IE63293B1 - New process for separating optical isomers of 1,4-dihydropyridine derivatives - Google Patents
New process for separating optical isomers of 1,4-dihydropyridine derivativesInfo
- Publication number
- IE63293B1 IE63293B1 IE2890A IE2890A IE63293B1 IE 63293 B1 IE63293 B1 IE 63293B1 IE 2890 A IE2890 A IE 2890A IE 2890 A IE2890 A IE 2890A IE 63293 B1 IE63293 B1 IE 63293B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- radical
- compound
- ppm
- mixture
- Prior art date
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
New process for separating optical isomers of the compounds of general formula I: <IMAGE> in which: - Ar denotes a phenyl radical optionally containing one to five identical or different substituents, each denoting a halogen atom, an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms, a trihalomethyl radical or a methylenedioxy radical, - each of Y, Z, Y1 and Z1, which are identical or different, denotes a hydrogen atom, a linear or branched lower alkyl radical containing from 1 to 4 carbon atoms, a cyclopropyl radical, a dicyclopropylmethyl radical, a 2,2-dicyclopropylethyl radical, a 2,2-dicyclopropylethylene radical, a 3,3-dicyclopropylpropyl radical, a 3,3-dicyclopropyl-1-propylene radical, a linear or branched alkylene radical containing from 2 to 5 carbon atoms or a phenyl radical optionally substituted by a nitro radical, and - n is equal to 1, 2 or 3.
Description
The present invention relates to a new process for the preparation of optical isomers of 1,4-dihydropyridine compounds.
Certain 1,4-dihydropyridine compounds have very valuable pharmacological properties and are used therapeutically, especially as inhibitors of the intracellular penetration of calcium. Depending upon the nature of the substituents at the 2-, 3-, 5- and 6-positions, these compounds may have a chiral centre at the 4-position. It is also known that the absolute configuration at the carbon atom in the 4-position may affect the pharmacological activity of the compounds. Several methods of separating the optical isomers are already known in the literature. However, either those methods are not applicable to all 1,4-dihydropyridine compounds, especially to those containing ether oxide groups in the 2-position (Chem. Pharm. Bull., 1980, 22(9), p. 2809-2812 and WO 88/07524), or they are lengthy and produce yields that are of little value (EP 125803), or they employ reaction intermediates that are difficult to handle (J. Med. Chem., 1986, 29, p. 1696-1702). Optical isomers of 1,4-dihydropyridines have also been prepared as described in Patent Applications EP-A-259 206 and EP-A-089 167. The preparation process to which the present Application relates is, however, completely original as compared with those prior art documents, and it produces pure stereoisomers in good yields, which is not the case with the conventional separation processes previously described.
The present invention relates more especially to a process for the preparation of optical isomers of the compounds of the general formula I: (I) N ' ‘CH2-(OCH2CH2)nNH2 I H in which: - Ar represents a phenyl radical optionally containing from one to five identical or different substituents each representing a halogen atom, an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms, a trihalomethyl radical, or a methylenedioxy radical, - each of Y, Z, Yj^ and Zit which may be identical or different, represents a hydrogen atom, a linear or branched lower alkyl radical containing from 1 to 4 carbon atoms, a cyclopropyl radical, a dicyclopropylmethyl radical, a 2,2-dicyclopropylethyl radical, a 2,2-dicyclopropylethenyl radical, a 3,3-dicyclopropylpropyl radical, a 3,3-dicyclopropyl-l-propenyl radical, a linear or branched alkenyl radical containing from 2 to 5 carbon atoms, or a phenyl radical optionally substituted by a nitro radical, and - n is 1, 2 or 3, characterised in that a compound of the general formula II: OH-CH2-CH2-(OCH2CH2)n-Cl (II), in which n has the same meaning as for formula I, is condensed with potassium phthalimide, in dimethylformamide, with heating, to form a compound of formula III: in which n has the same values as for formula I, which is converted with the aid of the Jones' reagent into a compound of formula IV: in which n has the same meaning as for formula I, which is treated with carbonyldiimidazole and Meldrum acid in the presence of pyridine in methylene chloride, to obtain the compound of formula V: which is then reacted with 2(R)-phenyl-2-methoxyethanol, compound of formula VI: (VI), to obtain a β-keto ester of formula VII: 0 (VII), in which n has the same meaning as for formula I, which is condensed in the presence of ammonium formate in ethanol, with a benzylidene of formula VIII: in which the meaning of Ar, and Ζχ is the same as that given for formula I, to obtain a mixture of two stereoisomers of a compound of formula IX: in which Ar, Y1# Z^ and n have the same meanings as for formula I, which is then: either subjected to the action of an aqueous sodium hydrogen carbonate solution, in solution in acetonitrile, to obtain a mixture of stereoisomers of a compound of formula X: COOH (X), in which Ar, Yj_, for formula I, Ζχ and n have the meanings given above which is separated by means of HPLC into its two stereoisomers, and each stereoisomer is then treated separately with a mixture of glyme and an alcoholate of formula XI: HCONa ./ (xi), in which the meaning of Y and Z is the same as that given for formula I, to obtain a mixture containing one of two stereoisomers of a compound of formula XII: (XII), in which Y, Z, Y^ , Zlr Ar and n have the meanings given for formula I, as well as its homologue substituted in the 5-position by an ethoxycarbonyl radical, QE the compound of formula IX is separated into its two stereoisomers by chromatography over a silica column, and then each stereoisomer is subjected, separately, to the action of an alcoholate of formula XI in the presence of glyme, in solution in ethanol, to obtain a mixture containing a stereoisomer of the compound of formula XII, and its homologue substituted in the 5-position by an ethoxycarbonyl radical, then the said mixture containing a stereoisomer of formula XII obtained by one of the above alternatives is subjected to the action of carbonyldiimidazole in solution in a halogenated alkane at room temperature to obtain a mixture containing a stereoisomer of the compound of formula XIII: in which Ar, Y, Z, Yj., Z^ and n have the same meaning as for formula I, and its homologue substituted in the 5-position by an ethoxycarbonyl radical, which mixture is then separated θ by means of HPLC to obtain one of the stereoisomers of the pure compound of formula XIII, which is then refluxed in ethanol in the presence of hydrazine hydrate to give one of the stereoisomers of the compound of formula I, which may then be converted into a salt with a pharmaceutically compatible mineral or organic acid to obtain the corresponding addition salts. 2(E)-phenyl-2-methoxyethanol, the compound of formula VI, is obtained by reduction of the correspon20 ding, optically active, acid. The latter compound is prepared according to the process described in J. Chem. SOC., 1962, p. 1519.
The compounds of formula VIII can be obtained by condensing the compounds of formula XIV: II HC-O-C c=o (XIV), H3C in which the definition of and is the same as that given for formula I, with an aromatic aldehyde of formula XV: Ar-CHO (XV), in which the definition of Ar is that given above for formula I. The condensation is carried out according to the method described in Can. J. Chem., 1967, 45, p. 1001.
The following Examples, which are not intended to be limiting, illustrate the invention.
The melting points given are measured by the micro-Kofler technique.
The proton nuclear magnetic resonance (NMR) spectra were recorded at 200 MHz.
The absolute configuration of certain synthesis intermediates is not known at the present time. Where the two isomers of an intermediate have a negative rotatory power, the compound that yields the dextrorotatory isomer of a compound of the general formula I is called isomer A.
EXAMPLE 1 2-f 2-(2-phthalimidoethoxy)ethoxy 1acetic acid STEP A 5 2—[2—(2-phthalimidoethoxy) ethoxy]ethanol 188 g of 2-[2-(2-chloroethoxy)ethoxy]ethanol and 146 g of potassium phthalimide in 700 ml of dimethylformamide are heated at 95*C for 17 hours. The mixture is diluted with methylene chloride, washed with a saturated sodium 10 chloride solution, dried and evaporated. Distillation is carried out using a bulb tube b.p.QQj mmHg: 180-185*C. Yield: 90% Proton nuclear magnetic resonance spectrum (solvent CPC13): 4H(m) 7.5 to 8 ppm; 12H(ra) 3.4 to 4 ppm; IH (unresolved peak exchangeable by D2O) 2.5 to 3 ppm STEP B g of the alcohol obtained in the preceding step are dissolved in 150 ml of acetone. The Jones7 reagent is added, with the temperature being maintained at between 20 and 25*C. The mixture is allowed to stand for one hour at room temperature. The mixture is concentrated, • then diluted with methylene chloride and washed with water. The product is dried and the solvent is evapora25 ted off, yielding the desired compound.
Melting point: 88-90*C Yield: 90% Proton nuclear magnetic re=:~.s.-re spectrum (solvent CDCI3I: IH (exchangeable unresolved peBR) e.8 to 9.5 ppm; 4H(m) 7.6 to 8.1 ppm; 2H(s) 4.1 pzm: ΞΗ(η) 3.6 to 4 ppm EXAMPLE 2 2( R) -phenyl-2-methoxyethanol g of 2(B)-phenyl-2-raethcxvacetic acid (prepared according to the method described in J. chem. Soc., 1962, p. 1519) are reduced with 16-5 g of lithium aluminium hydride in 300 ml of tetrahyircfuran.
The mixture is hydrolysed ar.-d the mineral salts are filtered off, and then the residual oil is distilled using a bulb tube b.p. 15 n-n-- = 105*C.
Yield: 76% Proton nuclear magnetic rescr.ar.ce spectrum (solvent CDCI3): 5H(ro) 7.35 ppm; lH(d) 4.35 ppm: IH(m) 3.65 ppm; 3H(s) 3.3 ppm; IH (exchangeable d) 2.1= ppm Rotatory power in a 1% solution in ethanol: λ(η·) UJ2VC j 539 - '22* i 578 - '21* 1 5^6 i - -45· U36 - 249* 365 - 396· EXAMPLE 3 2(RI-phenyl-2-methoxyethyl ester of 5.8-dioxa-3-oxo-10phthalimidodecanoic acid g of carbonyldiimidazole are added in a single batch to a suspension containing 34.7 g of the compound of Example 1 in 210 ml of methylene chloride.
The mixture is stirred until the evolution of gas has ceased. A mixture consisting of 17.7 g of Meldrum acid and 9.2 g of pyridine in 70 ml of methylene chloride is then rapidly added dropwise. The mixture is stirred under nitrogen overnight.
The mixture is transferred into a separating funnel, is washed with N sulphuric acid until the pH is acid and then once with water, and is dried, and the solvent is evaporated off. The resulting oil is heated in a water bath with 25 g of the alcohol obtained in Example 2, until evolution has ceased.
The reaction mixture is subjected to chromatography over a column (flash chromatography) containing 1.8 kg of silica, using a mixture of cyclohexane and ethyl acetate (1:1 v/v) as eluant, yielding the desired compound.
Yield: 70% Proton nuclear magnetic resonance spectrum (solvent CDCI3): 4H(m) 7.6 to 8.1 ppm; 5H(s) 7.35 ppm; 3H(m) 4 to 4.6 ppm; 2H(s) 4.1 ppm; 10H(m) 3.5 to 4 ppm; 3H(s) 3.3 ppm ll Rotatory power in a 1% solution in ethanol: λ(ηα) [a]21*C 589 - 35Je 578 - 36,5’ 546 - 41.4° 436 - 69.8· 365 - 107.2· EXAMPLE 4 2-f2.3-dichlorobenzylidene)-3-oxobutanoic acid methyl ester A mixture containing 8.7 g of 2, 3-dichlorobenzaldehyde, .8 g of methyl acetoacetate, 28 drops of pyridine and 38 drops of hexanoic acid in 280 ml of benzene is refluxed for 4 hours, with stirring. The mixture is transferred to a separating funnel and is washed with a 10% sodium hydrogen carbonate solution and then with a N hydrochloric acid solution, and then with water. The mixture is dried and evaporated. The resulting crystals are washed with diisopropyl ether.
Yield: 65% Proton nuclear magnetic resonance spectrum tS-Qj..y.ent CDCI3J.: lH(2s) 8 and 8.05 ppm; 3H(m) 7.1 to 7.8 ppm; 3H(2s) 3.9 20 and 3.75 ppm; 3H(2s) 2.45 and 2.2 ppm EXAMPLE 5 (4R.4'R/4S.4'R)-4-(2.3-dichlorophenyl)-5-methoxycarbonyl3—(2—methoxy-2—phenylethoxvcarbonyl)—6—methy1—2—(Γ2-(2phthalimidoethoxy)ethoxvlmethyl )-1.4-dihydropyridine (4R,4'R/4S,4'R) 0 A mixture containing 22.2 g of the compound described in Example 4, 38 g of the compound described in Example 3 and 6.3 g of ammonium formate in 200 ml of ethanol is stirred under nitrogen at 40*C for 48 hours. The •0 residual mixture is evaporated and purified over a column containing 4 kg of silica, using a mixture of methylene chloride and ethyl acetate (9:1 v/v) as eluant.
Proton nuclear magnetic resonance spectrum (solvent CDCI3): 2H(m) 7.8 ppm; 2H(m) 7.7 ppm; 7H(m) 7.3 to 7.1 ppm; lH(t) 7.05 ppm; lH(s) 5.45 ppm; 2H(m) 4.6 ppm; llH(m) 3.6 to 4.4 ppm; 3H(2s) 3.6 ppm; 3H(2s) 3.2 and 3.05 ppm; 3H(s) 2.3 ppm; lH(s) not exchangeable by D2O 7.4 ppm Rotatory power in a 1% solution in chloroform: • 20 λ(ηα) (ol21*C 589 - 13.3· 578 - 13.8· 546 - 15.1· '1» EXAMPLE 6 (4R.47 R/4S.47 R)-2-{Γ 2-Γ 2-(2-carboxyphenvlcarboxamido)ethoxyIethoxylmethvll-4-(2.3-dichlorophenvl)-5-methoxvcarbonyl-3-ί2-methoxy-2-phenylethoxycarbonvl)-6-methvl1.4-dihvdropyridine A mixture containing 16.5 g of the compound of Example 5, 100 ml of a 10% aqueous sodium hydrogen carbonate solution and 230 ml of acetonitrile is refluxed for 24 hours, with stirring. The solvent is evaporated off and the residue is taken up in water, acidified with N hydrochloric acid and extracted, yielding the desired compound.
Yield: 87% •5 Proton nuclear magnetic resonance spectrum (solvent CDCI3): lH(m) 7.9 ppm; 3H(m) 7.5 ppm; 7H(m) 7.4 to 7.15 ppm; lH(t) 7.05 ppm; lH(2s) 5.45 ppm; 2H(m) 4.8 ppm; 2H(m) 4.4 to 4.1 ppm; lH(m) 3.9 ppm; 8H(m) 3.8 to 3.5 ppm; 3H(2s) 3.6 ppm; 3H(2s) 3.2 and 3.05 ppm; 3H(s) 2.3 ppm; lH(t) 6.55 ppm; IH (masked signal exchanged by D20) 7.45 ppm; IH (flat signal) 7 to 5 ppm exchanged by D20 Rotatory power in a 1¾ solution in chloroform: X(nm) [o]21’C 589 - 14.2· 578 - 14.8* 546 - 16.3* EXAMPLE 7 Separation of the two isomers of (4R.4'R/4S.4'R)-2-{f25 f 2-(2-carboxyphenylcarboxamido)ethoxyΊethoxyImethyl1-4(2,3-dichlorophenvl1-5-methoxvcarbonvl-3-(2-methoxy-2phenylethoxvcarbonyl)-6-methyl-l.4-dihydropyridine The compound of Example 6 is dissolved in acetonitrile and separated into its two isomers by preparative HPLC 10 using a Lichroprep RP18 column and a mixture of methanol and 0.025M disodium phosphate (55:45 v/v) as eluant, flow rate 3 ml/min.. Detection at 350 nm.
Isomer A Isomer A is obtained after about 20 minutes' elution.
Rotatory power in a 1% solution in chloroform: λ(η·) (q]21*C 589 - 19.3° 578 - 20,0* 546 - 21.9* Isomer B Isomer B is obtained according to the process described above after about 23 minutes' elution.
EXAMPLE 8 Separation of the two isomers of (4R.4'R/4S.4/R)-4-(2.3dichlorophenyl)-5-methoxycarbony1-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methvl-2-(f 2-(2-phthalimidoethoxy)5 ethoxyImethy11-1.4-dihvdropyridine Isomer B The compound of Example 5 is chromatographed over a preparative column containing 4 kg of silica, using a mixture of methylene chloride and ethyl acetate (95:5 v/v) as eluant. The first compound produced by the separation, which is the least polar, is isolated.
Yield: 20% Proton nuclear magnetic resonance spectrum (solvent CDCI3): 2H(m) 7.8 ppm; 2H(m) 7.7 ppm; 7H(m) 7.4 to 7.1 ppm; lH(t) 7.05 ppm; lH(s) 5.45 ppm; 2H(ra) 4.4 ppm; Hr. m) 4 to 3.7 ppm; 3H(s) 3.6 ppm; 3H(s) 3.05 ppm; 3H(s 2.3 ppm; lH(s) 7.45 ppm (exchangeable with difficulty by D20) Rotatory power in a 1% solution in chloroform: λ(ηβ) Iaj21*C 589 - 9.0· 578 - 9.6· 546 - 10.4· Isomer A The second compound, the most polar, produced by the separation indicated above is isomer A.
Rotatory power in a 1% solution in chloroform: λ(ηα) [q]21’C 589 - 19.1’ 578 - 19.9° 5*»6 - 22,0· EXAMPLE 9 Mixture of (-)-2-(Γ2-Γ2-(2-carboxyphenylcarboxamido)5 ethoxylethoxvImethyl)-4-(2.3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l.4-dihydropvridine and its homologue substituted in the 5-position by an ethoxycarbonyl radical * First process 3 g of isomer B of Example 7 are refluxed with 30 ml of glyme and 42.9 ml of an ethanolic solution of 0.26M sodium ethanolate. The mixture is evaporated, taken up in water, acidified, and extracted with ethyl acetate, yielding the desired compounds.
* Second process g of isomer B, obtained in Example 8, are refluxed with 30 ml of glyme and 28.6 ml of an ethanolic solution of 0.26M sodium ethanolate. The mixture is evaporated, taken up in water, acidified, and extracted with ethyl acetate, yielding the desired compounds.
Yield: 65% EXAMPLE 10 Mixture of ( + )-2-( f 2-f 2-(2-carboxyphenylcarboxamido)ethoxy1ethoxy 1 methyl 1-4-(2.3-dichlorophenvl )-3-ethoxvcarbonyl-5-methoxycarbonyl-6-methyl-l. 4-dihydropyridine and its homoloque substituted in the 5-position by an ethoxycarbonyl radical Isomer A of Example 7 is treated according to the first process described in Example 9, or isomer A obtained in Example 8 is treated according to the second process described in Example 9, to give the desired compounds.
EXAMPLE 11 Mixture of (-)-4-(2.3-dichlorophenvl)-3-ethoxycarbonvl-5methoxycarbonvl-6-methvl-2-(Γ 2-( 2-phthaliaidoethoxvlethoxylmethyl )-1.4-dihydropvridine and its homoloque substituted in the 5-position by an ethoxycarbonyl radical 1.9 g of the mixture obtained in Example 9 are dissolved in 30 ml of methylene chloride, and 0.9 g of carbonyldiimidazole is added in a single batch. The mixture is stirred overnight.
The reaction mixture is transferred into a separating funnel and is washed with 10% sodium hydrogen carbonate and then with N hydrochloric acid and with water. The mixture is dried and evaporated, yielding the desired compounds.
Yield: 65% EXAMPLE 12 Mixture of (+)-4-(2.3-dichlorophenyl)-3-ethoxycarbonyl-5methoxycarbonyl-6-methyl-2-( f 2-(2-phthalimidoethoxy)ethoxyImethyl)-1.4-dihvdropyridine and its homologue substituted in the 5-position by an ethoxvcarbonyl radical 0.65 g of the mixture obtained in Example 10 is dissolved in 10 ml of methylene chloride, and 0.3 g of carbonyldiimidazole is added in a single batch. The procedure described in Example 11 is followed, yielding the desired compounds.
EXAMPLE 13 (-) -4-( 2.3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-( (2-( 2-phthalimidoethoxy)ethoxy 115 methyl)-1,4-dihvdropyridine The mixture obtained in Example 11 is separated by preparative HPLC using a 50 cm long Lichroprep RP 18 column and a mixture of ethanol, water and TFA (500:500:1) as eluant. The desired compound is isolated first.
Yield: 30% Rotatory power in a 1% solution in DMSO: λ(ηα) (q|20«C 589 - 34.6’ 578 - 36,5’ 546 - 43.9’ 436 - 119.0· EXAMPLE 14 (+)-4-(2.3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxv5 carbonyl-6-nethyl-2-(f 2-( 2-phtha limidoethoxy) ethoxy 1methyl) -1.4-dihydropyridine This compound was obtained according to the process described in Example 13, starting from the mixture of Example 12.
Rotatory power in a 1% solution in DMSO: A(na) (Q]20’C 589 * 27.8· 578 * 30.2· 546 ♦ 37.4· 436 ♦ 123.5’ EXAMPLE 15 (-)-2-(Γ 2-(2-aminoethoxy)ethoxy 1methyl )-4-(2.3-dichlorophenyl ) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l. 4dihydropyridine g of the compound prepared in Example 13 is refluxed for 4 hours with 10 ml of ethanol and 0.25 ml of hydrazine hydrate. The solvent is evaporated off, the residue is taken up in diethyl ether and washed with 5 ml of normal sodium hydroxide, and the ethereal phase is exhaustively extracted with N hydrochloric acid. The aqueous phases are then rendered basic and extracted with diethyl ether, yielding the desired compound.
Yield: 60% Melting point: 69-71*C Proton nuclear magnetic resonance spectrum (solvent CPC13): lH(m) 7.3 to 7.7 ppm exchangeable by D20; 3H(m) 7.6 to 6.9 ppm; lH(s) 5.5 ppm; 2H(s) 4.8 ppm; 2H(q) 4 ppm; 4H(s) 3.7 ppm; 2H(m) 3.4 to 3.7 ppm; 3H(s) 3.6 ppm; 2H(t) 2.9 ppm; 3H(s) 2.3 ppm; 2H(m) exchangeable by 020 1.4 to 1.8 ppm; 3H(t) 1.2 ppm Rotatory power in a 1% solution in chloroform: λ(η·) (a]20.5’C 589 - 36.5’ 578 - 38.7’ 546 - 46.8· 436 - 133.0· EXAMPLE 16 (+)-2-( Γ2—f 2-aminoethoxy)ethoxyImethyl)-4-(2.3-dichloro5 pheny 1)-3-ethoxvcarbonyl-5-methoxvcarbonyl-6-methvl-l. 4dihydropvridine This compound was prepared from (+)-4-(2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-21° ([ 2-( 2-phthal imidoethoxy) ethoxy ] methyl }-l, 4-dihydropyridine by means of the process described in Example 15 Melting point: 68-70*C Proton nuclear magnetic resonance spectrum (solvent CPC13): 2H(m) 7.3 ppm; lH(t) 7.1 ppm; lH(s) 5.5 ppm; 2H(m, syst A B) 4.8 ppm; 2H(q) 4.05 ppm; 4H(m) 3.7 ppm; 3H(s) 3.65 ppm; 2H(t) 3.6 ppm; 2H(t) 2.9 ppm; 3H(s) 2.3 ppm; 3H(t) 1.2 ppm; (lH(s) 7.4 ppm; 2H(s) 1.65 ppm exchanged by D20] V Rotatory power in a 1% solution in chloroform: λ(η·) (aj20*C 589 - 36.3’ 578 - 38.9° 546 - 46.9° 436 - 134.0* EXAMPLE 17 (-)-2-(Γ 2-(2-aminoethoxy)ethoxyImethyl)-4-(2.3-dichloro Phenyl)-3-ethoxvcarbonvl-5-methoxvcarbonvl-6-methy1-1.4 dihvdropyridine fumarate (-)-2-([2-(2-aminoethoxy)ethoxy]methyl )-4-(2,3-dichloro phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l,4 dihydropyridine fumarate is obtained after dissolving 10 4.2 g of the compound of Example 15 in 50 ml of an ethanolic solution of 0.172M fumaric acid and recrystal lising from acetonitrile.
Yield: 92% Melting point: 115*C Proton nuclear magnetic resonance spectrum (solvent CPC13 and DMSO-d6): 2H(2dd) 7.3 ppm; lH(t) 7.1 ppm; 2H(s) 6.7 ppm; lH(s) .45 ppm; 2H(m) 4.7 ppm; 2H(q) 4 ppm; 6H(m) 5.7 ppm; 3H(s) 3.6 ppm; 2H(m) 3.1 ppm; 3H(s) 2.3 ppm; 3H(t) 1.3 ppm; lH(s exchanged by D20) 7.7 ppm; 4H(s exchanged by D2O) 5.7 ppm Rotatory power in a 1% solution in DMSO: λ(η·) (a]20.5*C 589 - 33,1’ 578 - 35,2· 546 - 43.0· 436 - 134.6· EXAMPLE 18 (+)-2-( f 2-(2-aminoethoxy)ethoxyImethy1)-4-(2.3-dichlorophenv1)-3-ethoxycarbony1-5-methoxycarbony1-6-methy1-1.4dihydropvridine fumarate .45 g of the base described in Example 16 and 1.3 g of fumaric acid are dissolved, with heating, in 100 ml of ethanol. After evaporation, the residue is solidified with 3 ml of ethyl acetate, and the product is dried and recrystallised from 80 cc of acetonitrile. 6.2 g of the desired compound are obtained.
Melting point: 115*C Proton nuclear magnetic resonance spectrum (solvent CPC13): 2H(2dd) 7.3 ppm? lH(t) 7.1 ppm? 2H(s) 6.7 ppm; lH(s) .45 ppm; 2H(m syst A B) 4.7 ppm; 2H(q) 4 ppm; 6H(m) 3.7 ppm; 3H(s) 3.6 ppm; 2H(m) 3.1 ppm; 3H(s) 2.3 ppm; 3H(t) 1.3 ppm; lH(s) 7.7 ppm; 4H(s) 5.7 ppm Rotatory power in a 1% solution in ethanol: X(na) (Q]20.5*C 589 * 32.9’ 578 * 35.2· 546 ♦ 43.2· 436 ♦ 135.4· & EXAMPLE 19 (-)-2-( f 2-( 2-aminoethoxy)ethoxy Imethyl > -4-(2,3-dichlorophenyl )-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l . 4dihydropyridine (+)-tartrate 0.2 g of the compound of Example 15 is dissolved in 3.1 ml of an ethanolic solution of 0.133M (+)-tartaric acid. After evaporation of the solvent, 0.24 g of the desired salt is obtained.
Melting point: 150*C Rotatory power in a 1% solution in DMSO: λ(ηα) (q]21.5*C 589 - 29.9’ 578 - 32.5’ 546 - 40.5’ 436 - 133.9· EXAMPLE 20 (-)-2-( Γ 2-( 2-aminoethoxy)ethoxy)methyl )-4-( 2.3-dichlorophenyl )-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l . 4dihydropyridine (-)-tartrate 0.3 g of the compound of Example 15 are dissolved in 4.6 ml of an ethanolic solution of 0.133M (-)-tartaric acid. The desired salt is isolated after filtration. Melting point: 161-166*C (sublimation) Rotatory power in a 1% solution in DMSO: λ(ηο) (a]21.5*C 589 - 32.9’ 578 - 35.0· 546 - 42.8· 436 - 142,4· EXAMPLE 21 Racemic tartrate of (-)-2-(f2-(2-aminoethoxy)ethoxylmethyl)-4-(2.3-dichlorophenyl)-3-ethoxycarbony1-5methoxycarbonyl-6-methyl-l.4-dihydropyridine 5 0.45 g of the compound of Example 15 is dissolved in 6.9 ml of an ethanolic solution of 0.133M racemic tartaric acid. The desired salt is isolated after filtration.
Melting point: 160-170‘C Rotatory power in a 1% solution in DMSO: λ(ηα) [n]21.5’C 589 - 31.2° 578 - 33.5’ 546 - 41,T 436 - 135.9’
Claims (3)
1. Process for the preparation of optical isomers of the compounds of the general formula I: H in which: - Ar represents a phenyl radical optionally containing from one to five identical or different substituents each representing a halogen atom, an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms, a trihalomethyl radical, or a methylenedioxy radical, - each of Y, Z, Yj and Z lz which may be identical or different, represents a hydrogen atom, a linear or branched lower alkyl radical containing from 1 to 4 carbon atoms, a cyclopropyl radical, a dicyclopropylmethyl radical, a 2,2-dicyclopropylethyl radical, a
2. ,2-dicyclopropylethenyl radical, a 3,3-di cyclopropylpropyl radical, a 3,3-dicyclopropyl-l-propenyl radical, a linear or branched alkenyl radical containing from 2 to 5 carbon atoms, or a phenyl radical optionally substituted by a nitro radical, and - n is 1, 2 or 3, characterised in that a compound of the general formula II: OH-CH 2 -CH 2 -(OCH 2 CH 2 ) n -Cl (II), in which n has the same meaning as for formula I, is condensed with potassium phthalimide, in diroethylformamide, with heating, to form a compound of (III), formula III: in which n has the same values as for formula I, which is converted with the aid of the Jones' reagent into a compound of formula IV: (IV), in which n has the same meaning as for formula I, which is treated with carbonyldiimidazole and Meldrum acid in the presence of pyridine in methylene chloride, to obtain the compound of formula V: (V), which is then reacted with 2(E)-phenyl-2-methoxyethanol, compound of formula VI: (VI), to obtain a B-keto ester of formula VII: (VII), in which n has the same meaning as for formula I, which is condensed in the presence of ammonium formate in ethanol, with a benzylidene of formula VIII: in which the meaning of Ar, Y^ and Z^ is the same as that given for formula I, to obtain a mixture of two stereoisomers of a compound of formula IX: in which Ar, Y 1# Z^ and n have the same meanings as for formula I, which is then: either subjected to the action of an aqueous sodium hydrogen carbonate solution, in solution in acetonitrile, to obtain a mixture of stereoisomers of a compound of (UR.irR/US.VR) in which Ar, Y 1# Z^ and n have the meanings given above -4» for formula I, which is separated by means of HPLC into its two stereoisomers, and each stereoisomer is then treated separately with a mixture of glyme and an alcoholate of formula XI: HCONa / (XI). in which the meaning of Y and Z is the same as that given for formula I, to obtain a mixture containing one of two stereoisomers of a compound of formula XII: in which Y, Z, Υχ, Zj., Ar and n have the meanings given for formula I, as well as its homologue substituted in the 5-position by an ethoxycarbonyl radical, or the compound of formula IX is separated into its two stereoisomers by chromatography over a silica column, and then each stereoisomer is subjected, separately, to the action of an alcoholate of formula XI in the presence of glyme, in solution in ethanol, to obtain a mixture containing a stereoisomer of the compound of formula XII, and its homologue substituted in the 5-position by an ethoxycarbonyl radical, then the said mixture containing a stereoisomer of formula XII obtained by one of the above alternatives is subjected to the action of carbonyldiimidazole in solution in a halcgenated alkane at room temperature to obtain a mixture containing a stereoisomer of the r, 5 compound of formula XIII: in which Ar, Y, Z, Y 1# Zj^ and n have the same meaning as for formula I, and its homologue substituted in the 5-position by an 10 ethoxycarbonyl radical, which mixture is then separated by means of HPLC to obtain one of the stereoisomers of the pure compound of formula XIII, which is then refluxed in ethanol in the presence of hydrazine hydrate to give one of the stereoisomers of the 15 compound of formula I, which may then be converted into a salt with a pharmaceutically compatible mineral or organic acid to obtain the corresponding addition salts. (UR.U'R/US.K'R) in which Ar, Yj., Z± and n have the same meaning as for formula I according to claim 1, useful intermediates for the preparation process according to claim 1.
3. Process according to claim 1, characterised in that a compound of formula XIII: in which Ar, Y, Z, Yj^, Z± and n have the same meaning as for formula I according to claim 1, is obtained by subjecting a compound of formula XII: in which Y, Z, Υχ, Z^, Ar and n have the meanings given for formula I according to claim 1, to the action of carbonyldiimidazole in solution in a halogenated alkane, such as methylene chloride, at room temperature.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8912323A FR2652083B1 (en) | 1989-09-20 | 1989-09-20 | NOVEL PROCESS FOR SEPARATING OPTICAL ISOMERS OF 1,4-DIHYDRO PYRIDINE DERIVATIVES. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE900028A1 IE900028A1 (en) | 1991-03-27 |
| IE63293B1 true IE63293B1 (en) | 1995-04-05 |
Family
ID=9385673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2890A IE63293B1 (en) | 1989-09-20 | 1990-01-04 | New process for separating optical isomers of 1,4-dihydropyridine derivatives |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0419297B1 (en) |
| JP (1) | JPH03112965A (en) |
| AT (1) | ATE106870T1 (en) |
| AU (1) | AU618444B2 (en) |
| CA (1) | CA2007718A1 (en) |
| DE (1) | DE69009642T2 (en) |
| DK (1) | DK0419297T3 (en) |
| ES (1) | ES2057455T3 (en) |
| FR (1) | FR2652083B1 (en) |
| IE (1) | IE63293B1 (en) |
| NZ (1) | NZ232089A (en) |
| OA (1) | OA09436A (en) |
| PT (1) | PT92859B (en) |
| ZA (1) | ZA90231B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2686879B1 (en) * | 1992-02-05 | 1994-03-18 | Adir Cie | NOVEL 1,4-DIHYDROPYRIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK161312C (en) * | 1982-03-11 | 1991-12-09 | Pfizer | CHANGES FOR THE PREPARATION FOR THE PREPARATION OF 2-Amino-CO-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-2-D-Hydroxy |
| FR2602231B1 (en) * | 1986-08-04 | 1988-10-28 | Adir | NOVEL 1,4-DIHYDRO PYRIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2649395B1 (en) * | 1989-07-04 | 1992-11-06 | Adir | NEW DERIVATIVE OF 1,4-DIHYDRO PYRIDINE NAMED (-) I1(((2-AMINO ETHOXY)-2 ETHOXY) METHYLI1) -2 (2,3-DICHLORO-PHENYL)-4 ETHOXYCARBONYL-3 METHOXYCARBONYL -5 METHYL-6 DIHYDRO-1,4 PYRIDINE, ITS PREPARATION PROCESS AND THE COMPOSITIONS WHICH CONTAIN IT |
-
1989
- 1989-09-20 FR FR8912323A patent/FR2652083B1/en not_active Expired - Fee Related
-
1990
- 1990-01-04 IE IE2890A patent/IE63293B1/en not_active IP Right Cessation
- 1990-01-12 PT PT92859A patent/PT92859B/en not_active IP Right Cessation
- 1990-01-12 AU AU47926/90A patent/AU618444B2/en not_active Ceased
- 1990-01-12 JP JP2003680A patent/JPH03112965A/en active Pending
- 1990-01-12 OA OA59725A patent/OA09436A/en unknown
- 1990-01-12 ZA ZA90231A patent/ZA90231B/en unknown
- 1990-01-12 NZ NZ232089A patent/NZ232089A/en unknown
- 1990-01-12 CA CA002007718A patent/CA2007718A1/en not_active Abandoned
- 1990-01-15 EP EP90400096A patent/EP0419297B1/en not_active Expired - Lifetime
- 1990-01-15 DK DK90400096.5T patent/DK0419297T3/en active
- 1990-01-15 DE DE69009642T patent/DE69009642T2/en not_active Expired - Fee Related
- 1990-01-15 ES ES90400096T patent/ES2057455T3/en not_active Expired - Lifetime
- 1990-01-15 AT AT90400096T patent/ATE106870T1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0419297B1 (en) | 1994-06-08 |
| OA09436A (en) | 1992-10-15 |
| PT92859A (en) | 1990-07-31 |
| AU618444B2 (en) | 1991-12-19 |
| DE69009642D1 (en) | 1994-07-14 |
| IE900028A1 (en) | 1991-03-27 |
| ZA90231B (en) | 1990-11-28 |
| EP0419297A1 (en) | 1991-03-27 |
| PT92859B (en) | 1995-12-29 |
| NZ232089A (en) | 1991-09-25 |
| AU4792690A (en) | 1991-03-28 |
| DE69009642T2 (en) | 1994-10-27 |
| FR2652083A1 (en) | 1991-03-22 |
| DK0419297T3 (en) | 1994-10-31 |
| JPH03112965A (en) | 1991-05-14 |
| CA2007718A1 (en) | 1991-03-20 |
| ES2057455T3 (en) | 1994-10-16 |
| FR2652083B1 (en) | 1992-01-24 |
| ATE106870T1 (en) | 1994-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK169730B1 (en) | Arylimide derivatives and process for the preparation of arylpiperidinecarbinol derivatives | |
| JP3992666B2 (en) | Carboxylic acid derivatives | |
| HU187868B (en) | Process for producing dihydropyridine derivatives | |
| BG64649B1 (en) | New dihydropyrimidines | |
| EP0220518A2 (en) | Preparation of substituted and disubstituted pyridine-2,3-dicarboxylate esters | |
| FR2670491A1 (en) | NOVEL 1,4-DISUBSTITUTED PIPERAZINES, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME | |
| US5670525A (en) | Substituted 4-phenyl-6-amino-nicotinic acid compounds useful in the treatment of CNS disorders | |
| CZ2007455A3 (en) | Method of isolation and purification of montelukast | |
| KR20010093781A (en) | Intermediate for the synthesis of amlodipine, preparation process and corresponding utilization | |
| BG65889B1 (en) | A pyridine-1-oxide derivative, and process for its transformation into pharmaceutically efective compounds | |
| DK166584B1 (en) | SUBSTITUTED 4-BENZYL-1H-IMIDAZOLES, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM | |
| EP0215250B1 (en) | 2-substituted-1,4-dihydropyridines, method for their preparation and pharmaceutical compositions containing them | |
| EP0365064B1 (en) | Substituted aromatic compounds having an action on the central nervous system | |
| IE63293B1 (en) | New process for separating optical isomers of 1,4-dihydropyridine derivatives | |
| US4500527A (en) | Antihypertensive 4[(3-alkylamino-2-hydroxypropyl)-oxyiminomethyl phenyl]-1,4-dihydropyridines | |
| HU193785B (en) | Process for producing dihydropyridine derivatives | |
| ES2912409T3 (en) | Intermediates and processes for the preparation of linagliptin and its salts | |
| HU194172B (en) | Process for preparing 1,4-dihydro-pyridina derivatives | |
| EP0578849B1 (en) | Process for the preparation of 1,3-dioxane-4,6-dione derivates | |
| EP0110496B1 (en) | Improvements in keto intermediates, their use and preparation | |
| HU217981B (en) | N-(3-chlorophenyl)-piperazine derivatives and process for producing them | |
| IE67059B1 (en) | A process for the preparation of a 1,4-dihydropyridine derivative namely (-)-2-{[2-(aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine and its salts | |
| RU1816282C (en) | Process for preparing 2-aminoalkylthiomethyl-1,4-dihydropyridine derivatives or their optical isomers | |
| NO774456L (en) | PROCEDURE FOR THE PREPARATION OF NEW BASIC SUBSTITUTED O-PROPYLOXIMES AND THEIR USE AS MEDICINES | |
| NO862917L (en) | PROCEDURE FOR THE PREPARATION OF DIHYDROCHINOLINON DERIVATIVES, AND INTERMEDIATE PRODUCTS AND THEIR PREPARATION. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |