Title of Invention

A PROCESS FOR THE PREPARATION OF N- MONOSUBSTITUTED BETA-AMINO ALCOHOLS

Abstract

The invention relates to a process for the synthesis of N-monosubstituted p-amino alcohols of formula (I) and/or an addition salt of a proton acid, wherein R and R independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen via direct preparation of N-monosubstituted p-amino ketones of formula and its addition salts of proton acids, wherein R and R are as defined.

Full Text

The invention relates to a process for the preparation of N- monosubstituted β-amino alcohols of formula and/or an addition salt of a proton acid. N-Monosubstituted β-amino alcohols of formula I like (S)-(-)-3-N-methylamino-l-(2-thienyl)-1-propanol (LY293628) are useful key intermediates and building blocks for the preparation of pharmaceutically active compounds like (•S)-(+)-methyl-[3-(l-naphthyloxy)-3-(2-thienyl)-propyl]-amine ((5)-duloxetine) (Liu, H. et al., Chirality 12 (2000) 26-29) a potential neuro-active compound which strongly inhibits the serotonine and norephedrine uptake (Deeter, J. et al., Tetrahedron Lett 31 (1990) 7101-7104). In the following the terms "amine" or 'amines" include their corresponding addition salts of proton acids. Direct preparation of N-monosubstituted β-keto amines of formula 11 establishes an alternative and economically advantageous source for industrial production of N-monosubstituted β-amino alcohols of formula I. Compounds of formula II were first synthesized in 1922 by reacting ketones with formaldehyde and primary or secondary alkylamines in the presence of hydrochloric acid (Mannich, C. et al., Chem. Ber 55 (1922) 356-365). In said reactions with primary alkylamines formation of hydrochlorides of tertiary β-keto amines of formula prevails over formation of hydrochlorides of secondary β-keto amines of formula II. These findings were supported by Blicke et al. (X Am. Chem, Soc. 64 (1942) 4S1-454) and Becker et al. {Wiss. Z Tech Hochsck Chem. Lema-Merseburg. 11 (1969) 38-41). According to Mannich et al. steam destination of tertiary β-keto amines of formula III results in formation of secondary β-keto amines of formula II in fairly satisfactory yields, accompanied by vinyl compounds and other by-products. Also from Blicke, F.F., Organic reactions, vol. 1, Chapter 10, The Mannich Reaction, 1942, 303-341 is known that the mannich reaction using primary amines leads to many side products. Nobles, L.W. et al., J.Am. Pharm, Assoc, Sci.Ed., 67, 1958, 77-81 disclose among many compounds according to the compounds of formula II having a N, N-disubstituted amino group only one compound having a benzylamino group which is obtained in low yield. Another drawback in presently known preparation methods of β-keto amines is the need of isolation of the desired intermediate compounds of formula II from unwanted by-products of formula III. Eβ-A 457 559 and Eβ-A 650 965 disclose the preparation of N,N-dimethyl β-amino alcohols via Mannich-type reactions of methyl ketones with paraformaldehyde and dimethylamine followed by reduction of the carbonyl group. After reaction of the hydroxyl group affording alkyl or aryi ether derivatives one methyl radical is removed to obtain N=monosubstituted compounds which requires delicate and expensive reactions. Only Becker et al. disclose some few examples with yields of about 60% of N--monomethyl β-keto amines using N-methylammonium oxalates as nitrogen source. Nevertheless, the process disclosed by Becker et al. is not advantageous because it strictly depends on the use of amino oxalates. In contrast to the free amines or conesponding hydrochlorides oxalates of primary amines are not commercially available and their preparation requires further synthesis and purification steps. Using oxalates is also disadvantageous because it requires additional reduction equivalents in the next step, reducing the ketone intermediates to the title compounds. None of the known processes for the production of N-monosubstituted β-amino alcohols of formula I and ether derivatives thereof includes, intends or concerns intermediate products comparable to N-monosubstituted β-keto amines of formula II of the present invention. Although still many efforts were made to find new preparation processes, the pathway of the present invention for direct synthesis of N-monosubstituted β-keto amines and subsequent reduction to N-monosubstituted β-amino alcohols is not yet disclosed. The problem to be solved was to provide ian alternative and efficient process for the synthesis of A^-monosubstituted β-amino alcohols and derivatives thereof in high yields. Furthermore, the proposed process should provide high yields independently of steric aspects of the used amino or carbonyl compoimds. The problems mentioned above could be solved according to claim 1. Starting with commercially available methyl ketones and primary amines and/or an addition salt of a proton acid, which were reacted with formaldehyde in the presence a solvent and optionally of a proton acid at a pressure above 1,5 bar N-monosubstituted β- keto amines which could be directly reduced to the desired N-monosubstituted β-amino alcohols were obtained in high yields. As a further advantage of the instant process high yields of N-monomethyl β- keto amines can be obtained by direct usage of methylamine hydrochloride which is easily available, cheap and, since it is a solid compound, easy to handle. The present invention discloses a process for the preparation of a compound of formula and/or an addition salt ofa proton acid, wherein R1 and R2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises the steps of a) reacting a mixture comprising (i) a methyl ketone of formula and/or an addition salt of a proton acid, wherein R2 is as defined above, and (iii) fonnaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, l,3,S-trioxane, parafonnaldehyde and mixtures thereof, in the presence of a solvent selected from the group consisting of water, aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a proton acid to afford a compound of formula and/or an addition salt of a proton acid, and b) reducing the carbonyl group of said β- keto amines to afford a compound of formula I, and/or an addition salt of a proton acid, wherein the first step is carried out at a pressure above l.S bar. In a preferred embodiment R1 and R2 can independently represent linear or branched C1-8 alkyl, C3-8 cycloalkyl, phenyl, naphthyl, fiiranyl, benzofuranyl, thicnyl, benzo[b]thienyl or aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C1-4 alkyl- and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl, each aryl or aralkyl being optionally substituted with halogen, linear or branched C1-4 alkyl, Imear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5. It is particularly preferred that R' represents furanyl or thicnyl. It is also particularly preferred that R2 represents linear or branched C1-4 alkyl. More particularly preferred R represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or terh butyl. Preferably, the compound of formula V is used as a free amine and/or an addition salt of a proton acid. Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are free amines and/or hydrochlorides. In a preferred embodiment the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. Particularly preferrd the molar ratio of the compound of formula V to the compound of formula IV is between 1 and 2. In a preferred embodiment the solvent comprises water, an aliphatic or cycloaliphatic alcohol or a mixture thereof. Particularly preferred alcohols are linear or branched aliphatic C1-12 alcohols, cycloaliphatic C54 alcohols, di- and/or trimeric ethylene glycols or mono C1-4 alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups. Examples for said alcohols are methanol, ethanol, propanoic isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, l,4*butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether and triethylene glycol monoacetate. Preferably said alcohol is ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol* The proton acid can be any organic or inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H2SO4 and H3PO4. In a preferred embodiment the proton acid can be an acidic salt of a polybasic organic or inorganic acid like monoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates. More preferably the proton acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably it is selected from the group consisting of formic acid, acetic acid, HCl and HBr. Preferably reaction step a) is carried out either with added addition salts of amines or proton acids, since even distilled free β-amino ketones of formula II tend to decompose and form by- products while stored, whereas the corresponding additions salts can be stored over a longer period without decomposition. In the products> the ratio of free amine and its salt corresponds to the ratio of added addition salts of amines and proton acids to the whole amine amount during reaction step a). In a preferred embodiment the pressure during reaction step a) is above 1.5 bar, More preferably the pressure is in the range of 1.5 to 10 bar and particularly preferred in the range of 1.5 to 5 bar. In contrast to Becker et al. the inventive process generally allows direct preparation of N-monosubstituted β-keto amines and addition salts of proton acids thereof The products obtained by the inventive process can be reduced or subsequently reacted without further conversion into other salts. The present invention also provides a compound of formula The present invention also provides a compoimd of formula and/or an addition salt of a proton acid, wherein R1 and R2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises reacting a mixture comprising (i) a methyl ketone of formula and/or an addition salt of a proton acid, wherein R2 is as defined above, and (iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, l,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of a solvent selected firom the group consisting of water, aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a proton acid to afford a compoimd of formula and/or an addition salt of a proton acid, wherein R1 and R2 arc as defined above, and wherein the reaction is carried out at a pressure above 1.5 bar. In a preferred embodiment R and R independently represent linear or branched C1-4 alkyl, C34 cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C1-4 alkyl, and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl. each aryl or aralkyl being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5. It is particularly preferred that R1 represents furanyl or thienyl. It is also particularly preferred that R2 represents linear or branched C1-8 alkyl. More particularly preferred R2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. Preferably, the compound of formula V can be used as a free amine and/or an addition salt of a proton acid thereof. Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are free amines and/or hydrochlorides. In one preferred embodiment the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. Particularly preferred the molar ratio of the compound of formula V to the compound of formula IV is between 1 and 2. In a preferred embodiment the solvent comprises water, an aliphatic or cycloaliphatic alcohol or a mixture thereof. Particularly preferred alcohols are linear or branched aliphatic C1-12 alcohols, cycloaliphatic C5-8 alcohols, di- and/or trimeric ethylene glycols or mono C1-4 alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups. Examples for said alcohols are methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol,cyclohexanol, l,2-*ethanediol, 1,2-propanediol, l,2-butanediol,2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetrioI, diethylene glycol, diethylene glycol monomethy] ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether and triethylene glycol monoacetate. Preferably said alcohol is ethanol, propanol, isopropyl alcohol, butanol, isobutanol. tert-butanol, diethylcne glycol or triethylene glycol. The proton acid can be any organic or inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H2SO4 and H3PO4. In a preferred embodiment the proton acid is an acidic salt of a polybasic organic or inorganic acids like monoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates. More preferably the proton acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably it is selected from the group consisting of formic acid, acetic acid, HCl and HBr. In a preferred embodiment the pressure during the reaction is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and particularly preferred in the range of 1.5 to 5 bar. The present invention is illustrated by the following non-limiting examples. General Procedure for Examples 1 to 8 A mixture of methyl ketone (1 equivalent (eq)), primary alkyl amine and/or an addition salt thereof (1.1 to l.S eq), formaldehyde (1.4 to 1.5 eq), a solvent, optionally in the presence of a proton acid, is heated in an autoclave at a total pressure above l.S bar for S to 24 hours. Afterwards, the reaction solution is cooled to 20 °C. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product. The suspension is cooled (0 to 20 oC) and filtered after precipitation (O.S to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between SO and 7S %. The product can be rectystallized from isopropyl alcohol and/or ethyl acetate if necessary. If the stability of the free base is sufficient at ambient conditions, extracting with an organic solvent and an aqueous base affords the free base. General Procedure for Comparative Examples 1 to 6 A mixture of methyl ketone (1 eq), primary alkyl amine and/or an addition salt thereof (1 to l.S eq), formaldehyde (1.0 to l.S eq), optionally in the presence of a proton acid, is heated in refluxing solvent for S to 24 hours. Afterwards, the mixture is cooled to 20 oC. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product. The suspension is cooled (0 to 20 oC) and filtered after precipitation (O.S to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 30 and 45 %. The product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary. Example 10: 3-(Isobutylamino)-l-(thiophen-2-yl)propan-l-ol (I, R1 = thiophcn-2-yl, R2 = methyl) To a mixture of 3-(isobutylamino)-l-(thiophen-2-yl)propan-l-onc hydrochloride (4.2 g, 19.4 mmol) and ethanol (10 mL) at 4 o'C sodium hydroxide (1.6 g of a SO % aqueous solution) was added in about 20 minutes. Afterwards, neat sodium borhydride (0.37 g, 9.7 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 h at the same temperature, then acetone (10.0 mL) was added dropwise in 20 minutes and the mixture was stirred for 10 additional minutes. Afterwards the precipitate was removed by filtration and the mixture was concentrated under vacuum affording an orange oil. The crude product was purified by column chromatography using a 40:10 :1 (v: v: v) mixture of methylene chloride/methanol/ammonium hydroxide (25 % aqueous solution) affording 3.1 g (76 % yield) of product. 1H-NMR 5 (DMSO-d6) 400 MHz): 7.20 (1 H, dd, J - 4.8,1.0), 6.98 (1 H, dd), 6.94 (1 H, dd, J = 4.8,3.6), 5.20 (1 H, dd), 4.98 (2 H, br), 3.02 (1 H, m), 2.93 (1 H, m), 2.43 (2H, symm. m), 2.03 (1 H, m), 1.97 (1 H, m), 1.80 (1 H, sept), 0.95 (6 H, d). 13C-NMR δ (DMSO-d6,100 MHz): 150.9,126.3,123.8,122.5,72.1,57.8,48,5,37.4,28,2, 20.8. we claim: 1. A process for the preparation of a compound of formula and/or an addition salt of a proton acid, wherein R1 and R2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises reacting (i) a methyl ketone of formula and/or an addition salt of a proton acid, wherein R2 is as defmed above, and (iii) formaldehyde or a source of formaldehyde selected from the group consisting of fonnaldehyde in aqueous solution, l,3,S-trioxane, paraformaldehyde and mixtures thereof, in the presence of a solvent selected from the group consisting of water, aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a proton acid to afford a β-amino ketone of formula and/or an addition salt of a proton acid, wherein R1 and R2 are as defmed above, and wherein the reaction is carried out at a pressure above l.S bar. 2. The process as claimed in claim 1, wherein R1 is as defined in claim 1. 3. The process as claimed in claim 2 or 3, wherein R is as defined in claim 2. 4. The process as claimed in any of claims 1 to 3, wherein the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. 5. The process as claimed in any of claims 1 to 4, wherein the proton acid is a carboxylic or an inorganic acid, preferably the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCI, HBr, HI, H2SO4, H3PO4, mono alkali malonate, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogenecarbonates. 6. The process as claimed in claims 4 or 5, wherein aliphatic and cycloaliphatic alcohols are selected from the group consisting of linear or branched aliphatic C1-12 alcohols, cycloaliphatic C5-8 alcohols, di-triethylene glycols and mono C1-4 or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups. 7. The process as claimed in claim 6, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 1 -pentanol, 2-pentanol, 3-pentanol, 1 -hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1, 3-propanetriol, 1, 2, 6-hexanetriol, diethylene glycol; diethylene glycol monomethyl ether, diethylene galycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether triethylene glycol monoethyl ether, triethylene glycol monobutyl ether and triethylene glycol monoacetate. 8. The process as claimed in any of claim 3 to 7, wherein the pressure during the reaction is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and more particularly preferred in the range of 1.5 to 5 bar and its addition salts of proton acids. and its addition salts of proton acids. Dated this 02nd day of August 2007

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3399-CHENP-2007 CORRESPONDENCE OTHERS 13-05-2011.pdf

3399-CHENP-2007 CORRESPONDENCE OTHERS 19-07-2011.pdf

3399-CHENP-2007 AMENDED CLAIMS 13-08-2012.pdf

3399-CHENP-2007 CORRESPONDENCE OTHERS 13-08-2012.pdf

3399-CHENP-2007 CORRESPONDENCE OTHERS 09-08-2012.pdf

3399-CHENP-2007 AMENDED CLAIMS 18-06-2012.pdf

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3399-CHENP-2007 CORRESPONDENCE OTHERS 25-07-2012.pdf

3399-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 18-06-2012.pdf

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3399-CHENP-2007 OTHER PATENT DOCUMENT 18-06-2012.pdf

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