HK1115578B - Process for the preparation of enantiomerically pure 1-substituted-3-aminoalcohols - Google Patents

Description

Process for the preparation of enantiomerically pure 1-substituted-3-aminoalcohols

Technical Field

The invention relates to a method for producing N-monosubstituted beta-aminoalcohol sulfonates of general formulae Ia and Ib

And

in the formula, R¹Is C_6-20Aryl or C_4-12Heteroaryl, each optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R²Is selected from C_1-4Alkyl radical, C_3-8Cycloalkyl and C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Selected from the group consisting of: c_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

the method comprises the following steps:

a) reacting a mixture comprising components (i), (II) and (iii) in the presence of a sulfonic acid of formula VI, optionally in an organic solvent, to obtain a beta-aminoketonesulfonate of formula II,

(i) methyl ketones of the formula

In the formula R¹As defined above, the above-mentioned,

(ii) a primary amine of the formula

H₂N-R² V，

In the formula R²As defined above, the above-mentioned,

(iii) formaldehyde or a source of formaldehyde selected from the group consisting of: aqueous formaldehyde, 1, 3, 5-trioxane, paraformaldehyde, and mixtures thereof,

R³-SO₂-OH VI

in the formula R³As defined above, the organic solvent optionally contains water,

in the formula R¹、R²And R³As defined above, and

b) asymmetrically hydrogenating the sulfonate in a polar solvent, optionally in the presence of water, in the presence of a base and a catalyst under a hydrogen pressure of 5 to 50 bar to obtain a beta-aminoalcohol sulfonate of the general formula I, wherein R¹，R²And R³As defined above, the catalyst comprises a transition metal and a diphosphine ligand.

Background

(S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol is an intermediate useful in the preparation of (S) - (+) -methyl- [3- (1-naphthyloxy) -3- (2-thienyl) -propyl ] -amine (duloxetine), an agent for the treatment of depression and urinary incontinence (Huiling et al Chirality 2000, 12, 26-29, Sorbera et al, Drugs of the Future 2000, 25(9), 907-.

The reaction of step a) in the presence of a mineral acid or carboxylic acid has been disclosed in WO-A2004/005239 and gives a mineral acid salt or carboxylic acid salt of the compound of the general formula II. The disadvantage of this process is the long reaction time in the autoclave vessel, about 8 hours or more. The pressurized reaction has a risk of damage, which increases with increasing reaction time.

In 1992, N-monosubstituted β -amino ketones were first synthesized by reacting methyl ketones with formaldehyde and primary or secondary alkylamines in the presence of hydrochloric acid (Mannich, C. et al, chem. Ber.1922, 55, 356-365). In said reaction with a primary alkylamine, a tertiary beta-keto amino hydrochloric acid of the formula

The salt is formed prior to the secondary beta-keto amino hydrochloride. These findings were supported by Blicke et al (J.Am. chem.Soc.1942, 64, 451-454) and Becker et al (Wiss.Z.Tech.Hochsch. chem.Leuna-Merseburg.1969, 11, 38-41).

According to Mannich et al, steam distillation of tertiary beta-aminoketones results in the formation of secondary beta-aminoketones in reasonably satisfactory yields, accompanied by vinyl compound by-products and other by-products. The poor yield of tertiary beta-aminoketones of about 40-60% and the loss in subsequent cleavage of more than 50% make the Mannich process unsuitable for industrial production. In the steam distillation of beta-aminoketone hydrochloride of the general formula III (in the formula, R)¹Is thienyl, R²Is methyl), there is no evidence of the formation of the corresponding secondary N-monosubstituted β -aminoketone (Blicke et al).

Several methods for the asymmetric and racemic hydrogenation of thienylaminoketones, as well as for the chiral resolution (resolution) of 3-N-methylamino-1- (2-thienyl) -1-propanol, are known (WO-A2003/062219, FR-A2841899, WO-A2004/005220, WO-A2004/005307).

Huiling et al describe the preparation of (S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol from thiophene. Thiophene is converted with 3-chloropropionyl (propanoyl) chloride to 3-chloro-1- (2-thienyl) -1-propanone in benzene in the presence of tin tetrachloride, which is reduced with sodium borohydride to 3-chloro-1- (2-thienyl) -1-propanol in ethanol. Kinetic resolution by transesterification using vinyl butyrate and lipase B from Candida antarctica as catalysts in hexane gave (S) -3-chloro-1- (2-thienyl) -1-propanol which was converted to (S) -3-iodo-1- (2-thienyl) -1-propanol using sodium iodide in acetone. Followed by treatment with methylamine in tetrahydrofuran to give (S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol.

Sorbera et al disclose an alternative process for the preparation of (S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol from thiophene, which is essentially the same as the known process of Huiling et al, except that 3-chloro-1- (2-thienyl) -1-propanone is asymmetrically reduced to (S) -3-chloro-1- (2-thienyl) -1-propanol in THF using borane and a catalytic amount of (R) -3, 3-diphenyl-1-methyltetrahydro-3H-pyrrolo [1, 2-c ] [1, 3, 2] oxazaborole (oxazaborole). This asymmetric reduction gave (S) -3-chloro-1- (2-thienyl) -1-propanol from 3-chloro-1- (2-thienyl) -1-propanone in 86% yield (Wheeler et al, J.Label.Compd.radiopharm.1995, 36, 213-.

Asymmetric hydrogenation of hydrochloride salts of 3-N-methylamino-1-phenyl-1-propanol and 3-amino-1-phenyl-1-propanone is disclosed in chem.pharm.Bull. (1995, 43, 748-753) and JP-A50-70412, to Sakuraba et al. EP-A457559 discloses the preparation of hydrochloride salts of 3-dimethylamino-1- (2-thienyl) -1-propanone and (S) - (-) -N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine, and the preparation of oxalate salts of (S) - (+) -N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine and (S) - (-) -N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) -propylamine.

Although several processes for the asymmetric hydrogenation of aminoketones of the general formula II are known, the most stringent requirements of the national registry for the optical purity of chiral pharmaceutically active compounds necessitate constantly improved preparation processes.

The above-described process for preparing (S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol has the disadvantage of using toxic or carcinogenic compounds, such as tin tetrachloride and benzene, and/or expensive compounds, such as borane or sodium iodide, which are also difficult to handle. The disclosed asymmetric hydrogenation process using diphosphines is unsatisfactory for the hydrogenation of 3-N-methylamino-1- (2-thienyl) -1-propanone.

Disclosure of Invention

It is an object of the present invention to provide an economically and environmentally improved process for the preparation of enantiomerically pure N-monosubstituted-3-aminoalcohols, especially (S) - (-) -and (R) - (+) -3-N-methylamino-1- (2-thienyl) -1-propanol. The invention furthermore provides an improved process for preparing aminoketones of the general formula II, from which the sulfonic acid salts can be prepared directly.

These objects are achieved by the method of claim 1.

Provided is a process for preparing N-monosubstituted-beta-aminoalcohol sulfonates represented by the general formulae Ia and Ib

And

in the formula, R¹Is C_6-20Aryl or C_4-12Heteroaryl, each optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R²Is selected from C_1-4Alkyl radical, C_3-8Cycloalkyl and C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

the method comprises the following steps:

a) reacting a mixture comprising components (i), (II) and (iii) in the presence of a sulfonic acid of formula VI, optionally in an organic solvent, to obtain a beta-aminoketonesulfonate of formula II,

(i) methyl ketones of the formula

In the formula R¹As defined above, the above-mentioned,

(ii) a primary amine of the formula

H₂N-R² V，

In the formula R²As defined above, the above-mentioned,

(iii) formaldehyde or a source of formaldehyde selected from the group consisting of: aqueous formaldehyde, 1, 3, 5-trioxane, paraformaldehyde, and mixtures thereof,

R³-SO₂-OH VI

in the formula R³As defined above, the organic solvent optionally contains water,

in the formula R¹，R²And R³As defined above, and

b) asymmetrically hydrogenating the sulfonate in a polar solvent, optionally in the presence of water, in the presence of a base and a catalyst under a hydrogen pressure of 5 to 50 bar to obtain a beta-aminoalcohol sulfonate of the general formula I, wherein R¹，R²And R³As defined above, the catalyst comprises a transition metal and a diphosphine ligand.

The term "enantiomerically pure compound" includes optically active compounds with an enantiomeric excess of at least 85%.

The term "C_1-nAlkyl radicals ", e.g.“C_1-18Alkyl "denotes a straight-chain or branched alkyl group having 1 to n carbon atoms. C optionally substituted by one or more halogen atoms_1-18Alkyl represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl and octadecyl.

The term "C_1-nAlkoxy radicals, e.g. "C_1-6Alkoxy "denotes a straight or branched chain alkoxy group having 1 to n carbon atoms. C optionally substituted by one or more halogen atoms_1-6Alkoxy denotes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy and hexoxy.

The term "C_3-nCycloalkyl radicals, e.g. "C_3-10Cycloalkyl "denotes a cycloaliphatic radical having from 3 to n carbon atoms. C optionally substituted by one or more halogen atoms_3-10Cycloalkyl denotes, for example, a monocyclic or polycyclic ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or norbornyl.

The term "C_6-nAryl radicals, e.g. C_6-20Aryl, denotes an aromatic radical having 6 to n carbon atoms, optionally substituted by one or more halogen atoms, amino groups and/or C_1-6Alkyl radical, C_1-6Alkoxy or di-C_1-6Alkylamino, wherein the alkyl moiety is optionally substituted with one or more halogen atoms. C_6-20Aryl represents, for example, phenyl, naphthyl and the derivatives listed above.

The term "C_4-nHeteroaryl radicals, e.g. C_4-12Heteroaryl, representing a heteroaromatic group having 4 to n carbon atoms and containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted by one or more halogen atoms, amino groups and/or C optionally substituted_1-6Alkyl radical, C_1-6Alkoxy or di-C_1-6Alkylamino wherein the alkyl moiety is optionally substituted with one or moreAnd (3) halogen atom substitution. C_4-12Heteroaryl denotes, for example, furyl or thienyl and the derivatives listed above, preferably 2-furyl and 2-thienyl.

The term "C_7-nAralkyl radicals, e.g. C_7-20Aralkyl, denotes an aromatic group having 7 to n carbon atoms, wherein the alkyl moiety of the aralkyl residue is straight-chain C_1-8Alkyl, and the aryl moiety is selected from the group consisting of: phenyl, naphthyl, furyl, thienyl, benzo [ b]Furyl, benzo [ b ]]Thienyl, optionally substituted by one or more halogen atoms, amino and/or C_1-6Alkyl radical, C_1-6Alkoxy or di-C_1-6Alkyl amino substitution. C_7-20Aralkyl represents, for example, benzyl or phenylethyl and the derivatives listed above.

Further, a process for preparing N-monosubstituted beta-aminoalcohol sulfonates represented by the general formulae Ia and Ib

And

in the formula, R¹Is C_6-20Aryl or C_4-12Heteroaryl, each optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R²Is selected from C_1-4Alkyl radical, C_3-8Cycloalkyl and C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

the method comprises the following steps: asymmetrically hydrogenating a beta-aminoketone sulfonate of the formula II in a polar solvent, optionally in the presence of water, in the presence of a base and a catalyst comprising a transition metal and a diphosphine ligand, under a hydrogen pressure of 5 to 50 bar

In the formula, R¹，R²And R³As defined above.

In a preferred embodiment, the process comprises steps a) and b) or only step b), R)¹Selected from phenyl, 1-naphthyl, 2-furyl and 2-thienyl, each optionally substituted by halogen, straight or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-8Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅And (4) substitution.

In another preferred embodiment, R²Represents a residue selected from the group consisting of: straight or branched C_1-4Alkyl radical, C_3-8Cycloalkyl, phenyl, 1-naphthyl, benzyl and ethylbenzyl, each aryl or aralkyl being optionally substituted by halogen, straight or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-6Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅And (4) substitution. Particularly preferred methyl ketones in the general formula IV of step a) are 2-furylmethyl ketones (2-acetylfuran), methyl 2-thiophenones (acetylthiophene) or methylphenyl ketones (acetophenone).

The primary amines can be used as free bases of the formula IV, as described above, or as the corresponding sulfonates.

It is also particularly preferred that the primary amine in the formula V of step a) is a straight-chain or branched C_1-4Alkylamine, morePreference is given to methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine or tert-butylamine, each as a base or the corresponding sulfonate.

In a preferred embodiment, the primary amine of formula V in step a) is used in an amount at least equimolar to the methyl ketone of formula IV. It is particularly preferred that the molar ratio of the methyl ketone of the formula IV to the primary amine of the formula V is between 1: 1 and 1: 2.

Particularly preferred are processes comprising steps a) and b) or only step b), wherein R¹Is 2-thienyl or phenyl, each optionally substituted by one or more halogen atoms, R²Selected from methyl, ethyl, tert-butyl and cyclopropyl.

More preferably in the process comprising steps a) and b) or the process comprising only step b) the compound of formula I is selected from (S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol, (S) - (-) -3-N-methyl-amino-1- (3-chloro-2-thienyl) -1-propanol, (R) - (+) -3-N-methylamino-1- (2-thienyl) -1-propanol and (R) - (+) -3-N-methylamino-1- (3-chloro-2-thienyl) -1-propanol.

The use of sulfonic acids instead of mineral acids or carboxylic acids as disclosed in WO-A2004/005239 greatly shortens the reaction time required under the pressure of step a) from about 8 hours to about 1-4 hours. Furthermore, the corrosion problem can be neglected when using sulfonic acids, as compared to most mineral acids. Furthermore, sulfonic acids are generally solids or liquids with low vapor pressure and odor and are therefore easy to handle. Furthermore, the sulfonate is easily crystallized, thus facilitating the recovery of the product in step a) and/or b) of the process of the invention. A wide variety of sulfonic acids are available because these compounds have excellent technical usefulness as lubricants, softeners, emulsifiers and surfactants, for example for washing, oil drilling and spinning purposes.

In a preferred embodiment of the process comprising steps a) and b) or the process comprising only step b), R in the sulfonic acid of the formula VI³Selected from the group consisting of:

i) straight or branched alkyl residues consisting of 1 to 18 carbon atoms containing one or more substituents selected from the group consisting of amino, halogen and hydroxyl,

ii) monocyclic or polycyclic cycloalkyl residues consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents selected from amino, halogen and hydroxyl and oxygen,

iii) a mono-or polycyclic aromatic or aralkyl residue consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents selected from amino, halogen and hydroxyl.

Without limitation, R in the sulfonic acids of the formula VI according to i) above³Can be methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl, perfluoro C_1-6Alkyl, trifluoromethyl, trichloromethyl, perfluoroethyl, perchloroethyl, hydroxymethyl, 2-hydroxyethyl and 2-aminoethyl.

Without being limited thereto, an example of a polycyclic aliphatic sulfonic acid of the formula IV containing a ring-attached oxygen substituent according to ii) above is 7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonic acid.

Other non-limiting examples of sulfonic acids containing a monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic aryl or aralkyl residue are isopropylbenzenesulfonic acid, o-methoxyphenylsulfonic acid, morpholinopropanesulfonic acid, hydroxy- (2-hydroxy-phenyl) -methanesulfonic acid, benzenesulfonic acid, 3, 5-dihydroxybenzenesulfonic acid, 2-, 3-, or 4-aminobenzenesulfonic acid, diaminobenzenesulfonic acid, 4- (N-methylanilino) -benzenesulfonic acid, 2-, 3-, or 4-chlorobenzenesulfonic acid, 2-, 3-, or 4-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, 4-dodecylbenzenesulfonic acid, dodecyl-, 4-hydroxybenzenesulfonic acid, 2-, 3-, or 4-toluenesulfonic acid, anthraquinone-1-sulfonic acid, anthraquinone-2, 7-disulfonic acid, naphthalene-2-sulfonic acid, 4-amino-naphthalenesulfonic acid, 3-chloro-2-naphthalenesulfonic acid, 5-hydroxy-1-naphthalenesulfonic acid, naphthalene-1, 4-disulfonic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2, 6-disulfonic acid, 8-amino-naphthalene-1-sulfonic acid, 5-aminonaphthalene-2-sulfonic acid, 4-aminonaphthalene-1-sulfonic acid, 2-aminonaphthalene-1-sulfonic acid, 8-aminonaphthalene-2-sulfonic acid, 5-aminonaphthalene-1-sulfonic acid, 4-amino-3-hydroxynaphthalene-2-sulfonic acid, sodium salt, potassium salt, sodium salt, potassium chloride, potassium, 6-amino-4-hydroxynaphthalene sulfonic acid, 5-dimethylaminonaphthalene-1-sulfonic acid, 5-hydroxynaphthalene-1-sulfonic acid, 7-hydroxynaphthalene-2-sulfonic acid, 6-hydroxynaphthalene-2-sulfonic acid, 4-hydroxynaphthalene-1-sulfonic acid, 3-hydroxy-4- (2-imidazolylazo) -1-sulfonic acid, 6-hydroxy-5- (2-pyridylazo) -naphthalene-2-sulfonic acid, 6-hydroxynaphthalene-2-sulfonic acid, isatin-5-sulfonic acid and lignosulfonic acid.

Particularly preferred sulfonic acids are selected from the group consisting of: methanesulfonic acid, ethanesulfonic acid, (7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid.

In another preferred embodiment, the organic solvent of step a) is inert to the reaction conditions of step a). More preferably, the organic solvent comprises alcohols, carboxylic acid esters, ethers, thioethers, sulfones, sulfoxides, and mixtures thereof, optionally with other additives, co-solvents, or water. In a preferred embodiment, the alcohol is a linear or branched C_1-12An alkyl alcohol.

Particularly preferred aliphatic alcohols are linear or branched aliphatic or cycloaliphatic C_1-12Alcohols, including di-and/or tri-poly-ethylene glycol or mono-C thereof_1-4Alkyl or acetyl derivatives, said C_1-12The alcohols each contain 1 to 3 hydroxyl groups.

Suitably C_1-12Examples of alcohols are methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2, 2, 2-trifluoroethanol, 1, 2-ethanediol, 1, 2-propanediol, 1, 2-butanediol, 2, 3-butanediol, 1, 4-butanediol, 1, 2, 3-propanetriol, 1, 2, 6-hexanetriol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether or triethylene glycol monoacetate.

Particularly preferred alcohols may be selected from ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, diethylene glycol and triethylene glycol.

Carboxylic acid esters suitable for use in the reaction of step a) such as ethyl acetate or butyl acetate.

In a preferred embodiment, the ethers and thioethers are dialkyl or alkylaryl ethers or thioethers, the straight or branched alkyl moiety being independently C_1-6Alkyl, the aryl moiety being phenyl.

In another preferred embodiment, the ether and thioether are C_3-8Cycloalkyl ethers and C_3-8Cycloalkyl sulfides containing 1 to 2 oxygen or sulfur atoms.

Particularly preferred ethers, thioethers, sulfones and sulfoxides may be selected from the following group: dimethyl ether, diethyl ether, ethyl methyl ether and tert-butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, dimethyl sulfide, diethyl sulfide, ethyl methyl sulfide and tert-butyl methyl sulfide, 1, 4-dithiane, tetrahydrothiophene (thiolane), sulfolane and dimethyl sulfoxide.

In a preferred embodiment, the pressure in reaction step a) is greater than 1.5 bar, more preferably from 1.5 to 10 bar, most preferably from 1.5 to 5 bar.

In another preferred embodiment, the reaction of step a) is carried out at 80-150 ℃, more preferably at 100-130 ℃.

In step a) with respect to the residue R in the compounds of the formulae I, II and VI¹、R²And R³The preferences also apply to step b) in the following section.

Although we have found that the sulfonates of beta-aminoketones of the general formula II are easier to handle than the respective inorganic or organic salts, the asymmetric hydrogenation of the sulfonates using transition metals and diphosphine ligands in known manner gives only very low yields.

Surprisingly, in the presence of a base during the hydrogenation, the yield increases dramatically and even the enantiomeric excess (ee) of the β -aminoalcohol increases. Furthermore, in several examples, the substrate/catalyst ratio (S/C) has been significantly increased (table 4). Another surprising effect of adding base is that the temperature can be reduced during hydrogenation from about 50-80 ℃ to 25-50 ℃. This improves the stability of the chiral product and the starting material. We have found that there is no difference whether the beta-aminoketone has been added as a sulphonate or as the corresponding free base and sulphonic acid.

In a preferred embodiment, the base is present in a proportion of 0.05 to 0.5 molar equivalents (0.05 to 0.5 equivalents), based on the beta-aminoketone of the formula II.

Particularly preferably, the base is an inorganic base. More preferably, the inorganic base is a metal carbonate. More preferably, the metal carbonate is an alkali metal or alkaline earth metal carbonate. In a preferred embodiment, the base is selected from Li₂CO₃、Na₂CO₃And K₂CO₃。

The catalyst used in step b) comprises at least one transition metal and a diphosphine ligand.

In a preferred embodiment, the transition metal is selected from rhodium, ruthenium and iridium, preferably rhodium.

In another preferred embodiment, the diphosphine ligand is selected from the group consisting of:

(S，S)-“Me-DuPhos”，(R，R，S，S)-“TangPhos”，(S)-“C4-TunePhos”，

(S, S, S, S) - "Me-KetalPhos", (S) and (R) - "MeO-BiPhep" and "R_P，R_P，S_C，S_C-DuanPhos”。

Can be prepared by reacting ruthenium salt Ruⁿ⁺Y^- _nDissolving in a polar solvent and mixing with a suitable amount of a diphosphine ligand, optionally also with at least one stabilizing ligand (stabilizing ligand), to prepare in situ a catalyst solution, wherein n is 2 or 3, Y^-Is Cl^-、Br^-、I^-、BF₄ ^-、AsF₆ ^-、SbF₆ ^-、PF₆ ^-、ClO₄ ^-Or OTf^-(triflate) or other suitable counter ion.

Alternatively, the catalyst solution may be obtained by mixing the catalyst precursor complex (i.e. the preformed rhodium complex already containing one stabilizing ligand) with appropriate amounts of the other diphosphine ligand in a polar solvent. The catalyst precursor complex comprises at least one stabilizing ligand, such as a diene, olefin or arene. In a preferred embodiment, the stabilizing ligand is 1, 5-cyclooctadiene (cod), norbornadiene (nbd) or p-isopropylbenzene (cym). A particularly preferred stabilizing ligand is para-cumene.

In another preferred embodiment, the catalyst precursor complex comprises at least one chiral diphosphine ligand.

In another more preferred embodiment, the catalyst precursor complex comprises at least one polar solvent molecule as stabilizing ligand, such as dimethyl sulfoxide (DMSO), Dimethylformamide (DMF) or acetonitrile (MeCN).

An example of a catalyst precursor complex containing such a stabilizing ligand is [ Rh₂Cl₄(cym)₂]，[Rh₂Br₄(cym)₂][ RhCl ((Rp, Rp, Sc, Sc) -DuanPhos) (benzene)]Cl、[RhCl₂((Rp，Rp，Sc，Sc)-DuanPhos)·DMF]、[RhCl₂((Rp，Rp，Sc，Sc)-DuanPhos)·DMSO]And [ Rh ] and₂Cl₄(cod)₂·MeCN]。

furthermore, the catalyst solution can be obtained by dissolving a preformed chiral ruthenium complex already containing all the desired diphosphine ligands.

Examples of several methods commonly used to prepare catalysts and catalyst solutions are disclosed in S.Aft.J.Chem., 1987, 40, 183-30188, WO 00/29370 and J.org.Chem., 1994, 59, 3064-3076, Mashima, K.

In a particularly preferred embodiment, the catalyst composition corresponds to an idealized formula selected from the group consisting of: [ Rh ((R, R, S, S) -Tangphos) (norbornadiene)]BF4、[(S，S)-Me-Duphos-Rh]BF₄And [ Rh (NBD) (Rp, Rp, Sc, Sc-DuanPhoS)]BF4。

In another preferred embodiment, the catalyst contains a diphosphine ligand "(Rp, Sc) -DuanPhoS", optionally containing other components as listed above.

In a preferred embodiment, the pressure at the hydrogenation in reaction step b) is more than 1.5 bar, more preferably from 1.5 to 50 bar, most preferably from 5 to 40 bar.

In another preferred embodiment, the reaction of step a) is carried out at 0 to 80 ℃, more preferably at 20 to 50 ℃.

The hydrogenation is carried out with a catalyst solution in a polar solvent selected from C_1-4Alcohols, ethers, thioethers, dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), acetonitrile (MeCN) or mixtures thereof, and the polar solvent is inert to hydrogenation in the presence of a catalyst.

In a preferred embodiment, the ethers and thioethers are dialkyl or alkylaryl ethers or thioethers, the straight or branched alkyl moiety being independently C_1-6Alkyl, the aryl moiety being phenyl.

In another preferred embodiment, the ether and thioether are C_3-8Cycloalkyl ethers and C_3-8A cycloalkyl thioether.

Particularly preferred ethers and thioethers are selected from the group consisting of: dimethyl ether, diethyl ether, ethyl methyl ether and tert-butyl methyl ether, tetrahydrofuran, dimethyl sulfide, diethyl sulfide, ethyl methyl sulfide and tert-butyl methyl sulfide, tetrahydrothiophene and sulfolane.

Preferably, the polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, dimethyl ether, tetrahydrofuran, ethyl acetate, and mixtures thereof.

In any case, the solvent used in step b) may contain other solvent additives, such as dichloromethane.

In another preferred process, the free base of the compounds of formulae Ia and Ib may be in the presence of a base (preferably an alkali or alkaline earth metal hydroxide, e.g. NaOH, KOH, Ca (OH)₂Or Mg (OH)₂) Obtained from the corresponding salt by hydrolysis in the presence of (b).

The invention also provides beta-aminoketone sulfonates of the formula II and sulfonic acids of the formula VI

In the formula, R¹Is represented by C_6-20Aryl or C_4-12Heteroaryl, each optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R²Selected from straight or branched C_1-4Alkyl radical, C_3-8Cycloalkyl and C_6-20Aryl, the aryl moiety being optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_3-6Cycloalkyl substituted, R³Selected from the group consisting of: c_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

R³-SO₂-OH VI，

in the formula R³As defined above.

The invention also provides beta-aminoketone sulfonates of the formula VII

In the formula R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

The invention also provides beta-aminoketone sulfonates of the formula VIII

In the formula R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

In addition, the invention provides beta-aminoketone sulfonates of the formula IX

In the formula, R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

The invention also provides beta-aminoketone sulfonates of the formula X

In the formula R³As defined above, R⁴Represents methyl, ethyl, isobutylAnd a tert-butyl group.

The invention also provides beta-aminoalcohol sulfonates of the general formulae Ia and Ib and sulfonic acids of the general formula V

And

in the formula, R¹Represents C_6-20Aryl or C_4-12Heteroaryl, each optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R²Is selected from C_1-4Alkyl or C_6-20Aryl, the aryl moiety being optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

R³-SO₂-OH V，

in the formula R³As defined above.

The invention also provides beta-aminoalcohol sulfonates of the general formulae XIa and XIb

And

in the formula R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

The invention also provides beta-aminoalcohol sulfonates of the general formulae XIIa and XIIb

And

in the formula R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

The invention also provides beta-aminoalcohol sulfonates of the formulae XIIIa and XIIIb

And

in the formula R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

The invention also provides beta-aminoalcohol sulfonates of the general formulae XIVa and XIVb

And

in the formula R³As defined above, R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

Detailed Description

The invention is illustrated by the following non-limiting examples.

Steps a) and b) of the process of the invention are set forth in examples 1-17 and 21-26, respectively. Since the beta-aminoketone sulfonates of the formula II can in principle be obtained by acid exchange, the invention also provides a process which comprises only step b) starting from the beta-aminoketone sulfonates of the formula II, as outlined in examples 18 to 20 for the acid exchange of the individual hydrochloride salts. Examples 27 and 28 relate to the preparation of β -aminoalcohol sulfonates of formula I from the corresponding hydrochloride salts by acid exchange. The present invention thus provides a viable method of acid exchange.

Example 1:

a mixture of ethanol (40mL), Methyl Ammonium Methanesulfonate (MAMS) (16.5g, 130mmol), 2-acetylthiophene (11.0g, 87.2mmol) and paraformaldehyde (2.6g, 86.6 mmol) was heated to 120 ℃ in an autoclave at a total pressure of 4.5 bar. After 3 hours at this temperature, the autoclave was cooled to 25 ℃. The reaction mixture was concentrated to dryness, and a mixture of ethanol (20mL) and ethyl acetate (400mL) was added to the residue, and the resulting suspension was stirred at 25 ℃ for 30 minutes. Then, the precipitate was filtered off, washed with ethyl acetate (40mL) and removed from the filter. The crude material was then suspended in a mixture of ethyl acetate (200mL) and ethanol (50mL), heated to reflux and cooled to 0 ℃. Once cooled, the suspension was stirred at this temperature for 1 hour. Then filtered and precipitatedThe precipitate was washed with ethyl acetate (40mL) and dried under vacuum (20 mbar) at 40 ℃ for 15 h to give an off-white solid (19.4g, 50%, according to¹H-NMR is 3-methylamino-1-thiophen-2-yl-propan-1-one mesylate);¹H-NMR(DMSO-d₆400 MHz): 8.5(2H, s, broad), 8.1(1H, dm), 8.0(1H, dm), 7.30(1H, dd), 3.42(2H, t), 3.3(2H, s, broad), 2.6(3H, s, broad), 2.38(3H, s);¹³C-NMR(DMSO-d₆，100MHz)：189.9，142.6，135.4，133.9，128.0，43.2，39.6，34.5，32.7。

general procedure for examples 2-17:

a mixture of solvent, 1 equivalent (leq) of a methyl ketone of formula IV (R1 is illustrated in Table 1), a primary alkyl amine of formula V and/or a salt thereof (1.1 to 2.0 equivalents), a formaldehyde or formaldehyde source (1.1 to 1.5 equivalents), optionally with added sulfonic acid (total amount 1.0 to 1.1 equivalents) is heated in an autoclave at a total pressure of more than 1.5 bar for 1 to 5 hours. Then, the reaction solution was cooled to Room Temperature (RT). Optionally, the reaction solvent may be partially or completely removed and, if desired, a solvent such as ethyl acetate or isopropanol may be added with stirring to facilitate precipitation of the product. The suspension is cooled (0-20 ℃) and after precipitation (0.5-10 hours) filtered, optionally washed and dried to give an off-white to light brown powder with a yield of 40-60%. The product may be recrystallized from ethyl acetate/alcohol (preferably ethanol or isopropanol) as described above. The precipitate was then filtered, washed with ethyl acetate and dried under vacuum (about 20 mbar) at about 40 ℃ for 15 hours to give an off-white to light brown solid.

To facilitate the reaction continuity, all examples except examples 11 and 17 were carried out in the presence of methanesulfonic acid (MSA) or using alkyl-, aryl-or aralkylamine methanesulfonate. In example 11, (+) -camphor-10-sulfonic acid ((+) -CSA) was added to an ethanol solution of methylamine. In example 17, methyl ammonium p-toluenesulfonate was used. Further, in examples 13 and 16, the amine and the sulfonic acid were added separately and mixed in the reaction vessel. The total yield obtained in examples 1-16 was 40-60%. The desired reaction product may be isolated in a ratio of about 2: 1 to each of the starting amines. The starting amine of formula V remains unchanged and can be used for other reactions.

Comparative example 1 (C1):

a mixture of 2-butanol (40mL), MAMS (16.5g, 130mmol), 2-acetylthiophene (11.0g, 87.2mmol) and paraformaldehyde (2.6g, 86.6 mmol) was heated to 80 ℃ at normal pressure. After 4 hours at this temperature, the reaction mixture was cooled to 25 ℃. The reaction mixture was concentrated to dryness, and a mixture of ethanol (20mL) and ethyl acetate (400mL) was added to the residue, and the resulting suspension was stirred at 25 ℃ for 30 minutes. Then, the precipitate was filtered off, washed with ethyl acetate (40mL) and removed from the filter. The crude material was then suspended in a mixture of ethyl acetate (200mL) and ethanol (50mL), heated to reflux and cooled to 0 ℃. Once cooled, the suspension was stirred at this temperature for 1 hour, the precipitate was filtered, washed with ethyl acetate (40mL) and dried under vacuum (20 mbar) at 40 ℃ for 15 hours to give a rose-red solid. The compounds of formula II and III are formed in almost equal proportions with poor yields (approximately 40% overall). Data for 3, 3' - (methylamino) bis [1- (thien-2-yl) propan-1-one mesylate:¹H-NMR(DMSO-d₆400 MHz): 9.4(1H, s, broad), 8.1(4H, m), 7.3(2H, m), 3.4-3.6(8H, m), 2.90(3H, s), 2.38(3H, s);¹³C-NMR(DMSO-d₆，100MHz)：189.6，142.7，135.3，134.0，128.9，50.3，40.3，39.6，33.1。

comparative example 2 (C2):

a mixture of isopropanol (30mL), MAMS (5.6g, 44mmol), 2-acetylthiophene (10.1g, 80mmol) and paraformaldehyde (3.2g, 108mmnol) and MSA (ca. 0.1 g) was heated to reflux at 84 ℃ under normal pressure. After 20 hours at this temperature, the precipitate was filtered off at about 80 ℃, washed with isopropanol (3 × 20mL) and dried at 40 ℃ for 15 hours under vacuum (20 mbar) to give a white solid. The compound of formula I is isolated in only trace amounts. The compound of formula III (3, 3' - (methylamino) bis [1- (thien-2-yl) propan-1-one ] methanesulfonate) was isolated in about 40% overall yield.

Table 1: reaction conditions of example 1-C2

Numbering	Ketone R1	Amine R2	Solvent(s)	Temperature [ deg.C ]]	Pressure [ bar ]]	Time of day	Ketone [ mmol]	Amine [ mmol]	Acid [ mmol]	CH2O[mmol]
											1	Thienyl radical	Methyl radical	Ethanol	120	4.5	3 hours	87.2	130.0	130.0	86.6
2	Thienyl radical	Methyl radical	Ethanol	120	4.5	1 hour	87.2	130.0	130.0	86.6
											3	Thienyl radical	Methyl radical	Ethanol	120	4.5	3 hours	87.2	130.0	130.0	131.0
4	Thienyl radical	Methyl radical	Ethanol	120	4.5	3 hours	87.2	130.0	138.7	86.6
											5	Thienyl radical	Methyl radical	TFE	120	4.8	4 hours	87.2	130.0	130.0	130.0
6	Thienyl radical	Methyl radical	Methanol	115	5.8	4 hours	87.2	130.0	130.0	130.0
											7	Thienyl radical	Methyl radical	Isopropanol (I-propanol)	120	4	4 hours	87.2	130.0	130.0	86.6
8	Thienyl radical	Methyl radical	Sec-butyl alcohol	120	2.8	4 hours	87.2	130.0	130.0	86.6
											9	Thienyl radical	Methyl radical	DME	120	3.2	3 hours	87.2	130.0	130.0	86.6
10	Thienyl radical	Methyl radical	1, 4-dioxane	120	n.a.	4 hours	87.2	130.0	130.0	130.0

11	Thienyl radical	Methyl radical	Ethanol	120	4.5-4.8	4 hours	174.0	259.0	260.0	173.0
											12	Thienyl radical	Ethyl radical	Ethanol	120	5	5 hours	87.2	130.0	130.0	86.6
13	Thienyl radical	Benzyl radical	Ethanol	120	4.8	4 hours	87.2	130.0	130.0	130.0
											14	Phenyl radical	Ethyl radical	Ethanol	120	4.8	4 hours	87.2	130.0	130.0	130.0
15	Phenyl radical	Methyl radical	Ethanol	120	4.8	4 hours	87.2	130.0	130.0	130.0
											16	Phenyl radical	Benzyl radical	Ethanol	120	4.8	4 hours	87.2	130.0	130.0	130.0
17	Thienyl radical	Methyl radical	Ethanol	120	n.a.	4 hours	43.7	40.0	40.0	43.3
											C1	Thienyl radical	Methyl radical	Sec-butyl alcohol	80	1	4 hours	87.2	130.0	130.0	86.6
C2	Thienyl radical	Methyl radical	Isopropanol (I-propanol)	Refluxing	1	20h	80.0	44.0	44.0	44.9

n.a. no value obtained

TFE ═ 2, 2, 2-trifluoroethanol, DME ═ dimethyl ether.

NMR data for the novel compounds of examples 11-17 are given below:

example 11: 3-methylamino-1-thiophen-2-yl-propan-1-one 1- (S) - (7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonate

¹H-NMR(DMSO-d₆400 MHz): 8.4(2H, s, broad), 8.1(1H, dm), 8.0(1H, dm), 7.29(1H, dd), 3.44(2H, t), 3.27(2H, t), 2.92(1H, d), 2.64(3H, d)，s)，2.6(1H，m)，2.43(1H，d)，2.2(1H，m)，2.0(1H，m)，1.9(1H，m)，1.80(1H，d)，1.3(2H，m)，1.04(3H，s)，0.73(3H，s)。

Example 12: 3-ethylamino-1-thiophen-2-yl-propan-1-one methanesulfonate

¹H-NMR(DMSO-d₆400 MHz): 8.4(2H, s, broad), 8.1(1H, dm), 8.0(1H, dm), 7.3(1H, m), 3.40(2H, t), 3.3(2H, s, broad), 3.0(2H, s, broad), 2.32(3H, s), 1.20(3H, t).

Example 13: 3-benzylamino-1-thiophen-2-yl-propan-1-one methanesulfonate

¹H-NMR(DMSO-d₆400 MHz): 8.8(2H, s, broad), 8.1(1H, dm), 8.0(1H, dm), 7.5(5H, m), 7.3(1H, m), 4.23(2H, s), 3.44(2H, t), 3.30(2H, t), 2.31(3H, s).

Example 14: 3-methylamino-1-phenyl-propan-1-one methanesulfonate

¹H-NMR(DMSO-d₆400 MHz): 8.0(2H, dm), 7.7(1H, tm), 7.6(2H, tm), 7.5(2H, s, broad peak), 3.47(2H, t), 3.27(2H, t), 2.64(3H, s), 2.31(3H, s).

Example 15: 3-ethylamino-1-phenyl-propan-1-one methanesulfonate

¹H-NMR(DMSO-d₆400 MHz): 8.5(2H, s, broad), 8.0(2H, dm), 7.7(1H, tm), 7.6(2H, tm), 3.50(2H, t), 3.3(2H, s, broad), 3.0(2H, s, broad), 2.38(3H, s), 1.22(3H, t).

Example 16: 3-benzylamino-1-phenyl-propan-1-one methanesulfonate

¹H-NMR(DMSO-d₆400 MHz): 8.8(2H, s, broad), 8.0(2H, dm), 7.7(1H, m), 7.3-7.6(7H, m), 4.25(2H, s), 3.50(2H, t), 3.30(2H, t), 2.31(3H, s).

Example 17: 3-methylamino-1-thiophen-2-yl-propan-1-one p-toluenesulfonate salt

¹H-NMR(CDCl₃400 MHz): 8.8(2H, s, broad), 7.7(2H, dm), 7.6(2H, m), 7.1(2H, dm), 7.0(1H, m), 3.5(2H, m), 3.4(2H, m), 2.75(3H, m, symmetrical), 2.30(3H, s).

The compounds of the formula III obtained in comparative examples C1 and C2 can be cleaved in the presence of sulfonic acids and other amines to aminoketones of the formula II. The amine added in comparative examples C3-C6 was MAMS. Four different solvents were tested, diglyme, acetonitrile, methyl isobutyl ketone (MIBK) and N-methyl pyrrolidone (NMP). The reaction is carried out at a pressure of about 4-5 bar. Comparative examples C3-C6 (R)¹And R²The yield shown in Table 2) was less than 50%. In each case, the product contained unidentified by-products.

Table 2: cleavage of the Compounds of the formula III

Numbering

Ketone R1

Amine R2

Acid(s)

Solvent(s)

Temperature [ deg.C ]]

Container with a lid

Time of day

C3

Thienyl radical

Methyl radical

MSA

Diethylene glycol dimethyl ether

120

High pressure autoclave

5.5 hours

C4

Thienyl radical

Methyl radical

MSA

Acetonitrile

120

High pressure autoclave

5.5 hours

C5

Thienyl radical

Methyl radical

MSA

MIBK

120

High pressure autoclave

5.5 hours

C6

Thienyl radical

Methyl radical

MSA

NMP

120

High pressure autoclave

5.5 hours

The salts of the aminoketones of the formula II used for the asymmetric hydrogenation in step b) of the process of the invention with sulfonic acids can be obtained according to step a) by Mannich reaction at the pressures as outlined above for examples 1 to 17 or by a mixture of sulfonic acid and the free base of the beta-aminoketones of the formula II. The free base of the beta-aminoketones of formula II can be readily obtained by hydrolysis of a salt (e.g. the hydrochloride salt) in the presence of aqueous base (aquous base) and extraction with an organic solvent. Examples 18 to 20 in Table 3 show a two-step reaction starting from the hydrochloride salt of the beta-amino ketone (obtained according to the method in WO-A2004/005239), in which R¹And R²Shown in the table. The yield was at least 83%.

Example 18:

3-methylamino-1-thiophen-2-yl-propan-1-one methanesulfonate was prepared from 3-methylamino-1-thiophen-2-yl-propan-1-one hydrochloride according to the procedure of example 20, the amounts and conditions listed in Table 2.

Example 19:

1- (S) - (7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonate was prepared from 3-methylamino-1-thiophen-2-yl-propan-1-one hydrochloride according to the procedure of example 20, the amounts and conditions listed in Table 2.

Example 20:

3-methylamino-1-thiophen-2-yl-propan-1-one p-toluenesulfonate was prepared from 3-methylamino-1-thiophen-2-yl-propan-1-one hydrochloride according to Table 2. To a mixture of 3-methylamino-1-thiophen-2-yl-propan-1-one hydrochloride (29.2g, 0.142mol), methyl tert-butyl ether (MTBE) (510mL), and water (60mL) cooled to 5 ℃ was added aqueous sodium hydroxide (38.4g, 20 wt% aqueous solution, 0.192mol) over 15 minutes. After the end of the addition, the reaction mixture is,the reaction mixture was stirred at this temperature for a further 10 minutes and the two phases separated. The organic phase was washed with water (180mL) and the collected aqueous phase was extracted with MTBE (2X 150 mL). The collected organic phase was then cooled to 5 ℃ and once cooled, a mixture of p-toluenesulfonic acid hydrate (25.8g, 0.136mol) and methanol (20mL) was added dropwise over 15 minutes. The product crystallized automatically during the addition. At the end of the dropwise addition, the reaction mixture was kept at 25 ℃ and stirred at this temperature for 30 minutes, then the precipitate was filtered, washed with MTBE (50mL) and dried at 50 ℃ under vacuum (20 mbar) for 15 hours to give a pale brown-rose-red solid (39.5g, 85%, according to¹The H-NMR product was relatively pure). The crude product can be recrystallized from isopropanol (150mL) if necessary to give a pale rose-red solid (32.7g, 70%) as a pure product.

Table 3: preparation of salts by anion exchange

The hydrogenation of the beta-aminoketone sulfonate of formula II is shown in example 21-C16 below.

General procedure for examples 21-26:

a mixture of the catalyst shown in Table 4, beta-aminoketone sulfonate of general formula II (1 equivalent), potassium carbonate (0.05-0.5 equivalent), methanol (40-50mL), and water (10-12.5mL) was added to the autoclave under nitrogen. The autoclave was then closed, purged several times with nitrogen, and then hydrogen was added until the pressure at 25 ℃ reached 10 bar (examples 24 and 25) or 30 bar. After stirring at the respective temperatures for the times listed in Table 4, the remaining hydrogen was carefully released and the reaction mixture was diluted to about 100mL using a 4: 1 by volume mixture of methanol and water. Once cooled, it was transferred to a 50mL round bottom flask and concentrated to dryness to give the product as the sulfonate salt. The amounts of the starting aminoketones in table 4 correspond to the amount of sulfonic acid of the respective aminoketones. The second column of table 4 shows examples providing the respective starting β -aminoketone sulfonates.

In examples 21, 22, 23, 24 and 26, the β -aminoalcohol of formula Ia was isolated as the free base by treating the residue after concentration with a mixture of MTBE (10mL) and aqueous sodium hydroxide (5mL, 20% aqueous). The phases were then separated and the aqueous phase was extracted with MTBE (2X 5 mL). The collected organic phase (which contains a very fine precipitate) is then dried over sodium sulphate, filtered and concentrated to dryness to give a brown oil which usually crystallizes after a few hours. The liberation of the free base of the amino alcohol of formula I from the sulfonate salt corresponds to the procedure outlined in examples 18-20.

General procedure for comparative examples C12-C16:

a mixture of the salt of a β -amino alcohol of formula II (1 equivalent) as listed in table 4 in methanol (25mL) was added to the autoclave under nitrogen. Then, a methanol (10mL) solution of the catalyst prepared under nitrogen was added to the first mixture via syringe. The autoclave was then closed and purged several times with nitrogen, then hydrogen was added until the pressure reached 30 bar, and then the mixture was heated to the temperature listed in table 4. After stirring at this temperature for each time, the reaction mixture was cooled to 25 ℃. Once cooled, it was transferred to a 50mL round bottom flask and concentrated to dryness to give the product as the sulfonate salt.

Example 25: data for (S) -3-methylamino-1-thiophen-2-yl-propan-1-ol methanesulfonate of Table 4

mp (uncorrected): 62 to 65 ℃;¹H-NMR(DMSO-d₆400 MHz): 8.4(2H, s, broad), 7.4(1H, dm), 7.0(2H, m), 6.0(1H, s, broad), 4.94(1H, m, symmetrical), 3.00(2H, m, symmetrical), 2.59(3H, s), 2.39(3H, s), 2.0(2H, m).

Table 4: asymmetric hydrogenation of sulfonates of compounds of formula II

Numbering	Starting material ketones	Ketone [ mmol]	Catalyst and process for preparing same	Catalyst [ mu mol ]]	Temperature [ deg.C ]]	Time of day	S/C	Conversion rate	ee
										21	Example 17	1.05	DUAN	5.12	50	5 hours	205	100％	86％
22	Example 17	1.05	DUAN	5.12	25	5 hours	205	100％	94％
										23	Example 11	1.20	DUAN	11.0	25	5 hours	109	100％	94％
24	Example 5	27.10	DUAN	3.6	25	41 hours	7511	100％	98％
										25	Example 5	43.80	DUAN	4.4	40	For 21 hours	10029	100％	92％
26	Example 5	1.20	DUAN	11.0	25	5 hours	109	100％	94％

C7	Example 17	0.45	TANG	5.3	55	5 hours	85	15％	80％
										C8	Example 17	0.45	DUPH	4.5	55	5 hours	100	15％	99％
C9	Example 17	2.11	DUAN	10.0	50	18 hours	211	40％	87％
										C10	Example 11	1.20	DUPH	11.0	50	5 hours	109	20％	95％
C11	Example 11	1.20	DUAN	11.0	50	5 hours	109	20％	87％
										C12	Example 5	1.20	TANG	11.0	80	5 hours	109	50％	79％
C13	Example 5	1.20	DUPH	11.0	50	5 hours	109	15％	91％
										C14	Example 5	1.20	DUPH	11.0	80	4.5 hours	109	20％	88％
C15	Example 5	1.20	DUAN	11.0	50	5 hours	109	35％	88％
										C16	Example 5	1.20	DUAN	11.0	80	5 hours	109	40％	79％

Two used in examples 21-C16Phosphine ligands, available from, for example, Chiral Quest, Inc, MonmouthJunction (us, new jersey) are: [ Rh ((R, R, S, S) -Tangphos) (norbornadiene)]BF₄＝TANG，[(S，S)-Me-Duphos-Rh]BF₄＝DUPH，[Rh(NBD)(Rp，Rp，Sc，Sc-DuanPhos)]BF₄＝DUAN。

Example 27: (S) -3-methylamino-1-thiophen-2-yl-propan-1-ol p-toluenesulfonate salt

A mixture of (S) -3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0g, 29.2mmol), dichloromethane (50mL), p-toluenesulfonic acid hydrate (5.55g, 29.2mmol) and methanol (20mL) was stirred at 25 ℃ for 1 h. Then concentrated to dryness. The residue which solidified after a few hours (10.8g) was finally recrystallized from butanol (30mL) to give a white powder (6.0g, 60%);

¹H-NMR(DMSO-d₆400 MHz): 8.1(1H, s, broad), 7.5(2H, dm), 7.42(1H, dd), 7.1(2H, dm), 7.0(2H, m), 4.92(1H, dd), 2.97(2H, m, symmetric), 2.57(3H, s), 2.28(3H, s), 2.0(2H, m);¹³C-NMR(DMSO-d₆，100MHz)：149.3，145.5，137.6，128.0，126.6，125.4，124.4，123.0，66.1，45.8，35.1，32.7，20.7。

example 28: (S) -3-methylamino-1-thiophen-2-yl-propan-1-ol 1- (S) - (7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) -methanesulfonate

A mixture of (S) -3-methylamino-1-thiophen-2-yl-propan-1-ol (34.2g, 200mmol) and ethyl acetate (400mL) was heated to 30 ℃ and then a mixture of (+) -camphor-10-sulfonic acid (46.4g, 200mmol), ethyl acetate (100mL) and ethanol (100mL) was added dropwise over 40 minutes at 30 ℃. After the addition was complete, the resulting solution was heated to 50 ℃, stirred at this temperature for 15 minutes and then cooled to 25 ℃. Once cooled, the reaction was concentrated to dryness, and ethyl acetate (500mL) was added to the residue. The resulting mixture was then heated to reflux, held at this temperature for 15 minutes, then cooled to 25 ℃ over 30 minutes, and when the temperature reached about 40 ℃, seed crystals were added to the reaction mixture. Once cooled, the resulting suspension was stirred for an additional 30 minutes. The precipitate was then filtered, washed with ethyl acetate (2 × 50mL) and dried at 40 ℃ under vacuum (20 mbar) for 15 h to give a white solid (71.5g, 89%);

¹H-NMR(CDCl₃400 MHz): 7.2(1H, dm), 7.0(1H, m), 6.9(1H, m), 5.21(1H, t), 3.3(3H, m), 2.82(1H, d), 2.75(3H, s), 2.50(1H, m, symmetrical), 2.3(3H, m), 2.1(1H, m), 2.0(1H, m), 1.85(1H, d), 1.74(1H, m, symmetrical), 1.4(1H, m), 1.04(3H, s), 0.82(3H, s).

Claims (11)

1. A process for the preparation of N-monosubstituted beta-aminoalcohol sulfonates represented by the general formulae Ia and Ib,

and

in the formula, R¹Is phenyl, 1-naphthyl, 2-furyl or 2-thienyl, each optionally substituted by halogen, straight-chain or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-8Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅Substituted, R²Is selected from C_1-4Alkyl radical, C_3-8Cycloalkyl and C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

the method comprises the following steps

a) Reacting a mixture comprising components (i), (II) and (iii) in the presence of a sulfonic acid of formula VI, optionally in an organic solvent, to obtain a beta-aminoketonesulfonate of formula II,

(i) methyl ketones of the formula

In the formula R¹As defined above, the above-mentioned,

(ii) a primary amine of the formula

H₂N-R² V，

In the formula R²As defined above, the above-mentioned,

(iii) formaldehyde or a source of formaldehyde selected from the group consisting of: aqueous formaldehyde, 1, 3, 5-trioxane, paraformaldehyde, and mixtures thereof,

R³-SO₂-OH VI

in the formula R³As defined above, the organic solvent optionally contains water,

in the formula R¹、R²And R³As defined above, and

b) asymmetrically hydrogenating the sulfonate in a polar solvent, optionally in the presence of water, in the presence of an inorganic base and a catalyst under a hydrogen pressure of 5 to 50 bar to obtain a beta-aminoalcohol sulfonate of formula I, wherein R is¹、R²And R³As defined above, the catalyst comprises a transition metal and a diphosphine ligand.

2. A process for the preparation of N-monosubstituted beta-aminoalcohol sulfonates represented by the general formulae Ia and Ib

And

in the formula, R¹Is phenyl, 1-naphthyl, 2-furyl or 2-thienyl, each optionally substituted by halogen, straight-chain or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-8Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅Substituted, R²Is selected from C_1-4Alkyl radical, C_3-8Cycloalkyl and C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue, a substituent or a substituent,

the method comprises the following steps: asymmetrically hydrogenating a beta-aminoketone sulfonate of the general formula II in a polar solvent, optionally in the presence of water, in the presence of an inorganic base and a catalyst comprising a transition metal and a diphosphine ligand, under a hydrogen pressure of 5 to 50 bar,

in the formula, R¹，R²And R³As defined above.

3. The method of claim 1 or 2, wherein R is¹Is 2-thienyl, optionally substituted by one or more halogen atoms, R²Selected from methyl, ethyl, tert-butyl and cyclopropyl.

4. The method of any one of claims 1-3, the beta-aminoalcohol of formula I is selected from the group consisting of (S) - (-) -3-N-methylamino-1- (2-thienyl) -1-propanol, (S) - (-) -3-N-methyl-amino-1- (3-chloro-2-thienyl) -1-propanol, (R) - (+) -3-N-methylamino-1- (2-thienyl) -1-propanol and (R) - (+) -3-N-methylamino-1- (3-chloro-2-thienyl) -1-propanol.

5. The method of any one of claims 1-4, wherein R in the sulfonic acid of formula VI³Selected from the group consisting of:

i) straight or branched alkyl residues consisting of 1 to 18 carbon atoms containing one or more substituents selected from the group consisting of amino, halogen and hydroxyl,

ii) a cycloalkyl residue consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents selected from amino, halogen and hydroxyl,

iii) a mono-or polycyclic aromatic or araliphatic residue consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents selected from amino, halogen and hydroxyl.

6. The method of any one of claims 1-5, wherein the inorganic base is a metal carbonate.

7. The method of any one of claims 1-6, wherein the transition metal is selected from rhodium, ruthenium, or iridium.

8. The method of claim 7, wherein the transition metal is selected from rhodium.

9. The method of any one of claims 1 to 7, wherein the diphosphine ligand is selected from the group consisting of:

10. a beta-aminoketone sulfonate of the general formula II,

in the formula, R¹Is phenyl, 1-naphthyl, 2-furyl or 2-thienyl, each optionally substituted by halogen, straight-chain or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-8Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅Substituted, R²Is C_1-4Alkyl or C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy radicals are takenGeneration, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue.

11. Beta-aminoalcohol sulfonates of the general formula I,

in the formula, R¹Is phenyl, 1-naphthyl, 2-furyl or 2-thienyl, each optionally substituted by halogen, straight-chain or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-8Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅Substituted, R²Is C_1-4Alkyl or C_6-20Aryl, each aryl optionally substituted by one or more halogen atoms and/or one or more C_1-4Alkyl or C_1-4Alkoxy substituted, R³Is selected from C_1-18Alkyl radical, C_6-20Cycloalkyl radical, C_6-20Aryl and C_7-20An aralkyl residue.