HK1079765B - PROCESS FOR THE PREPARATION OF N-MONOSUBSTITUTED β-AMINO ALCOHOLS - Google Patents

Description

Process for the preparation of N-monosubstituted beta-amino alcohols

The invention relates to a method for producing N-monosubstituted beta-aminoalcohols and/or proton acid addition salts of the general formula,

the process is carried out by directly synthesizing N-monosubstituted beta-ketoamines of the general formula and/or addition salts of protic acids.

N-monosubstituted beta-aminoalcohols of the general formula I, like (S) - (-) -3-N-methylamino-1- (2-thiophenyl) -1-propanol (LY293628), are useful key intermediates and building blocks for the preparation of pharmaceutically active compounds, like (S) - (+) -methyl- [3- (1-naphthoxy) -3- (2-thiophenyl) -propyl ] -amine ((S) -duloxetine) (Liu, H. et al, Chirality 12(2000)26-29), which are potential neuroactive compounds that strongly inhibit the absorption of serotonin and norephedrine (Deeter, J. et al, Tetrahedron Lett.31(1990) 7101-7104).

The following terms "amine" or "amine" include the addition salts of their corresponding protic acids.

The direct preparation of N-monosubstituted beta-ketoamines of the general formula II determines an alternative and economically advantageous source for the industrial production of N-monosubstituted beta-aminoalcohols of the general formula I.

In 1922, compounds of the formula II were first synthesized by reacting a ketone with formaldehyde and a primary or tertiary alkylamine in the presence of hydrochloric acid (Mannich, C. et al, chem. Ber.55(1922) 356-365). In the reaction with a primary alkylamine, the formation of the hydrochloride of the tertiary beta-ketoamine of formula III is favored over the formation of the hydrochloride of the tertiary beta-ketoamine of formula II. These findings are supported by Blicke et al (J.Am.chem.Soc.64(1942)451-454) and Becker et al (Wiss.Z.Tech.Hochsch.chem.Leuna-Merseburg.11(1969) 38-41).

According to Mannich et al, steam distillation of the tertiary beta-ketoamine of formula III results in the formation of a quite satisfactory yield of the tertiary beta-ketoamine of formula II with vinyl compounds and other by-products.

This process is useful for the preparation of tertiary beta-ketoamines despite losses of more than 50% of the starting compound and due to the lack of alternative processes.

Another disadvantage of the currently known processes for the preparation of tertiary beta-ketoamines is the need to isolate the desired intermediate compounds of formula II from the undesired by-products of formula III.

EP-A457559 and EP-A650965 disclose the preparation of N, N-dimethyl β -aminoalcohols by Mannich-type reactions of methyl ketones with paraformaldehyde and dimethylamine, followed by reduction of the carbonyl group. After the hydroxyl group has reacted to give an alkyl or aryl ether derivative, a careful and expensive reaction is required to remove the methyl radical to give the N-monosubstituted compound.

Only Becker et al disclose examples of N-monomethyl β -ketoamines with a yield of about 60% using N-methyl ammonium oxalate as the nitrogen source. However, the method disclosed by Becker et al has no advantage because it is strictly dependent on the use of amino oxalate salts. In contrast to the free amine or the corresponding hydrochloride, the oxalate salt of a primary amine is not commercially available and its preparation requires further synthetic and purification steps.

The use of an oxalate salt is also disadvantageous because it requires the use of additional reducing equivalents in the next step to reduce the ketone intermediate to the title compound.

None of the known processes for the production of N-monosubstituted beta-amino alcohols of the general formula I and their ether derivatives comprises or relates to an intermediate product comparable to the N-monosubstituted beta-ketoamines of the general formula II according to the invention. Despite many attempts to find new preparation methods, the present invention has not yet been disclosed as a direct route to the synthesis of N-monosubstituted beta-ketoamines and subsequent reduction to N-monosubstituted beta-amino alcohols.

The problem to be solved is to provide an alternative and efficient process for the synthesis of N-monosubstituted beta-amino alcohols and derivatives thereof in high yields. Furthermore, the proposed method should provide high yields approximately independent of the steric circumstances of the amino or carbonyl compounds used.

The problem set out above can be solved according to claim 1.

Starting from commercially available methyl ketones and addition salts of primary amines and/or protic acids, these starting materials are reacted with formaldehyde in the presence of a solvent and optionally a protic acid at a pressure of more than 1.5 bar to give N-monosubstituted beta-amino ketones in high yields which can be directly reduced to the desired N-monosubstituted beta-amino alcohols.

Another advantage of the instant process is that N-monosubstituted beta-amino ketones can be obtained in high yields by the direct use of methylamine hydrochloride, which is readily available and inexpensive and which, because it is a solid, is easy to handle.

The invention discloses a compound shown as the following general formula

And/or a process for the preparation of addition salts of protic acids, wherein R¹，R²Independently represents alkyl, cycloalkyl, aryl or aralkyl, eachAryl or aralkyl optionally further substituted with alkyl, alkoxy and/or halogen, the process comprising the steps of:

a) a reaction mixture comprising

(i) Methyl ketones of the general formula (IV)

Wherein R is¹In accordance with the above-mentioned definition,

(ii) a compound of the formula

H₂N-R²V

And/or addition salts of protic acids, wherein R²In accordance with the above-mentioned definition,

(iii) formaldehyde or a source of formaldehyde selected from the group consisting of aqueous formaldehyde, 1, 3, 5-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 protic acid, to obtain a compound of the formula

And/or addition salts of protic acids, and

b) reducing the carbonyl group of said beta-aminoketone to obtain a compound of general formula I, and/or an addition salt of a protic acid,

wherein the first step is carried out at a pressure of more than 1.5 bar.

In a preferred embodiment, R¹And R²May independently represent a straight or branched chain C_1-8Alkyl radical, C_3-8Cycloalkyl, phenyl, naphthyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, and aralkyl, wherein the alkyl portion of the aralkyl residue is straight-chain C_1-4Alkyl, aryl moieties selected from phenyl, naphthyl, furyl, benzofuryl, thienyl and benzothienyl, each aryl or aralkyl group optionally being substituted by halogen, straight or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, CF₃，C₂F₅，OCF₃Or OC₂F₅And (4) substitution.

It is particularly preferred that R¹Represents a furyl group or a thiophene group.

It is also particularly preferred that R²Represents a straight or branched chain C_1-8An alkyl group. More particularly, R is preferred²Represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

The compounds of the formula V are preferably used as addition salts of free amines and/or protic acids. Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are the free amines and/or hydrochlorides.

In a preferred embodiment, the compound of formula V is present in at least an equimolar amount to the compound of formula IV. The molar ratio of compounds of the formula V to compounds of the formula IV is particularly preferably 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 straight or branched aliphatic C_1-12Alcohol, cycloaliphatic C_5-8Alcohols, diglycols and/or triglycerols or their mono-C_1-4Alkyl groups or their acetyl derivatives, each of said alcohols containing from 1 to 3 hydroxyl groups.

Examples of the alcohol are methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1, 2-ethylene glycol, 1, 2-propylene glycol, 1, 2-butylene glycol, 2, 3-butylene glycol, 1, 4-butylene glycol, 1, 2, 3-glycerol, 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 and triethylene glycol monoacetate.

The alcohol is preferably ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol.

The protic acid may be any carboxylic or mineral acid, preferably selected from formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H₂SO₄And H₃PO₄. In a preferred embodiment, the protic acid may be an acid salt of a polybasic organic or inorganic acid, such as monoalkali metal malonates, alkali metal hydrogen sulphates, alkali metal hydrogen phosphates and alkali metal hydrogen carbonates. The protic acid is more preferably selected from formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably from formic acid, acetic acid, HCl and HBr.

The reaction step a) is preferably carried out under added amine or protonic acid addition salt conditions, since even distillation of the free beta-aminoketones of the formula II leads to the formation of by-products which decompose on storage, while the corresponding addition salts can be stored for a longer period of time without decomposition. The proportion of free amine and its salt in the product corresponds to the proportion of the addition salt of amine and protic acid added during reaction step a) to the total amount of amine.

In a preferred embodiment, the pressure during reaction step a) is greater than 1.5 bar, more preferably between 1.5 and 10 bar, and a particularly preferred range is between 1.5 and 5 bar.

In contrast to the process of Becker et al, the process of the present invention generally allows the direct preparation of N-monosubstituted beta-ketoamines and the addition salts of their protic acids. The product obtained by the process of the invention can be reduced or subsequently reacted without further conversion to other salts.

The invention also provides a compound shown as the following general formula

And the addition salts thereof with a protic acid,

wherein R is¹Represents furyl, benzofuryl, isobenzofuryl, thienyl or benzothiophenyl, each optionally substituted by halogen, straight-chain or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-6Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅Is substituted, and

wherein R is²Selected from straight or branched C_1-8Alkyl radical, C_3-8Cycloalkyl, phenyl, naphthyl, furyl, benzofuryl, thienyl, benzothienyl and aralkyl, wherein the alkyl part of the aralkyl residue is a linear C_1-4Alkyl, aryl moieties selected from phenyl, furyl, benzofuryl, thienyl and benzothiophenyl, each aryl or aralkyl group optionally being substituted by halogen, straight or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-6Cycloalkyl, CF₃、C₂F₅、OCF₃Or OC₂F₅Substituted, R¹Is a thiophene group, R²Except for compounds that are benzyl methyl.

The invention also provides compounds of the general formula

And addition salts thereof with a protic acid, wherein R⁴Represents methyl, ethyl, isobutyl and tert-butyl.

The invention also provides compounds of the general formula

And addition salts thereof with a protic acid.

The invention also provides compounds of the general formula

And addition salts thereof with a protic acid.

The invention also provides a compound shown as the following general formula

And/or a process for the preparation of addition salts of protic acids, wherein R¹，R²Independently represents alkyl, cycloalkyl, aryl or aralkyl, each optionally further substituted by alkyl, alkoxy and/or halogen, which process comprises reacting a mixture comprising

(i) Methyl ketones of the general formula (IV)

Wherein R is¹According to the above definition, and

(ii) a compound of the formula

H₂N-R² V

And/or addition salts of protic acids, wherein R²According to the above definition, and

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

in the presence of a solvent selected from the group consisting of water, fatty alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a protic acid, to obtain a compound of the formula and/or an addition salt of a protic acid,

wherein R is¹And R²The reaction is carried out at a pressure of more than 1.5 bar, as defined above.

In a preferred embodiment, R¹And R²Independently represents a straight or branched chain C_1-8Alkyl radical, C_3-8Cycloalkyl, phenyl, naphthyl, furyl, benzofuryl, thienyl, benzothiophenyl or aralkyl, wherein the alkyl part of the aralkyl residue is a straight-chain C_1-4Alkyl, aryl moieties selected from phenyl, naphthyl, furyl, benzofuryl, thienyl and benzothienyl, each aryl or aralkyl group optionally being substituted by halogen, straight or branched C_1-4Alkyl, straight or branched C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, CF₃，C₂F₅，OCF₃Or OC₂F₅And (4) substitution.

Particular preference is given to R¹Represents furyl or thiophenyl. R is also particularly preferred²Represents a straight or branched chain C_1-8An alkyl group. More preferably, R²Represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

The compounds of formula V may preferably be used as free amines and/or as addition salts of their protic acids. Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More preferred are the free amines and/or hydrochlorides.

In a preferred embodiment, the compound of formula V is present in at least an equimolar amount to the compound of formula IV. The molar ratio of compounds of the formula V to compounds of the formula IV is particularly preferably 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 straight or branched aliphatic C_1-12Alcohol, cycloaliphatic C_5-8Alcohols, diglycols and/or triglycerols or their mono-C_1-4Alkyl or acetyl derivatives, each of said alcohols containing from 1 to 3 hydroxyl groups.

Examples of the alcohol are methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1, 2-ethylene glycol, 1, 2-propylene glycol, 1, 2-butylene glycol, 2, 3-butylene glycol, 1, 4-butylene glycol, 1, 2, 3-glycerol, 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 and triethylene glycol monoacetate.

The alcohol is preferably ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol.

The protic acid may be any organic or inorganic acid, preferably selected from formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H₂SO₄And H₃PO₄. In a preferred embodiment, the protic acid may be an acid salt of a polybasic organic or inorganic acid, such as monobasic malonates, alkali metal hydrogen sulfates, alkali metal hydrogen phosphates and alkali metal hydrogen carbonates. The protic acid is more preferably selected from formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, and more preferably from formic acid, acetic acid, HCl and HBr.

In a preferred embodiment, the pressure during the reaction is greater than 1.5 bar, more preferably between 1.5 and 10 bar, and particularly preferably between 1.5 and 5 bar.

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

General procedure for examples 1 to 8

In an autoclave, the mixture of methyl ketone (1 equivalent), primary alkylamine and/or addition salt thereof (1.1 to 1.5 equivalents), formaldehyde (1.4 to 1.5 equivalents), solvent, optionally in the presence of a protic acid, is heated at a total pressure of greater than 1.5 bar for 5 to 24 hours. After that, the reaction solution was cooled to 20 ℃. However, if it is desired to promote precipitation of the product, a solvent such as ethyl acetate or isopropanol may be added with vigorous stirring, optionally with partial or complete removal of the reaction solvent. The suspension is cooled (0 to 20 ℃) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried, to give a pale yellow to white powder with a yield of between about 50% and 75%. If desired, the product may be recrystallized from isopropanol and/or ethyl acetate. The aqueous base provides the free base upon extraction with an organic solvent if the free base is sufficiently stable in the surrounding environment.

General procedure for comparative examples 1 to 6

A mixture of methyl ketone (1 equivalent), primary alkylamine and/or an addition salt thereof (1 to 1.5 equivalents), formaldehyde (1.0 to 1.5 equivalents) is heated in a refluxing solvent, optionally in the presence of a protic acid, for 5 to 24 hours. After that, the reaction solution was cooled to 20 ℃. Optionally, the reaction solvent is partially or completely removed, and if necessary to promote precipitation of the product, a solvent such as ethyl acetate or isopropanol may be added with vigorous stirring. The suspension is cooled (0 to 20 ℃) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried, to give a pale yellow to white powder with a yield of between about 30% and 45%. If desired, the product may be recrystallized from isopropanol and/or ethyl acetate.

Example 1: 3- (methylamino) -1- (thiophenyl-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Armenine methyl

2-Acetylthiophene (25.5g, 200 mmol); methylamine hydrochloride (14.9g, 220mmol, 1.1 equiv); paraformaldehyde (8.2g, 280mmol, 1.4 equivalents); HCl concentrate (1.0 g); ethanol (100 mL); 110 ℃ for 9 hours; about 2 to 2.5 bar; remove ethanol in vacuo (50 mL); ethyl acetate (200mL) was added; the yield was about 71%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.16(2H，s，br)，8.07(1H，dd，J＝5.0，1.0)，8.01(1H，dd，J＝3.8，1.0)，7.29(1H，dd，J＝5.0，3.8)，3.49(2H，t)，3.20(2H，t)，2.56(3H，s)。

¹³C-NMR δ(DMSO-d₆，100MHz)：189.9，142.7，135.4，133.8，128.8，43.1，34.6，32.4。

Example 2: 3- (methylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Armenine methyl

2-Acetylthiophene (24.9g, 197 mmol); methylamine hydrochloride (14.8g, 219mmol, 1.1 equiv); paraformaldehyde (8.3g, 276mmol, 1.4 equivalents); HCl concentrate (1.1 g); isopropanol (100 mL); 110 ℃ for 8 hours; about 2 to 2.5 bar; isopropanol (50mL) was removed in vacuo; the yield was about 65%.

Comparative example 1: 3- (methylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Armenine methyl

2-Acetylthiophene (79g, 300 mmol); methylamine hydrochloride (30.4g, 450mmol, 1.5 equivalents); paraformaldehyde (12.6g, 420mmol, 1.4 equivalents); HCl concentrate (1.5 g); isopropanol (200 mL); heating at reflux (82 ℃) for 8 hours; ethyl acetate (200mL) was added; the yield was about 43%.

Example 3: 3- (ethylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Becoming ethyl)

2-Acetylthiophene (6.3g, 50 mmol); ethylamine hydrochloride (6.1g, 75mmol, 1.5 equiv); paraformaldehyde (2.1g, 75mmol, 1.5 equivalents); HCl concentrate (0.3 g); ethanol (35 mL); 110 ℃ for 9 hours; about 2 to 2.5 bar; remove ethanol (25mL) in vacuo; ethyl acetate (50mL) was added; the yield was about 73%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.3(2H，s，br)，8.08(1H，dd)，8.00(1H，dd)，7.28(1H，dd)，3.51(2H，t)，3.20(2H，t)，2.96(2H，q)，1.23(3H，t)。

Comparative example 2: 3- (ethylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Becoming ethyl)

2-Acetylthiophene (12.6g, 100 mmol); ethylamine hydrochloride (12.2g, 150mmol, 1.5 equiv); paraformaldehyde (4.1g, 140mmol, 1.4 equivalents); HCl concentrate (0.5 g); ethanol (70 mL); heating at reflux (78 deg.C) for 6 hours; remove ethanol (25mL) in vacuo; ethyl acetate (70mL) was added; the yield was about 31%.

Example 4: 3- (isobutylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²All-round of isobutyl)

2-Acetylthiophene (6.3g, 50 mmol); isobutylamine hydrochloride (8.3g, 75mmol, 1.5 equiv); paraformaldehyde (2.1g, 75mmol, 1.5 equivalents); HCl concentrate (0.3 g); ethanol (35 mL); 110 ℃ for 9 hours; about 2 to 2.5 bar; ethanol (35mL) was removed in vacuo; ethyl acetate (50mL) was added; the yield was about 56%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.0(2H，s，br)，8.08(1H，dd)，7.99(1H，dd)，7.29(1H，dd)，3.55(2H，t)，3.22(2H，t)，2.78(2H，d)，2.03(1H，m)，0.96(6H，d)。

Comparative example 3: 3- (isobutylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²All-round of isobutyl)

2-Acetylthiophene (12.6g, 100 mmol); isobutylamine hydrochloride (16.5g, 150mmol, 1.5 equiv); paraformaldehyde (4.1g, 140mmol, 1.4 equivalents); HCl concentrate (0.5 g); butanol (70 mL); heating at reflux (108 ℃) for 6 hours; ethyl acetate (100mL) was added; the yield was about 40%.

Example 5: 3- (tert-butylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Tertbutyl ═

2-Acetylthiophene (6.3g, 50 mmol); tert-butylamine hydrochloride (8.3g, 75mmol, 1.5 equiv); paraformaldehyde (2.1g, 75mmol, 1.5 equivalents); HCl concentrate (0.3 g); butanol (35 mL); 117 ℃ for 9 hours; about 2 to 2.5 bar; ethyl acetate (50mL) was added; the yield was about 52%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.2(2H，s，br)，8.08(1H，dd)，7.98(1H，dd)，7.30(1H，dd)，3.54(2H，t)，3.19(2H，t)，1.34(9H，s)。

Comparative example 4: 3- (tert-butylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (II, R)¹2-thienyl, R²Tertbutyl ═

2-Acetylthiophene (12.6g, 100 mmol); tert-butylamine hydrochloride (16.5g, 150mmol, 1.5 equiv); paraformaldehyde (4.1g, 140mmol, 1.4 equivalents); HCl concentrate (0.5 g); butanol (70 mL); heating at reflux (108 ℃) for 18 hours; ethyl acetate (100mL) was added; the yield was about 37%.

Example 6: 3- (methylamino) -1- (furanyl-2-yl) propan-1-one hydrochloride (II, R)¹Furan-2-yl, R²Armenine methyl

2-acetylfuran (7.5g, 68 mmol); methylamine hydrochloride (6.9g, 102mmol, 1.5 equivalents); paraformaldehyde (3.1g, 102mmol, 1.5 equivalents); HCl concentrate (1.15 g); ethanol (35 mL); 110 ℃ for 8 hours; about 2 to 2.5 bar; remove ethanol (30mL) in vacuo; ethyl acetate (50mL) was added; the yield was about 64%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.0(2H，s，br)，8.05(1H，m)，7.53(1H，m)，6.77(1H，m)，3.34(2H，t)，3.2(2H，m)，2.57(3H，s，br)。

Comparative example 5: 3- (methylamino) -1- (furanyl-2-yl) propan-1-one hydrochloride (II, R)¹Furan-2-yl, R²Armenine methyl

2-acetylfuran (11.0g, 100 mmol); methylamine hydrochloride (10.1g, 150mmol, 1.5 equivalents); paraformaldehyde (4.1g, 140mmol, 1.4 equivalents); HCl concentrate (0.5 g); butanol (70 mL); heating at reflux (108 ℃) for 7 hours; ethyl acetate (100mL) was added; the yield was about 44%.

Example 7: 3- (methylamino) -1-phenylpropan-1-one hydrochloride (II, R)¹Is phenyl, R²Armenine methyl

2-acetophenone (21.0g, 175 mmol); methylamine hydrochloride (17.5g, 263mmol, 1.5 equiv); paraformaldehyde (7.9g, 263mmol, 1.5 equivalents); HCl concentrate (1.1 g); ethanol (130 mL); at 115 ℃ for 24 hours; about 2 to 2.5 bar; ethyl acetate (50mL) was added; the yield was about 52%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.2(2H，s，br)，8.0(2H，m)，7.7(1H，m)，7.6(2H，m)，3.55(2H，t)，3.21(2H，m)，2.59(3H，s)。

Example 8: 3- (methylamino) -1- (2-naphthyl) propan-1-one hydrochloride (II, R)¹2-naphthyl, R²Armenine methyl

2-acetonaphthone (8.5g, 50 mmol); methylamine hydrochloride (5.1g, 75mmol, 1.5 equivalents); paraformaldehyde (2.1g, 75mmol, 1.5 equivalents); HCl concentrate (0.3 g); ethanol (35 mL); at 117 ℃ for 14 hours; about 2 to 2.5 bar; ethanol (35mL) was removed in vacuo; ethyl acetate (50mL) was added; the yield was about 60%.

¹H-NMR δ(DMSO-d₆，400MHz)：9.3(2H，s，br)，8.74(1H，s)，8.17(1H，d)，8.0(3H，m)，7.7(2H，m)，3.70(2H，t)，3.28(2H，m)，2.60(3H，s)。

Comparative example 6: 3- (methylamino) -1- (2-naphthyl) propan-1-one hydrochloride (II, R)¹2-naphthyl, R²Armenine methyl

2-acetonaphthone (17.0g, 100 mmol); methylamine hydrochloride (10.1g, 150mmol, 1.5 equivalents); paraformaldehyde (4.1g, 140mmol, 1.4 equivalents); HCl concentrate (0.5 g); ethanol (70 mL); heating at reflux (78 deg.C) for 5 hours; remove ethanol (30mL) in vacuo; ethyl acetate (100mL) was added; the yield was about 42%.

Example 9: 3- (methylamino) -1- (thiophen-2-yl) propan-1-one (I, R)¹2-thienyl, R²Armenine methyl

To a mixture of 3- (methylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (10.3g, 50mmol) and ethanol (35mL) at 4 deg.C was added sodium hydroxide (4.0g of a 50% aqueous solution) over about 5 minutes. Later, neat sodium hydroxide (0.95g, 25mmol, 1.0 equiv.) was added in portions over my 30 minutes. At the end of the addition, the suspension was stirred at the same temperature for 4 hours, then acetone (10.0mL) was added dropwise over 5 minutes and the mixture was stirred for a further 10 minutes. Water (20mL) was added. Thereafter, the mixture was concentrated under vacuum by a factor of about 5 and the residue was extracted with tert-butyl methyl ether (2X 20 mL). Finally the collected organic phase was concentrated in vacuo to give an orange oil which crystallized spontaneously after a few hours. Finally, an orange solid was obtained (7.2g, 84% yield ca). The compound can then be used without further purification.

¹H-NMR δ(DMSO-d₆，400MHz)：7.35(1H，dd，J＝4.8，1.0)，6.94(1H，dd，J＝4.8，3.6)，6.90(1H，dd，J＝3.6，1.0)，4.90(1H，t)，3.7(2H，m)，2.56(2H，m)，2.25(3H，s)，1.79(2H，q)。

¹³C-NMR δ(DMSO-d₆，400MHz)：150.9，126.3，123.7，122.3，67.8，48.5，38.7，36.0。

Example 10: 3- (isobutylamino) -1- (thiophen-2-yl)Propane-1-ol (I, R)¹2-thienyl, R²All-round of isobutyl)

To a mixture of 3- (isobutylamino) -1- (thiophen-2-yl) propan-1-one hydrochloride (4.2g, 19.4mmol) and ethanol (10mL) at 4 deg.C was added sodium hydroxide (1.6g of a 50% aqueous solution) over about 20 minutes. Neat sodium hydroxide (0.37g, 9.7mmol, 1.0 equiv) was then added in portions over about 30 minutes. At the end of the addition, the suspension was stirred at the same temperature for 4 hours, then acetone (10.0mL) was added dropwise over 20 minutes and the mixture was stirred for a further 10 minutes. After that, the precipitate was removed by filtration, and the mixture was concentrated in vacuo to give an orange oil. The crude product was purified by column chromatography using a 40:10:1(v: v: v) dichloromethane/methanol/ammonium hydroxide (25% aqueous solution) mixture.

¹H-NMR δ(DMSO-d₆，400MHz)：7.20(1H，dd，J＝4.8，1.0)，6.98(1H，dd)，6.94(1H，dd，J＝4.8，3.6)，5.20(1H，dd)，4.98(2H，br)，3.02(1H，m)，2.93(1H，m)，2.43(2H，symm.m)，2.03(1H，m)，1.97(1H，m)，1.80(2H，sept)，0.95(6H，d)。

¹³C-NMR δ(DMSO-d₆，100MHz)：150.9，126.3，123.8，122.5，72.1，57.8，48.5，37.4，28.2，20.8。

Claims (22)

1. A process for the preparation of a compound of the formula and/or a protic acid addition salt thereof,

characterized in that R is¹，R²Independently represents an alkyl, cycloalkyl, aryl or aralkyl group, each aryl or aralkyl group being optionally further substituted by an alkyl, alkoxy and/or halogen, which process comprises the following steps:

a) a reaction mixture comprising

(i) Methyl ketones of the general formula (IV)

Wherein R is¹According to the above definition, and

(ii) a compound of the general formula and/or a protic acid addition salt thereof,

H₂N-R²V

wherein R is²According to the above definition, and

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

in the presence of a solvent selected from the group consisting of water, fatty alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a protic acid, to obtain a beta-aminoketone of the formula and/or a protic acid addition salt thereof, and

b) reducing the carbonyl group of said beta-aminoketone to obtain a compound of formula I, and/or a protic acid addition salt thereof,

wherein the first step is carried out at a pressure of more than 1.5 bar.

2. The method of claim 1, wherein R is¹Selected from straight or branched C_1-8Alkyl radical, C_3-8Cycloalkyl, phenyl, naphthyl, furyl, benzofuryl, thienyl, benzothienyl and aralkyl, the alkyl part of the aralkyl residue being a straight-chain C_1-4Alkyl, aryl moieties selected from phenyl, naphthyl, furyl, benzofuryl, thienyl and benzothienyl, 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 radical, CF₃，C₂F₅，OCF₃Or OC₂F₅And (4) substitution.

3. The method of claim 1 or 2, wherein R is²Selected from straight or branched C_1-8Alkyl radical, C_3-8Cycloalkyl, phenyl, naphthyl, furyl, benzofuryl, thienyl, benzothienyl and aralkyl, the alkyl part of the aralkyl residue being a straight-chain C_1-4Alkyl, aryl moieties selected from phenyl, naphthyl, furyl, benzofuryl, thienyl and benzothienyl, 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 radical, CF₃，C₂F₅，OCF₃Or OC₂F₅And (4) substitution.

4. The method of claim 1 or 2, wherein the compound of formula V is present in at least an equimolar amount to the compound of formula IV.

5. The method of claim 1 or 2, wherein the protic acid is a carboxylic acid or a mineral acid.

6. The method of claim 5, wherein the protic acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H₂SO₄、H₃PO₄Monobasic malonic acid salts, alkali hydrogen sulfates, alkali hydrogen phosphates and alkali hydrogen carbonates.

7. The method of claim 1 or 2, wherein the aliphatic and cyclic aliphatic alcohols are selected from the group consisting of linear or branched aliphatic C_1-12Alcohol, cycloaliphatic C_5-8Alcohols, diglycols and/or triglycerols or their mono-C_1-4Alkyl or acetyl derivatives, each of said alcohols containing from 1 to 3 hydroxyl groups.

8. The method of claim 7, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-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, 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, and triethylene glycol monoacetate.

9. The process according to claim 1 or 2, wherein the pressure during reaction step a) is greater than 1.5 bar.

10. The process according to claim 1 or 2, wherein the pressure during reaction step a) is between 1.5 and 10 bar.

11. The process according to claim 1 or 2, wherein the pressure during reaction step a) is between 1.5 and 5 bar.

12. A process for the preparation of a compound having the formula and/or a protic acid addition salt thereof,

characterized in that R is¹，R²Independently represents alkyl, cycloalkyl, aryl or aralkyl, each optionally further substituted by alkyl, alkoxy and/or halogen, which process comprises reacting

(i) Methyl ketones of the general formula (IV)

Wherein R is¹According to the above definition, and

(ii) a compound of the general formula and/or a protic acid addition salt thereof,

H₂N-R²V

wherein R is²According to the above definition, and

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

in the presence of a solvent selected from the group consisting of water, fatty alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a protic acid, to obtain a compound of the formula and/or a protic acid addition salt thereof,

characterized in that R is¹And R²The reaction is carried out at a pressure of more than 1.5 bar, as defined above.

13. The method of claim 12, wherein R is¹As defined in claim 2.

14. The method of claim 12 or 13, wherein R is²As defined in claim 3.

15. The method of claim 12 or 13, wherein the compound of formula V is present in at least an equimolar amount to the compound of formula IV.

16. The method of claim 12 or 13, wherein the protic acid is a carboxylic acid or a mineral acid

17. The method of claim 16, wherein the method comprisesThe protonic acid is selected from formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H₂SO₄、H₃PO₄Monobasic malonic acid salts, alkali hydrogen sulfates, alkali hydrogen phosphates and alkali hydrogen carbonates.

18. The method of claim 12 or 13, wherein the aliphatic and cyclic aliphatic alcohols are selected from linear or branched aliphatic C_1-12Alcohol, cycloaliphatic C_5-8Alcohols, diglycols and/or triglycerols or their mono-C_1-4Alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxyl groups.

19. The method of claim 18, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-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, 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, and triethylene glycol monoacetate.

20. The process of claim 12 or 13, wherein the pressure during the reaction is greater than 1.5 bar.

21. The process according to claim 12 or 13, wherein the pressure during reaction step a) is between 1.5 and 10 bar.

22. The process according to claim 12 or 13, wherein the pressure during reaction step a) is between 1.5 and 5 bar.