MXPA01006111A - 3-phenyl-2,6-dioxopiperidin-3-yl propionamide derivatives and method for preparing same - Google Patents
3-phenyl-2,6-dioxopiperidin-3-yl propionamide derivatives and method for preparing sameInfo
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- MXPA01006111A MXPA01006111A MXPA/A/2001/006111A MXPA01006111A MXPA01006111A MX PA01006111 A MXPA01006111 A MX PA01006111A MX PA01006111 A MXPA01006111 A MX PA01006111A MX PA01006111 A MXPA01006111 A MX PA01006111A
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- DXAYTAPLEIOXTJ-UHFFFAOYSA-N N-(2,6-dioxo-3-phenylpiperidin-3-yl)propanamide Chemical class C=1C=CC=CC=1C1(NC(=O)CC)CCC(=O)NC1=O DXAYTAPLEIOXTJ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 150000001412 amines Chemical class 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 20
- -1 azetidinyl-1-yl Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- UORMPYQLQRCWRN-UHFFFAOYSA-N N-methyl-4-phenylpiperidin-4-amine Chemical compound C=1C=CC=CC=1C1(NC)CCNCC1 UORMPYQLQRCWRN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000004429 atoms Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 1
- 238000004458 analytical method Methods 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000001808 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- HXMKDQGJBDSOIM-UHFFFAOYSA-N 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propanoic acid Chemical compound C=1C=C(Cl)C(Cl)=CC=1C1(CCC(=O)O)CCC(=O)NC1=O HXMKDQGJBDSOIM-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N Borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 2
- MGEVGECQZUIPSV-UHFFFAOYSA-N BOP reagent Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 MGEVGECQZUIPSV-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 229910000090 borane Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VHCVPWSUVMHJLL-UHFFFAOYSA-N 2-acetamido-N-methylpropanamide Chemical compound CNC(=O)C(C)NC(C)=O VHCVPWSUVMHJLL-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical class CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N Methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- DZOJBGLFWINFBF-UMSFTDKQSA-N Osanetant Chemical group C([C@](C1)(CCCN2CCC(CC2)(N(C(C)=O)C)C=2C=CC=CC=2)C=2C=C(Cl)C(Cl)=CC=2)CCN1C(=O)C1=CC=CC=C1 DZOJBGLFWINFBF-UMSFTDKQSA-N 0.000 description 1
- 229950009875 Osanetant Drugs 0.000 description 1
- 229960005190 Phenylalanine Drugs 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- UPBWIICFGYMCPC-UHFFFAOYSA-N bis(2-methoxyethoxy)aluminum Chemical compound COCCO[Al]OCCOC UPBWIICFGYMCPC-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N dimethylsulfide Substances CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- MNYCIYRTKITUKR-UHFFFAOYSA-N sodium tetrahydroaluminate Chemical compound [Na+].[AlH4-] MNYCIYRTKITUKR-UHFFFAOYSA-N 0.000 description 1
- CKVKLEFDNAHFMO-UHFFFAOYSA-N sodium;bis(2-methoxyethoxy)alumanide Chemical compound [Na+].COCCO[Al-]OCCOC CKVKLEFDNAHFMO-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000002462 tachykinin receptor antagonist Substances 0.000 description 1
Abstract
The invention concerns a compound of formula (I). Said compound is prepared by cyclizing a compound of formula (VI) or by the action of an amine on a compound of formula (VIII).
Description
D ERIVATIVES OF 3-FENI L-2.6-DIOXOPI PERIDI N-3-I L-PROPIONAMIDE AND METHOD FOR PREPARING THEM
The aim of the present invention is the 3- (3-phenyl-2,6-dioxopiperidin-3-yl) propionamide derivatives, the method for their preparation and their use. 3- (3,4-Dichlorophenyl) -2,6-dioxopiperidine-3-propionic acid is described in patent application WO 97/32852. We have now found a novel compound of the formula:
wherein: X represents a halogen, preferably a chlorine atom or a fluorine atom; - each of R and R2 independently represents hydrogen, an alkyl of 1 to 6 carbon atoms, which is unsubstituted or substituted by a hydroxyl, a benzyl which is unsubstituted, or which is substituted by an alkyl of 1 to 4 carbon atoms, a hydroxyl, or R1 and R2 constitute, together with the nitrogen atom to which they are attached, a heterocyclic radical selected from azetidinyl-1-yl, pi-1-yl, piperidin-1-yl and morpholin-4-yl; it being possible that the heterocyclic radicals mentioned are monosubstituted or disubstituted. As substituents of the heterocyclic radicals there can be mentioned groups which are similar or different, selected from an alkyl of 1 to 4 carbon atoms, a phenyl, a benzyl, an amino, an alkyl (of 1 to 4 carbon atoms) amino and a dialkyl (of 1 to 4 carbon atoms) amino. The compound (I) exists in racemic form or in two enantiomerically pure forms. The compound having the configuration described by the formula is preferred:
W] E¡ (ID
Preferred are compounds of formula (I) or formula (II) in which NR ^ 2 represents a dialkylamino group, such as dimethylamino, butylamino, ethanolamino, (N-methyl) ethanolamino, benzylamino, morpholino or piperidino. Also preferred are compounds of formula (I) or formula (II) in which NR1R2 represents a 4-methylamino-4-phenylpiperidin-1-yl group. The compounds of the formula (I) or the formula (II) are intermediates that are useful for the preparation of the compounds of the formula:
where X is as defined above for (I). In the patent application WO 97/03852 it appears that the compounds of the formula (III) or (IV) are useful for the preparation of neurokinin antagonist compounds, such as those described in the publication of X. Emonds-AIt and co-authors, Life Sci., 1995, 56 (1), 27-32, that is, (S) -N- [1- [3-. { 1-benzoyl-3- (3,4-dichlorophenyl) piperidin-3-yl} propyl] -4-phenylpiperidin-4-yl] -N-methylacetamide or SR 142801, whose non-reserved or generic international name is osanetant.
In particular, the object of the present invention is a compound of the formula:
where X is as defined above for (I). It is also an object of the present invention a method for preparing a compound of the formula (I). Said method is characterized in that a compound of the formula is cyclized:
wherein X is as defined above for (I), by water removal. The compound of the formula (VI) can be obtained by the action of an amine of the formula HNR? R2, in which Rt and R2 are as defined above for (I), on a compound of the formula:
The preparation of the compound of the formula (VI) is carried out in water, in an alcohol solvent, in an ethereal solvent, in a chlorinated solvent or in an aromatic solvent, at a temperature between room temperature and the reflux temperature of the solvent. It is preferred to use water or methanol. The cyclization of the compound of the formula is carried out
(VI) by removing a molecule of water, after activating the carboxyl group of the compound of the formula (VI) by means of the formation of a mixed anhydride. For this, an excess of anhydride, for example, of acetic anhydride or methanesulfonic anhydride, is used at a temperature between room temperature and 100 ° C. The compounds of the formula (VI) are novel and form part of the present invention. The compounds of the formula (III) are described in the patent application WO 97/32852. According to the present invention it has been observed thatstarting with a compound of the formula (III) in racemic form, a racemic compound of the formula (VI) is obtained, in which the two enantiomers are in the same proportion as in the starting compound. A racemic compound of the formula (I) is then obtained by cyclization, in which the two enantiomers are in the same proportion as in the starting compound. In accordance with the present invention it has been found that, using as the starting material a pure enantiomer of the compound of the formula (III), the formation of the hexanoic acid derivative of the formula (VI) occurs with configuration retention; and then cyclization occurs with inversion of the configuration. In such a way, the method according to the invention is applied to the preparation of compounds in optically pure form. Thus, advantageously, the present invention relates to a method for preparing a compound of the formula (II), characterized in that a compound of the formula is cyclized:
wherein X is as defined above for (I), by removal of water, to give a compound of the formula:
(YOU)
The compound of the formula (Vil) can be obtained by the action of an amine of the formula HNRÍR ^ in which Rn and R are as defined above for (I), on a compound of the formula:
According to the present invention, a compound of the formula (I) can be prepared using another method, characterized in that an amine of the formula H NR1 R2 is reacted, in which Ri and R2 are as defined above for ( I), with a compound of the formula:
where X is as defined above for (I). The compounds of the formula (VI I I) can be obtained from an acid of the formula:
The compounds of the formula (VI I I) are novel and constitute a subsequent aspect of the present invention. The action of an amine on an acid chloride of the formula (VI II) is preferred for the preparation of a compound of the formula (V) and, very particularly, for the preparation of an enantiomer of the compound of the formula (V ) of the formula:
This method is characterized in that 4-methylamino-4-phenylpiperidine is reacted with a compound of the formula:
The compound of the formula (X) can be prepared from the acid of the formula:
The acid chloride is prepared in a known manner, for example by the action of thionyl chloride, in the absence of a solvent or in an anhydrous solvent, such as toluene, d-methylformamide or dichloromethane or, alternatively, in a mixture of these solvents. The action of 4-methylamino-4-phenylpiperidine is carried out in an anhydrous solvent, in a basic medium, for example, in the presence of triethylamine. 4-Methylamino-4-phenylpiperidine is prepared according to Biorg. Med. Chem. Letters, 1996, 4 (19), 2307-2310. According to the present invention, the compound of the formula (I) makes it possible to obtain, by acidolysis, the acid of the formula (11). Similarly, according to the present invention, the compound of the formula (I I) makes it possible to obtain, by acidolysis, the acid of the formula:
Acidolysis is carried out in a manner known to those skilled in the art, for example, with a carboxylic acid of 1 to 4 carbon atoms. Thus, the present invention relates to a method for preparing a compound of the formula (11) by hydrolysis of a compound of the formula (I). It also relates to a method for preparing a compound of the formula (IV) by hydrolysis of a compound of the formula (I I). According to a subsequent aspect of the present invention, the compound of the formula (I) makes it possible to obtain, by means of reduction, a compound of the formula:
wherein X, R ^ and R2 are as defined for (I). Reduction is carried out by means known to the person skilled in the art. The reducing agents used are borane complexes, such as, for example, borane-tetrahydrofuran or boirane-dimethyl sulfide or, alternatively, a mixed alkali metal hydride, such as lithium aluminum hydride, or sodium hydride and bis ( 2-methoxyethoxy) aluminum, in solution in toluene (Red-Al®, the borane-tetrahydrofuran complex being preferred.) The reduction is carried out with borane in a solvent, preferably an aprotic solvent, such as tetrahydrofuran, at the reflux of the solvent In general, after heating for one to six hours, the reduction is completed and the 3,3-disubstituted piperidine is isolated according to conventional methods, first destroying the excess borane with methanol. free evaporating the solvent, and then the residue is taken up in water, the medium is acidified with hydrochloric acid, treated with a base, preferably with sodium hydroxide and extracted with a solvent. ar, by reducing a compound of the formula (IX) wherein X = Cl, a compound of the formula is prepared:
Thus, the present invention relates to a method for preparing a compound of the formula (XI) by reducing a compound of the formula (I). Likewise, the present invention relates to a method for preparing a compound of the formula (XII) by reducing a compound of the formula (IX). The following abbreviations are used in the examples and in the description: TA = room temperature Me = methyl TH F = tetrahydrofuran DM F = dimethylformamide L-PheOMe = methyl ester of L-phenylalanine BOP (Castro's reagent) = benzotriazole hexafluorophosphate-1 -i I oxitris (d imeti lamino) phosphonium M IBK = methyl isobutyl ketone. The NMR (nuclear magnetic resonance) spectra are recorded at 250 or 300 MHz. For the analysis of the products, high performance liquid chromatography on C18 (HPLC-C18) is used under the following conditions: Dilute 10 to 15 μmol of product dissolved in 50 μl of methanol, with 1 50 μl of eluent and 20 μl is injected onto a column of Alltima® C18 5 μ (length, 250 mm, inner diameter, 4.6 mm), eluting with a Socratic mixture A / B: 32/69; flow rate, 1 ml / minute;
A = 2.6 aqueous regulator; B = methanol; the compounds are detected at 280 nm. H PLC-C18 chiral is also used under the following analytical conditions: 2 to 3 μmol of product is dissolved in a mixture of 100 μl of DM F, 15 μl of triethylamine, with 15 μl of (S) -methylbenzylamine or 15 mg of L-PheOMe. 10 mg of BOP (Castro's reagent) is added and the medium is left for 30 minutes at 50 ° C. The reaction mixture is subjected to acid extraction with ethyl acetate / 1N HCl: 1 ml / 1 ml. 100 μl of the organic phase is then removed by evaporation, then the medium is taken up in 250 μl of eluent or taken up in 50 μl of methanol, and then diluted with 150 μl of eluent. 20 μl of this solution is injected. The procedure is carried out in 250 mm long columns, having an internal diameter of 4.6 mm, eluting with a 70/30 mixture of hexane / isopropanol, flow rate 1 ml / minute. The compounds are detected at 280 nm. The other conditions of the analysis vary according to the compounds that are being analyzed.
PREPARATION 1 ACID 4.6-DICARBAMOIL-4- (3,4-DICHLOROPHENYL) HEXANOIC (VI): X to Cl. NR R = NH ^
3.30 g of racemic 3- (3,4-dichlorophenyl) -2,6-dioxopiperidine-3-propionic acid are placed in 20 ml of an aqueous solution of 30% aqueous ammonia, and stirred at room temperature. After two hours the solution is degassed in vacuo to remove excess aqueous ammonia, and then diluted to 50 ml, with water. The medium is acidified slowly to pH 2-3 with 1N HCl. The formed precipitate is filtered, drained and then dried over KOH to give 3.13 g of the expected compound. 1 H NMR (DMSO): 1.70 to 2.12 ppm (4 CH2, m); 7.43 ppm (1 aromatic H, s); 7.60 and 7.24 ppm (2 aromatic H, d); 6.7 and 7.22 ppm (NH2 groups). The starting compound and the obtained compound are subjected to analysis by HPLC-C18; the retention times are Tr = 6.2 minutes and Tr = 3.7 minutes, respectively. Additionally, the obtained product is subjected to chiral analysis by means of HPLC-C18, after coupling its free carboxyl with
L-PheOMe. Two peaks are observed (Tr = 9.8 minutes and Tr = 70.7 minutes) showing that the product obtained is in racemic form.
PREPARATION 2 ACID 4.6-DlCARBAMOIL-4- (3,4-DICHLOROPHENYL) HEXANOIC. IN
CONFIGURATION S. (HIV): x = Cl. NR R ^ = Nr?
The procedure is carried out as described in Preparation 1, starting with 3.30 g of 3 - [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic acid, of configuration ( S). 3.13 g of the expected compound are obtained, the analysis of which is carried out by HPLC-C18. A peak is observed at Tr = 3.74 minutes. The chiral analysis, after coupling with L-PheOMe, gives a main peak at 10.7 minutes and a secondary peak at Tr = 9.8 minutes. It is observed that the optical purity is equal to that of the starting compound.
PREPARATION 2A ACID 4.6-DICARBAMOIL-4- (3,4-DICHLOROPHENYL) HEXANOIC. IN CONFIGURATION R. Tlacunal: X = Cl. NRLR ^ = NH ^
The procedure is carried out as in Preparation 2, using as starting material the R isomer of 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic acid. The chiral analysis, after coupling with L-PheOMe, gives a main peak at Tr = 9.8 minutes, and a secondary peak at Tr = 10.7 minutes.
PREPARATION 3 ACID 4-CARBAMOIL-4- (3,4-PICLOROFENIL) -6- (PLPERIDIN-1- IDCARBONILHEXANOICO
(VI): X
Place 0.3 g of 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic acid, 1 ml of methanol and 0.5 ml of piperidine, at 60 ° C, for 15 hours , in a round bottom flask. The reaction medium is diluted with 10 ml of water and acidified with 1N HCl to pH 2-3. The white crystals formed are filtered, drained and then dried to give 0.3 g of the expected compound. 1 H NMR (DMSO): 1.36 to 1.56 ppm (3 CH2; m), 2.04 to 2.50 ppm (4 CH2, m), 3.3 ppm (2 CH2, m), 7.25 and 7.6 ppm (2 H aromatic, d); 7.45 ppm (1 aromatic H, d); 10.98 ppm (COOH, s).
The HPLC-C18 analysis shows a peak at Tr = 8.2 minutes. The chiral HPLC-C18 analysis, after coupling with L-PheOMe, shows the formation of two peaks with identical surface area: Tr = 7.9 minutes and Tr = 8.8 minutes. Therefore, the compound obtained is in racemic form.
PREPARATION 4 ACID 4-CARBAMOIOL-4- (3,4-DICHLOROPHENYL) -6- (PIPERIDIN-1 IDCARBONILHEXANOICO IN CONFIGURATION S
0.3 g of 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic acid, of S configuration, is treated with piperidine, as described in Preparation 3, to give 0.3 g of the expected compound. The HPLC-C18 analysis shows a peak at Tr = 8.2 minutes. Chiral HPLC-C18 analysis, after coupling with L-PheOMe, shows a peak at Tr = 8.8 minutes. It is noted that the optical purity is identical to that of the starting material. -6.4 ° (c = 1K CH3OH / NaOH a20 1N: 9.7 / 0.3).
PREPARATION 4a 4-CARBAMOIL-4-ACID. { 3.4-DICHLOROPHENYL) -6- (PIPERIDIN-1 I DCARBON I LH EXANOICO. IN FIGURE R
The procedure is carried out as in Preparation 4, using as starting material 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic acid, in R-configuration. chiral after coupling with L-PheOMe shows a peak at Tr = 7.9 minutes. In carrying out the procedure as in preparations 1 and 3, described above, starting with racemic 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic and various amines, prepared the compounds described in Table 1 below. These compounds are characterized in HPLC by means of their capacity factor. By way of comparison, the values k 'are indicated for the compounds of preparations 1 and 3.
TABLE 1
EXAMPLE 1 3- (3,4-DICHLOROPHENYL -3-f (PIPERIDIN-1-IL) -3- OXOPROPIL1PIPERIDI A-2.6-DIONA
0.3 g of the compound obtained in preparation 3 is placed in a closed vessel, with 1.5 ml of acetic anhydride and heated at 95-100 ° C for thirty minutes. After cooling to RT, ethyl ether is added and the medium is allowed to stand in a cold room at 4 ° C. The crystals formed are filtered and drained to give 270 mg of the expected compound. The HPLC-C18 analysis shows a single peak at Tr = 14 minutes. This product obtained is identical to that obtained by coupling 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-ylpropionic acid with piperidine.
EXAMPLE 2 3- (3,4-DICHLOROPHENYL) -3-f (PIPERIDIN-1-I) -3- OXOPROPYL1PIPERIDINE-2.6-DIONA. IN CONFIGURATION R
0.2 g of the compound obtained in preparation 4 and 0.8 ml of acetic anhydride are placed in a closed tube at 95-100 ° C for 30 minutes. After cooling to RT, 10 ml of distilled water is added and the medium is left stirring for 30 to 40 minutes. It is extracted with 10 ml of ethyl acetate and then the ethyl acetate phase is dried and evaporated under reduced pressure. 0.18 g of the expected compound is obtained. The HPLC-C18 analysis shows a single peak at Tr = 14 minutes.
EXAMPLE 2a 3- (3,4-DICHLOROPHENYL) -3-r (PIPERlDIN-1-IL) -3- OXOPROPIL1PIPERIDINE-2,6-DIONA. IN CONFIGURATION R
The procedure is carried out as in example 2, starting with the compound obtained in preparation 4. The HPLC-C18 analysis of the compound obtained shows a single peak at Tr = 14 minutes.
EXAMPLE 3 ACID 3-f3- (3,4-DICHLOROPHENYL) -2.6-DIOXOPIPERIDIN-3-PROPIONIC ILL. IN CONFIGURATION S f llll = X = Cl
The compound obtained in Example 2 is taken up in 0.5 ml of propionic acid and placed in a vacuum sealed tube. After 18 hours at 145 ° C, the reaction mixture is diluted with 10 ml of 1N HCl. After one day the product that crystallizes, drains and dries is filtered. 100 mg of the expected compound is obtained. The HPLC-C18 analysis shows a peak at Tr = 6.2 minutes. Chiral analysis after coupling with (S) -methylbenzylamine shows a peak at 7.13 minutes.
EXAMPLE 3a ACID 3-r3- (3.4-DICLOROFE IL) -2.6-DIOXOPIPERIDIN-3- IL1PROPIONIC. IN CONFIGURATION S
The process according to claim 3 is carried out, starting with the compound obtained in example 2a. The HPLC-C18 analysis of the obtained compound shows a peak at Tr = 6.2 minutes. Chiral analysis after coupling with (S) -methylbenzylamine shows a peak at 9.13 minutes.
EXAMPLE 4 3- (3,4-DICHLOROPHENYL) -3-r3- (4-METHYLAMINO-4-PHENYLPIPERIPIN-1-IL) -3-OXOPROPYL1PIPERIPIN-2.6-PIONA. IN CONFIGURATION S (IX): X - Cl
(A) .- ACID CHLORIDE 3-r3- (3,4-DICHLOROPHENYL) -2.6- DIOXOPIPERIPIN-3-IL1PROPIONIC. IN CONFIGURATION S
Under a nitrogen atmosphere, 20 g of 3- [3- (3,4-dichlorophenyl) -2,6-dioxopiperidin-3-yl] propionic acid, 200 ml of toluene and 0.5 ml of DMF are mixed. The medium is heated to 60 ° C and 14.9 g of thionyl chloride and 40 ml of toluene are introduced dropwise. Stirring is maintained for five hours at 60 ° C. Toluene and excess thionyl chloride are removed by evaporation, and then the reaction medium is dried in an oven (at 40 ° C) overnight. The product obtained as such is used in the next step. IB) .- 3- (3,4-PICLOROPHENYL) -3-r3- (4-METHYLAMIN-4-PHENYLPIPERIPIN-1-IL) -3-OXOPROPYL1PIPERIPIN-2.6-PIONA. IN CONFIGURATION S
Under a nitrogen atmosphere, 11.5 g of 4-methylamino-4-phenylpiperidine in solution in 100 ml of THF and 8.52 ml of triethylamine are introduced; and then the reaction medium is cooled to 0 ° C ± 5 ° C, with an ice bath. The acid chloride prepared in the preceding step is added dropwise to 150 ml of THF, and the medium is left stirring for one hour. After evaporating the THF, the medium is washed with 100 ml of water and 100 ml of dichloromethane. The organic phase is separated after sedimenting and then washed three times with 100 ml of water. The dichloromethane is evaporated off and the medium is then dried in an oven at 40 ° C and 32.1 g of the expected compound are obtained. 29.1 g of this compound is recrystallized in the hot state, in MIBK to give 17 g of the pure compound. In addition, the recrystallization mother liquors are filtered on silica to give an additional 5.2 g of pure compound. 1 H NMR (CDCl 3): 1.65 to 2.69 ppm (16 H, m); 3.25 to 3.98 ppm (4H, m), 7.06 to 7.46 ppm (8H aromatics and CO-NH-CO). aD25 = + 77.8 ° (c = 1, methanol).
Claims (22)
1. - The compound of the formula: wherein: X represents a halogen, preferably a chlorine atom or a fluorine atom; - each of R and R2 independently represents hydrogen, an alkyl of 1 to 6 carbon atoms, which is unsubstituted or substituted by a hydroxyl, a benzyl which is unsubstituted, or which is substituted by an alkyl of 1 to 4 atoms of carbon, a hydroxyl, or R, and R2 constitute, together with the nitrogen atom to which they are attached, a heterocyclic radical selected from azetidinyl-1-yl, pyrrolidin-1-yl, piperidin-1-yl and morpholin-4 -ilo; it being possible that the heterocyclic radicals mentioned are monosubstituted or disubstituted.
2. The compound according to claim 1, further characterized in that it has the configuration described by the formula:
3. - The compound according to any of claims 1 or 2, of the formula (I), wherein the substituents Ri and R2 together constitute a heterocyclic radical, which is monosubstituted or disubstituted with one or more groups, which are similar or different, selected from an alkyl of 1 to 4 carbon atoms, a benzyl, an amino, an alkyl (of 1 to 4 carbon atoms) amino and a dialkyl (of 1 to 4 carbon atoms) amino.
4. The compound according to claim 3, of the formula: wherein X is as defined for (I) in claim 1.
5- The compound according to claim 4, of the formula:
6. The compound according to any of claims 1 to 5, further characterized in that X represents a chlorine atom or a fluorine atom.
7. The method for preparing a compound of the formula (I) according to claim 1, characterized in that a compound of the formula is cyclized: wherein X is as defined for (I) in claim 1, eliminating water.
8. The method according to claim 7, further characterized in that the compound of the formula (VI) is obtained by means of the action of an amine of the formula HNR ^^ in which R ^ and R2 are as defined above for (I), on a compound of the formula:
9. - The method according to claim 7, further characterized in that a compound of the formula is cyclized: wherein X is as defined for (I), in claim 1, by removal of water, to give a compound of the formula:
10. - The method according to claim 9, further characterized in that the compound of the formula (Vil) is obtained by the action of an amine of the formula HNRÍR ^ in which RÍ and R2 are as defined for (I) in the Claim 1, on a compound of the formula:
11. - The method for preparing a compound of the formula (I) according to claim 1, further characterized in that an amine of the formula HNRIR is reacted, wherein RT and R2 are as defined for (I) in the Claim 1, with a compound of the formula: wherein X is as defined for (I) in claim 1.
12. The method according to claim 11, characterized in that the compound of the formula (VIII) is prepared from an acid of the formula: HN-
13. The method according to claim 11, further characterized in that 4-methylamino-4-phenylpiperidine is reacted with a compound of the formula: to give a compound of the formula:
14. - The method according to claim 13, further characterized in that the compound of the formula (X) is prepared from an acid of the formula:
15. - The compound of the formula: (VI) that X, R1t R2 are as defined for (I) in the claim
16. - The compound according to claim, of the formula:
17. - The compound of the formula: wherein X is as defined for (I) in claim 1.
18. The compound according to claim 17, of the formula:
19. - The use of a compound of the formula: wherein X, R and R2 are as defined in claim 1, for the preparation of a compound of the formula: by acidolysis.
20. The use according to claim 19, of a compound of the formula: for the preparation of an acid of the formula:
21. - The use of a compound of the formula: wherein X, R ^ - R2 are as defined in claim 1, for the preparation of a compound of the formula: by reduction.
22. The use according to claim 21, of a compound of the formula: for the preparation of a compound of the formula:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR98/16088 | 1998-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01006111A true MXPA01006111A (en) | 2002-05-09 |
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