanol yields 10.1 g (i6~) of a white solid, m.p. 225 230C (d), corresponding to the hydrochloride.
IR Spectrum (KBr), cm 3140-2400, 1675, 1555, 1400, 1~35, 860.
H-NMR (d6-DMSO), ppm: 1.33 (d, 6H, J= 7Hz;
CH(CH3)2), 1.58 ( , 3H, J= 7Hz; CH3-), 3.38 (m, lH;
CH(CH3)2), 5.20 (~, lH, J= 7Hz; CO-CH-), 8.25 (d, lH, J=
1.5Hz; H-thiophene) and 8.54 (d, lH, J= 1.5Hz; H-thiophene).
EXA~PLE 27: 2-C~-(n-propylaminopropionyl)~-4-chlorothio-phene hydrochloride From 36.3 g of ~-bromo-4-chloro-2-propionylthio-.. ..
65;3 phene in 45 ml of acetonitrile and 20.42 g of n-propylamine, and processing as described in the above examples, 32.05 g of crude material are isolated, and respective hydrochloride (31.5 g) in ethyl ether is recrystallized in ethyl acetate/
acetonitrile to give 12.7 g (33%) of a white solid, m.p.
192.5-193.5C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1680, 1440, 1405, 1230, ll90, 1110, 940, 770.
H-NMR (CD30D), ppm: 0.99 (t, 3H, J= 7Hz; CH3-), 1-62 (d, 3H, J= 7Hz; CH3-), 1.76 (m, 2H, J= 7Hz; CH2-CH3), 3.0 (m, 2H; CH2-NH), 5.00 (~, lH, J= 7Hz; CH-CO), 7.90 (d, lH, J= 1.5Hz; H-thiophene) and 8.05 (d, lH, J= 1.5Hz; H-thiophene).
..~
~2~'7~5~
SUPPLEMENTARY DISCLOSURE
Disclosed hereinafter are other preferred embodi-ments of the inven-tion.
According to these preferred embodiments, the invention relates to a process for preparing thiophene derivatives of general formula (I'):
O
X ~ C - CH - CH (I') S NHR
wherein - C - CH - CH3 is in position 2 on the thiophene ring and either NHR
X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R
represents a sec-butyl or. n-propyl radical or X, in position
IR Spectrum (KBr), cm l 3140-2400, 1665, 1500, 1460, 1210, 1100, 1010, 840, 745.
H-NMR (D2O), ppm: 1.37 (d, 6H, J= 6.5Hz;
-CH(CH3)2), 1.64 (d, 3H, J= 7Hz; CH3), 2.50 (s, 3H; CH3-`~"
~L~V
thiophene), 3.48 ~m, lH, J= 6.5Hz; -CH(CH312), 5.02 (q, lH, J= 7Hz; - CO-CH~ ), 7.31 ~d, lH, J= 1.5Hz; H-thiophene~ and 8.37 (d, lH, J= 1.5Hz; H-thiophene)~
EXAMPLE 26: 2-C~-(iso-propylaminopropionyl)]-4-chlorothio-phene hydrochloride To 63.8 g of a-bromo-4-chloro-2-propionylthiophene obtained according to Example 3 in 70 ml of acetonitrile, 37.2 g of iso-propylamine are gently added without exceeding 32C. When the exothermia stops, the mixture is left under stirring for 20 hours at room temperature. The solvent is evaporated at vacuum (below 35C), taken in methylene chloride (150 ml) and water (150 ml); the aqueous phase is removed with methylene chloride, and the organic extracts are washed with water, dried and evaporated to dryness. The crude material (51 g) is dissolved in 400 ml of dry ethyl ether, and by cooling in a water-ice bath a HCl (g) stream is spread; the insolubilized hydrochloride is filtered off, washed with ether and dried at vacuum to give 17.04 g of a white-yellowish solid whose recrystallization in ethanol yields 10.1 g (i6~) of a white solid, m.p. 225 230C (d), corresponding to the hydrochloride.
IR Spectrum (KBr), cm 3140-2400, 1675, 1555, 1400, 1~35, 860.
H-NMR (d6-DMSO), ppm: 1.33 (d, 6H, J= 7Hz;
CH(CH3)2), 1.58 ( , 3H, J= 7Hz; CH3-), 3.38 (m, lH;
CH(CH3)2), 5.20 (~, lH, J= 7Hz; CO-CH-), 8.25 (d, lH, J=
1.5Hz; H-thiophene) and 8.54 (d, lH, J= 1.5Hz; H-thiophene).
EXA~PLE 27: 2-C~-(n-propylaminopropionyl)~-4-chlorothio-phene hydrochloride From 36.3 g of ~-bromo-4-chloro-2-propionylthio-.. ..
65;3 phene in 45 ml of acetonitrile and 20.42 g of n-propylamine, and processing as described in the above examples, 32.05 g of crude material are isolated, and respective hydrochloride (31.5 g) in ethyl ether is recrystallized in ethyl acetate/
acetonitrile to give 12.7 g (33%) of a white solid, m.p.
192.5-193.5C and elemental analysis correct.
IR Spectrum (KBr), cm 1 3100-2400, 1680, 1440, 1405, 1230, ll90, 1110, 940, 770.
H-NMR (CD30D), ppm: 0.99 (t, 3H, J= 7Hz; CH3-), 1-62 (d, 3H, J= 7Hz; CH3-), 1.76 (m, 2H, J= 7Hz; CH2-CH3), 3.0 (m, 2H; CH2-NH), 5.00 (~, lH, J= 7Hz; CH-CO), 7.90 (d, lH, J= 1.5Hz; H-thiophene) and 8.05 (d, lH, J= 1.5Hz; H-thiophene).
..~
~2~'7~5~
SUPPLEMENTARY DISCLOSURE
Disclosed hereinafter are other preferred embodi-ments of the inven-tion.
According to these preferred embodiments, the invention relates to a process for preparing thiophene derivatives of general formula (I'):
O
X ~ C - CH - CH (I') S NHR
wherein - C - CH - CH3 is in position 2 on the thiophene ring and either NHR
X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R
represents a sec-butyl or. n-propyl radical or X, in position
5 on the thiophene ring, represents a chlorine atom and R
represents a lso-propyl, n-propyl or sec-butyl radical; or O
- C - CH - CH3 is in position 4 on the thiophene ring, X, NHR
in position 2 on the thiophene ring,represents a chlorine atom and R represents a iso-propyl or sec-butyl radical;
and their pharmaceu-tically acceptable acid addition salts characterized in that:
a) for obtaining a thiophene derivative of formula ( A) X ~ C - CH - CH3 (IA) S NHR
wherein R represents a sec-butyl radical and X represents a chlorine atom, a compound of formula (II'):
- .. ,~
~2~ 76~ii3 Cl 11 (II') S C - ~CH - CH3 Br is reacted with an amine of formula (III):
wherein R represents a sec-butyl radical, in an inert medium and at a maximal temperature of 50 C; or b) for obtaining thiophene derivatives of formula (IB) X
~S ~ C - CH - C~13 (IB) NHR
~5 wherein R represents a n-propyl or sec-butyl radical and X
represents a methyl radical, a compound of formula (II"):
Br is reacted with an amine of formula (III):
wherein R represents a n-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50 C; or c) for obtaining thiophene derivatives of formula (IC) X ~ C - ~CH - CH3 (Ic) NHR
~3 .; ,.~,,~"
~7653 wherein R represents a n-propyl, iso-butyl or sec-butyl radical and X represents a chlorine atom, a compound oE
formula (II"'):
Cl ~ C - CH - CH3 (II"') Br is reacted with an amine of formula (III):
wherein R represents a n-propyl, lso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50 C; or d) for ob-taining thiophene derivatives of formula (ID):
CH3 - CH - C ~ (ID) NHR ~ X
wherein R represents a iso-propyl or sec-butyl radical and X represents a chlorine atom, a compound of formula (II""):
o ~1 CH3 - CH -C ~ Cl (II"') is reacted with an amine of formula (III):
HzN - R
wherein R represents a iso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50 C;
and in that the obtained free base derivativesof formula (IA), (IB), (Ic) or (ID) are isolated and, if desired, treated in an inert medium, with an acid to give corresponding phar-maceutically acceptable acid addition salts.
~?~
~7~
The invention also relates to preferred thiophene derivatives of general Eormula (I'):
X ~ ~ CH - CH (I') S O NHR
characterized in that -C - CH - CH3 is in position 2 on the NHR
thiophene ring and either X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R represents a sec-butyl or n-propyl radical, or X, in position 5 on the thiophene ring, represents a chlorine atom and R represents a iso-propyl, n-propyl or sec-butyl radical; or 1l - C - ~H - CH3 is in position 4 on the thiophene ring, X, NHR
in position 2 on the thiophene ringlrepresents a chlorine atom and R represents a iso-propyl on sec-butyl radical 0 and their pharmaceutically acceptable acid addition salts.
The preferred addition salts are the hydrochlorides.
Bromine displacement in the compounds of formula (II'), (II"), (II"') or tII"1') by the amines of formula (III), wherein R is as defined above for (I'), occurs preferably in acetonitrile, and at a maximal temperature of 50 C, followed by vacuum evaporation of solvent, removal and evaporation to dryness of extracts. From the residue thus obtained, corres-ponding to the compounds of formula (IA), (IB), (Ic) or (ID) it is possible to form their pharmaceutically acceptable salts, preferably hydrochlorides, by treating the respective acids in ethers, specially diethyl ether is preferred.
Then the formed precipita-te is separated by filtration.
~ -(Bromopropionyl)-thiophene precursors of general formula (II'), (II"), (II"') and (II"") are obtained by ~ ~ .
; ~
s~
conventional methods in Organic Chemistry; the reaction of propionyl-thiophenes with bromine in a medium composed by an aliphatic-chlorinated hydrocarbon, for example,methylene chloride, chloroform or carbon tetrachloride, are preferred.
In turn, propionyl-thiophenes are susceptible to be obtained either by acylation of respective thiophenes with a derivative of propionic acid, preferably propionyl chloride, under suitable conditions of Friedel-Crafts' reaction, or by reacting lithium derivatives of respective thiophenes with propionitrile. When X is chlorine, starting compounds such as commercially-available chlorothiophenes or dichlorothio-phenes are, if possible, used, and the substituent X=Cl may be introduced into the synthesis sequence on intermediate steps depending on the desired position. Sulphuryl chloride is preferred as a chlorinating agent. When X is methyl, respective methylthiophenes are, if possible, also used.
The preparation of ~-(bromopropionyl)-thiophene precursors of formula ~II) is hereinafter illustrated.
ClCQC H O Cl SO
~ 2 5 ~ ~ C - C H 7 7 -\S/ 4 \ S/ 2 5 ~13Al Cl Cl ~ 2 5 ~ Br (II, X= 4-Cl; chain position= 2) , ..
i7~
.. ..
Cl ~3 ClC~ Cl~C-C2H5 ~r~
Cl ~ C-CH-CH3 br ~II, X- 5-Cl; chain position= 2) CH3~ N-butyllithium CH3~ 0 CzH5CN ~S~ Cz~5 ~r2 CH3~ ~r (II, X= 4-CH3, chain positiona Z) q '.
Cl~ ClCOC2H5 _~_CE2H5 O , C 1~ ~r 2 Cl ~ C - C H -C 113 (II, X= 5-Cl, cl~ain position= 3) .c~ 7 .,~''~ .
~L~6~53 The above mentionned preEerred compounds have an eEfective antidepressant activity as evidenced by R. D.
Porsolt (Immobility beha~ioural despair -test in mice:
Arch. Int. Pharmacodyn., 229, 327-336, 1977), which differ from the thiophene ring non-substituted ~-(alkylaminopropio-nyl)-thiophenes, as disclosed in French Patent N. 3414M
and British Patent N 1313150, because these knowncompounds have anorexic activity devoided of central excitatory action or cardiovascular action, and neuroleptic, tranquillizing and analgesic action respectively. Consequently, the presence of an X group different from hydrogen, selected between methyl or chlorine, in the compounds of formula (IA), (IB), (Ic) and (ID) leads to compounds having a very effective anti-depressant action. Thus, the above preferred compounds are useful as a medicament for treating depressions.
The above mentionned preferred compounds mixed with pharmaceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, coated tablets, syrups, solutions, etc., by injectable route and by 20 rectal route at dialy doses ranging from 2.5 to 250 mg/kg.
By way of a non-limitative illustration within the essence of the invention, some examples are described herein-below referring to the possible way to obtain compounds of formula (I') by following the steps of the disclosed process.
EXAMPLE 28:
2-f~-(sec-butylaminopropionyl)¦-4-chlorothiophene hydrochloride To 26.05 g of ~-bromo-4-chloro-2-propionylthiophene prepared according to example 3 in 30 ml of acetonitrile, 18.8 g of sec-butylamine are slowly added without exceeding 32 C. As the exothermia diminishes, the mixture is left under stirring at room temperature. The solvent is evaporated at vacuum (below 35 C), taken in methylene chloride (150 ml) ~;, ~ILZ~5~3 and water (150 ml); the aqueous phase is removed with methylene chloride, the organic extracts are washed with water, dried and evaporated to dryness. The crude product (21.2 g) is dissolved in 400 ml o-f dry ethyl ether, cooled with water-ice bath and a dry HCl (g) stream is passed through; the insolubilized hydrochloride (20.0 g) is recrystallized from isopropanol to give 9.5 g (32%) of a white solid, m.p. 208-209 C and analysis correct.
IR Spectrum (KBr) cm l 3200-2440, 1670, 1550, 1400, 1230, 1110, lO90, 860.
H-NMR (d6-DMSO -~ D2O) ppm: 0.87 (t, 3H, J= 7Hz;
CH3-), 1.14 (d, 5H, J= 6Hz; CH3-CH-NH-), 1.47 (d + wide band, 5H, J= 7Hz; CH3- and -CH2-), 2.87 (m, lH;~ CH-NH-), 4.48 (_, lH;~ CH-CH3), 8.11 (s, lH; H-thiophene) and 8.26 (s, lH: H-thiophene).
2- ~-(sec-butylaminopropionvl~-4-methylthiophene hydrochloride From 33.9 g of ~-bromo-4-methyl-2-propionylthiophene prepared according to example 18,26.6 g of sec-butylamine in 45 ml of acetonitrile, and operating as described in Ex. 28, 41.9 g of crude product are isolated, respective hydrochloride (23.1 g) formed in ethyl ether is recrystallized in absolute ethanol to give 12.4 g (32%) of a white solid, m.p. 227-229 C
and analysis correct.
IR Spectrum (KBr) cm 1 3200-2400, 1665, 1545, 1410, 1225i 1100, 885, 860.
H-NMR Spectrum (d6-DMSO) ppm: 0.90 (t, 3H, J= 7Hz;
CH3-), 1.25 (d, 3H, J= 7Hz; CH3-CH-NH-), 1.57 (d + wide band, 5H, J= 7Hz; CH3- and CH2-), 2.26 (s, 3H; CH3--thiophene), 3.00 ( , lH;~CH-NH-), 5.10 (_, lH; CH-CH3), 7.80 (s, lE~; H-thiophene) and 8.20 (s, lH; H-thiophene).
~.q ~,"
~Z6~7~5~
2-[~-(n-propylaminopropionyl)~-4-methylthiophene hydrochlorlde From 33.9 g of ~-bromo-4-methyl-2-propionylthiophene in 45 ml of acetonitrile and 21.5 g of n-propylamine, and operating as described in Ex. 28, 42.1 g of crude product are isolated, respective hydrochloride (26.1 g) formed in ethyl ether is recrystallized in acetonitrile-isopropanol (1:1) to give 11.8 g (33~) of a white solid, m.p. 211.3-212 C and analysis correct.
IR Spectrum (KBr) cm : 3200-2400, 1660, 1410, 1230, 1215, 1105, 920, 780.
~I-NMR (d6-DMSO) ppm: 0.90 (t, 3H, J= 7Hz; CH3-), 1.56 (d, 3H, J= 7Hz; CH3-CH-CO-), 1.74 (_, 2H, J= 8Hz; -CH2-), 2.27 (s, 3H; CH3-thiophene), 2.82 (m, 2H, J= 8Hz; -CH2-NH-), 5.00 (q, lH, J= 7Hz; -CH-CO-), 7.81(s, lH; H-thiophene) and 8.07 (s, lH; H-thiophene).
2- ~ (isopropylaminopropionyl)~-5-chlorothiophene hydrochloride From 32.0 g of ~-bromo-5-chloro-2-propionylthiophene prepared as described in example 6,/in 40 ml of acetonitrile and 18.62 g of isopropylamine, and operating as described in Ex. 28, 30 g of crude product are isolated, respective ; hydrochloride (28.7 g) formed in ethyl ether is recrystalllzed from isopropanol to give 13.5 g (39~) of a white solid, m.p.
222.2-223 C and analysis correct.
IR Spectrum (KBr) cm : 3160-2400, 1660, 1555, 1410, 1320, 1240, 1075, 1010, 825.
H-NMR (d6-DMSO) ppm: 1.30 (d, 6H, J= 6Hz -CH(CH3)2), 1.57 (d, 3H, J= 7Hz; CH3-), 3.37 (_, lH; CH(CH3)2), 5-17 (m, lH; -CO-CH-), 7.42 (d, lH, J= 4Hz; H-thiophene) and 8.37 (d, lH, J= 4Hz; H-thiophene).
~", r765~
2-[~-(n-propylaminopropionyl)~-5-ehlorothiophene hydrochloride From 35.7 g of ~-bromo-5-chloro-2-propionylthiophene in 45 ml of acetonitrile and 20.9 g of a-propylamine, and operating as described in Ex. 28, 31 g of erude produet are isolated, respeetive hydrochloride (12 g) is recrystal-lized from isopropanol to give 7.73 g (20%) of a white solid, m.p. l90-190.3 C and analysis correct.
IR Spectrum (KBr) cm : 3180-2400, 1665, 1410, 1320, 1230, lO10, ~15, 720.
1H-NMR Spectrum (D2O) ppm: 1.00 (t, 3H, J= 7.5Hz;
CH3-), 1.68 (d, 3H, J= 7Hz; CH3-CH-CO-), 1.82 (m, 2H; -CH2-), 3-10 (m, 2H; -CH2-N~ ), 5.00 (q, lH, J= 7.0Hz; CH-CO-), 7.25 15 (d, lH, J= 4Hz, H-thiophene) and 7.94 (d, lH, J= 4Hz; H-thiophene).
2-C~-(see-butylaminopropionyl)~-5-chlorothiophene hydrochloride From 32.9 g of ~-bromo-5-chloro-2-propionylthiophene in 40 ml of acetonitrile and 23.8 g of sec-butylamine, and operating as described in Ex. 28, 28.4 g of crude product are isolated, respective hydrochloride (20.5 g) is recrystallized from isopropanol to give 9.2 g (26%) of a white solid, m.p.
191.3-192 C and analysis correct.
IR Spectrum (KBr) em 1 3120-2400, 1660, 1550, 1420, 1235, 1010, 820.
1H-NMR (d6-DMSO + D2O) ppm: 0.90 (2t, 3H, J= 7Hz;
30 CH3-), 1.27 (d, 3H, J= 7Hz; CH3-CH-NH-), 1.59 (d ~ wide band, 5H, J= 7Hz; CH3- and -CH2-), 3.05 (_, lH; _CH-NH), 5.15 (qt, lH, J= 7Hz; ~CH-CO-), 7.40 (d, lH, J= 4Hz; H-thiophene) and 8.32 (d, lH, J= 4Hz; H-thiophene).
- ~z~
EXAMPLE34:
4~ sopropylaminopropionyl)~-2-chlorothiophene hydrochloride From 33.9 g of ~-bromo-2-chloro -4-propionylthiophene prepared according to example l~,in 40 ml of acetonitrile and 19.8 g of isopropylamine, and operating as described in Ex.
28, 31.0 g of crude product are isolated, respective hydro-~ chloride (28.5 g) formed in ethyl ether is recrystallized in 10 ethanol to give 9.3 g (30%) of a white solid, m.p. 244-245C
and analysis correct.
IR Spectrum (KBr) cm 1 3200-2420, 1670, 1550, 1455, 1420, 1210, 1190, 1170, 1100, 1000, 830.
H-NMR (D2O) ppm: 1.35 (d, 6H, J= 6Hz; -CH(CH3~2), 15 1.62 (d, 3H, J= 7Hz; CH3-), 3.50 (_, lH, J= 7Hz; CH(CH3)2), 5.00 (~, lH, J- 7Hz; -CO-CH-), 7.52 (d, lH, J= 2Hz; H-thiophene) and 8.44 (d, lH, J= 2Hz; H-thiophene~.
EXAMPLE3s 4- Cd~-(sec-butylaminopropionyl~ -2-chlorothiophene hydrochloride From 32.2 g of ~-bromo-2-chloro-4-propionylthiophene in 40 ml of acetonitrile and 23.5 g of sec-butylamine, and operating as described in Ex. 28, 30 g of crude product are isolated, respective hydrochloride (20 g) formed in ethyl ether is recrystallized in isopropanol to give 6.55 g (21%) of a white solid, m.p. 206-207 C and analysis correct.
IR Spectrum (KBr) cm 1 3160-2400, 1680, 1550, 1420, 1210, 1195, 1105, 1005, 870, 805.
lH-NMR Spectrum (CD30D) ppm: 1.00 (2t, 3H, J= 7.0Hz;
CH3-CH2-), 1.38 (d, 3H, J= 6.5Hz; CH3-CH-NH-), 1.63 (d + wide band, 5H, J= 7Hz; CH3 and -CH2), 3.14 (_, lH -CH-NH-), 5.12 (m, lH; CH-CO-), 7.53 (d, lH, J= 2Hz; H-thiophene) and 8.60 (d, lH, J= 2Hz; H-thiophene).
3~
represents a lso-propyl, n-propyl or sec-butyl radical; or O
- C - CH - CH3 is in position 4 on the thiophene ring, X, NHR
in position 2 on the thiophene ring,represents a chlorine atom and R represents a iso-propyl or sec-butyl radical;
and their pharmaceu-tically acceptable acid addition salts characterized in that:
a) for obtaining a thiophene derivative of formula ( A) X ~ C - CH - CH3 (IA) S NHR
wherein R represents a sec-butyl radical and X represents a chlorine atom, a compound of formula (II'):
- .. ,~
~2~ 76~ii3 Cl 11 (II') S C - ~CH - CH3 Br is reacted with an amine of formula (III):
wherein R represents a sec-butyl radical, in an inert medium and at a maximal temperature of 50 C; or b) for obtaining thiophene derivatives of formula (IB) X
~S ~ C - CH - C~13 (IB) NHR
~5 wherein R represents a n-propyl or sec-butyl radical and X
represents a methyl radical, a compound of formula (II"):
Br is reacted with an amine of formula (III):
wherein R represents a n-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50 C; or c) for obtaining thiophene derivatives of formula (IC) X ~ C - ~CH - CH3 (Ic) NHR
~3 .; ,.~,,~"
~7653 wherein R represents a n-propyl, iso-butyl or sec-butyl radical and X represents a chlorine atom, a compound oE
formula (II"'):
Cl ~ C - CH - CH3 (II"') Br is reacted with an amine of formula (III):
wherein R represents a n-propyl, lso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50 C; or d) for ob-taining thiophene derivatives of formula (ID):
CH3 - CH - C ~ (ID) NHR ~ X
wherein R represents a iso-propyl or sec-butyl radical and X represents a chlorine atom, a compound of formula (II""):
o ~1 CH3 - CH -C ~ Cl (II"') is reacted with an amine of formula (III):
HzN - R
wherein R represents a iso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50 C;
and in that the obtained free base derivativesof formula (IA), (IB), (Ic) or (ID) are isolated and, if desired, treated in an inert medium, with an acid to give corresponding phar-maceutically acceptable acid addition salts.
~?~
~7~
The invention also relates to preferred thiophene derivatives of general Eormula (I'):
X ~ ~ CH - CH (I') S O NHR
characterized in that -C - CH - CH3 is in position 2 on the NHR
thiophene ring and either X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R represents a sec-butyl or n-propyl radical, or X, in position 5 on the thiophene ring, represents a chlorine atom and R represents a iso-propyl, n-propyl or sec-butyl radical; or 1l - C - ~H - CH3 is in position 4 on the thiophene ring, X, NHR
in position 2 on the thiophene ringlrepresents a chlorine atom and R represents a iso-propyl on sec-butyl radical 0 and their pharmaceutically acceptable acid addition salts.
The preferred addition salts are the hydrochlorides.
Bromine displacement in the compounds of formula (II'), (II"), (II"') or tII"1') by the amines of formula (III), wherein R is as defined above for (I'), occurs preferably in acetonitrile, and at a maximal temperature of 50 C, followed by vacuum evaporation of solvent, removal and evaporation to dryness of extracts. From the residue thus obtained, corres-ponding to the compounds of formula (IA), (IB), (Ic) or (ID) it is possible to form their pharmaceutically acceptable salts, preferably hydrochlorides, by treating the respective acids in ethers, specially diethyl ether is preferred.
Then the formed precipita-te is separated by filtration.
~ -(Bromopropionyl)-thiophene precursors of general formula (II'), (II"), (II"') and (II"") are obtained by ~ ~ .
; ~
s~
conventional methods in Organic Chemistry; the reaction of propionyl-thiophenes with bromine in a medium composed by an aliphatic-chlorinated hydrocarbon, for example,methylene chloride, chloroform or carbon tetrachloride, are preferred.
In turn, propionyl-thiophenes are susceptible to be obtained either by acylation of respective thiophenes with a derivative of propionic acid, preferably propionyl chloride, under suitable conditions of Friedel-Crafts' reaction, or by reacting lithium derivatives of respective thiophenes with propionitrile. When X is chlorine, starting compounds such as commercially-available chlorothiophenes or dichlorothio-phenes are, if possible, used, and the substituent X=Cl may be introduced into the synthesis sequence on intermediate steps depending on the desired position. Sulphuryl chloride is preferred as a chlorinating agent. When X is methyl, respective methylthiophenes are, if possible, also used.
The preparation of ~-(bromopropionyl)-thiophene precursors of formula ~II) is hereinafter illustrated.
ClCQC H O Cl SO
~ 2 5 ~ ~ C - C H 7 7 -\S/ 4 \ S/ 2 5 ~13Al Cl Cl ~ 2 5 ~ Br (II, X= 4-Cl; chain position= 2) , ..
i7~
.. ..
Cl ~3 ClC~ Cl~C-C2H5 ~r~
Cl ~ C-CH-CH3 br ~II, X- 5-Cl; chain position= 2) CH3~ N-butyllithium CH3~ 0 CzH5CN ~S~ Cz~5 ~r2 CH3~ ~r (II, X= 4-CH3, chain positiona Z) q '.
Cl~ ClCOC2H5 _~_CE2H5 O , C 1~ ~r 2 Cl ~ C - C H -C 113 (II, X= 5-Cl, cl~ain position= 3) .c~ 7 .,~''~ .
~L~6~53 The above mentionned preEerred compounds have an eEfective antidepressant activity as evidenced by R. D.
Porsolt (Immobility beha~ioural despair -test in mice:
Arch. Int. Pharmacodyn., 229, 327-336, 1977), which differ from the thiophene ring non-substituted ~-(alkylaminopropio-nyl)-thiophenes, as disclosed in French Patent N. 3414M
and British Patent N 1313150, because these knowncompounds have anorexic activity devoided of central excitatory action or cardiovascular action, and neuroleptic, tranquillizing and analgesic action respectively. Consequently, the presence of an X group different from hydrogen, selected between methyl or chlorine, in the compounds of formula (IA), (IB), (Ic) and (ID) leads to compounds having a very effective anti-depressant action. Thus, the above preferred compounds are useful as a medicament for treating depressions.
The above mentionned preferred compounds mixed with pharmaceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, coated tablets, syrups, solutions, etc., by injectable route and by 20 rectal route at dialy doses ranging from 2.5 to 250 mg/kg.
By way of a non-limitative illustration within the essence of the invention, some examples are described herein-below referring to the possible way to obtain compounds of formula (I') by following the steps of the disclosed process.
EXAMPLE 28:
2-f~-(sec-butylaminopropionyl)¦-4-chlorothiophene hydrochloride To 26.05 g of ~-bromo-4-chloro-2-propionylthiophene prepared according to example 3 in 30 ml of acetonitrile, 18.8 g of sec-butylamine are slowly added without exceeding 32 C. As the exothermia diminishes, the mixture is left under stirring at room temperature. The solvent is evaporated at vacuum (below 35 C), taken in methylene chloride (150 ml) ~;, ~ILZ~5~3 and water (150 ml); the aqueous phase is removed with methylene chloride, the organic extracts are washed with water, dried and evaporated to dryness. The crude product (21.2 g) is dissolved in 400 ml o-f dry ethyl ether, cooled with water-ice bath and a dry HCl (g) stream is passed through; the insolubilized hydrochloride (20.0 g) is recrystallized from isopropanol to give 9.5 g (32%) of a white solid, m.p. 208-209 C and analysis correct.
IR Spectrum (KBr) cm l 3200-2440, 1670, 1550, 1400, 1230, 1110, lO90, 860.
H-NMR (d6-DMSO -~ D2O) ppm: 0.87 (t, 3H, J= 7Hz;
CH3-), 1.14 (d, 5H, J= 6Hz; CH3-CH-NH-), 1.47 (d + wide band, 5H, J= 7Hz; CH3- and -CH2-), 2.87 (m, lH;~ CH-NH-), 4.48 (_, lH;~ CH-CH3), 8.11 (s, lH; H-thiophene) and 8.26 (s, lH: H-thiophene).
2- ~-(sec-butylaminopropionvl~-4-methylthiophene hydrochloride From 33.9 g of ~-bromo-4-methyl-2-propionylthiophene prepared according to example 18,26.6 g of sec-butylamine in 45 ml of acetonitrile, and operating as described in Ex. 28, 41.9 g of crude product are isolated, respective hydrochloride (23.1 g) formed in ethyl ether is recrystallized in absolute ethanol to give 12.4 g (32%) of a white solid, m.p. 227-229 C
and analysis correct.
IR Spectrum (KBr) cm 1 3200-2400, 1665, 1545, 1410, 1225i 1100, 885, 860.
H-NMR Spectrum (d6-DMSO) ppm: 0.90 (t, 3H, J= 7Hz;
CH3-), 1.25 (d, 3H, J= 7Hz; CH3-CH-NH-), 1.57 (d + wide band, 5H, J= 7Hz; CH3- and CH2-), 2.26 (s, 3H; CH3--thiophene), 3.00 ( , lH;~CH-NH-), 5.10 (_, lH; CH-CH3), 7.80 (s, lE~; H-thiophene) and 8.20 (s, lH; H-thiophene).
~.q ~,"
~Z6~7~5~
2-[~-(n-propylaminopropionyl)~-4-methylthiophene hydrochlorlde From 33.9 g of ~-bromo-4-methyl-2-propionylthiophene in 45 ml of acetonitrile and 21.5 g of n-propylamine, and operating as described in Ex. 28, 42.1 g of crude product are isolated, respective hydrochloride (26.1 g) formed in ethyl ether is recrystallized in acetonitrile-isopropanol (1:1) to give 11.8 g (33~) of a white solid, m.p. 211.3-212 C and analysis correct.
IR Spectrum (KBr) cm : 3200-2400, 1660, 1410, 1230, 1215, 1105, 920, 780.
~I-NMR (d6-DMSO) ppm: 0.90 (t, 3H, J= 7Hz; CH3-), 1.56 (d, 3H, J= 7Hz; CH3-CH-CO-), 1.74 (_, 2H, J= 8Hz; -CH2-), 2.27 (s, 3H; CH3-thiophene), 2.82 (m, 2H, J= 8Hz; -CH2-NH-), 5.00 (q, lH, J= 7Hz; -CH-CO-), 7.81(s, lH; H-thiophene) and 8.07 (s, lH; H-thiophene).
2- ~ (isopropylaminopropionyl)~-5-chlorothiophene hydrochloride From 32.0 g of ~-bromo-5-chloro-2-propionylthiophene prepared as described in example 6,/in 40 ml of acetonitrile and 18.62 g of isopropylamine, and operating as described in Ex. 28, 30 g of crude product are isolated, respective ; hydrochloride (28.7 g) formed in ethyl ether is recrystalllzed from isopropanol to give 13.5 g (39~) of a white solid, m.p.
222.2-223 C and analysis correct.
IR Spectrum (KBr) cm : 3160-2400, 1660, 1555, 1410, 1320, 1240, 1075, 1010, 825.
H-NMR (d6-DMSO) ppm: 1.30 (d, 6H, J= 6Hz -CH(CH3)2), 1.57 (d, 3H, J= 7Hz; CH3-), 3.37 (_, lH; CH(CH3)2), 5-17 (m, lH; -CO-CH-), 7.42 (d, lH, J= 4Hz; H-thiophene) and 8.37 (d, lH, J= 4Hz; H-thiophene).
~", r765~
2-[~-(n-propylaminopropionyl)~-5-ehlorothiophene hydrochloride From 35.7 g of ~-bromo-5-chloro-2-propionylthiophene in 45 ml of acetonitrile and 20.9 g of a-propylamine, and operating as described in Ex. 28, 31 g of erude produet are isolated, respeetive hydrochloride (12 g) is recrystal-lized from isopropanol to give 7.73 g (20%) of a white solid, m.p. l90-190.3 C and analysis correct.
IR Spectrum (KBr) cm : 3180-2400, 1665, 1410, 1320, 1230, lO10, ~15, 720.
1H-NMR Spectrum (D2O) ppm: 1.00 (t, 3H, J= 7.5Hz;
CH3-), 1.68 (d, 3H, J= 7Hz; CH3-CH-CO-), 1.82 (m, 2H; -CH2-), 3-10 (m, 2H; -CH2-N~ ), 5.00 (q, lH, J= 7.0Hz; CH-CO-), 7.25 15 (d, lH, J= 4Hz, H-thiophene) and 7.94 (d, lH, J= 4Hz; H-thiophene).
2-C~-(see-butylaminopropionyl)~-5-chlorothiophene hydrochloride From 32.9 g of ~-bromo-5-chloro-2-propionylthiophene in 40 ml of acetonitrile and 23.8 g of sec-butylamine, and operating as described in Ex. 28, 28.4 g of crude product are isolated, respective hydrochloride (20.5 g) is recrystallized from isopropanol to give 9.2 g (26%) of a white solid, m.p.
191.3-192 C and analysis correct.
IR Spectrum (KBr) em 1 3120-2400, 1660, 1550, 1420, 1235, 1010, 820.
1H-NMR (d6-DMSO + D2O) ppm: 0.90 (2t, 3H, J= 7Hz;
30 CH3-), 1.27 (d, 3H, J= 7Hz; CH3-CH-NH-), 1.59 (d ~ wide band, 5H, J= 7Hz; CH3- and -CH2-), 3.05 (_, lH; _CH-NH), 5.15 (qt, lH, J= 7Hz; ~CH-CO-), 7.40 (d, lH, J= 4Hz; H-thiophene) and 8.32 (d, lH, J= 4Hz; H-thiophene).
- ~z~
EXAMPLE34:
4~ sopropylaminopropionyl)~-2-chlorothiophene hydrochloride From 33.9 g of ~-bromo-2-chloro -4-propionylthiophene prepared according to example l~,in 40 ml of acetonitrile and 19.8 g of isopropylamine, and operating as described in Ex.
28, 31.0 g of crude product are isolated, respective hydro-~ chloride (28.5 g) formed in ethyl ether is recrystallized in 10 ethanol to give 9.3 g (30%) of a white solid, m.p. 244-245C
and analysis correct.
IR Spectrum (KBr) cm 1 3200-2420, 1670, 1550, 1455, 1420, 1210, 1190, 1170, 1100, 1000, 830.
H-NMR (D2O) ppm: 1.35 (d, 6H, J= 6Hz; -CH(CH3~2), 15 1.62 (d, 3H, J= 7Hz; CH3-), 3.50 (_, lH, J= 7Hz; CH(CH3)2), 5.00 (~, lH, J- 7Hz; -CO-CH-), 7.52 (d, lH, J= 2Hz; H-thiophene) and 8.44 (d, lH, J= 2Hz; H-thiophene~.
EXAMPLE3s 4- Cd~-(sec-butylaminopropionyl~ -2-chlorothiophene hydrochloride From 32.2 g of ~-bromo-2-chloro-4-propionylthiophene in 40 ml of acetonitrile and 23.5 g of sec-butylamine, and operating as described in Ex. 28, 30 g of crude product are isolated, respective hydrochloride (20 g) formed in ethyl ether is recrystallized in isopropanol to give 6.55 g (21%) of a white solid, m.p. 206-207 C and analysis correct.
IR Spectrum (KBr) cm 1 3160-2400, 1680, 1550, 1420, 1210, 1195, 1105, 1005, 870, 805.
lH-NMR Spectrum (CD30D) ppm: 1.00 (2t, 3H, J= 7.0Hz;
CH3-CH2-), 1.38 (d, 3H, J= 6.5Hz; CH3-CH-NH-), 1.63 (d + wide band, 5H, J= 7Hz; CH3 and -CH2), 3.14 (_, lH -CH-NH-), 5.12 (m, lH; CH-CO-), 7.53 (d, lH, J= 2Hz; H-thiophene) and 8.60 (d, lH, J= 2Hz; H-thiophene).
3~
Claims (27)
1. Thiophene ring-substituted .alpha.-(alkylaminopropionyl)-thiophene derivatives having the general formula (I):
(I) wherein X is methyl or chlorine, R is alkyl, linear or branched, having 3 to 4 carbon atoms, ana the nontoxic addition salts thereof.
(I) wherein X is methyl or chlorine, R is alkyl, linear or branched, having 3 to 4 carbon atoms, ana the nontoxic addition salts thereof.
2. A process for preparing the compounds according to Claim 1, characterized in that an .alpha.-(alkylaminopropionyl)-thiophene of the general formula (II):
(II) wherein X has the same meaning as defined in claim 1, is reacted with an amine of the general formula (III):
H2N-R (III) wherein R has the same meaning as defined in claim 1, in an inert medium, and at a maximal temperature of 50?C, and the nontoxic addition salts can be obtained by treating respective acids in an inert medium, and rsspective free bases can be obtained by neutralization.
(II) wherein X has the same meaning as defined in claim 1, is reacted with an amine of the general formula (III):
H2N-R (III) wherein R has the same meaning as defined in claim 1, in an inert medium, and at a maximal temperature of 50?C, and the nontoxic addition salts can be obtained by treating respective acids in an inert medium, and rsspective free bases can be obtained by neutralization.
3. The process of Claim 2, characterized in that acetonitrile is used as inert medium in the reaction between (II) and (III).
4. The process of Claim 2, characterized in that a chlorinated hydrocarbon or an ether is used as inert medium in the formation of the nontoxic addition salts.
5. The process of Claim 2 according to Claim 4, wherein the chlorinated hydrocarbon is methylene chloride and the ether is diethyl ether.
6. Pharmaceutical composition comprising at least one of the compounds of Claim 1, optionally together with pharma-ceutical carriers and/or adjuvants.
CLAIMS SUPPORTED BY THE
SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY THE
SUPPLEMENTARY DISCLOSURE
7. Process for preparing thiophene derivatives of general formula (I'):
(I') wherein is in position 2 on the thiophene ring and either X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R represents a sec-butyl or n-propyl radical, or X, in position 5 on the thiophene ring, represents a chlorine atom and R represents a iso-propyl, n-propyl or sec-butyl radical; or is in position 4 on the thiophene ring, X, in position 2 on the thiophene ring, represents a chlorine atom and R represents a isopropyl or sec-butyl radical; and their pharmaceutically acceptable acid addition salts, characterized in that:
a) for obtaining a thiophene derivative of formula (IA):
(IA) wherein R represents a sec-butyl radical and X represents a chlorine atom, a compound of formula (II'):
(II') is reacted with an amine of formula (III):
wherein R represents a sec-butyl radical, in an inert medium and at a maximal temperature of 50° C; or b) for obtaining thiophene derivatives of formula (IB):
(IB) wherein R represents a n-propyl or sec-butyl radical and X
represents a methyl radical, a compound of formula (II"):
(II") is reacted with an amine of formula (III):
wherein R represents a n-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50° C; or c) for obtaining thiophene derivatives of formula (IC):
(IC) wherein R represents a n-propyl, iso-butyl or sec-butyl radical and X represents a chlorine atom, a compound of formula (II"'):
(II"') is reacted with an amine of formula (III):
wherein R represents a n-propyl, iso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50° C; or d) for obtaining thiophene derivatives of formula (ID):
(ID) wherein R represents a iso-propyl or sec-butyl radical and X represents a chlorine atom, a compound of formula (II""):
(II"") is reacted with an amine of formula (III):
wherein R represents a iso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50° C;
and in that the obtained free base derivatives of formula (IA), (IB), (IC) or (ID) are isolated and, if desired, treated in an inert medium, with an acid to give corresponding pharmaceutically acceptable acid addition salts.
(I') wherein is in position 2 on the thiophene ring and either X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R represents a sec-butyl or n-propyl radical, or X, in position 5 on the thiophene ring, represents a chlorine atom and R represents a iso-propyl, n-propyl or sec-butyl radical; or is in position 4 on the thiophene ring, X, in position 2 on the thiophene ring, represents a chlorine atom and R represents a isopropyl or sec-butyl radical; and their pharmaceutically acceptable acid addition salts, characterized in that:
a) for obtaining a thiophene derivative of formula (IA):
(IA) wherein R represents a sec-butyl radical and X represents a chlorine atom, a compound of formula (II'):
(II') is reacted with an amine of formula (III):
wherein R represents a sec-butyl radical, in an inert medium and at a maximal temperature of 50° C; or b) for obtaining thiophene derivatives of formula (IB):
(IB) wherein R represents a n-propyl or sec-butyl radical and X
represents a methyl radical, a compound of formula (II"):
(II") is reacted with an amine of formula (III):
wherein R represents a n-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50° C; or c) for obtaining thiophene derivatives of formula (IC):
(IC) wherein R represents a n-propyl, iso-butyl or sec-butyl radical and X represents a chlorine atom, a compound of formula (II"'):
(II"') is reacted with an amine of formula (III):
wherein R represents a n-propyl, iso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50° C; or d) for obtaining thiophene derivatives of formula (ID):
(ID) wherein R represents a iso-propyl or sec-butyl radical and X represents a chlorine atom, a compound of formula (II""):
(II"") is reacted with an amine of formula (III):
wherein R represents a iso-propyl or sec-butyl radical, in an inert medium and at a maximal temperature of 50° C;
and in that the obtained free base derivatives of formula (IA), (IB), (IC) or (ID) are isolated and, if desired, treated in an inert medium, with an acid to give corresponding pharmaceutically acceptable acid addition salts.
8. Process according to claim 7, characterized in that the inert medium in which the reaction between compounds of formula (II'), (II"), (II"') or (II"") and (III) is carried out, is acetonitrile.
9. Process according to claim 7, characterized in that the inert medium in which the formation of the pharma-ceutically acceptable acid additon salt is carried out, is an ether.
10. Process according to claim 7, characterized in that the inert medium in which the formation of the pharma-ceutically acceptable acid addition salt is carried out, is diethylether.
11. Process for preparing 2-[?-(sec-butylaminopropio-nyl)] 4-chlorothiophene and its hydrochloride, characterized in that ?-bromo 4-chloro 2-propionylthiophene is reacted with sec-butylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
12. Process for preparing 2-[?(sec-butylaminopro-pionyl)] 4-methylthiophene and its hydrochloride, characte-rized in that ?-bromo 4-methyl 2-propionylthiophene is reacted with sec-butylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
13. Process for preparing 2-[?-(n-propylaminopro-pionyl)] 4-methylthiophene and its hydrochloride, characte-rized in that ?-bromo 4-methyl 2-propionylthiophene is reacted with n-propylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
14. Process for preparing 2-[?-(iso-propylamino-propionyl)] 5-chlorothiophene and its hydrochloride, cha-racterized in that ?-bromo 5-chloro 2-propionylthiophene is reacted with iso-propylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
15. Process for preparing 2- [?-(n-propylaminopro-pionyl)] 5-chlorothiophene and its hydrochloride, characte-rized in that ?-bromo 5-chloro 2-propionylthiophene is reacted with n-propylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
16. Process for preparing 2-[?-(sec-butylamino-propionyl)] 5-chlorothiophene and its hydrochloride, charac-terized in that ?-bromo 5-chloro 2-propionylthiophene is reacted with sec-butylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
17. Process for preparing 4-[?-(iso-propylamino-propionyl)] 2-chlorothiophene and its hydrochloride, charac-terized in that ?-bromo 2-chloro 4-propionylthiophene is reacted with iso-propylamine in acetonitrile at a maximal temperature of 50° C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
18. Process for preparing 4-[?-(sec-butylaminopro-pionyl)] 2-chlorothiophene and its hydrochloride, characte-rized in that ?-bromo 2-chloro 4-propionylthiophene is reacted with sec-butylamine in acetonitrile at a maximal temperature of 50°C, and in that the obtained compound is isolated and, if desired, treated with hydrochloric acid in ethylether to give the corresponding hydrochloride which is then isolated.
19. Thiophene derivatives of general formula (I'):
(I') characterized in that is in position 2 on the thiophene ring and either X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R represents a sec-butyl or n-propyl radical, or X, in position 5 on the thiophene ring, represents a chlorine atom and R represents a iso-propyl, n-propyl or sec-butyl radical; or is in position 4 on the thiophene ring, X, in position 2 on the thiophene ring,represents a chlorine atom and R represents a o-propyl or sec-butyl radical; and their pharmaceutically acceptable acid addition salts.
(I') characterized in that is in position 2 on the thiophene ring and either X, in position 4 on the thiophene ring, represents a chlorine atom and R represents a sec-butyl radical, or X, in position 4 on the thiophene ring, represents a methyl radical and R represents a sec-butyl or n-propyl radical, or X, in position 5 on the thiophene ring, represents a chlorine atom and R represents a iso-propyl, n-propyl or sec-butyl radical; or is in position 4 on the thiophene ring, X, in position 2 on the thiophene ring,represents a chlorine atom and R represents a o-propyl or sec-butyl radical; and their pharmaceutically acceptable acid addition salts.
20. 2-[? -(sec-butylaminopropionyl)] 4-chloro-thiophene and its hydrochloride or its obvious chemical equivalent.
21. 2-[?-(sec-butylaminopropionyl)] 4-methyl-thiophene and its hydrochloride or its obvious chemical equivalent.
22. 2- [? -(n-propylaminopropionyl)] 4-methyl-thiophene and its hydrochloride or its obvious chemical equivalent.
23. 2-[? -(iso-propylaminopropionyl)] 5-chlorothiophene and its hydrochloride or its obvious chemical equivalent.
24. 2- [?-(n-propylaminopropionyl)] 5-chloro-thiophene and its hydrochloride or its obvious chemical equivalent.
25. 2-[?-(sec-butylaminopropionyl)] 5-chloro-thiophene and its hydrochloride or its obvious chemical equivalent.
26. 4-[?-(iso-propylaminopropionyl)] 2-chloro-thiophene and its hydrochlorideor its obvious chemical equivalent.
27. 4-[?-(sec-butylaminopropionyl)] 2-chloro-thiophene and its hydrochloride or its obvious chemical equivalent.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES541,911 | 1985-03-20 | ||
| ES541911A ES8602744A1 (en) | 1985-03-20 | 1985-03-20 | Thiophene ring-substituted alpha -(alkylaminopropionyl)-thiophenes and the method for preparing the same |
| ES552,220 | 1986-02-20 | ||
| ES552220A ES8704922A2 (en) | 1986-02-20 | 1986-02-20 | Improvements to the subject matter of patent of invention no. 541,911 relating to Process for obtaining new [alpha]- (alkylaminopropionyl)-thiophen derivatives substituted in the thiophen ring |
| ES556311A ES8707505A2 (en) | 1986-06-03 | 1986-06-03 | Thiophene ring-substituted alpha-(alkylaminopropionyl)-thiophene derivatives, a process for preparing them and pharmacuetical compositions containing them. |
| ES556,311 | 1986-06-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1267653A true CA1267653A (en) | 1990-04-10 |
Family
ID=27240803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000503190A Expired - Fee Related CA1267653A (en) | 1985-03-20 | 1986-03-04 | THIOPHENE RING-SUBTITUTED .alpha.-(ALKYLAMINOPROPIONYL)- THIOPHENE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1267653A (en) |
-
1986
- 1986-03-04 CA CA000503190A patent/CA1267653A/en not_active Expired - Fee Related
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