CA1182117A - Process for making 5,6,7,7a-tetrahydro-4h- thieno- [)3,2,-c]pyridin-2-one - Google Patents
Process for making 5,6,7,7a-tetrahydro-4h- thieno- [)3,2,-c]pyridin-2-oneInfo
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- CA1182117A CA1182117A CA000391073A CA391073A CA1182117A CA 1182117 A CA1182117 A CA 1182117A CA 000391073 A CA000391073 A CA 000391073A CA 391073 A CA391073 A CA 391073A CA 1182117 A CA1182117 A CA 1182117A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides a process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one derivatives of the general formula:
(I) in which R is a hydrogen atom or a phenyl radical optionally substituted by at least one halogen atom, lower alkyl radi-cal, lower alkoxy radical, nitro group, carboxy group, alkoxycarbonyl radical or cyano group; R' is a hydrogen atom or a lower alkyl radical; and n is 0, 1, 2, 3 or 4; and of their acid addition salts with mineral and organic acids, wherein a) a compound of the general formula:
(II) in which R, R' and n have the same meanings as above, is treated with a solution of hydrogen peroxide in a mixture of acetic acid and hydrobromic acid to give a brominated derivative of the general formula:
(III) in which R, R' and n have the same meanings as above;
b) the brominated derivative (III) is converted into an organo-magnesium compound in an inert anhydrous solvent, this organo-magnesium compound then being condensed with tert.-butyl perbenzoate to give a compound of the general formula:
The present invention provides a process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one derivatives of the general formula:
(I) in which R is a hydrogen atom or a phenyl radical optionally substituted by at least one halogen atom, lower alkyl radi-cal, lower alkoxy radical, nitro group, carboxy group, alkoxycarbonyl radical or cyano group; R' is a hydrogen atom or a lower alkyl radical; and n is 0, 1, 2, 3 or 4; and of their acid addition salts with mineral and organic acids, wherein a) a compound of the general formula:
(II) in which R, R' and n have the same meanings as above, is treated with a solution of hydrogen peroxide in a mixture of acetic acid and hydrobromic acid to give a brominated derivative of the general formula:
(III) in which R, R' and n have the same meanings as above;
b) the brominated derivative (III) is converted into an organo-magnesium compound in an inert anhydrous solvent, this organo-magnesium compound then being condensed with tert.-butyl perbenzoate to give a compound of the general formula:
Description
The present invention is concerned with a novel process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-one derivatives.
The 5,6,7,7a-tetrahydro~4H-thieno(3,2-c)-pyridin-2-one derivatives with which the present invention is concerned are compounds of the general formula:
~ ~(cHR')n-R
O ~ S ~ (I) in which R is a hydrogen atom or a phenyl radical optionally substituted by at least one halogen atom, lower alkyl radi-cal, lower alkoxy radical, nitro group, carboxy group, alkoxycarbonyl radical or cyano group; R' is a hydrogen atom or a lower alkyl radical and n is 0, 1, 2, 3 or 4; as well as the addition salts thereof with mineral and organic acids.
These compounds (I) have platelet anti-aggregant properties and anti-thrombotic properties and are the subject matter of CanO Appl. S.N. 391,052 filed Nov. 27, 1981.
Furthermore, they are included in a general formula given in French Patent Specifications Nos. 2,215,948 and
The 5,6,7,7a-tetrahydro~4H-thieno(3,2-c)-pyridin-2-one derivatives with which the present invention is concerned are compounds of the general formula:
~ ~(cHR')n-R
O ~ S ~ (I) in which R is a hydrogen atom or a phenyl radical optionally substituted by at least one halogen atom, lower alkyl radi-cal, lower alkoxy radical, nitro group, carboxy group, alkoxycarbonyl radical or cyano group; R' is a hydrogen atom or a lower alkyl radical and n is 0, 1, 2, 3 or 4; as well as the addition salts thereof with mineral and organic acids.
These compounds (I) have platelet anti-aggregant properties and anti-thrombotic properties and are the subject matter of CanO Appl. S.N. 391,052 filed Nov. 27, 1981.
Furthermore, they are included in a general formula given in French Patent Specifications Nos. 2,215,948 and
2,345,150 in the following tautomeric form:
HO ~ ~ (CHR')n-R
in which R, R' and n have the same meanings as above.
However, none of the compounds (I) is specifically described therein.
According to the present invention, there is pro-vided a process for the preparation of compounds of general formula (I), wherein a) a compound of the general formula:
.,~
'7 ,~ ~( CH:E~ ' ) n~ R
~ ~ J (II) S
in which R, R' and n have the same meanings as above, is treated with a solution of hydrogen peroxlde in a mixture of acetic acid and hydrobromic acid to give a bromi.nated derivative of the general formula:
~ ~(CHR')n-R
Br ~ S ~ (III) in which R, R' and _ have the same meanings as above;
b) the brominated derivative (III) is converted into an organo-magnesium compound in an inert anhydrous solvent, this organo-magnesium compound then being condensed with -tert.-butyl perbenzoate to give a compound of the general formula:
_GN / ( ) n (IV) H C CO S
c~3 in which R~ R' and n have the same meanings as above; and c) the compound (IV) is heated to a ternperature of from 80 to 180C. in the presence of a mineral or organic acid to give the desired derivative of general formula (I).
The mixture of acetic acid and hydrobromic acid used in step a) is preferably within the limits of 50/50 to 80/20.
The hydrobromic acid used in step a) is preferably 48~ hydrobromic acid and the acetic acid used is preferably pure.
The hydrogen peroxide solution employed in step a) is preferably an alcoholic solution of hydrogen peroxide, such as a methanolic solution of 30% hydrogen peroxide.
In step b), the inert solvent, such as tetrahydro-furan, may be used not only for the preparation of the organo-magnesium compound but also for the subsequent conden-sation of this organo-magnesium compound with tert.-butyl perbenzoate.
The organo-magnesium compound is prepared in con-ventional manner~ for example with the use of metallic mag-nesium and an alkyl halide, such as isopropyl bromide, in ananhydrous medium.
It is not necessary to isolate the organo-magnesium compound from the reaction mixture prior to condensation thereof with tert.-butyl perbenzoate.
In step c), a mineral or organic acid is added, an example of a preferred acid being _-toluenesulphonic acid.
The process according to the present invention may be represented by the following reaction scheme:
~(cHR')n-R ~(CHR')n-R
J I H2O2/Hsr I N
S ~ E~r S ~`~-~' (II) (III) 1) Mg 3 ~ /(CHR')n-R
6H5COO-t. C4Hg H3C-fo ~S ~
c~3 (IV) The starting materials of general formula (II) may be prepared by means of the processes described in the liter-'7 ature, for example, by means of the processes described in the above~mentioned French Patent Specifications Nos.
73 03 503 and 75 2~ 486.
The following Examples are given for the purpose of illustrating the present lnvention.
5-(2-Chloro ~ )-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-. Formula (I); R = 2-Cl.C6E14; R' - H; _ = l;
Derivative No. l A mixture of 3 cc. 30~ hydrogen peroxide and 10 cc.
methanol is added dropwise to a solution, cooled to 0C., of 2.63 g. 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro(3,2~c)-pyridine in 10 cc. acetic acid and 6 cc. 48~ hydrobromic acid.
When the addition is finished, the reaction mixture is stirred at ambient temperature for lO minutes, then a so-lution of sodium hydrosulphite is added thereto, followed by a solution of sodium carbonate, whereafter the reaction mixture is extracted with a mixture of benzene and chloro-form. The organic extracts are washed with water, dried with anhydrous sodium sulphate and filtered. A solution of gase-ous hydrogen chloride in methanol is added to the filtrate, followed by concentration in a vacuum. Recrystallisation of the solid residue obtained from ethanol gives 2.0 g. of beige crystals in platelet form, this product being 2-bromo-2-(2-chlorobenzyl)-~,5,6,7-te-trahydro-thieno(3,2-c)-pyridine;
m.p. with decomposition at about 180C.
A mixture of 1~075 g. of the free base, 0.19 g.
magnesium, 0.57 g. isopropyl bromide and 10 cc. tetrahydro-furan is heated under reflux for 2 hours under an atmosphere of nitrogen. After cooling, 1.5 g. tert.-butyl perbenzoate is added thereto and the reaction mixture then stirred for 15 hours at ambient temperature and subsequently for 1 hour under reflux. The reaction mixture is poured into an aqueous solution of sodium citrate and sodium carbonate and then ex-tracted with benzene. The organic extracts are washed with water, dried with anhydrous sodium sulphate and concentrated under reduced pressure. The oily residue obtained is puri-fied by chromatography on a column of silica, 0.25 g. of a yellow oil being obtained.
100 mg. of this compound and 100 mg. _-toluene-sulphonic acid are heated to 150C. for 9 minutes. Afterrapid cooling, the reaction mixture is added to a mixture of 10 cc. 0.15M phosphate buffer (pH 5.5) and 20 cc. butanol.
The organic phase is evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column to give 5-(2-chlorobenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-py:ridin-2-one; m.p. 73 - 74.5C. (recrystal-lised from ethanol).
The corresponding oxalate melts at 168 - 170C., after recrystallisation from ethanol; IR (KBr): v CO = 1660 cm~l (large).
The corresponding hydrochloride semihydrate, after precipitation from acetone, melts with decomposition at about The base melts at 73 - 74.5C., after recrystalli-sation from ethanol; NMR (CDC13): 7.1-7.6 (m,4H); 6.2 (s,lH);
4.2-4.7 (m,lH); 3.9 (s,2H); 1.5-4.2 (m,6H).
5-Benzyl-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-p ridin-2-one Formula (I); R = C6H5; R' = H; _ = l; Derivative No. 2 This is prepared according to the method of E~ample 1, starting from 5-benzyl-4,5,6,7-te-trahydro-thieno(3,2-c)-.~
pyridine. Maleate: beige crystals; m.p. 132 - 134Cor re-crysta]lised from isopropanol; IR (KBr): v CO = 1680 cm Base: NMR (CDC13): 7.25 (m,5H); 5.90 (s,lH); 3.60 (s,2H).
5 (4-Chlorobenzyl)~5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one. Formula (I); R = 4-Cl.C H ; R' = H; n = l;
_ _ _ 6 4 Derivative No. 3 This is prepared according to the method of Example 1, starting from 5-(4-chlorobenzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. Maleate: beige crystals; m.p. 158 -160 C., recrystallised from ethanol; IR (KBr): v CO = 1680 cm 1. Base: NMR (CDC13): 7.30 (m,4H); 6.0 (s,lH); 3.50 (s,2~) 5-(2-Methylbenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-.
pyridin-2-one. Formula (I); R = 2-H3C.C6H4; R' = H; _ = l;
Derivative No. 4 This is prepared according to the method of Example 1, starting from 5-(2-methylbenzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. Oxalate: beige crystals, m.p. 195 -197 C., recrystallised from methanol; IR (KBr): v CO = 1690 cm 1. Base~ NMR (CDC13): 7.10 (s,4H); 5.90 (s,l~l); 3.55 (s,2H); 2.30 (s,3H).
5~ ~-(2-Chlorophenyl)-ethy ~-5,6,7,7a-tetrahydro-~H-thieno-(3,2-c)-pyridin-2-one. Formula (I); R = 2-Cl.C6H4; R' = CH3;
. . .
n = l; Derivative No. 5 This is prepared according to the method of Example 1, starting from 5- ~-(2-chlorophenyl ~-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. ~Iydrochloride: yellow crystals;
m.p. 140 - 142 C.; IR (KBr): v CO = 1690 cm . Base: NMR
(CDC13): 7.30 (m,4H); 6.05 and 5.95 (2s,1H); two diastereo-'7 isomers.
EXA~PLE 6 5- ~-(2-Chloxophenyl)-pro~y ~-5,6,7,7~-tetrahydro(3,2-c)-. . _ . . _ . ,. . ~
pyridin-2-one. Formula (I); R = 2 Cl-C6H4; R' -- C2H5; n = l;
Derivative No. 6 This is prepared according to the method of Example 1, starting from 5- ~-(2-chlorophenyl ~-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. Hydrochloride: beige crystals; m.p.
124 - 126 C.; IR (KBr): v CO = 1690 cm l Base: NMR (CDC13):
7.30 (m,4H); 6.05 and 5.90 (2s,lH); two diastereoisomers.
5-(2-Cyanobenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-. ~
pyridin-?-one. Formula (I); R = 2-CN.C6H4; R' = H; n = l;
Derivative No. 7 This is prepared according to the method of Example 1, starting from 5-(2-cyanobenzyl)-4,5,6,7-tetrahydro-thieno-(3,2-c)-pyridine. Oxalate: beige crystals; m.p. 176 - 178C.
(recrystallised from acetonitrile); IR (KBr): v CO = 1700 cm ; v CN = 2210 cm l Base: N~R (CDC13): 7.50 (m,4H); 6.00 (s,lH); 3.80 (s,2H).
5-(2-Nitrobenzyl)-5,6,7,7a--tetrahydro-4H-thieno~3,2-c)-pyridin-2-one. Formula (I); R = 2-O2N.C6H4; R' = H; _ = l;
Derivative No. 8 This is prepared according to the me-thod of Example l, starting from 5-(2-nitrobenzyl)-4,5,6,7-tetrahydro-thieno-(3,2-c)-pyridine. Oxalate: beige crys-tals; m.p. 186 - 188C., recrystallised from isopropanol-ethanol. Base: NMR (CDC13):
7.50 (m,4H); 5.95 (s,lH); 3.90 (s,2H).
5-(2-Bromobenzyl)-5,6,7,7a-tetrahydro-4H~-thieno(3,2-c)-pyridin-2-one. Formula (I); R - 2-Br.C6H4; R' = H; n = 1;
Derivative No. 9 l l 7 This is prepared according to the method of Example 1, starting from 5-(2-bromobenzyl)-4,5,6,7-tetrahydro thieno-(3,2-c)-pyridine. Oxalate: beige crystals; m.p. 151 - 153C., recrystallised from isopropanol; IR (KBr): v CO = 1690 cm Base (CDC13): 7.30 (m,4H); 5.95 (s,lH); 3.75 (s,2H).
The proton ~MR spectra were obtained with the use of a Hitachi-Perkin~Elmer R-24A apparatus, the chemical dis-placements being expressed in ppm with reference to TMS as internal reference.
HO ~ ~ (CHR')n-R
in which R, R' and n have the same meanings as above.
However, none of the compounds (I) is specifically described therein.
According to the present invention, there is pro-vided a process for the preparation of compounds of general formula (I), wherein a) a compound of the general formula:
.,~
'7 ,~ ~( CH:E~ ' ) n~ R
~ ~ J (II) S
in which R, R' and n have the same meanings as above, is treated with a solution of hydrogen peroxlde in a mixture of acetic acid and hydrobromic acid to give a bromi.nated derivative of the general formula:
~ ~(CHR')n-R
Br ~ S ~ (III) in which R, R' and _ have the same meanings as above;
b) the brominated derivative (III) is converted into an organo-magnesium compound in an inert anhydrous solvent, this organo-magnesium compound then being condensed with -tert.-butyl perbenzoate to give a compound of the general formula:
_GN / ( ) n (IV) H C CO S
c~3 in which R~ R' and n have the same meanings as above; and c) the compound (IV) is heated to a ternperature of from 80 to 180C. in the presence of a mineral or organic acid to give the desired derivative of general formula (I).
The mixture of acetic acid and hydrobromic acid used in step a) is preferably within the limits of 50/50 to 80/20.
The hydrobromic acid used in step a) is preferably 48~ hydrobromic acid and the acetic acid used is preferably pure.
The hydrogen peroxide solution employed in step a) is preferably an alcoholic solution of hydrogen peroxide, such as a methanolic solution of 30% hydrogen peroxide.
In step b), the inert solvent, such as tetrahydro-furan, may be used not only for the preparation of the organo-magnesium compound but also for the subsequent conden-sation of this organo-magnesium compound with tert.-butyl perbenzoate.
The organo-magnesium compound is prepared in con-ventional manner~ for example with the use of metallic mag-nesium and an alkyl halide, such as isopropyl bromide, in ananhydrous medium.
It is not necessary to isolate the organo-magnesium compound from the reaction mixture prior to condensation thereof with tert.-butyl perbenzoate.
In step c), a mineral or organic acid is added, an example of a preferred acid being _-toluenesulphonic acid.
The process according to the present invention may be represented by the following reaction scheme:
~(cHR')n-R ~(CHR')n-R
J I H2O2/Hsr I N
S ~ E~r S ~`~-~' (II) (III) 1) Mg 3 ~ /(CHR')n-R
6H5COO-t. C4Hg H3C-fo ~S ~
c~3 (IV) The starting materials of general formula (II) may be prepared by means of the processes described in the liter-'7 ature, for example, by means of the processes described in the above~mentioned French Patent Specifications Nos.
73 03 503 and 75 2~ 486.
The following Examples are given for the purpose of illustrating the present lnvention.
5-(2-Chloro ~ )-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-. Formula (I); R = 2-Cl.C6E14; R' - H; _ = l;
Derivative No. l A mixture of 3 cc. 30~ hydrogen peroxide and 10 cc.
methanol is added dropwise to a solution, cooled to 0C., of 2.63 g. 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro(3,2~c)-pyridine in 10 cc. acetic acid and 6 cc. 48~ hydrobromic acid.
When the addition is finished, the reaction mixture is stirred at ambient temperature for lO minutes, then a so-lution of sodium hydrosulphite is added thereto, followed by a solution of sodium carbonate, whereafter the reaction mixture is extracted with a mixture of benzene and chloro-form. The organic extracts are washed with water, dried with anhydrous sodium sulphate and filtered. A solution of gase-ous hydrogen chloride in methanol is added to the filtrate, followed by concentration in a vacuum. Recrystallisation of the solid residue obtained from ethanol gives 2.0 g. of beige crystals in platelet form, this product being 2-bromo-2-(2-chlorobenzyl)-~,5,6,7-te-trahydro-thieno(3,2-c)-pyridine;
m.p. with decomposition at about 180C.
A mixture of 1~075 g. of the free base, 0.19 g.
magnesium, 0.57 g. isopropyl bromide and 10 cc. tetrahydro-furan is heated under reflux for 2 hours under an atmosphere of nitrogen. After cooling, 1.5 g. tert.-butyl perbenzoate is added thereto and the reaction mixture then stirred for 15 hours at ambient temperature and subsequently for 1 hour under reflux. The reaction mixture is poured into an aqueous solution of sodium citrate and sodium carbonate and then ex-tracted with benzene. The organic extracts are washed with water, dried with anhydrous sodium sulphate and concentrated under reduced pressure. The oily residue obtained is puri-fied by chromatography on a column of silica, 0.25 g. of a yellow oil being obtained.
100 mg. of this compound and 100 mg. _-toluene-sulphonic acid are heated to 150C. for 9 minutes. Afterrapid cooling, the reaction mixture is added to a mixture of 10 cc. 0.15M phosphate buffer (pH 5.5) and 20 cc. butanol.
The organic phase is evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column to give 5-(2-chlorobenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-py:ridin-2-one; m.p. 73 - 74.5C. (recrystal-lised from ethanol).
The corresponding oxalate melts at 168 - 170C., after recrystallisation from ethanol; IR (KBr): v CO = 1660 cm~l (large).
The corresponding hydrochloride semihydrate, after precipitation from acetone, melts with decomposition at about The base melts at 73 - 74.5C., after recrystalli-sation from ethanol; NMR (CDC13): 7.1-7.6 (m,4H); 6.2 (s,lH);
4.2-4.7 (m,lH); 3.9 (s,2H); 1.5-4.2 (m,6H).
5-Benzyl-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-p ridin-2-one Formula (I); R = C6H5; R' = H; _ = l; Derivative No. 2 This is prepared according to the method of E~ample 1, starting from 5-benzyl-4,5,6,7-te-trahydro-thieno(3,2-c)-.~
pyridine. Maleate: beige crystals; m.p. 132 - 134Cor re-crysta]lised from isopropanol; IR (KBr): v CO = 1680 cm Base: NMR (CDC13): 7.25 (m,5H); 5.90 (s,lH); 3.60 (s,2H).
5 (4-Chlorobenzyl)~5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one. Formula (I); R = 4-Cl.C H ; R' = H; n = l;
_ _ _ 6 4 Derivative No. 3 This is prepared according to the method of Example 1, starting from 5-(4-chlorobenzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. Maleate: beige crystals; m.p. 158 -160 C., recrystallised from ethanol; IR (KBr): v CO = 1680 cm 1. Base: NMR (CDC13): 7.30 (m,4H); 6.0 (s,lH); 3.50 (s,2~) 5-(2-Methylbenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-.
pyridin-2-one. Formula (I); R = 2-H3C.C6H4; R' = H; _ = l;
Derivative No. 4 This is prepared according to the method of Example 1, starting from 5-(2-methylbenzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. Oxalate: beige crystals, m.p. 195 -197 C., recrystallised from methanol; IR (KBr): v CO = 1690 cm 1. Base~ NMR (CDC13): 7.10 (s,4H); 5.90 (s,l~l); 3.55 (s,2H); 2.30 (s,3H).
5~ ~-(2-Chlorophenyl)-ethy ~-5,6,7,7a-tetrahydro-~H-thieno-(3,2-c)-pyridin-2-one. Formula (I); R = 2-Cl.C6H4; R' = CH3;
. . .
n = l; Derivative No. 5 This is prepared according to the method of Example 1, starting from 5- ~-(2-chlorophenyl ~-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. ~Iydrochloride: yellow crystals;
m.p. 140 - 142 C.; IR (KBr): v CO = 1690 cm . Base: NMR
(CDC13): 7.30 (m,4H); 6.05 and 5.95 (2s,1H); two diastereo-'7 isomers.
EXA~PLE 6 5- ~-(2-Chloxophenyl)-pro~y ~-5,6,7,7~-tetrahydro(3,2-c)-. . _ . . _ . ,. . ~
pyridin-2-one. Formula (I); R = 2 Cl-C6H4; R' -- C2H5; n = l;
Derivative No. 6 This is prepared according to the method of Example 1, starting from 5- ~-(2-chlorophenyl ~-4,5,6,7-tetrahydro-thieno(3,2-c)-pyridine. Hydrochloride: beige crystals; m.p.
124 - 126 C.; IR (KBr): v CO = 1690 cm l Base: NMR (CDC13):
7.30 (m,4H); 6.05 and 5.90 (2s,lH); two diastereoisomers.
5-(2-Cyanobenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-. ~
pyridin-?-one. Formula (I); R = 2-CN.C6H4; R' = H; n = l;
Derivative No. 7 This is prepared according to the method of Example 1, starting from 5-(2-cyanobenzyl)-4,5,6,7-tetrahydro-thieno-(3,2-c)-pyridine. Oxalate: beige crystals; m.p. 176 - 178C.
(recrystallised from acetonitrile); IR (KBr): v CO = 1700 cm ; v CN = 2210 cm l Base: N~R (CDC13): 7.50 (m,4H); 6.00 (s,lH); 3.80 (s,2H).
5-(2-Nitrobenzyl)-5,6,7,7a--tetrahydro-4H-thieno~3,2-c)-pyridin-2-one. Formula (I); R = 2-O2N.C6H4; R' = H; _ = l;
Derivative No. 8 This is prepared according to the me-thod of Example l, starting from 5-(2-nitrobenzyl)-4,5,6,7-tetrahydro-thieno-(3,2-c)-pyridine. Oxalate: beige crys-tals; m.p. 186 - 188C., recrystallised from isopropanol-ethanol. Base: NMR (CDC13):
7.50 (m,4H); 5.95 (s,lH); 3.90 (s,2H).
5-(2-Bromobenzyl)-5,6,7,7a-tetrahydro-4H~-thieno(3,2-c)-pyridin-2-one. Formula (I); R - 2-Br.C6H4; R' = H; n = 1;
Derivative No. 9 l l 7 This is prepared according to the method of Example 1, starting from 5-(2-bromobenzyl)-4,5,6,7-tetrahydro thieno-(3,2-c)-pyridine. Oxalate: beige crystals; m.p. 151 - 153C., recrystallised from isopropanol; IR (KBr): v CO = 1690 cm Base (CDC13): 7.30 (m,4H); 5.95 (s,lH); 3.75 (s,2H).
The proton ~MR spectra were obtained with the use of a Hitachi-Perkin~Elmer R-24A apparatus, the chemical dis-placements being expressed in ppm with reference to TMS as internal reference.
Claims (15)
1. Process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)pyridin-2-one derivatives of the general formula:- (I) in which R is hydrogen or phenyl substituted by at least one halogen, lower alkyl, lower alkoxy, nitro, carboxy, alkoxycar-bonyl or cyano; R' is hydrogen or lower alkyl; and n is 0, 1, 2, 3 or 4, and of their acid addition salts with mineral and organic acids, wherein a) a compound of the general formula:- (II) in which R, R' and n have the same meanings as above, is treated with a solution of hydrogen peroxide in a mixture of acetic acid and hydrobromic acid to give a brominated deriva-tive of the general formula:- (III) in which R, R' and n have the same meanings as above; b) the brominated derivative (III) is converted into an organo-magnesium compound in an inert anhydrous solvent, this organo-magnesium compound then being condensed with tert.-butyl perbenzoate to give a compound of the general formula:- (IV) in which R, R' and n have the same meanings as above; and c) the compound (IV) is heated to a temperature of from 80°
to 180°C. in the presence of a mineral or organic acid to give the desired derivative of general formula (I).
to 180°C. in the presence of a mineral or organic acid to give the desired derivative of general formula (I).
2. Process according to claim 1, wherein the hydrogen peroxide solution used in step a) is an alcoholic solution of hydrogen peroxide.
3. Process according to claim 2, wherein the alcoholic solution of hydrogen peroxide is a methanolic solution of 30% hydrogen peroxide.
4. Process according to claim 1 wherein the mixture of acetic acid and hydrobromic acid used in step a) contains the two acids in a ratio of from 50/50 to 80/20.
5. Process according to claim 1 wherein the acetic acid used is pure acetic acid.
6. Process according to claim 1, wherein the hydrobromic acid used is 48% acid.
7. Process according to claim 1 wherein the organo-magnesium compound prepared in step b) is obtained by reacting the brominated derivative (III) with metallic magnesium and an alkyl halide.
8. Process according to claim 7, wherein the alkyl halide used is isopropyl bromide.
9. Process according to claim 1, wherein the inert solvent used in step b) is anhydrous tetrahydrofuran.
10. Process according to claim 1, wherein the condensation reaction with tert.-butyl perbenzoate in step b) is carried out in the same reaction medium as that used for the prepa-ration of the organo-magnesium compound without isolation thereof.
11. Process according to claim 1, wherein the acid used in step e) is p-toluenesulphonic acid.
12. Derivatives of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one of claim 1, when prepared by the process ac-cording to claims 1, 2 and 3.
13. Derivatives of 5,6,7,7a tetrahydro-4H-thieno(3,2-c)-pyridin-2-one of claim 1, when prepared by the process ac-cording to claims 4, 5 and 6.
14. Derivatives of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one of claim 1, when prepared by the process ac-cording to claims 7, 8 and 9.
15. Derivatives of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-2-one of claim 1, when prepared by the process ac-cording to claims 10 and 11.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8025276A FR2495158A1 (en) | 1980-11-28 | 1980-11-28 | NEW PROCESS FOR THE PREPARATION OF TETRAHYDRO-5,6,7,7A 4H-THIENO (3,2-C) PYRIDINONE-2 DERIVATIVES |
| FR8025276 | 1980-11-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1182117A true CA1182117A (en) | 1985-02-05 |
Family
ID=9248450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000391073A Expired CA1182117A (en) | 1980-11-28 | 1981-11-27 | Process for making 5,6,7,7a-tetrahydro-4h- thieno- [)3,2,-c]pyridin-2-one |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0053950A1 (en) |
| AR (1) | AR227565A1 (en) |
| AU (1) | AU7743081A (en) |
| BG (1) | BG36937A3 (en) |
| CA (1) | CA1182117A (en) |
| CS (1) | CS227020B2 (en) |
| DD (1) | DD202162A5 (en) |
| DK (1) | DK480781A (en) |
| ES (1) | ES8207179A1 (en) |
| FI (1) | FI813729L (en) |
| FR (1) | FR2495158A1 (en) |
| GR (1) | GR78023B (en) |
| HU (1) | HU185069B (en) |
| IL (1) | IL64147A (en) |
| IN (1) | IN155640B (en) |
| MA (1) | MA19333A1 (en) |
| NO (1) | NO814057L (en) |
| NZ (1) | NZ199022A (en) |
| OA (1) | OA06953A (en) |
| PL (1) | PL127917B1 (en) |
| PT (1) | PT73990B (en) |
| SU (1) | SU1145931A3 (en) |
| TR (1) | TR21319A (en) |
| YU (1) | YU279181A (en) |
| ZA (1) | ZA817875B (en) |
| ZW (1) | ZW27381A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2508459A1 (en) * | 1981-06-30 | 1982-12-31 | Sanofi Sa | PROCESS FOR THE PREPARATION OF TETRAHYDRO-5,6,7,7A 4H THIENO (3,2-C) PYRIDINONE-2 DERIVATIVES |
| WO1996011203A1 (en) * | 1994-10-07 | 1996-04-18 | Ube Industries, Ltd. | 2-silyloxytetrahydrothienopyridine, salt thereof, and process for producing the same |
| RU2526624C2 (en) * | 2010-05-13 | 2014-08-27 | Таньцзинь Инститьют Оф Фармасьютикал Рисёрч | Thienopyridine ester derivative, containing cyanogroup, method of its obtaining, its application and based on it composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2215948B1 (en) * | 1973-02-01 | 1976-05-14 | Centre Etd Ind Pharma |
-
1980
- 1980-11-28 FR FR8025276A patent/FR2495158A1/en active Granted
-
1981
- 1981-10-16 EP EP81401625A patent/EP0053950A1/en not_active Withdrawn
- 1981-10-28 IL IL64147A patent/IL64147A/en unknown
- 1981-10-30 DK DK480781A patent/DK480781A/en not_active Application Discontinuation
- 1981-11-06 IN IN1236/CAL/81A patent/IN155640B/en unknown
- 1981-11-11 ZW ZW273/81A patent/ZW27381A1/en unknown
- 1981-11-12 AU AU77430/81A patent/AU7743081A/en not_active Abandoned
- 1981-11-13 ZA ZA817875A patent/ZA817875B/en unknown
- 1981-11-13 PT PT73990A patent/PT73990B/en unknown
- 1981-11-13 MA MA19537A patent/MA19333A1/en unknown
- 1981-11-14 OA OA57549A patent/OA06953A/en unknown
- 1981-11-16 ES ES507704A patent/ES8207179A1/en not_active Expired
- 1981-11-17 GR GR66545A patent/GR78023B/el unknown
- 1981-11-17 BG BG8154189A patent/BG36937A3/en unknown
- 1981-11-18 AR AR287459A patent/AR227565A1/en active
- 1981-11-20 NZ NZ199022A patent/NZ199022A/en unknown
- 1981-11-23 FI FI813729A patent/FI813729L/en not_active Application Discontinuation
- 1981-11-24 TR TR21319A patent/TR21319A/en unknown
- 1981-11-25 CS CS818685A patent/CS227020B2/en unknown
- 1981-11-26 PL PL1981233980A patent/PL127917B1/en unknown
- 1981-11-27 HU HU813560A patent/HU185069B/en unknown
- 1981-11-27 SU SU813357199A patent/SU1145931A3/en active
- 1981-11-27 CA CA000391073A patent/CA1182117A/en not_active Expired
- 1981-11-27 YU YU02791/81A patent/YU279181A/en unknown
- 1981-11-27 NO NO814057A patent/NO814057L/en unknown
- 1981-11-27 DD DD81235204A patent/DD202162A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU185069B (en) | 1984-11-28 |
| ES507704A0 (en) | 1982-09-01 |
| ES8207179A1 (en) | 1982-09-01 |
| IL64147A0 (en) | 1982-01-31 |
| ZW27381A1 (en) | 1982-04-28 |
| IL64147A (en) | 1984-12-31 |
| CS227020B2 (en) | 1984-04-16 |
| SU1145931A3 (en) | 1985-03-15 |
| PT73990A (en) | 1981-12-01 |
| FR2495158B1 (en) | 1983-07-22 |
| NZ199022A (en) | 1984-03-30 |
| AU7743081A (en) | 1982-06-03 |
| DD202162A5 (en) | 1983-08-31 |
| FR2495158A1 (en) | 1982-06-04 |
| PT73990B (en) | 1983-04-14 |
| MA19333A1 (en) | 1982-07-01 |
| YU279181A (en) | 1984-02-29 |
| PL233980A1 (en) | 1982-08-02 |
| AR227565A1 (en) | 1982-11-15 |
| ZA817875B (en) | 1982-10-27 |
| PL127917B1 (en) | 1983-12-31 |
| DK480781A (en) | 1982-05-29 |
| OA06953A (en) | 1983-07-31 |
| IN155640B (en) | 1985-02-16 |
| FI813729L (en) | 1982-05-29 |
| GR78023B (en) | 1984-09-26 |
| NO814057L (en) | 1982-06-01 |
| BG36937A3 (en) | 1985-02-15 |
| EP0053950A1 (en) | 1982-06-16 |
| TR21319A (en) | 1984-03-01 |
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