HK1129365A - Process for the preparation of adamantanamines - Google Patents

Description

Process for producing adamantanamine

The present invention relates to a process for producing a specific adamantylamine compound, an intermediate used in the process, and a process for producing the intermediate.

Adamantanamines have long been known to be a valuable class of drugs. For example, Memantine (Memantine) hydrochloride (1-amino-3, 5-dimethyladamantane hydrochloride, formula IVa) is an uncompetitive NMDA (N-methyl-D-aspartate) receptor antagonist,

it is useful as a novel means of treating alzheimer's disease. AsMemantine hydrochloride is the first therapeutic compound for AD to act through this mechanism of action to be marketed. Memantine has been marketed in germany for over 20 years for the treatment of spastic and dementia syndromes.

Amantadine hydrochloride (Amantadine) 1-aminoadamantane, formula IVb) is an antiviral drug used to treat specific influenza infections (type a).

The compound is also an anti-dyskinesia drug for the treatment of parkinson's disease.

US 3,391,142 discloses a process for the preparation of memantine hydrochloride starting from 1-bromo-3, 5-dimethyladamantane, which is reacted with acetonitrile in concentrated sulfuric acid to form the acetamido derivative, which is then cleaved under basic hydrolysis conditions.

According to WO 01/053234, adamantane is converted to N- (1-adamantyl) acetamide in a reaction medium containing anhydrous acetonitrile, fluorine and a Lewis acid. The compound can be cleaved under acidic or basic conditions to produce aminoadamantane.

In order to avoid reactions with highly toxic HCN, several methods describe the reaction of dimethyladamantanes with urea or formamide (WO 05/023753, RU 2246482, DE 23184461, EP0392059, CZ 288445).

Conventional methods for preparing adamantanamines have many problems. The yields of at least some of the steps are low, the reaction times are relatively long, hazardous reaction conditions and/or solvents are required, and/or the use of some solvents can cause difficulties in the purification of the final product.

There is therefore a need for an improved process for the preparation of highly pure adamantanamines, in particular memantine hydrochloride or amantadine hydrochloride, which overcomes the above problems and thus provides a process which is economically viable on an industrial scale.

Accordingly, one aspect of the present invention relates to a process for preparing an adamantyl amine of formula (IV),

wherein R and R' are each methyl, and X is halogen,

the method comprises the following steps:

(i) reacting a compound of formula (I) with thiourea,

wherein R, R' and X are each as defined above;

(ii) subjecting the resulting compound of formula (II) to an acid treatment;

and

(iii) separating the resulting adamantanamine or its hydrohalide salt.

In general, X can be any halogen, such as chlorine, bromine, iodine. In a particular embodiment of the invention, X is chlorine or bromine.

The process of the present invention is particularly useful for the preparation of memantine hydrohalide salts, especially memantine hydrochloride, by using as starting material a compound of formula (I) wherein R and R' are each methyl and X is halogen, especially chlorine or bromine.

Another aspect of the invention relates to compounds of formula (I),

wherein R and R' are each methyl, and X is chlorine or bromine.

The compounds of formula (I) may be prepared by reacting a compound of formula (III)

Wherein R1 is hydroxy or halogen,

with haloacetonitrile X-CH₂-CN, in which X is halogen, in particular chlorine or bromine, in an acidic medium.

R1 is, for example, hydroxy, bromo or chloro, especially hydroxy or bromo.

Throughout this application, X is, for example, bromine or chlorine, in particular chlorine. The compounds of the formula (III) are known or can be obtained according to methods known per se.

The acidic medium used for the reaction of the compound of formula (III) with haloacetonitrile, in particular chloroacetonitrile, suitably comprises a strong mineral acid, in particular sulphuric acid. Other optional components in the acidic medium comprise one or more solvents, for example organic acids, such as propionic acid or especially acetic acid; and/or polar aprotic solvents such as N, N-Dimethylformamide (DMF); and metal salt catalysts, such as iron (III) sulfate.

One embodiment of the invention comprises reacting 1-hydroxy-3, 5-dimethyladamantane (a compound of formula (III) wherein R is hydroxy) with chloroacetonitrile in the presence of sulfuric acid; organic acids, especially acetic acid; and optionally DMF.

Another embodiment comprises reacting 1-bromo-3, 5-dimethyladamantane (a compound of formula (III) wherein R is bromo) with chloroacetonitrile in a solution comprising sulfuric acid, DMF, iron (III) sulfate, and optionally an organic acid, especially acetic acid.

The reaction of the compound of the formula (III) with haloacetonitrile is advantageously carried out under mild conditions, for example at a temperature of from 0 to 70 ℃, preferably from 0 to room temperature, in particular from 0 to 10 ℃. Typically, the strong mineral acid is added to the mixture of reactants, solvent and optional catalyst in such a way that the temperature does not exceed the above limits. After the addition of the mineral acid, the reaction mixture may, if desired, be kept at room temperature or at elevated temperature for a period of time suitable for the completion of the reaction, for example at a temperature of from 50 to 100 ℃, preferably from 70 to 80 ℃, for example for up to 120 minutes, preferably from 30 to 90 minutes. Finally, the reaction mixture is worked up in the usual manner, for example by hydrolyzing the reaction mixture with water at ambient conditions, washing, isolating and drying the organic residue to give the compound of formula (I) wherein R and R' are each methyl.

Compounds of formula (I) wherein R and R' are each hydrogen are known, for example, from a. jirgensons et al Synthesis 2000, 12, 1709 and can be prepared as described therein.

The reaction of the compound of formula (I) with thiourea is advantageously carried out in a suitable solvent at a temperature of, for example, 60 to 120 ℃, preferably at the reflux temperature of the reaction mixture, for a period of time, for example about 4 hours to about 10 hours. Suitable solvents are, for example, C₁-C₄Alcohols, for example methanol, ethanol or n-or isopropanol, in particular ethanol or isopropanol. The resulting compound of formula (II) may be isolated in a conventional manner, for example by removal of solvent, washing, crystallization and/or drying.

Accordingly, the present invention relates to a process as described above, wherein the reaction step (i) is carried out in C as solvent₁-C₄In alcohol.

It is a further object of the present invention to provide compounds of formula (II),

wherein R and R' are each methyl, and X is chlorine or bromine.

The compound of formula (II) is then treated in an acidic medium to give the desired adamantanamine or its hydrohalide salt. Preferred acidic media are, for example, aqueous acidic media or C₁-C₄Mixtures of alcohols and acids, or C₁-C₄A mixture of alcohol, water and acid. In the conversion step of the compound of formula (II), a suitable acid is, for example, organic C₁-C₄Carboxylic acids, such as acetic acid, propionic acid or butyric acid, in particular acetic acid. Useful alcohols are as described above, for example ethanol or isopropanol. Typically, the compound of formula (II) is treated in an acidic medium under reflux for a time sufficient to complete the conversion, for example up to 12 hours, preferably 4 to 8 hours.

Thus, it is possible to provideThe present invention also relates to a process as described above, wherein the acid treatment in step (ii) comprises a treatment with an acid comprising C₁-C₄Carboxylic acid, especially acetic acid and a compound selected from water and C₁-C₄Treating the compound of formula (II) in a medium of one or more solvents of the group consisting of alcohols.

The step of isolating the compound of formula (II) may be omitted and the compound of formula (I) may be converted directly to the desired adamantanamine or its hydrohalide salt by treating the compound of formula (I) with thiourea, for example in a reaction medium as described above under reflux, particularly in a reaction medium comprising an acid, water and/or C as described above₁-C₄In the reaction medium of an alcohol.

The adamantanamines obtained in each case can be isolated from the reaction mixture in the form of their free bases, for example by basifying the reaction solution and isolating and purifying the product obtained in a known manner. For example, the reaction mixture is treated with an alkali metal hydroxide, such as sodium hydroxide. After addition of a suitable organic solvent, a phase separation may be carried out, and the organic layer may then be subjected to typical finishing steps, such as concentration, crystallization and/or drying steps.

Accordingly, the present invention relates to a process according to the above defined process, wherein, in step (iii), the adamantanamine is isolated as the free base by basifying the reaction solution.

The free base form of the adamantanamine may be prepared by reacting the corresponding hydrohalic acid in a solvent containing, for example, C₁-C₄Alcohol and optionally water, to the corresponding hydrohalide salt.

The invention therefore also relates to a method as described above, comprising the additional steps of: the adamantyl amine free base is converted to the adamantyl amine hydrohalide by treatment with a hydrohalide acid, particularly hydrochloric acid.

Preferred adamantyl amines, memantine hydrochloride or amantadine hydrochloride, advantageously by containing C₁-C₄Alcohol, especially ethanol or isopropanol, and aqueous hydrochloric acid. Preferably, concentrated hydrochloric acid is slowly added to the C of memantine or amantadine₁-C₄In an alcoholic solution.

Instead of isolating memantine or amantadine in free base form, the above-described reaction mixture comprising the original memantine or amantadine can be converted directly to the corresponding memantine or amantadine hydrohalide salt by adding the hydrohalide acid directly to the reaction mixture and isolating, for example, the memantine or amantadine hydrohalide salt as described above without isolating the free base.

The invention therefore also relates to a process as described above, wherein the compound of formula (I) is prepared by reacting a compound of formula (I) with a compound containing C₁-C₄Carboxylic acid and a carboxylic acid selected from the group consisting of water and C₁-C₄The reaction with thiourea in a medium of one or more solvents from the group of alcohols leads directly to the adamantanamine without isolation of the compound of formula (II). Still further, the present invention relates to such a process wherein the adamantyl amine is directly converted to the adamantyl amine hydrohalide salt by adding the hydrohalide acid to the reaction mixture comprising the original adamantyl amine without isolating the free base.

The following examples further illustrate the invention.

Example 1

Preparation of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide(method 1)

To a 0.50 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-hydroxy-dimethyladamantane (10.00g, 55.47mmol), chloroacetonitrile (8.38g, 110.94mmol) and acetic acid (17.74ml, 307.48 mmol). The resulting suspension was cooled to 0 ℃ with vigorous stirring. Sulfuric acid (96%, 17.74ml, 332.80mmol) was added to the cold reaction mixture, maintaining the temperature below 10 ℃. After the addition was complete, the clear reaction mixture was allowed to reach room temperature. Obtained byThe suspension was slowly treated with water (0 ℃, 100ml) and further stirred at 0-5 ℃ for 30 minutes. After separation, the colorless crystalline solid was washed in a stream of water (0 ℃, 100ml, 2 ×) and dried under reduced pressure (40 ℃, 72h, 25 mbar) to give 13.25g (51.80mmol, 93.4%) of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide.¹H NMR(300MHz，DMSO-d6，ppm)：δ 7.66.(b，1H，NH)，3.93(s，2H，RCH₂Cl)，2.08(m，1H，R₃CH)，1.75(m，2H，RCH₂R)，1.57(m，4H，RCH₂R)，1.28(m，4H，RCH₂R)，1.11(s，2H，RCH₂R)，0.82(s，6H，RCH₃)。¹³C NMR(75MHz，DMSO-d6，ppm)：δ 164.82(CO)，52.73，50.12，46.69，43.42，42.17，31.81，29.43。MS(EI，m/z)：255[M^+·，220[M-Cl^+·，163[M-C₂H₃ClNO^+·。IR(KBr，cm^-1)：1661s(ν_RCONHRAmide I), 1574s (amide II). E.a. (chn,%): c₁₄H₂₂ClNO 0.1HAc theoretical value: c, 65.15; h, 8.00; and (5) N5.15. Measured value: c65.15, H8.62, N5.35 melting point: 106.8 ℃.

Example 2

Preparation of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide(method 2)

To a 4.0 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-hydroxy-dimethyladamantane (47.50g, 263.48mmol), dimethylformamide (42.13ml), chloroacetonitrile (39.81g, 526.97mmol) and acetic acid (84.27ml, 1.46 mol). The resulting suspension was slowly treated with sulfuric acid (96%, 84.27ml, 1.58mol) at room temperature with vigorous stirring, whereupon the reaction mixture reached about 70 ℃. After the addition was complete, the clear reaction mixture was allowed to cool to room temperature. The resulting suspension was slowly treated with water (0 ℃, 475ml) and further stirred at 0-5 ℃ for 60 minutes. After separation, the colorless crystalline solid was washed in a stream of water (0 ℃, 475ml, 2 ×) and dried under reduced pressure (40 ℃, 72h, 25 mbar) to give 62.18g (243.09mmol, 92.26%) 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide.

Example 3

Preparation of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide(method 3)

To a 0.50 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-hydroxy-dimethyladamantane (10.00g, 55.47mmol), chloroacetonitrile (8.38g, 110.94mmol), dimethylformamide (8.87ml) and acetic acid (17.74ml, 307.48 mmol). The resulting suspension was slowly treated with sulfuric acid (96%, 17.74ml, 332.80mmol) at room temperature with vigorous stirring, whereupon the reaction mixture reached about 70 ℃. After the addition was complete, the clear reaction mixture was slowly treated with water (15 ℃, 100ml) at 70 ℃. The product crystallized at the end of the exothermic reaction. The resulting suspension was cooled to 0-5 ℃ and stirred at this temperature for a further 60 minutes. After filtration, the colorless crystalline solid was washed in a stream of water (20 ℃, 50ml, 4 ×) and dried under reduced pressure (40 ℃, 72h, 25 mbar) to give 13.71g (53.59mmol, 96.61%) of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide.

Example 4

Preparation of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide(method 4)

To a 0.50 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-hydroxy-dimethyladamantane (10.00g, 55.47mmol), chloroacetonitrile (8.38g, 110.94mmol) and acetic acid (17.74ml, 307.48 mmol). The resulting suspension was slowly treated with sulfuric acid (96%, 17.74ml, 332.80mmol) at room temperature with vigorous stirring, whereupon the reaction mixture reached about 70 ℃. After the addition was complete, the clear reaction mixture was slowly treated with water (15 ℃, 100ml) at 70 ℃. The product crystallized at the end of the exothermic reaction. The resulting suspension was cooled to 0-5 ℃ and stirred at this temperature for a further 60 minutes. After filtration, the colorless crystalline solid was washed in a stream of water (20 ℃, 50ml, 4 ×) and dried under reduced pressure (40 ℃, 72h, 25 mbar) to give 13.61g (53.19mmol, 95.89%) of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide.

Example 5

Preparation of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide(method 5)

To a 0.25 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-bromo-3, 5-dimethyladamantane compound (5.00g, 20.56mmol), iron (III) sulfate (84mg, 0.21mmol), dimethylformamide (6.00ml), chloroacetonitrile (4.19g, 55.50mmol) and acetic acid (9.23g, 153.73 mmol). The reaction mixture is cooled to 5-10 ℃ with stirring. Sulfuric acid (96%, 8.87ml, 166.4mmol) was added dropwise, maintaining the temperature at 5-10 ℃. After the addition was complete, the resulting suspension was heated to 80 ℃ for about 90 minutes. The reaction mixture was cooled to room temperature and hydrolyzed with water (50 ml). After cooling to 5 ℃, stirring was further carried out for 30 minutes. The residue was separated, washed with a stream of water (150ml) and dried under reduced pressure (40 ℃, 72h, 25 mbar) to give 3.23g (12.63mmol, 61.4%) of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide as a colourless powder, as described above.

Example 6

Preparation of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide(method 6)

To a 0.25 liter round bottom three neck flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-bromo-3, 5-dimethyladamantane (5.00g, 20.56mmol), iron (III) sulfate (84mg, 0.21mmol) and dimethylformamide (6.00 ml). The reaction mixture is cooled to 5-10 ℃ with stirring. Sulfuric acid (96%, 8.87ml, 166.4mmol) was added dropwise, maintaining the temperature at 5-10 ℃. After the addition was complete, the resulting suspension was treated with chloroacetonitrile (4.19g, 55.50mmol) at 5 ℃ and then heated to 70-80 ℃ for 30 min. The reaction mixture was cooled to room temperature and hydrolyzed with water (50 ml). After cooling to 5 ℃, stirring was further carried out for 30 minutes. The residue was separated, washed with a stream of water (150ml) and dried under reduced pressure (40 ℃, 72h, 25 mbar) to give 3.52g (13.76mmol, 66.9%) of 2-chloro-N- (3, 5-dimethyladamantan-1-yl) -acetamide as described above.

Example 7

2-Aminoiminomethylthio (Carbamimimidosylamino) -N- (3, 5-dimethyladamantan-1-yl) ethyl ester Preparation of amides

To a 0.25 liter round bottom two necked flask equipped with a reflux condenser, oil valve (oil vent) and magnetic stir bar was added 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide (2.00g, 7.82mmol), ethanol (16ml) and thiourea (718mg, 9.43 mmol). The suspension was heated to reflux with stirring. After 10 minutes, the solvent was removed under reduced pressure to give a colorless oil. Upon addition of acetonitrile (76ml) with stirring, the residue crystallized. The resulting suspension was cooled to 0 ℃ and stirring was continued for a further 60 minutes. The colourless precipitate was separated off, washed with acetonitrile (10ml, 3X) and dried under reduced pressure (40 ℃, 60 mbar, 8h) to give 1.96g (5.90mmol, 75.5%) of a colourless powder2-Hydroxyiminomethanes Sulfur based radicals(carbamimidosulfamoyl) -N- (3, 5-dimethyladamantan-1-yl) acetamide.¹H NMR(300MHz，DMSO-d6，ppm)：9.52.(b，1H，NH)，9.27.(b，1H，NH)，3.90(s，2H，RCH₂S)，2.08(m，1H，R₃CH)，1.73(m，2H，RCH₂R)，1.57(m，4H，RCH₂R)，1.28(m，4H，RCH₂R)，1.09(s，2H，RCH₂R)，0.80(s，6H，RCH₃)。¹³C NMR(75MHz，DMSO-d6，ppm)：δ 170.13，166.69(CO)，53.21，50.05，46.49，42.09，34.07，31.77，29.92，29.35。MS(ESI，m/z)：296.0[M-Cl]⁺。IR(KBr，cm^-1)：1663s(ν_RCONHRAmide I), 1553s (amide II). Melting point: 212.3℃(dec.)。E.A.(C，H，N；％)：C₁₅H₂₆ClN₃Theoretical value of OS: c, 54.18; h, 7.90; and N12.66. Measured value: c54.11, H6.94, N12.56.

Example 8

Preparation of 1-amino-3, 5-dimethyladamantane (memantine base)

To a 0.50 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide (10.00g, 39.10mmol), ethanol (77.52ml), acetic acid (15.5ml) and thiourea (3.57g, 46.92 mmol). The resulting suspension was heated to reflux (70 ℃) with stirring and the temperature was maintained for 6 h. The cloudy solution was basified with sodium hydroxide (50%, 15.5ml) and treated with toluene at about 60 ℃. The phases were separated and the aqueous layer was discarded. The organic layer was concentrated under vacuum, dissolved in isopropanol (5ml) and filtered. The residue was dried to give 5.22g (29.12mmol, 74.5%) of liquid 1-amino-3, 5-dimethyladamantane, which crystallized during storage.¹H NMR(300MHz，DMSO-d6，ppm)：δ 2.04(m，1H，R₃CH)，1.45(b，1.5H，RNH₂)，1.33(m，2H，RCH₂R)，1.25-0.98(m，10H，RCH₂R)，0.80(s，6H，RCH₃)。¹³C NMR(75MHz，DMSO-d6，ppm)：δ 52.31，50.39，48.39，44.43，42.37，32.16，30.13，30.00。MS(EI，m/z)：179[M^+·. IR (film, cm)^-1)：3342，3268cm^-1(m，ν_NH)，1593(m，δ_NH)。

Example 9

Preparation of 1-amino-3, 5-dimethyladamantane hydrochloride (memantine hydrochloride)(method 1)

In a 0.05 liter round bottom flask equipped with a magnetic stir bar, nitrogen inlet and oil valve (oil ventile), 1-amino-3, 5-dimethyladamantane (2.69g, 15.00mmol) was dissolved in isopropanol (2.7 ml).To the stirred clear solution was added dropwise aqueous hydrochloric acid (31%, 2ml) at room temperature. The resulting suspension was cooled to 0 ℃ and stirred for a further 60 minutes. The colorless crystalline solid was collected by filtration, washed with isopropanol (0.5ml, 3 ×), and dried under reduced pressure (48h, 30 ℃, 50 mbar) to give 2.24g (10.38mmol, 69.2%) of memantine hydrochloride.¹H NMR(300MHz，DMSO-d6，ppm)：δ 8.24(s，3H，NH)，2.11(m，1H，R₃CH)，1.65(m，2H，RCH₂R)，1.46(m，4H，RCH₂R)，1.28(s，4H，RCH₂R)，1.10(m，2H，RCH₂R)，0.83(s，6H，RCH₃)。¹³C NMR (75MHz, DMSO-d6, ppm): δ 52.81, 49.96, 46.31, 41.96, 38.91, 32.37, 30.05, 29.54. MS (EI, m/z, free base): 179[ M ]]^+·。IR(KBr，cm^-1)：3435(m，ν_NH). Melting point:>300 (sublimation). E.A. (C, H, N;%): c₁₂H₂₂ClN·H₂Theoretical value of O: c, 66.25; h, 10.28; n, 6.44. Measured value: c, 66.31%; h, 9.40; and N, 6.20. GC (rel. ar.): 99.85 percent.

Example 10

Preparation of 1-amino-3, 5-dimethyladamantane hydrochloride (memantine hydrochloride)(method 2)

To a 0.50 liter round bottom flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide (10.00g, 39.10mmol), thiourea (3.571g, 46.92mmol), water (77.5ml) and acetic acid (15.5 ml). Heat to reflux with stirring and maintain the temperature for 6 h. The reaction mixture was cooled to about 60 ℃ and treated by dropwise addition of aqueous hydrochloric acid (31%, 25 ml). The resulting suspension was cooled to room temperature. The precipitate was collected by filtration, washed with water (10ml) and dried under reduced pressure (30 ℃, 25 mbar, 12h) to give 5.78g (26.87mmol, 68.7%) of memantine hydrochloride as a colorless crystalline solid as described in example 9.

Example 11

Preparation of 1-amino-3, 5-dimethyladamantane hydrochloride (memantine hydrochloride)(method 3)

To a 4.0 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 2-chloro-N- (3, 5-dimethyladamantan-1-yl) acetamide (106.7g, 0.42mol), thiourea (38.1g, 0.50mol), acetic acid (165.4ml) and ethanol (827.1 ml). The reaction mixture was heated to reflux with stirring and kept at this temperature for 8 h. After completion of the reaction, the contents of the vessel were allowed to reach room temperature. The cloudy solution was filtered and the clear filtrate was treated first with water (1070ml) and then with aqueous sodium hydroxide (50%, 165.4ml) without external cooling within 15 minutes. The temperature may be as high as 60 ℃. Toluene (215ml) was added and the mixture was stirred vigorously for 15 minutes. The phases were separated. The aqueous phase was extracted with toluene (220ml) at 45-55 ℃. The phases were separated, the organic layers were combined and the aqueous layer was discarded. To the combined organic phases was added sodium hydroxide (50%, 100ml) and the biphasic system was vigorously stirred at 45-55 ℃ for 15 minutes. The phases were separated and the aqueous layer was discarded. The organic layer was treated with water (100ml) to ensure that the temperature was maintained between 45-55 ℃. The phases were separated and the aqueous layer was discarded. The organic layer was treated with sodium chloride (aq., conc, 100ml) with stirring, maintaining the temperature at 45-55 ℃. The phases were separated and the aqueous layer was discarded. The organic phase was filtered and transferred to a 2.0 liter round bottom three neck flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel. The contents of the vessel are cooled to 0-5 ℃ with stirring. Aqueous hydrochloric acid (31%, 53ml) was added maintaining the temperature below 20 ℃. After the addition was complete, the resulting suspension was cooled to 0-5 ℃ and further stirred for 30 minutes. The colorless microcrystalline solid was collected by filtration, washed with toluene (100ml, 3 ×), and dried under reduced pressure (40 ℃, 30 mbar, 18.5h) to yield 71.25g (0.33mol, 71.16%) of memantine hydrochloride as a crystalline solid as described in example 9.

Example 12

N-diamondSynthesis of alk-1-yl-2-chloroacetamide

To a 0.50 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added 1-hydroxyadamantane (10.00g, 65.69mmol), chloroacetonitrile (9.92g, 131.38mmol), dimethylformamide (11ml) and acetic acid (21ml, 363.96 mmol). The resulting suspension was slowly treated with sulfuric acid (96%, 21ml) at room temperature with vigorous stirring, whereupon the reaction mixture reached approximately 80 ℃. After the addition was complete, the clear reaction mixture was slowly treated with water (15 ℃, 118ml) at 70 ℃. The product crystallized at the end of the exothermic reaction. And (3) cooling the obtained suspension to 0-5 ℃ under stirring. After filtration, the colorless crystalline solid was washed in a stream of water and dried under reduced pressure (40 ℃, 19h, 25 mbar) to give 14.90g (65.43mmol, 99.60%) of N-adamantan-1-yl-2-chloroacetamide.¹H NMR(300MHz，CDCl₃，ppm)：6.24(b，1H，NH)，3.94(s，2H，RCH₂CI)，2.10(m，3H，R₃CH)，2.03(m，6H，RCH₂R)，1.70(m，6H，RCH₂R)。¹³C NMR(75MHz，DMSO-d6，ppm)：δ 164.61(CO)，52.39，42.89，41.37，36.22，29.38。MS(EI，m/z)：227[M^+·。IR(KBr，cm^-1)：1662s(ν_RCONHRAmide I), 1569s (amide II). Melting point: 123.4 ℃.

Example 13

N-adamantan-1-yl-2-aminoiminomethylthio (carbamimidoylsulfanyl) -acetamide hydrochloride Preparation of salts

To a 0.25 liter round bottom two necked flask equipped with a reflux condenser, oil valve (oil vent) and magnetic stir bar was added N-adamantan-1-yl-2-chloroacetamide (2.00g, 8.78mmol), ethanol (16ml) and thiourea (802mg, 10.54 mmol). The suspension was heated to reflux with stirring. After 15 minutes, the solvent was removed under reduced pressure. Acetonitrile (76ml) was added to the oily residue with stirring. The resulting suspension was stirred for a further 30 minutes. At room temperature without separationThe colored precipitate was washed with acetonitrile (10ml, 3 ×) and dried under reduced pressure (40 ℃, 60 mbar, 19h) to yield 2.18g (7.16mmol, 81.6%) of the title compound as a colorless microcrystalline powder.¹H NMR(300MHz，DMSO-d6，ppm)：9.42(b，3H，NH)，8.32(s，1H，NH)，3.95(s，2H，RCH₂S)，2.07-1.81(m，9H，R₃CH，RCH₂R)，1.61(s，6H，RCH₂R)。¹³C NMR(75MHz，DMSO-d6，ppm)：δ 170.18，166.65(CO)，51.67，40.57，35.84，34.14，28.70。MS(ESI，m/z)：298.0[MH-Cl]⁺。IR(KBr，cm^-1)：1662s(ν_RCONHRAmide I), 1555s (amide II). Melting point: 180 ℃ (dec.). E.A. (C, H, N;%): c₁₅H₂₆ClN₃OS·0.1H₂Theoretical value of O: c, 51.08; h, 7.32; n13.75 found: c51.07, H7.22, N13.65.

Example 14

Synthesis of amantadine HCl

To a 2.0 liter round bottom three necked flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel was added N-adamantan-1-yl-2-chloroacetamide (71.0g, 0.31mol), thiourea (28.5g, 0.37mol), acetic acid (123.6ml) and ethanol (550.2 ml). The reaction mixture was heated to reflux with stirring and kept at this temperature for 8 h. After completion of the reaction, the contents of the vessel were allowed to reach room temperature. The suspension was filtered over cellite and the clear filtrate was treated first with water (710ml) and then with aqueous sodium hydroxide (50%, 124ml) without external cooling over 10 minutes. The temperature may be as high as 50 ℃. Toluene (142ml) was added and the mixture was stirred vigorously for 15 minutes. The phases were separated. The aqueous phase was extracted with toluene (142ml) at 45-55 ℃. The phases were separated, the organic layers were combined and the aqueous layer was discarded. To the combined organic phases was added sodium hydroxide (50%, 71ml) and the biphasic system was vigorously stirred at 45-55 ℃ for 15 minutes. The phases were separated and the aqueous layer was discarded. The organic layer was diluted with toluene (20ml) at 50-60 ℃ and washed with sodium hydroxide (50%, 71ml) and the aqueous layer was discarded. With water (71ml)And treating the organic layer to ensure that the temperature is kept between 50 and 60 ℃. The phases were separated and the aqueous layer was discarded. The organic layer was treated with sodium chloride (aq., sat., 71ml) with stirring, maintaining the temperature at 45-55 ℃. The phases were separated and the aqueous layer was discarded. The organic phase was filtered over cellite and transferred to a 2.0 liter round bottom three neck flask equipped with a reflux condenser, oil valve (oil vent), mechanical stirrer, thermometer and dropping funnel. The transfer line was flushed with toluene (20ml, 2 ×). The contents of the vessel are cooled to 0-5 ℃ with stirring. Aqueous hydrochloric acid (31%, 53ml) was added maintaining the temperature below 20 ℃. After the addition was complete, the resulting suspension was cooled to 0-5 ℃ and stirred for a further 60 minutes. The colorless microcrystalline solid was collected by filtration, washed with toluene and dried under reduced pressure (40 ℃, 30 mbar, 18.5h) to yield 47.34g (0.25mol, 80.89%) of microcrystalline solid amantadine HCl. Melting point:>300 deg.C (sublimation).¹H NMR(300MHz，DMSO-d6，ppm)：δ 7.24.(b，3H，NH)，2.06(m，3H，R₃CH)，1.82(s，6H，RCH₂R)，1.60(m，6H，RCH₂R)。

Claims (12)

1. A process for preparing an adamantylamine of formula (IV),

wherein R and R' are each methyl, and X is halogen,

the method comprises the following steps:

(i) reacting a compound of formula (I) with thiourea,

wherein R, R' and X are each as defined above;

(ii) subjecting the resulting compound of formula (II) to an acid treatment;

and

(iii) separating the resulting adamantanamine or its hydrohalide salt.

2. The process of claim 1, wherein reaction step (i) is carried out in C as a solvent₁-C₄In alcohol.

3. The process of claim 1 or 2, wherein the acid treatment in step (ii) is comprised in a composition comprising C₁-C₄Carboxylic acid, especially acetic acid and a compound selected from water and C₁-C₄Treating the compound of formula (II) in a medium of one or more solvents of the group consisting of alcohols.

4. A process as claimed in any one of claims 1 to 3, wherein in step (iii) the adamantanamine is isolated as the free base by basifying the reaction solution.

5. A process according to claim 4, comprising the additional step of converting the adamantyl amine free base to an adamantyl amine hydrohalide salt by treatment with a hydrohalide acid, particularly hydrochloric acid.

6. A process according to any one of claims 1 to 5, wherein the compound of formula (I) is prepared by reacting a compound comprising C₁-C₄Carboxylic acid and a carboxylic acid selected from the group consisting of water and C₁-C₄One or more of the group consisting of alcoholsThe reaction with thiourea in a medium of solvent is carried out directly into the adamantanamine without isolation of the compound of formula (II).

7. The process of claim 6, wherein the adamantylamine is directly converted to the adamantylamine hydrohalide salt by adding hydrohalide acid to the reaction mixture comprising the original adamantylamine without isolating the free base.

8. A compound of the formula (I),

wherein X is chlorine or bromine.

9. A process for the preparation of a compound of formula (I) according to claim 8, wherein a compound of formula (III) is reacted

Wherein R1 is hydroxy or halogen,

with haloacetonitrile X-CH₂-CN is reacted in an acidic medium, wherein X is halogen.

10. A compound of the formula (II),

wherein R and R' are each methyl, and X is chlorine or bromine.

11. Use of a compound of formula (I) according to claim 8 in the preparation of memantine or a hydrohalide salt thereof.

12. Use of a compound of formula (II) according to claim 10 in the preparation of memantine or a hydrohalide salt thereof.