CA2250747A1 - Propagylglycine derivatives, preparation and utilisation thereof as synthesis intermediates - Google Patents
Propagylglycine derivatives, preparation and utilisation thereof as synthesis intermediates Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
Compounds of formula (I) wherein R2 is -CH2CCH or -CH2CC-Het where Het is a 2-aminopyridyl, 2-aminopyrimidyl, 6-aminopyridazinyl, imidazol-4-yl group, R3 and R4 each represent hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, ArCH2CO2-or ArSO2- where Ar is an aryl group, or a group (a) where R7 is hydrogen or -COR, R being straight or branched (C1-C7) alkyl, -(CH2)nOCH3 or -CH2O(C2H4O)nCH3 (n is 1, 2 or 3) and A is chosen among the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups, R6 represents either a straight or branched (C1-C4) alkoxy group, or a benzyloxy group or a group (b) where R12 is a hydrogen atom or a carboxylic or (C1-C4)alkoxycarbonyl group and R13 is a straight or branched (C1-C4)alkyl group. They constitute synthesis intermediates.
Description
CA 022~0747 1998-09-30 Proparq~lqlYcine derivatives, preparation thereof and use thereof as synthetic intermediates The subject-matter of the present invention is propargylglycine derivatives, the preparation thereof and the use thereof as synthetic intermediates.
The compounds of the invention correspond to the formula (I) ~5 O
R2 ,~I'R6 (~) R,N~R
in which R2 represents a -CH2C-C-Het group, where Het is a 2-aminopyridyl, 2-aminopyrimidyl or 6-aminopyridazinyl group (it being possible for the said heterocycles optionally to be substituted on the other positions by a straight or branched (C -C~)alkyl group) or an imidazol-4-yl group optionally substituted in the 2 and/or 5 position by (C;-C~)alkyl groups and in the 1 or 3 position by a protective group, such as, for example, a trityl, benzenesulphonyl, toluenesulphonyl or dimethylaminosulphonyl group, ~.. and R each represent, independent y of one another, either a hydrogen atom or a ~C1-C~)aikyl group or a ~C1-C)alkoxycarbonyl group or an ArCH CO - group or an ArSOi- group, where Ar is an aryl grol~p, in particular a A~-~n SEEET
CA 022~0747 1998-09-30 3-methylquinol-8-yl or 3-methyl-1,2,3,4-tetrahydroquinol-8-yl group, or Ar is a group ~,~N ~ with R7 chosen from the hydrogen atom and the -COR group, R being a straight or branched (C1-C7)alkyl, -(CH2)nOCH3 or -CH20(C2H40)nCH3 group (n is equal to 1, 2 or 3), and A chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, formyl, -CH20R1o, -cH20cORlo/ -cH20cONRloRll~ -COORlo/
-CONRloR1l/ nitro, -NR1oR11l -NHCORlo or -NH(CH2)MORlo groups, R1o and R11 each being, independently of one another, a hydrogen atom or a straight or branched (C1-C4)alkyl group and m = 0 to 6) and the cyclo(C5-C8)alkyl group, Rs represents either a hydrogen atom or a straight or branched (C1-C4)alkyl group or a (C1-C4)alkoxycarbonyl group or an aryl group or an aryl (Cl-C4)alkyl group, R6 represents either a straight or branched (Cl-C4)alkoxy group or a benzyloxy group or a group F~ , where Rl2 is a hydrogen atom or a carboxyl or (Cl-C,)alkoxycarbonyl group and Rl, is a straight or branched (Cl-C,)alkyl group.
Depending on the definitions of the various substituents, the compounds of the invention possess up to 3 asymmetric centres.
When R6 represents a group - N ~ ~, the preferred configuration is [2R, 4R].
The compounds of the invention can exist in the form of racemates, of enantiomers or of mixtures of these various forms. All these forms form part of the invention.
According to the invention, the compounds of formula (I) can be prepared according to Scheme 1.
Scheme 1 Rs O
HC~
R~ R, ~ R~
Het-X ~ ~ct R~ R~
tII) (I) A compound of formula (II), in which Het is as defined above and X represents a halogen atom, is reacted with a compound of formula (III), in which R3, CA 022~0747 1998-09-30 R" Rs and R6 are as defined above, in the presence of a base, such as piperidine, diethylamine, triethylamine, triphenylphosphine, tri-o-tolylphosphine or trifurylphosphine, and of a palladium-based catalyst, such as, for example, palladium chloride, palladium acetate, palladium bis(dibenzylideneacetone) or tetrakis(triphenylphosphine)palladium/cuprous iodide, dichlorobis(triphenylphosphine)palladium/cuprous iodide or tetra(triphenylphosphine)palladium/cuprous iodide complexes.
The compounds of formula (III) in which R6 represents a group , where Rl2 is a carboxyl or (C~-C~)alkoxycarbonyl group and Rl3 is a straight or branched (Cl-C4)alkyl group, R3 represents either a hydrogen atom or a (Cl-C4)alkyl group or a (Cl-Cs)alkoxycarbonyl group or an ArCH2CO2- group or an ArSO2- group, where Ar is as defined above, and R4 represents either an ArCH2CO~~ group or an ArSO,- group, where Ar is as defined above, a.e novel and form part of the invention.
The starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to a person skilled in the art.
CA 022~0747 1998-09-30 Thus, diethyl 2-(acetylamino)-2-(prop-2-ynyl)propanedioate and ethyl 2-(acetylamino)pent-4-ynoate are prepared according to the method described by O. Leukart et al., Helv. Chim. Acta., (1976), S9, 2181.
The preparation of 8-(chlorosulphonyl)-3-methylquinoline is disclosed in Japanese Patent JP 59184161.
8-(Chlorosulphonyl)-3-methyl-1,2,3,4-tetrahydroc~uinoline can be prepared from 8-(chlorosulphonyl)-3-methylquinoline according to the method disclosed in European Patent Application EP 0,565,396.
The introduction of the heterocyclic groups onto the compounds of formula (III) was carried out by a coupling reaction of Heck type under conditions analogous to those described by Crips et al. in Tetrahedron, (1990), 48, No. 15, 3239-3250.
4-Iodo-1-(triphenylmethyl)-lH-imidazole is prepared according to the method described by K. L. Kirk, J.
Heterocycl. Chem. (1985), 22, 57.
Tne following examples illustra.e the preparation of some compounds in accordance with the invention.
The microanalyses and the IR and NMR spec,ra confirm the structures of the compounds obtained.
The numbers of the compounds given as ex~mples refer to those in the Table given later, in which the chemical CA 022~0747 1998-09-30 structures and the physical properties of some compounds according to the invention are illustrated.
Example 1 (Compound 1~
Diethyl 2-(acetylamino)-2-[3-[1-[(dimethylamino)sulphonyl]-5-methyl-lH-imidazol-4-yl]prop-2-ynyl]propanedioate 1.1. 4-Iodo-N,N,5-trimethyl-1~-imidazole-1-sulphonamide 1.1.1. 4-Iodo-5-methyl-lH-imidazole 1.5 kg (18.27 mol) of 4(5)-methyl-lH-imidazole, 3.28 kg (19.75 mol) of potassium iodide and lS l of water are introduced into a 25 1 reactor under a nitrogen atmosphere. The solution is cooled to -5~C and 9 l (19.3 mol) of 48~ bleach are added at this temperature.
The reaction mixture is allowed to return to room temperature over 18 hours. The solid is drained off and taken up in 10 l of water. Acidification is carried out to pH 1 with a 12N hydrochloric acid solution.
Neutralization is carried out to pH 7-8 by addition of a lON sodium hydroxide solution. The product is filtered off, washed with water and d_ied in a ventilated oven.
2775 g of product are obtained in the form of a white solid.
Melting point = 169-170~C.
CA 022~0747 1998-09-30 1.1.2. 4-Iodo-N,N,S-trimethyl-lH-imidazole-1-sulphonamide 3.4 g (70 mmol) of 50% sodium hydride and 30 ml of dimethylformamide are introduced into a 250 ml three-necked flask under a nitrogen atmosphere. A solution of13 g (62.3 mmol) of 4-iodo-5-methyl-lH-imidazole in 95 ml of dimethylformamide is added to this mixture at 10~C. After 15 minutes, N,N-dimethylsulphamoyl chloride is slowly added and the mixture is stirred for 1 hour at room temperature. The mixture is evaporated to dryness and the residue is taken up in 100 ml of water.
The product is filtered off and washed with water and then with hexane. It is dried in an oven under vacuum.
17.40 g of product are obtained in the form of a beige solid.
Melting point = 107-109~C.
1.2. Diethyl 2-(acetylamino)-2-[3-[1-[(dimethylamino)sulphonyl]-5-methyl-lH-imidazol-4-yl]prop-2-ynyl]propanedioate 4.50 g (14.3 mmol) of 4-iodo-.~,N,5-trimethyl-lH-imidazole-1-sulphonamide, 4.5 g (17.6 mmol) of diethyl 2-(acetylamino)-2-(prop-2-ynyl)propanedioate and 75 ml of diethylamine are introduced into a 250 ml round-bottomed flask under a nitrogen atmosphere. 105 mg (0.14 mmol) of dichlorobis(.ri?henylphosphine)palladium and 50 mg (0.25 mmol) of copper iodide are added to this solution and heating is carried out at reflux for CA 022~0747 1998-09-30 1.25 hours. The solvent is evaporated and then the residue is taken up in 50 ml of ethyl acetate and washed with 20 ml of an ammonium chloride solution. It is dried over magnesium sulphate and evaporated to dryness.
5.1 g of product are obtained in the form of beige crystals.
Melting point = 156-158~C.
Example 2 (Compound 6) -Ethyl 2-tacetylamino)-5-[5-methyl-1-[(4-~methylphenyl)sulphonyl]-lH-imidazol-4-yl]pent-4-ynoate 2.1. 4-Iodo-S-methyl-1-[(4-methylphenyl)sulphonyl]-1~-imidazole 2.5 g (52 mmol) of 50% sodium hydride in oil and 30 ml of dimethylformamide are introàuced into a 250 ml three-necked round-bottomed flask under a nitrogen atmosphere. A solution of 10 g (48 mmol) of 4-iodo-5-methyl-lH-imidazole is added to this mixture at 0~C.
After 30 minutes, 10.4 g (54 mmol) of (4- --methylphenyl)sulphonyl chloride are aaded portionwisewhile maintaining the temperature below 10~C. After returning to room temperature, the mixture is stirred for 1 hour and is poured onto 150 ml of ice. Tne product is filtered off, washed with ~ate, and tnen with hexane and dried in an oven under vacuum.
15.76 g of product are obtained in the form of a white CA 022~0747 1998-09-30 solid.
Melting point = 145-146~C.
2.2. Ethyl 2-(acetylamino)-5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]pent-4-ynoate 1.5 g (4.1 mmol) of 4-iodo-5-methyl-1-[(4-methylphenyl)sulphonyl]-1~-imidazole, 830 mg (4.3 mmol) of ethyl 2-(acetylamino)pent-4-ynoate and 20 ml of diethylamine are introduced into a 100 ml round-bottomed flask under a nitrogen atmosphere. 43 mg (O.06 mmol) of dichlorobis(triphenylphosphine)palladium and 23 mg (0.12 mmol) of copper iodide are added to this solution. Heating is carried out at reflux for 1 hour, then the mixture is allowed to cool to room temperature and 50 ml of water are added. The product is filtered off, washed with water and dried in an oven under vacuum.
1.3 g of product are obtained in the form of beige crystals.
2û Melting point = 146-148~C.
ExamDle 3 (Compound 8) Methyl 5-[5-methyl-1-[(~-methylphenyl)sulphonyl]-1~-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate CA 022~;0747 1998-09-30 3.1. Methyl (S)-2-l~(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate 3.1.1. (S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]pent-4-S ynoic acid 11.5 g (77 mmol) of (5)-2-aminopent-4-ynoic acid hydrochloride, 100 ml of dioxane, 50 ml of water and 80 ml of 2N sodium hydroxide solution are introduced into a 250 ml round-bottomed flask under a nitrogen 10 atmosphere. 17.9 g (82 mmol) of tert-butyl dicarbonate are added to this solution and the mixture is stirred for 3 hours at room temperature. 200 ml of ethyl acetate are added and acidification is carried out to pH 2 by addition of 2N hydrochloric acid. The phases are separated and the ac~ueous phase is extracted with 50 ml of ethyl acetate. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness.
18.78 g of product are obtained in the form of a colourless oil.
3.1.2. Methyl (5)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate 13 g (0.154 mol) of sodium hydrogencarbonate are added to a solution OL 18.78 g (0.077 mol) of (5)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoic acid in 150 ml of dimethylformamide in a 250 ml round-bottomed CA 022~0747 1998-09-30 flask under a nitrogen atmosphere. 20 ml (0.318 mol) of methyl iodide are added and the mixture is stirred for 18 hours at room temperature. The mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water and is then dried over magnesium sulphate. Evaporation is carried out to dryness.
15.85 g of product are obtained in the form of a yellow oll .
3.1.3. Methyl 2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate 2.15 g (16.9 mmol) of methyl 2-aminopent-4-ynoate, 30 ml of dichloromethane and 3 ml of pyridine are introduced into a 50 ml round-bottomed flask under a nitrogen atmosphere. The solution is cooled to -10~C
znd 4.10 g (16.9 mmol) of 8-(chlorosulphonyl)-3-methylquinoline are added. The mixture is stirred for 1 hour at -10~C and then for 30 minutes at room temperature. The solution is washed with 15 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness.
The compounds of the invention correspond to the formula (I) ~5 O
R2 ,~I'R6 (~) R,N~R
in which R2 represents a -CH2C-C-Het group, where Het is a 2-aminopyridyl, 2-aminopyrimidyl or 6-aminopyridazinyl group (it being possible for the said heterocycles optionally to be substituted on the other positions by a straight or branched (C -C~)alkyl group) or an imidazol-4-yl group optionally substituted in the 2 and/or 5 position by (C;-C~)alkyl groups and in the 1 or 3 position by a protective group, such as, for example, a trityl, benzenesulphonyl, toluenesulphonyl or dimethylaminosulphonyl group, ~.. and R each represent, independent y of one another, either a hydrogen atom or a ~C1-C~)aikyl group or a ~C1-C)alkoxycarbonyl group or an ArCH CO - group or an ArSOi- group, where Ar is an aryl grol~p, in particular a A~-~n SEEET
CA 022~0747 1998-09-30 3-methylquinol-8-yl or 3-methyl-1,2,3,4-tetrahydroquinol-8-yl group, or Ar is a group ~,~N ~ with R7 chosen from the hydrogen atom and the -COR group, R being a straight or branched (C1-C7)alkyl, -(CH2)nOCH3 or -CH20(C2H40)nCH3 group (n is equal to 1, 2 or 3), and A chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, formyl, -CH20R1o, -cH20cORlo/ -cH20cONRloRll~ -COORlo/
-CONRloR1l/ nitro, -NR1oR11l -NHCORlo or -NH(CH2)MORlo groups, R1o and R11 each being, independently of one another, a hydrogen atom or a straight or branched (C1-C4)alkyl group and m = 0 to 6) and the cyclo(C5-C8)alkyl group, Rs represents either a hydrogen atom or a straight or branched (C1-C4)alkyl group or a (C1-C4)alkoxycarbonyl group or an aryl group or an aryl (Cl-C4)alkyl group, R6 represents either a straight or branched (Cl-C4)alkoxy group or a benzyloxy group or a group F~ , where Rl2 is a hydrogen atom or a carboxyl or (Cl-C,)alkoxycarbonyl group and Rl, is a straight or branched (Cl-C,)alkyl group.
Depending on the definitions of the various substituents, the compounds of the invention possess up to 3 asymmetric centres.
When R6 represents a group - N ~ ~, the preferred configuration is [2R, 4R].
The compounds of the invention can exist in the form of racemates, of enantiomers or of mixtures of these various forms. All these forms form part of the invention.
According to the invention, the compounds of formula (I) can be prepared according to Scheme 1.
Scheme 1 Rs O
HC~
R~ R, ~ R~
Het-X ~ ~ct R~ R~
tII) (I) A compound of formula (II), in which Het is as defined above and X represents a halogen atom, is reacted with a compound of formula (III), in which R3, CA 022~0747 1998-09-30 R" Rs and R6 are as defined above, in the presence of a base, such as piperidine, diethylamine, triethylamine, triphenylphosphine, tri-o-tolylphosphine or trifurylphosphine, and of a palladium-based catalyst, such as, for example, palladium chloride, palladium acetate, palladium bis(dibenzylideneacetone) or tetrakis(triphenylphosphine)palladium/cuprous iodide, dichlorobis(triphenylphosphine)palladium/cuprous iodide or tetra(triphenylphosphine)palladium/cuprous iodide complexes.
The compounds of formula (III) in which R6 represents a group , where Rl2 is a carboxyl or (C~-C~)alkoxycarbonyl group and Rl3 is a straight or branched (Cl-C4)alkyl group, R3 represents either a hydrogen atom or a (Cl-C4)alkyl group or a (Cl-Cs)alkoxycarbonyl group or an ArCH2CO2- group or an ArSO2- group, where Ar is as defined above, and R4 represents either an ArCH2CO~~ group or an ArSO,- group, where Ar is as defined above, a.e novel and form part of the invention.
The starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to a person skilled in the art.
CA 022~0747 1998-09-30 Thus, diethyl 2-(acetylamino)-2-(prop-2-ynyl)propanedioate and ethyl 2-(acetylamino)pent-4-ynoate are prepared according to the method described by O. Leukart et al., Helv. Chim. Acta., (1976), S9, 2181.
The preparation of 8-(chlorosulphonyl)-3-methylquinoline is disclosed in Japanese Patent JP 59184161.
8-(Chlorosulphonyl)-3-methyl-1,2,3,4-tetrahydroc~uinoline can be prepared from 8-(chlorosulphonyl)-3-methylquinoline according to the method disclosed in European Patent Application EP 0,565,396.
The introduction of the heterocyclic groups onto the compounds of formula (III) was carried out by a coupling reaction of Heck type under conditions analogous to those described by Crips et al. in Tetrahedron, (1990), 48, No. 15, 3239-3250.
4-Iodo-1-(triphenylmethyl)-lH-imidazole is prepared according to the method described by K. L. Kirk, J.
Heterocycl. Chem. (1985), 22, 57.
Tne following examples illustra.e the preparation of some compounds in accordance with the invention.
The microanalyses and the IR and NMR spec,ra confirm the structures of the compounds obtained.
The numbers of the compounds given as ex~mples refer to those in the Table given later, in which the chemical CA 022~0747 1998-09-30 structures and the physical properties of some compounds according to the invention are illustrated.
Example 1 (Compound 1~
Diethyl 2-(acetylamino)-2-[3-[1-[(dimethylamino)sulphonyl]-5-methyl-lH-imidazol-4-yl]prop-2-ynyl]propanedioate 1.1. 4-Iodo-N,N,5-trimethyl-1~-imidazole-1-sulphonamide 1.1.1. 4-Iodo-5-methyl-lH-imidazole 1.5 kg (18.27 mol) of 4(5)-methyl-lH-imidazole, 3.28 kg (19.75 mol) of potassium iodide and lS l of water are introduced into a 25 1 reactor under a nitrogen atmosphere. The solution is cooled to -5~C and 9 l (19.3 mol) of 48~ bleach are added at this temperature.
The reaction mixture is allowed to return to room temperature over 18 hours. The solid is drained off and taken up in 10 l of water. Acidification is carried out to pH 1 with a 12N hydrochloric acid solution.
Neutralization is carried out to pH 7-8 by addition of a lON sodium hydroxide solution. The product is filtered off, washed with water and d_ied in a ventilated oven.
2775 g of product are obtained in the form of a white solid.
Melting point = 169-170~C.
CA 022~0747 1998-09-30 1.1.2. 4-Iodo-N,N,S-trimethyl-lH-imidazole-1-sulphonamide 3.4 g (70 mmol) of 50% sodium hydride and 30 ml of dimethylformamide are introduced into a 250 ml three-necked flask under a nitrogen atmosphere. A solution of13 g (62.3 mmol) of 4-iodo-5-methyl-lH-imidazole in 95 ml of dimethylformamide is added to this mixture at 10~C. After 15 minutes, N,N-dimethylsulphamoyl chloride is slowly added and the mixture is stirred for 1 hour at room temperature. The mixture is evaporated to dryness and the residue is taken up in 100 ml of water.
The product is filtered off and washed with water and then with hexane. It is dried in an oven under vacuum.
17.40 g of product are obtained in the form of a beige solid.
Melting point = 107-109~C.
1.2. Diethyl 2-(acetylamino)-2-[3-[1-[(dimethylamino)sulphonyl]-5-methyl-lH-imidazol-4-yl]prop-2-ynyl]propanedioate 4.50 g (14.3 mmol) of 4-iodo-.~,N,5-trimethyl-lH-imidazole-1-sulphonamide, 4.5 g (17.6 mmol) of diethyl 2-(acetylamino)-2-(prop-2-ynyl)propanedioate and 75 ml of diethylamine are introduced into a 250 ml round-bottomed flask under a nitrogen atmosphere. 105 mg (0.14 mmol) of dichlorobis(.ri?henylphosphine)palladium and 50 mg (0.25 mmol) of copper iodide are added to this solution and heating is carried out at reflux for CA 022~0747 1998-09-30 1.25 hours. The solvent is evaporated and then the residue is taken up in 50 ml of ethyl acetate and washed with 20 ml of an ammonium chloride solution. It is dried over magnesium sulphate and evaporated to dryness.
5.1 g of product are obtained in the form of beige crystals.
Melting point = 156-158~C.
Example 2 (Compound 6) -Ethyl 2-tacetylamino)-5-[5-methyl-1-[(4-~methylphenyl)sulphonyl]-lH-imidazol-4-yl]pent-4-ynoate 2.1. 4-Iodo-S-methyl-1-[(4-methylphenyl)sulphonyl]-1~-imidazole 2.5 g (52 mmol) of 50% sodium hydride in oil and 30 ml of dimethylformamide are introàuced into a 250 ml three-necked round-bottomed flask under a nitrogen atmosphere. A solution of 10 g (48 mmol) of 4-iodo-5-methyl-lH-imidazole is added to this mixture at 0~C.
After 30 minutes, 10.4 g (54 mmol) of (4- --methylphenyl)sulphonyl chloride are aaded portionwisewhile maintaining the temperature below 10~C. After returning to room temperature, the mixture is stirred for 1 hour and is poured onto 150 ml of ice. Tne product is filtered off, washed with ~ate, and tnen with hexane and dried in an oven under vacuum.
15.76 g of product are obtained in the form of a white CA 022~0747 1998-09-30 solid.
Melting point = 145-146~C.
2.2. Ethyl 2-(acetylamino)-5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]pent-4-ynoate 1.5 g (4.1 mmol) of 4-iodo-5-methyl-1-[(4-methylphenyl)sulphonyl]-1~-imidazole, 830 mg (4.3 mmol) of ethyl 2-(acetylamino)pent-4-ynoate and 20 ml of diethylamine are introduced into a 100 ml round-bottomed flask under a nitrogen atmosphere. 43 mg (O.06 mmol) of dichlorobis(triphenylphosphine)palladium and 23 mg (0.12 mmol) of copper iodide are added to this solution. Heating is carried out at reflux for 1 hour, then the mixture is allowed to cool to room temperature and 50 ml of water are added. The product is filtered off, washed with water and dried in an oven under vacuum.
1.3 g of product are obtained in the form of beige crystals.
2û Melting point = 146-148~C.
ExamDle 3 (Compound 8) Methyl 5-[5-methyl-1-[(~-methylphenyl)sulphonyl]-1~-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate CA 022~;0747 1998-09-30 3.1. Methyl (S)-2-l~(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate 3.1.1. (S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]pent-4-S ynoic acid 11.5 g (77 mmol) of (5)-2-aminopent-4-ynoic acid hydrochloride, 100 ml of dioxane, 50 ml of water and 80 ml of 2N sodium hydroxide solution are introduced into a 250 ml round-bottomed flask under a nitrogen 10 atmosphere. 17.9 g (82 mmol) of tert-butyl dicarbonate are added to this solution and the mixture is stirred for 3 hours at room temperature. 200 ml of ethyl acetate are added and acidification is carried out to pH 2 by addition of 2N hydrochloric acid. The phases are separated and the ac~ueous phase is extracted with 50 ml of ethyl acetate. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness.
18.78 g of product are obtained in the form of a colourless oil.
3.1.2. Methyl (5)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate 13 g (0.154 mol) of sodium hydrogencarbonate are added to a solution OL 18.78 g (0.077 mol) of (5)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoic acid in 150 ml of dimethylformamide in a 250 ml round-bottomed CA 022~0747 1998-09-30 flask under a nitrogen atmosphere. 20 ml (0.318 mol) of methyl iodide are added and the mixture is stirred for 18 hours at room temperature. The mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water and is then dried over magnesium sulphate. Evaporation is carried out to dryness.
15.85 g of product are obtained in the form of a yellow oll .
3.1.3. Methyl 2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate 2.15 g (16.9 mmol) of methyl 2-aminopent-4-ynoate, 30 ml of dichloromethane and 3 ml of pyridine are introduced into a 50 ml round-bottomed flask under a nitrogen atmosphere. The solution is cooled to -10~C
znd 4.10 g (16.9 mmol) of 8-(chlorosulphonyl)-3-methylquinoline are added. The mixture is stirred for 1 hour at -10~C and then for 30 minutes at room temperature. The solution is washed with 15 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness.
4.4 g of beige solid are obtained.
Melting point = 125-127~C
3.2. Methyl 5-[5-methyl-1-[(4-me.hylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-yr.oate CA 022~0747 1998-09-30 .
700 mg (1.93 mmol) of 4-iodo-5-methyl-l-[(4-methylphenyl)sulphonyl]-lH-imidazole, 700 mg (2.10 mmol) of methyl 2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate, 10 ml of diethylamine and lO ml of dimethylformamide are introduced into a 50 ml three-necked round-bottomed flask under a nitrogen atmosphere. 25 mg (0.035 mmol) of dichlorobis(triphenylphosphine)palladium and 12 mg (0.07 mmol) of copper iodide are added to the solution.
Heating is carried out at 50~C for 4 hours and then the mixture is evaporated to dryness. The residue is taken up in 25 ml of dichloromethane and is washed with 15 ml of an ammonium chloride solution. It is dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from methanol. 700 mg of product are obtained in the form of beige crystals.
Melting point = 151-153~C.
Example 4 (Compound 11) Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[1-(triphenylmethyl)-lH-imidazol-4-yl]pent-4-ynoate ~-179 g (0.410 mol) of 4-iodo-1-(triphenylmethyl)-lH-imidazole, 98 g (0.431 mol) of methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pen~-4-ynoate, 1.8 l of diethylamine and 1.8 l of dimethylformamide a-e introduced into a 6 1 reactor under a nitrogen atmosphere. The mixture is heated to 50~C, 7.2 g CA 022~0747 1998-09-30 (10.26 mmol) of dichlorobis(triphenylphosphine)-palladium and 3.6 g (18.90 mmol) of copper iodide are added and then the mixture is heated at 65~C for 3.5 hours. The mixture is poured onto 12 1 of water and extracted with ethyl acetate. Drying is carried out over magnesium sulphate and evaporation is carried out under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with an ethyl acetate/hexane mixture.
158.2 g of oily product are obtained.
M+H = 536 [a] 20 = +40.2~ (c = 1, chloroform).
Example 5 Ethyl 1-[2-[(benzyloxycarbonyl)amino]-S-[5-methyl-1-[(4-methylphenyl)sulphonyl]-1~-imidazol-4-yl]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate 5.1. Ethyl 1-~2-[(benzyloxycarbonyl)amino]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate 4.83 g (19.5 ~mol) of 2-[(benzyloxycarbonyl)amino]pent 4-y~oic acid and 100 ml of tetrahydrofuran are introduced into a 150 ml three-necked flask under a nitrogen atmosphere. The mixture is allowed to cool to 0~C and 2.71 ml (19.5 mmol) of triethylamine and 2 40 ml (19.5 ~mol) of pivaloyl chloride are added at this tempe-ature. The temperature of the reaction mixture is allowed to return to room temperature o~er 2 CA 022~0747 l998-09-30 hours and 2.40 ml (19.5 mmol) of triethylamine and 3.62 g (19.5 mmol) of ethyl (2R,trans)-4-ethylpiperidine-2-carboxylate are added. The mixture is brought to 45~C for 3.5 hours, filtered and the filtrate is evaporated to dryness. The residue is taken up in 100 ml of ethyl acetate and washed successively with S0 ml of a 2N aqueous hydrochloric acid solution, with 50 ml of a saturated sodium carbonate solution and with 50 ml of water containing 10 ml of a saturated sodium chloride solution. The organic phase is recovered, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate (7/3) mixture.
Melting point = 125-127~C
3.2. Methyl 5-[5-methyl-1-[(4-me.hylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-yr.oate CA 022~0747 1998-09-30 .
700 mg (1.93 mmol) of 4-iodo-5-methyl-l-[(4-methylphenyl)sulphonyl]-lH-imidazole, 700 mg (2.10 mmol) of methyl 2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoate, 10 ml of diethylamine and lO ml of dimethylformamide are introduced into a 50 ml three-necked round-bottomed flask under a nitrogen atmosphere. 25 mg (0.035 mmol) of dichlorobis(triphenylphosphine)palladium and 12 mg (0.07 mmol) of copper iodide are added to the solution.
Heating is carried out at 50~C for 4 hours and then the mixture is evaporated to dryness. The residue is taken up in 25 ml of dichloromethane and is washed with 15 ml of an ammonium chloride solution. It is dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from methanol. 700 mg of product are obtained in the form of beige crystals.
Melting point = 151-153~C.
Example 4 (Compound 11) Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[1-(triphenylmethyl)-lH-imidazol-4-yl]pent-4-ynoate ~-179 g (0.410 mol) of 4-iodo-1-(triphenylmethyl)-lH-imidazole, 98 g (0.431 mol) of methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pen~-4-ynoate, 1.8 l of diethylamine and 1.8 l of dimethylformamide a-e introduced into a 6 1 reactor under a nitrogen atmosphere. The mixture is heated to 50~C, 7.2 g CA 022~0747 1998-09-30 (10.26 mmol) of dichlorobis(triphenylphosphine)-palladium and 3.6 g (18.90 mmol) of copper iodide are added and then the mixture is heated at 65~C for 3.5 hours. The mixture is poured onto 12 1 of water and extracted with ethyl acetate. Drying is carried out over magnesium sulphate and evaporation is carried out under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with an ethyl acetate/hexane mixture.
158.2 g of oily product are obtained.
M+H = 536 [a] 20 = +40.2~ (c = 1, chloroform).
Example 5 Ethyl 1-[2-[(benzyloxycarbonyl)amino]-S-[5-methyl-1-[(4-methylphenyl)sulphonyl]-1~-imidazol-4-yl]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate 5.1. Ethyl 1-~2-[(benzyloxycarbonyl)amino]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate 4.83 g (19.5 ~mol) of 2-[(benzyloxycarbonyl)amino]pent 4-y~oic acid and 100 ml of tetrahydrofuran are introduced into a 150 ml three-necked flask under a nitrogen atmosphere. The mixture is allowed to cool to 0~C and 2.71 ml (19.5 mmol) of triethylamine and 2 40 ml (19.5 ~mol) of pivaloyl chloride are added at this tempe-ature. The temperature of the reaction mixture is allowed to return to room temperature o~er 2 CA 022~0747 l998-09-30 hours and 2.40 ml (19.5 mmol) of triethylamine and 3.62 g (19.5 mmol) of ethyl (2R,trans)-4-ethylpiperidine-2-carboxylate are added. The mixture is brought to 45~C for 3.5 hours, filtered and the filtrate is evaporated to dryness. The residue is taken up in 100 ml of ethyl acetate and washed successively with S0 ml of a 2N aqueous hydrochloric acid solution, with 50 ml of a saturated sodium carbonate solution and with 50 ml of water containing 10 ml of a saturated sodium chloride solution. The organic phase is recovered, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate (7/3) mixture.
6.03 g of product are obtained in the form of a colourless oil.
Yield = 75%
M+H = 415 5.2. Ethyl 1-[2-[(benzyloxycarbonyl)amino]-5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate 1.202 g (2.9 ~mol) of ethyl 1-[2-[(benzyloxycarbonyl)amino]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate and 10 ml of diethylamine are introduced into a 25 ml three-necked flask under a nitrogen atmosphere. 1 g (2.76 mmol) of 4-iodo-5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazole, CA 022~0747 1998-09-30 O.032 g (0.168 mmol) of copper iodide and 0.058 g (0.083 mmol) of dichlorobis(triphenylphosphine)-palladium are added to this mixture and the mixture is heated at 60~C for 1.5 hours. The solvent is evaporated and the residue is taken up in 20 ml of ethyl acetate and washed successively with 20 ml of 2N hydrochloric acid solution, with 3 times 20 ml of a 5% aqueous ammonia solution and with 20 ml of water. The organic phase is dried ,over magnesium sulphate and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a hexane/ethyl acetate (6/4) mixture.
1.466 g of product are obtained in the form of a pale-yellow oil.
M+H = 649 Exam~le 6 (Compound No. 14) Ethyl [2~-[1(5),2a,4~]]-4-methyl-1-[5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl~piperidine-2-carboxylate 6 1. 2-[[(3-Methylquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid 11.2 g (75 ~mol) of (5)-2-am~inopent-4-ynoic acid hyàrochloride, 150 ml of tetrahydrofuran, 80 ml of water and 16 g of sodium carbonate are introduced into a 500 ml round-bottomed flask under a nitrogen CA 022~0747 1998-09-30 atmosphere. The mixture is cooled to 0~C and 18.5 g (76.6 mmol) of 8-(chlorosulphonyl)-3-methylquinoline are added. The mixture is stirred for 3 hours at 20~C, the reaction mixture is acidified to pH 2 by aàdition of 6N hydrochloric acid and is saturated with sodium chloride. The phases are separated and the aqueous phase is extracted with 10 ml of ethyl acetate. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness.
25 g of crude product are obtained, which product is used as is in the following stage.
6.2. Ethyl [2R- ~1 (S), 2a, 4~]]-4-methyl-1-~2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate 25 g (0.075 mol) of 2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid and 350 ml of acetonitrile are introduced into a 500 ml round-bottomed flask. The mixture is cooled to 0~C and 33.17 g (75 mmol) of benzotriazol-1-20 yloxytris(dimethylamino)phosphoni~m ~-hexafluorophosphate, 16.5 ml of N-methylmorpholine and 12.85 g (0.075 mol) of ethyl ~2R, tr2ns) -4-methylpiperidine-2-carboxylate in 15 ml of dichloromethane are added. The mix~ure is stirred for 2 hours at 0~C and then for 1 hour a. room temperature.
Hydrolysis is carried out with 20 ml of a saturated sodium chloride solution and extraction is carried out CA 022~0747 1998-09-30 with 2 times 100 ml of ethyl acetate. Washing is carried out successively with 150 ml of a 2N aqueous hydrochloric acid solution and then with 150 ml of a saturated sodium hydrogencarbonate solution. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness. The residue is purified by chromatography on a column of silica gel, elution being carried out with a hexane/ethyl acetate (7/3) mixture.
31.5 g of product are obtained in the form of a yellow oil.
M+H = 472 6.3. Ethyl [2R- [1 (S), 2a, 4~]]-4-methyl-1-[5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate 12 g (33.13 mmol) of 4-iodo-S-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazole, 16 g (33.95 mmol) of ethyl [2R- [1 (S), 2a,4~]]-4-methyl-1-[2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate, 350 mg (1.8 mmol) of-copper iodide, 700 mg (1 ~mol) of dichlorobis(triphenylphosphine)palladium and 200 ml of triethylamine are introduced into a 500 ml round-bottomed flask under a nitrogen atmosphere. The mix~ure 2, is heated for 1.5 hours at 45~C and evaporated to dryness and the residue is taken up in 600 ml of ethyl acetate. Washing is carried out successively with CA 022~0747 1998-09-30 200 ml of a 2N aqueous hydrochloric acid solution, 3 times 100 ml of a 5% aqueous ammonia solution and then 200 ml of water. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness.
28.4 g of product are obtained in the oil form.
Example 7 (Compound 16) Ethyl [2R-[1(5),2~,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]-4-methylpiperidine-2-carboxylate 1.5 g (3.18 mmol) of ethyl [2R-[l(S),2~,4~]]-4-methyl-1-[2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate, 83.4 mg (0.32 mmol) of triphenylphosphine, 609 mg (3.5 mmol) of 5-bromopyrimidin-2-amine, 83.4 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium and 60.6 mg (0.32 mmol) of copper iodide are introduced into 100 ml of piperidine, degassed beforehand, under an argon atmosphere. The mixture is brought to the reflux 23 temperature for lS minutes and the solvent is evaporated under vaccum. The residue is taken up in dichloromethane and washed wi.h water and the solvent is again evaporated. The res due is purified by chromatography on a column o~ silica gel, elution being 2~ carried out with a toluene/ethyl acetate/triethylamine ~25/75/0.12) mixture.
CA 022~0747 1998-09-30 l.S g of product are obtained.
Yield = 83.5~
Mass: M+H (FAB) = 565 Exam~le 8 (Compound ~o. 19) S Ethyl [2R-[1(5),2~,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]-4-methylpiperidine-2-carboxylate 8.1. 2-[[(3-Methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid 3.42 g (14 mmol) of 3-methyl-1,2,3,4-tetrahydroquinoline-8-sulphonyl chloride are added with cooling to 1.5 g (13 mmol) of 2-aminopent-4-ynoic acid hydrochloride in solution in 50 ml of a water/acetone (70/30) mixture at a pH of lG-11. The mixture is stirred at 10~C, the pH is adjusted to 3 and the solvent is evaporated. The gum obtained is extracted with ethyl acetate and the residue is purified by chromatography on a colu~n of silica gel, elution ~eing carried out with a dichloromethane/methanol/acetic acid (95/5/O.S) mixture.
2.8 g of product are obtained.
Yield = 67%
~ (CDCl3, 200 ~z): -C- Cr. (S, 2 . 35), -CH- (m, 4.05), aromatics (t: 6.6, d: 7.1, d: 7.5) CA 022~0747 1998-09-30 8.2. Ethyl [2R-~l(S),2~,4~]~-4-methyl-1-[2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate 2.7 g (8.38 mmol) of 2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid, 4.38 ml (25 mmol) of diisopropylethylamine, 1.8 g (8.71 mmol) of ethyl (2R,trans)-4-methylpiperidine-2-carboxylate and then 4.55 g (8.7 mmol) of benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate are added to 100 ml of dichloromethane cooled to 0~C.
The temperature of the mixture is allowed to return to room temperature and the mixture is left stirring at this temperature for 4 hours. The reaction mixture is washed with a 10% aqueous citric acid solution and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane/methanol (97.5/2.5) mixture.
1.9 g of product are obtained.
Yield = 38%
Mass: M+H (FAB) = 556 -~
8.3. Ethyl [2R-[1(5),2~,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[(3-methyl-1,2,3,4-te~rahydroquinol-8-yl)sulphonyl]amino]-1-oxope-,t-4-ynyl~-4-methylpiperidine-2-carboxyla.e 0.5 g (1.05 mmol) of ethyl [22-[l(S),2~,4~]]-4-methyl-1-[2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-CA 022~0747 1998-09-30 yl)sulphonyl]amino]-1-oxopent-4-ynyl~piperidine-2-carboxylate, 2S.6 mg (0.11 mmol) of triphenylphosphine, 201 mg (1.16 mmol) of S-bromopyrimidine-2-amine, 61 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium and 20 mg (0.11 mmol) of copper iodide are introduced into 34 ml of piperidine, degassed beforehand, under an argon atmosphere. The mixture is brought to the reflux temperature for 15 minutes and the solvent is evaporated under vaccum. The residue is taken up in dichloromethane and washed with water and the solvent is again evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a toluene/ethyl acetate/triethylamine (25/75/0.12) mixture.
0.4 g of product is obtained.
Yield = 67%
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~ _ r~,) CA 022~0747 l998-09-30 WO 97/qO052 31 PC5'/FR97~0o7oo The compounds of the invention are of use as intermediates, for example in the synthesis of compounds of formula ~1) N
Het in which S R3 represents either a hydrogen atom or a straight or branched (C;-C~)alkyl group, R~ represents either a hydrogen atom or a straight or branched (C -C4) alkyl group, Het represents a 2-aminopyridyl, 2-aminopyrimidyl, 2-amino-1,2,3,4-tetrahydropyrimidyl or 6-aminopyridazinyl group (it being possible for the said heterocycles optionally to be substituted on the other positions by a straight or branched (C1-C~)alkyl group) or an imidazol-4-yl group optionally substituted in the 2 1, andtor 5 position by (Cl-C~)alky' groups and in the-l or 3 position by a protective grou?, such as, for example, a trityl, benzenesulphonyl, tolue~esulphonyl or dimethylaminosulphonyl group, and ~r represents either an aryl gro1l?, in particular a 3-2~ r.ethyl~inol-8-yl or 3-methyl-1,2,3,4-tetrahydro~uinol-.~
~, 8-yl group, or a group ~ with R, chosen from the hydrogen atom and the -COR group, R being a straight or branched (C1-C,)alkyl, -(CH2)nOCH3 or -CH2O(C2H4O~nCH3 group (n is equal to 1, 2 or 3), and A
chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (Cl-C~)alkyl, straight or branched (C.-C~)alkoxy, trifluoromethyl, formyl, -CH2ORl~, -CH20CORLo, -CH20CONRloR;1, -COORlC, -CONRloRl, nitro, -N~I~Rl" -NHCORl~ or -NH(CH2)~0R,o groups, R~o and R.. each being, independently of one another, a hydrogen atom or a straight or branched (C1-C~)alkyl group and m = 0 to 6) and the cyclo (Cs-C3) alkyl group.
Compounds of formula (1) are disclosed in ruropean Patent Application 0,565,396 and in French -?atent FR 2,718,442. These compounàs have an antithrombotic activity.
Examples A and B which follow illustrate, without limiting it, the synthesis of a compound of formula (1) from compounds of formula (I).
CA 022~0747 1998-09-30 Example A
Ethyl [ 2R- [ 1 ( S), 2a, 4~]]-4-methyl-1-[ 2 - [ [ ( 3-methyl-1,2,3,~-tetrahydroquinol-8-yl)sulphonyl]amino~-1-oxo-5-[(5-methyl-lH-imidazol-4-yl)]pentyl]piperidine-2-carboxylate hydrochloride 23 g (32.6 mmol) of ethyl [2R-[l(S),2~,4~]]-4-methyl-1-[5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate and 200 ml of tetrahydrofuran are introduced into a 500 ml round-bottomed flask under a nitrogen atmosphere. 10.5 g (77.7 mmol) of 4-hydroxybenzotriazole hydrate are added at room temperature and the mixture is stirred for 3.5 hours. The reaction mixture is evaporated to dryness and the residue is taken up in 500 ml of ethyl acetate and then extracted with a 2N aqueous hydrochloric acid solution. The aqueous phase is recovered, washed with 150 ml of tert-butyl methyl ether and then neutralized by adding 80 g of solid sodium hydrogencarbonate.
Extraction is carried out 3 times with ethyl acetate, drying is carried out over masnesium sulphate and evaporation is carried out to dryness. The residue is ta~en up in 200 ml of ethanol and 40 ml of acetic acid and 15 g of 10% palladi~m-on-charcoal are addea.
;-.ydrogenation is carried out a~ 603C for 24 hours at a ?ressure of 1.5 MPa (15 bar). The catalyst is filtered off and evaporation is carried out to dryness. The CA 022~0747 1998-09-30 residue thus obtained is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane/methanol t95/5) mixture.
6.56 g of product are obtained in the base form.
The hydrochloride is prepared by dissolving the base in an aqueous hydrochloric acid solution and then lyophilizing.
Melting point = 80~C
~]20 = +67.5~ (c = 0.2, methanol) Ex&m~le B
Ethyl [2R-[l(S),2a,4~]]-1-[5-(2-&minopyrimidin-5-yl)-2-[[~3-methylquinol-8-yl)sulphonyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate 800 mg ~1.42 mmol) of ethyl [2R-[1(5),2a,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[~3-methyl~uinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]-4-methylpiperidine-2-carboxylate are dissolved in 55 ml of ethanol, to which are added 424 mg (6.73 mmol) of &mmonium formate and 670 mg of 10~ palladium-on-charcoal. The mixture is brought t3 the reflux~emperature and is left fo- one hour at this temperature under an argon atmosphere. The catalyst is remo~ed, the solvent is eva?o~a~ed and the residue is treated with a mix~ure of ~ater a-.d dichloromethane.
The organic phase is then purified by chromatography on a column of silica gel, elution being carried out with Wo 97/40052 35 PCT/F~97/00700 a dichloromethane/ethanol (95/5) mixture.
400 mg of product are obtained.
IR: -COO- (1734 cm~1), -CON- (1639 cm~~).
Yield = 75%
M+H = 415 5.2. Ethyl 1-[2-[(benzyloxycarbonyl)amino]-5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate 1.202 g (2.9 ~mol) of ethyl 1-[2-[(benzyloxycarbonyl)amino]-1-oxopent-4-ynyl]-4-ethylpiperidine-2-carboxylate and 10 ml of diethylamine are introduced into a 25 ml three-necked flask under a nitrogen atmosphere. 1 g (2.76 mmol) of 4-iodo-5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazole, CA 022~0747 1998-09-30 O.032 g (0.168 mmol) of copper iodide and 0.058 g (0.083 mmol) of dichlorobis(triphenylphosphine)-palladium are added to this mixture and the mixture is heated at 60~C for 1.5 hours. The solvent is evaporated and the residue is taken up in 20 ml of ethyl acetate and washed successively with 20 ml of 2N hydrochloric acid solution, with 3 times 20 ml of a 5% aqueous ammonia solution and with 20 ml of water. The organic phase is dried ,over magnesium sulphate and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a hexane/ethyl acetate (6/4) mixture.
1.466 g of product are obtained in the form of a pale-yellow oil.
M+H = 649 Exam~le 6 (Compound No. 14) Ethyl [2~-[1(5),2a,4~]]-4-methyl-1-[5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl~piperidine-2-carboxylate 6 1. 2-[[(3-Methylquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid 11.2 g (75 ~mol) of (5)-2-am~inopent-4-ynoic acid hyàrochloride, 150 ml of tetrahydrofuran, 80 ml of water and 16 g of sodium carbonate are introduced into a 500 ml round-bottomed flask under a nitrogen CA 022~0747 1998-09-30 atmosphere. The mixture is cooled to 0~C and 18.5 g (76.6 mmol) of 8-(chlorosulphonyl)-3-methylquinoline are added. The mixture is stirred for 3 hours at 20~C, the reaction mixture is acidified to pH 2 by aàdition of 6N hydrochloric acid and is saturated with sodium chloride. The phases are separated and the aqueous phase is extracted with 10 ml of ethyl acetate. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness.
25 g of crude product are obtained, which product is used as is in the following stage.
6.2. Ethyl [2R- ~1 (S), 2a, 4~]]-4-methyl-1-~2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate 25 g (0.075 mol) of 2-[[(3-methylquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid and 350 ml of acetonitrile are introduced into a 500 ml round-bottomed flask. The mixture is cooled to 0~C and 33.17 g (75 mmol) of benzotriazol-1-20 yloxytris(dimethylamino)phosphoni~m ~-hexafluorophosphate, 16.5 ml of N-methylmorpholine and 12.85 g (0.075 mol) of ethyl ~2R, tr2ns) -4-methylpiperidine-2-carboxylate in 15 ml of dichloromethane are added. The mix~ure is stirred for 2 hours at 0~C and then for 1 hour a. room temperature.
Hydrolysis is carried out with 20 ml of a saturated sodium chloride solution and extraction is carried out CA 022~0747 1998-09-30 with 2 times 100 ml of ethyl acetate. Washing is carried out successively with 150 ml of a 2N aqueous hydrochloric acid solution and then with 150 ml of a saturated sodium hydrogencarbonate solution. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness. The residue is purified by chromatography on a column of silica gel, elution being carried out with a hexane/ethyl acetate (7/3) mixture.
31.5 g of product are obtained in the form of a yellow oil.
M+H = 472 6.3. Ethyl [2R- [1 (S), 2a, 4~]]-4-methyl-1-[5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate 12 g (33.13 mmol) of 4-iodo-S-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazole, 16 g (33.95 mmol) of ethyl [2R- [1 (S), 2a,4~]]-4-methyl-1-[2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate, 350 mg (1.8 mmol) of-copper iodide, 700 mg (1 ~mol) of dichlorobis(triphenylphosphine)palladium and 200 ml of triethylamine are introduced into a 500 ml round-bottomed flask under a nitrogen atmosphere. The mix~ure 2, is heated for 1.5 hours at 45~C and evaporated to dryness and the residue is taken up in 600 ml of ethyl acetate. Washing is carried out successively with CA 022~0747 1998-09-30 200 ml of a 2N aqueous hydrochloric acid solution, 3 times 100 ml of a 5% aqueous ammonia solution and then 200 ml of water. Drying is carried out over magnesium sulphate and evaporation is carried out to dryness.
28.4 g of product are obtained in the oil form.
Example 7 (Compound 16) Ethyl [2R-[1(5),2~,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]-4-methylpiperidine-2-carboxylate 1.5 g (3.18 mmol) of ethyl [2R-[l(S),2~,4~]]-4-methyl-1-[2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate, 83.4 mg (0.32 mmol) of triphenylphosphine, 609 mg (3.5 mmol) of 5-bromopyrimidin-2-amine, 83.4 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium and 60.6 mg (0.32 mmol) of copper iodide are introduced into 100 ml of piperidine, degassed beforehand, under an argon atmosphere. The mixture is brought to the reflux 23 temperature for lS minutes and the solvent is evaporated under vaccum. The residue is taken up in dichloromethane and washed wi.h water and the solvent is again evaporated. The res due is purified by chromatography on a column o~ silica gel, elution being 2~ carried out with a toluene/ethyl acetate/triethylamine ~25/75/0.12) mixture.
CA 022~0747 1998-09-30 l.S g of product are obtained.
Yield = 83.5~
Mass: M+H (FAB) = 565 Exam~le 8 (Compound ~o. 19) S Ethyl [2R-[1(5),2~,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]-4-methylpiperidine-2-carboxylate 8.1. 2-[[(3-Methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid 3.42 g (14 mmol) of 3-methyl-1,2,3,4-tetrahydroquinoline-8-sulphonyl chloride are added with cooling to 1.5 g (13 mmol) of 2-aminopent-4-ynoic acid hydrochloride in solution in 50 ml of a water/acetone (70/30) mixture at a pH of lG-11. The mixture is stirred at 10~C, the pH is adjusted to 3 and the solvent is evaporated. The gum obtained is extracted with ethyl acetate and the residue is purified by chromatography on a colu~n of silica gel, elution ~eing carried out with a dichloromethane/methanol/acetic acid (95/5/O.S) mixture.
2.8 g of product are obtained.
Yield = 67%
~ (CDCl3, 200 ~z): -C- Cr. (S, 2 . 35), -CH- (m, 4.05), aromatics (t: 6.6, d: 7.1, d: 7.5) CA 022~0747 1998-09-30 8.2. Ethyl [2R-~l(S),2~,4~]~-4-methyl-1-[2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate 2.7 g (8.38 mmol) of 2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-yl)sulphonyl]amino]pent-4-ynoic acid, 4.38 ml (25 mmol) of diisopropylethylamine, 1.8 g (8.71 mmol) of ethyl (2R,trans)-4-methylpiperidine-2-carboxylate and then 4.55 g (8.7 mmol) of benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate are added to 100 ml of dichloromethane cooled to 0~C.
The temperature of the mixture is allowed to return to room temperature and the mixture is left stirring at this temperature for 4 hours. The reaction mixture is washed with a 10% aqueous citric acid solution and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane/methanol (97.5/2.5) mixture.
1.9 g of product are obtained.
Yield = 38%
Mass: M+H (FAB) = 556 -~
8.3. Ethyl [2R-[1(5),2~,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[(3-methyl-1,2,3,4-te~rahydroquinol-8-yl)sulphonyl]amino]-1-oxope-,t-4-ynyl~-4-methylpiperidine-2-carboxyla.e 0.5 g (1.05 mmol) of ethyl [22-[l(S),2~,4~]]-4-methyl-1-[2-[[(3-methyl-1,2,3,4-tetrahydroquinol-8-CA 022~0747 1998-09-30 yl)sulphonyl]amino]-1-oxopent-4-ynyl~piperidine-2-carboxylate, 2S.6 mg (0.11 mmol) of triphenylphosphine, 201 mg (1.16 mmol) of S-bromopyrimidine-2-amine, 61 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium and 20 mg (0.11 mmol) of copper iodide are introduced into 34 ml of piperidine, degassed beforehand, under an argon atmosphere. The mixture is brought to the reflux temperature for 15 minutes and the solvent is evaporated under vaccum. The residue is taken up in dichloromethane and washed with water and the solvent is again evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a toluene/ethyl acetate/triethylamine (25/75/0.12) mixture.
0.4 g of product is obtained.
Yield = 67%
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~ _ r~,) CA 022~0747 l998-09-30 WO 97/qO052 31 PC5'/FR97~0o7oo The compounds of the invention are of use as intermediates, for example in the synthesis of compounds of formula ~1) N
Het in which S R3 represents either a hydrogen atom or a straight or branched (C;-C~)alkyl group, R~ represents either a hydrogen atom or a straight or branched (C -C4) alkyl group, Het represents a 2-aminopyridyl, 2-aminopyrimidyl, 2-amino-1,2,3,4-tetrahydropyrimidyl or 6-aminopyridazinyl group (it being possible for the said heterocycles optionally to be substituted on the other positions by a straight or branched (C1-C~)alkyl group) or an imidazol-4-yl group optionally substituted in the 2 1, andtor 5 position by (Cl-C~)alky' groups and in the-l or 3 position by a protective grou?, such as, for example, a trityl, benzenesulphonyl, tolue~esulphonyl or dimethylaminosulphonyl group, and ~r represents either an aryl gro1l?, in particular a 3-2~ r.ethyl~inol-8-yl or 3-methyl-1,2,3,4-tetrahydro~uinol-.~
~, 8-yl group, or a group ~ with R, chosen from the hydrogen atom and the -COR group, R being a straight or branched (C1-C,)alkyl, -(CH2)nOCH3 or -CH2O(C2H4O~nCH3 group (n is equal to 1, 2 or 3), and A
chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (Cl-C~)alkyl, straight or branched (C.-C~)alkoxy, trifluoromethyl, formyl, -CH2ORl~, -CH20CORLo, -CH20CONRloR;1, -COORlC, -CONRloRl, nitro, -N~I~Rl" -NHCORl~ or -NH(CH2)~0R,o groups, R~o and R.. each being, independently of one another, a hydrogen atom or a straight or branched (C1-C~)alkyl group and m = 0 to 6) and the cyclo (Cs-C3) alkyl group.
Compounds of formula (1) are disclosed in ruropean Patent Application 0,565,396 and in French -?atent FR 2,718,442. These compounàs have an antithrombotic activity.
Examples A and B which follow illustrate, without limiting it, the synthesis of a compound of formula (1) from compounds of formula (I).
CA 022~0747 1998-09-30 Example A
Ethyl [ 2R- [ 1 ( S), 2a, 4~]]-4-methyl-1-[ 2 - [ [ ( 3-methyl-1,2,3,~-tetrahydroquinol-8-yl)sulphonyl]amino~-1-oxo-5-[(5-methyl-lH-imidazol-4-yl)]pentyl]piperidine-2-carboxylate hydrochloride 23 g (32.6 mmol) of ethyl [2R-[l(S),2~,4~]]-4-methyl-1-[5-[5-methyl-1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]-2-[[(3-methylquinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]piperidine-2-carboxylate and 200 ml of tetrahydrofuran are introduced into a 500 ml round-bottomed flask under a nitrogen atmosphere. 10.5 g (77.7 mmol) of 4-hydroxybenzotriazole hydrate are added at room temperature and the mixture is stirred for 3.5 hours. The reaction mixture is evaporated to dryness and the residue is taken up in 500 ml of ethyl acetate and then extracted with a 2N aqueous hydrochloric acid solution. The aqueous phase is recovered, washed with 150 ml of tert-butyl methyl ether and then neutralized by adding 80 g of solid sodium hydrogencarbonate.
Extraction is carried out 3 times with ethyl acetate, drying is carried out over masnesium sulphate and evaporation is carried out to dryness. The residue is ta~en up in 200 ml of ethanol and 40 ml of acetic acid and 15 g of 10% palladi~m-on-charcoal are addea.
;-.ydrogenation is carried out a~ 603C for 24 hours at a ?ressure of 1.5 MPa (15 bar). The catalyst is filtered off and evaporation is carried out to dryness. The CA 022~0747 1998-09-30 residue thus obtained is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane/methanol t95/5) mixture.
6.56 g of product are obtained in the base form.
The hydrochloride is prepared by dissolving the base in an aqueous hydrochloric acid solution and then lyophilizing.
Melting point = 80~C
~]20 = +67.5~ (c = 0.2, methanol) Ex&m~le B
Ethyl [2R-[l(S),2a,4~]]-1-[5-(2-&minopyrimidin-5-yl)-2-[[~3-methylquinol-8-yl)sulphonyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate 800 mg ~1.42 mmol) of ethyl [2R-[1(5),2a,4~]]-1-[5-(2-aminopyrimidin-5-yl)-2-[[~3-methyl~uinol-8-yl)sulphonyl]amino]-1-oxopent-4-ynyl]-4-methylpiperidine-2-carboxylate are dissolved in 55 ml of ethanol, to which are added 424 mg (6.73 mmol) of &mmonium formate and 670 mg of 10~ palladium-on-charcoal. The mixture is brought t3 the reflux~emperature and is left fo- one hour at this temperature under an argon atmosphere. The catalyst is remo~ed, the solvent is eva?o~a~ed and the residue is treated with a mix~ure of ~ater a-.d dichloromethane.
The organic phase is then purified by chromatography on a column of silica gel, elution being carried out with Wo 97/40052 35 PCT/F~97/00700 a dichloromethane/ethanol (95/5) mixture.
400 mg of product are obtained.
IR: -COO- (1734 cm~1), -CON- (1639 cm~~).
Claims (6)
1. Compounds of formula (I) in which R2 represents a -CH2C~C-Het group, where Het is a 2-aminopyridyl, 2-aminopyrimidyl or 6-aminopyridazinyl group (it being possible for the said heterocycles optionally to be substituted on the other positions by a straight or branched (C1-C4)alkyl group) or an imidazol-4-yl group optionally substituted in the 2 and/or 5 position by (C1-C4)alkyl groups and in the 1 or 3 position by a protective group, such as, for example, a trityl, benzenesulphonyl, toluenesulphonyl or dimethylaminosulphonyl group, R3 and R4 each represent, independently of one another, either a hydrogen atom or a (C1-C4)alkyl group or a (C1-C4)alkoxycarbonyl group or an ArCH3CO2- group or an ArSO2- group, where Ar is an aryl group, in particular a 3-methylquinol-8-yl or 3-methyl-1,2,3,4-tetrahydroquinol-8-yl group, or Ar is a group with R7 chosen from the hydrogen atom 36a and the -COR group, R being a straight or branched (C1-C7)alkyl, -(CH2)n OCH3 or -CH2O(C2H4O)n CH3 group (n is equal to 1, 2 or 3), and A chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, formyl, -CH2OR13, -CH2OCOR10, and the -COR group, R being a straight or branched (C1-C7)alkyl, -(CH2)n OCH3 or -CH2O(C2H4O)n CH3 group (n is equal to 1, 2 or 3), and A chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, formyl, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, -NR10R11, -NHCOR10 groups, R5 represents either a hydrogen atom or a straight or branched (C1-C4 ) alkyl group or a (C1-C4) alkoxycarbonyl group or an aryl group or an aryl (C1-C4)alkyl group, R6 represents either a straight or branched (C1-C4)alkoxy group or a benzyloxy group or a group , where R12 is a hydrogen atom or a carboxyl or (C1-C4)alkoxycarbonyl group and R13 is a straight or branched (C1-C4)alkyl group, in the form of racemates, of enantiomers or of mixtures.
2. Process for the preparation of the compounds according to Claim 1, characterized in that a compound of formula (III) in which R3, R4, R5 and R6 are as defined in Claim 1, is reacted with a compound of formula (II) Het-X (II) in which Het is as defined in Claim 1 and X represents a halogen atom, in the presence of a base and of a catalyst.
3. Process according to Claim 2, characterized in that the base is piperidine, diethylamine, triethylamine, triphenylphosphine, tri-.sigma.-tolylphosphine or trifurylphosphine.
4. Process according to Claim 2, characterized in that the catalyst is palladium chloride, pailaclium acetate, palladium bis(dibenzylideneacetone) or tetrakis(triphenylphosphine)palladium/cuprous iodide, dichlorobis(triphenylphosphine)palladium/cuprous iodide or tetra(triphenylphosphine)palladium/cuprous iodide complexes.
5. Use of the compounds according to Claim 1 for the synthesis of compounds of formula (1) in which R3 represents either a hydrogen atom or a straight or branched (C1-C4)alkyl group, R3 represents either a hydrogen atom or a straight or branched (C1-C4)alkyl group, Het represents a 2-aminopyridyl, 2-aminopyrimidyl, 2-amino-1,2,3,4-tetrahydropyrimidyl or 6-aminopyridazinyl group (it being possible for the said heterocycles optionally to be substituted on the other positions by a straight or branched (C1-C4)alkyl group) or an imidazol-4-yl group optionally substituted in the 2 and/or 5 position by (C1-C4)alkyl groups and in the 1 position by a protective group, such as, for example, a trityl, benzenesulphonyl, toluenesulphonyl or dimethylaminosulphonyl group, and Ar represents either ar aryl group, in particular a 3-methylquinol-8-yl group or a group with R7 chosen from the hydrogen atom and the -COR group, R
being a straight or branched (C1-C7)alkyl, -(CH2)n OCH3 or -CH2O(C2H4O)n CH3 group (n is equal to 1, 2 or 3), and A
chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, formyl, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, -NR10R11, -NHCOR10 or -NH(CH2)m OR10 groups, R10 and R11 each being, independently of one another, a hydrogen atom or a straight or branched (C1-C4)alkyl group and m = 0 to 6) and the cyclo(C5-C8)alkyl group.
being a straight or branched (C1-C7)alkyl, -(CH2)n OCH3 or -CH2O(C2H4O)n CH3 group (n is equal to 1, 2 or 3), and A
chosen from the phenyl, pyrimidyl, pyridinyl, thienyl, thiazolyl and furyl groups (it being possible for the said groups to be substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, formyl, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, -NR10R11, -NHCOR10 or -NH(CH2)m OR10 groups, R10 and R11 each being, independently of one another, a hydrogen atom or a straight or branched (C1-C4)alkyl group and m = 0 to 6) and the cyclo(C5-C8)alkyl group.
6. Compounds of formula (III) in which R6 represents either a methoxy group when R4 represents a phenylsulfonyl group , 3-methylquinolylsulfonyl group, benzyloxycarbonyl group or -COOC(CH3)3 and R5 represents a hydrogen atom, or R6 represents an ethoxy group when R4 represents a -COCH3 group or benzyloxycarbonyl group and R5 represents a hydrogen atom or when R4 represents a -COCH3 group and R5 represents an ethoxycarbonyl group, or R6 represents a benzyloxy group when R4 represents a -COOC(CH3)3 group or a benzyloxycarbonyl group and Rs represents a hydrogen atom, or R6 represents a group , where R12 is a carboxyl or (C1-C4)alkoxycarbonyl group and R15 is a straight or branched (C1-C4)alkyl group, R3 represents either a hydrogen atom or a (C1-C4)alkyl group or a (C1-C4)alkoxycarbonyl group or an ArCH2CO2- group or an ArSO2- group, where Ar is as defined in Claim 1, and R4 represents either an ArCH2CO2- group or an ArSO2- group, where Ar is as defined in Claim 1, of use for the synthesis of the compounds of formula (I).
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR96/05000 | 1996-04-22 | ||
| FR96/04999 | 1996-04-22 | ||
| FR9604999A FR2747677B1 (en) | 1996-04-22 | 1996-04-22 | PROPARGYLGLYCIN DERIVATIVES, THEIR PREPARATION AND THEIR USE AS SYNTHESIS INTERMEDIATES |
| FR9605000A FR2747676B1 (en) | 1996-04-22 | 1996-04-22 | [1-OXO-2- (SULFONYLAMINO) ETHYL] PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2250747A1 true CA2250747A1 (en) | 1997-10-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002250747A Abandoned CA2250747A1 (en) | 1996-04-22 | 1997-04-18 | Propagylglycine derivatives, preparation and utilisation thereof as synthesis intermediates |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0900224A1 (en) |
| JP (1) | JP2001500842A (en) |
| KR (1) | KR20000010594A (en) |
| BR (1) | BR9708814A (en) |
| CA (1) | CA2250747A1 (en) |
| IL (1) | IL125918A0 (en) |
| WO (1) | WO1997040052A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2689130B1 (en) * | 1992-03-30 | 1994-05-27 | Synthelabo | DERIVATIVES OF 1- [2 (ARYLSULFONYLAMINO) ETHYL-1-OXO] PIPERIDINE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| US5508466A (en) * | 1994-04-13 | 1996-04-16 | G.D. Searle & Co. | Synthesis of N-protected-α-substituted-glycine racemic esters by zinc-mediated addition of organic halide to glycine cation equivalent |
-
1997
- 1997-04-18 IL IL12591897A patent/IL125918A0/en unknown
- 1997-04-18 KR KR1019980708470A patent/KR20000010594A/en not_active Application Discontinuation
- 1997-04-18 JP JP09537780A patent/JP2001500842A/en active Pending
- 1997-04-18 CA CA002250747A patent/CA2250747A1/en not_active Abandoned
- 1997-04-18 WO PCT/FR1997/000700 patent/WO1997040052A1/en not_active Application Discontinuation
- 1997-04-18 BR BR9708814A patent/BR9708814A/en not_active Application Discontinuation
- 1997-04-18 EP EP97920783A patent/EP0900224A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997040052A1 (en) | 1997-10-30 |
| KR20000010594A (en) | 2000-02-15 |
| IL125918A0 (en) | 1999-04-11 |
| EP0900224A1 (en) | 1999-03-10 |
| BR9708814A (en) | 1999-08-03 |
| JP2001500842A (en) | 2001-01-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |