ES2357413T3 - INTERMEDIATE PRODUCTS FOR THE PREPARATION OF PRAMIPEXOL. - Google Patents

Abstract

Compound of formula (I) or of formula (II), as an individual enantiomer (S), or a salt thereof, in which R is an amino group protected in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group; R1 is linear or branched C1-C6 alkyl optionally substituted with phenyl; and the asterisk * indicates the stereogenic carbon atom.

Description

FIELD OF THE INVENTION

The present invention relates to novel intermediates useful in the preparation of pramipexole or (S) -2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole and a novel method for its preparation. 5

TECHNOLOGICAL BACKGROUND

Pramipexole, of formula (A)

It is a dopamine agonist, known from US 4,843,086, used in the treatment of Parkinson's disease in the form of monohydrate dihydrochloride. 10

US 2002/0103240 discloses among other things a method for the resolution or enrichment of (R, S) -2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole in the enantiomers (R) or (S) individual, in particular in the enantiomer (S). The same application illustrates in detail the known synthetic routes for the preparation of pramipexole, in particular those described in US 4,886,812, EP 186087, EP 207696 and J. Med. Chem. 30. 494 (1987). From what is reported, it is clear that the synthetic routes available so far employ synthetic stages 15 that do not meet the requirements for the production of pramipexole on an industrial scale. Therefore, there is a need for an improved process, which is simpler, easier to perform and meets the requirements for industrial production of pramipexole.

SUMMARY OF THE INVENTION

A process for the preparation of pramipexole has now been found, which uses novel intermediates and meets the requirements for production in industrial quantities.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I), as enantiomer (S), or a salt thereof,

wherein R is a protected amino group; and the asterisk * indicates the stereogenic carbon atom. 25

A salt of a compound of formula (I) may be a salt with bases or acids, organic or inorganic. Preferred examples of salts with bases are those with inorganic bases, such as sodium, lithium or potassium salts, or salts with primary, secondary or tertiary amines, such as salts of N-methyl-, N, N-dimethyl- and triethyl- ammonium, benzylammonium salts, -methylbenzylamine, N-methyl-D-glucamine, cinconidine or cinconine. Preferred examples of salts with acids are those with hydrochloric, sulfuric, acetic, oxalic or methanesulfonic acids, preferably with an optically active acid, such as tartaric acid or camphorsulfonic acid.

Preferably a compound of formula (I), or a salt thereof, is in the form of the individual enantiomer (S), usually with an enantiomeric purity of at least about 96%, more preferably at least about 99%.

Preferred examples of the compounds of formula (I) are:

• (S) -2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid;

• (S) -2-Propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid.

A compound of formula (I), as defined above, can be obtained with a process comprising the hydrolysis of an ester of formula (II) or a salt thereof, or as a mixture of enantiomers (R, S) or well as individual enantiomer (S) 40

wherein R1 is linear or branched C1-C6 alkyl, optionally substituted with phenyl; and the asterisk * and R have the meanings defined above;

and, if necessary, the resolution of the mixture of enantiomers (R, S) of the compound of formula (I) to give the individual enantiomer (S). 5

R1 is preferably a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular ethyl or propyl; or benzyl or phenylethyl.

A salt of a compound of formula (II) is for example a salt with a mineral acid, preferably a hydrochloric acid, in particular hydrochloric or hydrobromic acid, or an organic acid, such as acetic, oxalic or methanesulfonic acid, preferably an optically active acid. , such as tartaric acid or camphorsulfonic acid. 10

According to the present invention, a protected amino group R is a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group.

In an acylamino group, acyl is for example formyl or C1-C6-CO- alkyl, preferably acetyl, propionyl or pivaloyl, optionally substituted with 1 to 3 halogen atoms, such as chlorine, fluorine, bromine or iodine.

In a carbamoyl group, the amino group is attached, for example, to a C1-C6 alkoxycarbonyl group, in which the alkyl residue is linear or branched, optionally substituted with phenyl. The alkyl residue is preferably a C1-C4 alkyl group, optionally substituted with phenyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl or phenylethyl, in particular tert-butyl.

In an arylmethylamino group, for example a mono, di or particularly tri-arylmethylamino group, the aryl moiety is preferably a phenyl group. Said group is for example benzyl-, diphenylmethyl- or trityl-amino; more particularly a 1-methyl-1-phenyl-ethylamino group.

A silylamino group is for example a trimethylsilylamino or tert-butyl dimethylsilylamino group.

A protected amino group R is preferably a protected amino group such as an acylamino or arylmethylamino group, in particular acylamino, in which acyl is formyl, acetyl, propionyl or pivaloyl, the last three being optionally substituted with 1 to 3 halogen atoms ; such as chlorine, fluorine, bromine or iodine. More preferably the group R is acetylamino, propionylamino or pivaloylamino.

The hydrolysis of a compound of formula (II) can be carried out by reaction with an alkali hydroxide, for example sodium or potassium hydroxide, in amounts of from about 1 to 4 equivalents, preferably from 1.5 to 2.5 equivalents, in a polar protic solvent, for example water or C1-C4 alkanols, in particular methanol, ethanol, i-propanol or mixtures thereof; at a temperature ranging from about 0 ° C to 30 reflux of the solvent, preferably from about 10 to 50 ° C, in particular at about 20 ° C.

According to the invention, a mixture of enantiomers (R, S) can contain the two individual enantiomers in any ratio with respect to each other. The enantiomeric purity is generally expressed as "enantiomeric excess" and is defined for the enantiomer (S) as (SR) / (R + S) x100 in which S and R are respectively the amounts of the enantiomers (S) and (R ). According to the invention, the individual "S" enantiomer expression means that the enantiomeric purity is usually at least about 96%, preferably at least about 99%.

The resolution of the mixture of enantiomers (R, S) of a compound of formula (I) in the individual enantiomer (S) can be carried out, for example, by fractional crystallization of the diastereomeric salts of a compound of formula (I) obtained by reaction with enantiomerically pure, optically active bases or acids. An example is the reaction of the compound of formula (I) with an enantiomerically pure aliphatic or aromatic amine, for example -methylbenzylamine, N-methyl-D-glucamine, cinconidine and cinconine; or with an enantiomerically pure acid, for example tartaric acid or camphorsulfonic acid, in a solvent that can promote salt formation and subsequent precipitation of the desired diastereomer. Examples of such solvents are C1-C4 alkanols, such as methanol, ethanol and i-propanol; ketones, such as acetone; ethers such as tetrahydrofuran and dioxane; alkyl esters, such as ethyl acetate; amides, such as dimethylformamide and dimethylacetamide; dimethylsulfoxide; or mixtures thereof or mixtures of one or more of them with water. The temperature may range from room temperature to the reflux temperature of the solvent. Alternatively, the resolution can be carried out by means of preparative chromatography using an optically active chiral stationary phase, including "simulated moving bed" (SMB) technology. An additional alternative is the enzymatic resolution, or by hydrolysis.

selective of a stereoisomer of an ester of formula (II) to give an acid of formula (I), or by selective esterification of a stereoisomer of an acid of formula (I) to give an ester of formula (II).

The conversion of a compound of formula (I) into a salt thereof can be obtained by known methods.

An object of the invention is also a compound of formula (II), and salts thereof, as an individual enantiomer (S), usually with an enantiomeric purity of at least about 96%, more preferably of at least about 99 %.

US 4,988,699 generally discloses compounds of formula (I) and formula (II) as mixtures (R, S) in which the substituent R is an amino group optionally substituted with various groups, among other groups lower alkanoyl. On the other hand, this patent only describes compounds with unsubstituted amino groups. The following specific acids and esters, as well as salts thereof, although generically included within the general formula of US 4,988,699, should be considered novel and are a further object of the invention:

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid;

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid;

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid methyl ester;

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester; fifteen

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid propyl ester;

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid methyl ester;

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester; Y

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid propyl ester.

WO 2004/083218 discloses guanidine derivatives that are active as antagonists of the FF neuropeptide receptor 20, including 2-guanidino-4,5,6,7-tetrahydro-benzothiazol-6 ethyl ester hydrobromide -carboxylic (example C-42).

A compound of formula (II), and salts thereof, can be obtained by converting the amino group of a compound of formula (III)

 25

in which R1 and the asterisk * have the meanings notified above,

in a protected amino group R as defined above, and the optional resolution of the mixture of enantiomers (R, S) of a compound of formula (II) resulting in the individual (R) or (S) enantiomers thereof, and / or salification of it.

The conversion of the amino group of a compound of formula (II) into a protected amino group R, specifically an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group, as well as salification, can be carried out according to known methods. The protection as an acylamino or carbamoyl group is preferably carried out by reaction with the corresponding anhydride, in particular acetic anhydride, or acyl chloride or alkoxycarbonyl chloride, in particular acetyl chloride or methoxy or ethoxycarbonyl chloride, in a solvent selected for example from acetone, acetonitrile, tetrahydrofuran, dioxane, dichloromethane or toluene; in the presence of a basic agent, preferably triethylamine, diisopropylamine or pyridine. The reaction is carried out from about -15 ° C to solvent reflux, preferably between about 0 ° C and 50 ° C, in particular at room temperature. The resolution of a mixture of enantiomers (R, S) of a compound of formula (II) to provide the individual enantiomer (S) can be obtained, for example, by reaction with an organic acid, according to the procedures notified above for the resolution of a mixture of enantiomers (R, S) of a compound of formula (I). A compound of formula (III) can be prepared by reacting a compound of formula (IV),

in which R1 is as defined above, with thiourea. The cyclization reaction is carried out in an organic solvent, for example a C1-C4 alkanol, acetone, tetrahydrofuran, dioxane or mixtures thereof, at a temperature ranging from about 0 ° C to the reflux temperature of the solvent, during a time ranging from 1 hour to 8 hours, in particular between 2 hours and 5 hours. First, the hydrobromide salt 5 of a compound of formula (III) is formed and then converted into the free base form by suspending it for example in water, C1-C6 alkanols or acetone, preferably methanol or ethanol; at a temperature ranging from room temperature to the reflux temperature of the solvent; and adding from 1 to 1.5 equivalents, preferably from 1 to 1.1 equivalents, of an inorganic base, preferably sodium or potassium bicarbonate. After filtration, a compound of formula (III) is separated as a free base. 10

In particular, a compound of formula (II), as defined above, in which the protected amino group R is in the form of an acylamino or carbamoyl group, can be prepared by reacting a compound of formula (IV), such as defined above, with a compound of formula (V)

wherein R2 is respectively a linear or branched C1-C6 alkyl or alkoxy group, optionally substituted with phenyl.

R2 is preferably a C1-C4 alkyl group, optionally substituted with phenyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl or phenylethyl, in particular methyl. Alternatively, it is preferably a C1-C4 alkoxy group, optionally substituted with phenyl, for example methoxy, ethoxy, propoxy or benzyloxy, in particular methoxy. twenty

First, the hydrobromide salt of a compound of formula (II) is obtained, which is then converted into the free base form.

The reaction between a compound of formula (IV) and a compound of formula (V) can be carried out according to the procedure reported above by reaction between a compound of formula (IV) and thiourea. The hydrobromide salt of a compound of formula (II) can be converted into the free base form according to the procedure previously reported for the transformation of a hydrobromide salt of a compound of formula (III) into the free base form.

The compounds of formula (IV) and (V) can be prepared by known methods. For example, a compound of formula (IV) can be prepared by monobromating the corresponding ketone of formula (VI)

 30

wherein R1 is as defined above, with 0.8-1.5 equivalents, preferably 1 equivalent, of bromine in a solvent selected for example from dichloromethane, toluene, acetic acid or a C1-C4 alkanol, in the presence of hydrobromic acid in amounts ranging from about 0 to 0.2 equivalents. The reaction is carried out at a temperature ranging from about -15 ° C to 40 ° C, preferably from 0 ° C to 15 ° C, for a time ranging from 1 hour to 6 hours, preferably between 2 hours and 5 hours. A compound of formula 35 (VI) is commercially available.

A compound of formula (I) as an individual enantiomer (S) is particularly useful in the preparation of pramipexole. Said compound is subjected to transposition, thus obtaining intermediate products useful in the preparation of pramipexole, according to the synthetic route disclosed in US 4,843,086.

Therefore, a further object of the invention is the use of a compound of formula (I) as an individual enantiomer (S) in a process for the preparation of pramipexole or a pharmaceutically acceptable salt thereof.

In particular, in a process comprising the alkylation of a compound of formula (VII), as an individual enantiomer (S),

 5

wherein Ra is a free or protected amino group, R3 is hydrogen or an R4-O-CO- group, in which R4 is linear or branched C1-C4 alkyl and the asterisk * has the meaning defined above,

to obtain a compound of formula (VIII)

wherein Ra, R3 and the asterisk * are as defined above, and, if necessary, the removal of the primary amino protecting group 10 and / or the R4-O-CO- group from the secondary amino group and , if desired, its conversion into a pharmaceutically acceptable salt thereof, characterized in that:

a) a compound of formula (VII), wherein Ra is a protected amino group and R3 is as defined above, as an individual enantiomer (S), is prepared by transposition of a compound of formula (I), as an enantiomer (S) individually, by formation of the isocyanate, and subsequent addition of a nucleophilic solvent or subsequent extinction in water in the presence of an acidic agent; or

b) a compound of formula (VII), in which Ra is a free amino group and R3 is hydrogen, as an individual enantiomer (S), is prepared by transposition of a compound of formula (I), as an individual enantiomer (S) , by formation of the isocyanate, and subsequent addition of water, to obtain a compound of formula (Ie)

 twenty

in which R ’has the same meaning as R, and subsequent hydrolysis.

An acidic agent is for example a mineral or organic acid, in particular hydrochloric, sulfuric, formic or acetic acid.

A nucleophilic solvent can be for example a C1-C4 alkanol, usually methanol, ethanol or i-propanol.

According to the process variant a) notified above, extinction in water in the presence of an acidic agent or the addition of a nucleophilic solvent respectively provides a compound of formula (VII) as defined above in which R3 is hydrogen or R3 it is an R4-O-CO- group as defined above.

Transposition can be carried out, for example, according to the reactions of Schmidt, Lossen, Hofmann or Curtius.

The sequence of the products formed during the transposition reaction is as follows:

in which Y is NHOCOR4, N3 or NH2, in which R4 is as defined above; R5 is hydrogen or linear or branched C1-C4 alkyl; and R and R3 are as defined above.

The compounds of formulas (Ia), (Ib), (Ic) and (Id) can optionally be isolated during the reaction. The compounds of formulas (Ia), (Ib), (Ic) and (Ie), as individual enantiomer (S), are novel compounds and are a further object of the invention.

The reactions of Schmidt, Lossen, Hofmann and Curtius all resort to an isocyanate of formula (Ic) as defined above.

A compound of formula (Ic) can be prepared according to the Schmidt reaction, treating a compound of formula (I) with hydrazoic acid in the presence of sulfuric acid, to obtain a compound of formula (Ia), in which Y is N3 and R 10 is as defined above, which is converted into the corresponding compound of formula (Ic) by heating.

Alternatively, a compound of formula (Ic) may be prepared according to the Lossen reaction, by reaction of a compound of formula (I) with a halogenating agent, preferably thionyl chloride or oxalyl chloride, and subsequent reaction with an acyl hydroxylamine , preferably acetyl hydroxylamine, thus obtaining the respective acylated hydroxamic acid, that is to say a compound of formula (Ia) in which Y is NHOCOR4 and R is as defined above. Treatment of the latter with an alkaline hydroxide provides a compound of formula (Ic).

Again, a compound of formula (Ic) can be prepared according to the Hofmann reaction, transforming the carboxylic acid into amide according to known methods, that is, in a compound of formula (Ia) in which Y is NH2 and R is as defined above, then treating it with an alkaline hypohalogenite, preferably sodium hypochlorite. twenty

Finally, a compound of formula (Ic) can be prepared according to the Curtius reaction, by reaction of a compound of formula (I) with a halogenating agent, preferably thionyl chloride or oxalyl chloride, and subsequent treatment with sodium azide to obtaining the acyl azide of the respective formula (Ia) in which Y is N3 and R is as defined above; or directly with diphenylphosphorylazide, in the presence of an organic base, in particular triethylamine, diisopropylethylamine or pyridine. The acyl azide of formula (Ia) is converted into the corresponding compound of formula (Ic) by heating.

The transposition reactions reported above are carried out according to known methods, for example at a temperature ranging from about 10 ° C to reflux temperature, for a time ranging from 2 hours to 15 hours, preferably between 5 hours and 10 hours .

More particularly, a compound of formula (Ia), in which Y is N3, is poured into water in the presence of an acidic agent, thus converting it into a compound of formula (Id) as defined above. An acidic agent is for example a mineral or organic acid, in particular hydrochloric, sulfuric, formic or acetic acid, in amounts ranging from about 2 to about 5 moles, preferably from about 2.5 to about 3.5 moles. The reaction is carried out at a temperature ranging from room temperature to reflux of the reaction mixture, preferably from about 50 to about 80 ° C. When the nucleophilic solvent is for example water, in the compound of formula (Id) resulting R5 is hydrogen. Alternatively, when the nucleophilic solvent is for example a C1-C4 alkanol, in particular methanol, ethanol or i-propanol, in the resulting compound of formula (Id) R5 is alkyl.

According to a preferred aspect, the transposition reaction to form the acyl azide of formula (Ia) in which Y is N3 is carried out according to Curtius in a nucleophilic solvent, as defined above. The reaction proceeds to the formation of a compound of formula (Id) in which R5 is a linear or branched C1-C4 alkyl group, without the need to isolate any intermediate product.

A compound of formula (Id) in which R5 is hydrogen is spontaneously transformed into a compound of formula (VII), in which Ra is a protected amino group, R is as defined above and R3 is hydrogen. A compound of formula (Id) in which R5 is alkyl is a compound of formula (VII) in which R3 is an R4-O-CO- group, as defined above and Ra is a protected amino group.

Alternatively, when a compound of formula (Ia) is poured, in which Y is N3, in water, or vice versa, a compound of formula (Ie) is obtained

wherein R and R ’are as defined above, which is hydrolyzed to give a compound of formula (VII) in which Ra is a free amino group, R3 is hydrogen and the asterisk * has the meaning defined above. Hydrolysis is normally an acid hydrolysis, for example by treatment with hydrochloric acid according to known methods. 10

The alkylation of a compound of formula (VII) and, if necessary, the removal of the primary amino group protecting group and, if present, of the R4-O-CO- group from the secondary amino group present in a compound of formula (VIII), can be carried out according to US 4,886,812.

A particularly advantageous process has now been found for the conversion of a compound of formula (VII) into a compound of formula (VIII) in which R3 is hydrogen and Ra is as defined above. It should be noted that a compound of formula (VIII) in which R3 is hydrogen and Ra is -NH2 is pramipexole. Therefore, the invention provides a process for the preparation of pramipexole or a pharmaceutically acceptable salt thereof, which comprises acylation of a compound of formula (VII), wherein R 3 is hydrogen and Ra is as defined above, or either as a mixture of enantiomers (R, S) or as an individual enantiomer (S), by reaction with propionic anhydride and subsequent reduction of the compound of formula (IX) thus obtained,

wherein Ra is as defined above, by treatment with alkali metal borohydride and molecular iodine to obtain a compound of formula (VIII) in which R3 is hydrogen and Ra is as defined above; followed, if necessary, by deprotection of the primary amino group and / or by resolution of the mixture of the enantiomers (R, S) in the individual enantiomer (S) and, if desired, by converting pramipexole into a pharmaceutically salt acceptable of it.

The acylation is preferably carried out in a compound of formula (VII), as an individual enantiomer (S), in particular having the enantiomeric purity as can be obtained according to the present invention. The acylation of a compound of formula (VII) with propionic anhydride can be carried out according to known methods.

An alkali metal borohydride is for example NaBH4 or KBH4, preferably NaBH4. The amount of alkali metal borohydride used in the reduction, for example NaBH4, is about 1-5 moles per mole of compound of formula (IX), preferably from about 2 to 4 moles, while the molar amount of iodine is from about 0.5-3 moles per mole of compound of formula (IX), preferably from about 1 to 2. The reduction of a compound of formula (IX) is preferably carried out in an ether solvent, such as tetrahydrofuran, dioxane or diethyl ether, in particular tetrahydrofuran. The reaction can be carried out at a temperature ranging from about 0 ° C to the reflux temperature, preferably at about 20-40 ° C.

A pharmaceutically acceptable salt of pramipexole is for example an addition salt with an organic or mineral acid, as reported in US 4,886,812, preferably the dihydrochloride, and can be obtained by known procedures. 40

The process of the invention for the preparation of pramipexole is particularly advantageous for production on an industrial scale. In fact, the resolution of the enantiomers takes place during the first stages of synthesis and in addition the discarded enantiomer can be recovered by racemization and recycled. This achieves a reduction in the by-products of the most expensive end products and higher yields.

The following examples illustrate the invention.

Example 1 - 2-Amino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester hydrobromide [(III), R1 = ethyl]

A 3 liter reactor equipped with a mechanical stirrer, thermometer and condenser with 1500 ml of ethanol and 200 g of 4-oxo-cyclohexanecarboxylic acid ethyl ester was charged. After cooling to 0 ° C, 188 g of bromine were added thereto in about 1 hour. The temperature was increased to 10 ° C, then to room temperature after discoloration. After 1 hour, 89.32 g of thiourea were added portionwise to obtain a suspension, which was refluxed to obtain a gradual dissolution of the solid. After 4 hours the solution was concentrated to a small volume to obtain a solid mass, which was suspended in 800 ml of acetone and refluxed to obtain a solution. The solution was then cooled to room temperature to precipitate a solid, then 10 to 0 ° C and after 4 hours the solid was filtered, washed twice with 100 ml of cold acetone and dried to obtain 170 g of the title product.

1 H-NMR in DMSO: 1.20 ppm (t, 3 H); 1.79 ppm (m, 1 H); 2.05 ppm (m, 1 H); 2.43 ppm (t, 2H); 2.70 ppm (m, 3H); 4.08 ppm (q, 2H); 6.63 ppm (s, 2H).

Example 2 - 2-Amino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester [(III), R1 = ethyl]

A 2-liter reactor equipped with a mechanical stirrer, thermometer and condenser was charged with 600 ml of water, 110 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl hydrobromide [ (III), R1 = ethyl] and 120 ml of methanol. The mixture was refluxed and filtered hot on a bed of Celite. To the resulting solution was added a solution of 32 g of sodium bicarbonate in 300 ml of water (final pH = 7-8). After 2 hours at room temperature, the precipitated white solid was filtered, washed with 100 ml of water and dried to obtain 72 g of the title product.

1 H-NMR in DMSO: 1.20 ppm (t, 3 H); 1.79 ppm (m, 1 H); 2.05 ppm (m, 1 H); 2.43 ppm (t, 2H); 2.70 ppm (m, 3H); 4.08 ppm (q, 2H); 6.63 ppm (s, 2H).

Example 3 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester [(II), R1 = ethyl, R = -NH-CO-CH3]

A 500 ml reactor equipped with a mechanical stirrer, thermometer and condenser was charged with 280 ml of acetonitrile, 71 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(III ), R1 = ethyl] and 38.75 g of acetic anhydride. 38.03 g of triethylamine were added dropwise to the resulting suspension in approximately 10 minutes. The suspension was refluxed, obtaining a complete solution at a temperature ranging from 70 to 75 ° C. After approximately 2 hours and 30 minutes the solution was concentrated to dryness, and residue 30 was crystallized from 450 ml of isopropanol to obtain 74.5 g of 2-acetylamino-4,5,6,7-tetrahydro- ethyl ester benzothiazol-6-carboxylic.

1 H-NMR in DMSO: 1.19 ppm (t, 3 H); 1.80 ppm (m, 1 H); 2.09 ppm (s, 3H); 2.11 ppm (m, 1 H); 2.61 ppm (t, 2H); 2.82 ppm (m, 3H), 4.08 ppm (q, 2H).

According to the same procedure, the following compounds are obtained:

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid methyl ester;

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid propyl ester;

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid methyl ester;

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester; Y

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid propyl ester. 40

Example 4 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester hydrobromide [(II), R1 = ethyl, R = -NH-CO-CH3]

A 500 ml reactor equipped with a mechanical stirrer, thermometer and condenser was charged with 200 ml of methylene chloride, 20 g of ethyl ester of 4-oxo-cyclohexanecarboxylic acid, 2 g of 48% hydrobromic acid. The resulting clear solution was cooled to 0 ° C and 18.88 g of bromine was added dropwise in about 45 hours. Two hours after completing the addition, 100 ml of water was added and the phases were separated, discarding the aqueous one. 80 ml of water was added and the mixture was neutralized to pH = 7-8 with sodium bicarbonate. The organic phase was separated and concentrated to one third of the original volume, then 150 ml of ethanol and 13.95 g of acetyl thiourea were added to obtain a suspension. After reflux, the solid gradually dissolved to obtain a clear solution. After 3 hours the solution was concentrated to a small volume to obtain a solid mass, which was crystallized from 200 ml of i-propanol to obtain 15.9 g of solid.

1 H-NMR in DMSO: 1.2 ppm (t, 3H); 1.81 ppm (m, 1 H); 2.09 ppm (m, 1 H); 2.11 ppm (s, 3H); 2.60 ppm (t, 2H); 2.81 ppm (m, 3H); 4.08 ppm (q, 2H).

According to the same procedure, the following compounds are obtained, such as hydrobromide:

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid methyl ester; Y

• 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid propyl ester; 5

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid methyl ester;

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid ethyl ester; Y

• 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid propyl ester.

Example 5 - 2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO-CH3]

A 500 ml reactor equipped with a mechanical stirrer, thermometer and condenser was charged with 200 ml of water, 30 g 10 of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [( II), R1 = ethyl, R = -NHCO-CH3] and 52.2 g of 30% sodium hydroxide, keeping the temperature below 30 ° C; during the addition the solid was gradually solubilized until complete dissolution. After 2 hours, glacial acetic acid was added dropwise to a pH = 4.5-5.5; After about 1 hour the precipitated white solid was filtered, washed with 70 ml of water and dried to obtain 24.8 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid. fifteen

1 H-NMR in DMSO: 1.75 ppm (m, 1 H); 2.09 ppm (s, 3H); 2.11 ppm (m, 1 H); 2.58 ppm (m, 3H); 2.78 ppm (m, 2H).

13 C-NMR in DMSO: 22.48 ppm; 24.72 ppm; 25.04 ppm; 25.5 ppm; 39.37 ppm; 119.77 ppm; 143.4 ppm; 155.27 ppm; 167.99 ppm; 175.69 ppm.

According to the same procedure, 2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid is obtained.

Example 6 - N- (6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl) -acetamide dihydrochloride, [(VII), Ra = -NH-CO-CH3, R3 = -H ]

A 500 ml reactor equipped with a mechanical stirrer, thermometer and condenser was charged with 10 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO -CH3] suspended in 146 ml of N, N-dimethylformamide, and 4.63 g of triethylamine were added. After that, a solution consisting of 12.57 g of diphenylphosphoryl azide (DPPA) dissolved in 10 ml of N, N-dimethylformamide therein was added dropwise therein in 2 hours. The reaction mixture was gradually solubilized during the addition until complete dissolution. After 5 hours the reaction solution in 1.3 liters of an aqueous solution containing 14 ml of 37% hydrochloric acid was added at 60 ° C. The mixture was allowed to cool, then extracted twice with 200 ml of methylene chloride, discarding the organic phase. The aqueous phase was concentrated to a residue, which was crystallized from i-propanol-water to obtain 4.5 g of a white solid. 30

1 H-NMR in DMSO: 1.91 ppm (m, 1 H); 2.17 ppm (s, 3H); 2.19 ppm (m, 1 H); 2.73 pm (m, 3H); 3.07 ppm (dd, 1H); 3.49 ppm (s, width, 1H); 8.39 ppm (s, width, 2H).

13 C-NMR in DMSO: 22.50 ppm; 23.64 ppm; 26.49 ppm; 26.66 ppm; 46.56 ppm; 117.39 ppm; 142.89 ppm; 156.06 ppm; 168.28 ppm.

According to the same procedure, starting from (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid, (S) N- (6-amino-4,5-dihydrochloride) is obtained. 6,7-tetrahydro-benzothiazol-2-yl) -acetamide.

Example 7 - (2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl) -carbamic acid methyl ester hydrochloride [(VII), Ra = -NH-CO-CH3, R3 = -CO -O-CH3]

A 500 ml reactor equipped with a mechanical stirrer, thermometer and condenser is charged with 5 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO -CH3] suspended in 80 ml of N, N-40 dimethylformamide; then 2.32 g of triethylamine are added. A solution consisting of 6.3 g of diphenylphosphoryl azide (DPPA) dissolved in 7 ml of N, N-dimethylformamide therein in 2 hours is added. The reaction mixture gradually solubilizes during the addition until complete dissolution. After 6 hours the reaction solution in 1 liter of a methanol solution containing 8 ml of 37% hydrochloric acid is added at 60 ° C. The mixture is allowed to cool, then extracted twice with 100 ml of methylene chloride, discarding the organic phase. The aqueous phase is concentrated to a residue that crystallizes from i-propanol-water to obtain 3.6 g of a white solid.

According to the same procedure, starting from (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid, (S) (2-acetylamino-4,5) methyl ester hydrochloride is obtained , 6,7-tetrahydro-benzothiazol-6-yl) -carbamic.

Example 8 - Resolution of (S) 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO-CH3]

A 1-liter reactor equipped with a mechanical stirrer, thermometer and condenser is charged with 50 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO -CH3] suspended in 250 ml of methanol and 50 ml of water. The mixture is heated to dissolution, 37.3 g of (S) - (-) - -methylbenzylamine are added and then cooled to 25 ° C. The precipitated product is filtered off, washed with methanol and dried to obtain 42.8 g of a solid. It is suspended in 250 ml of methanol and 50 ml of water, heated until dissolved for 1 hour and cooled to room temperature. The suspended solid is filtered, washed with methanol and dried to obtain 32.3 g of (S) -2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid, which has an enantiomeric purity > 99.5%.

According to the same procedure, (S) -2-propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid with enantiomeric purity> 99.5% is obtained.

Example 9 - N- {6- [3- (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl) -ureido] -4,5,6,7-tetrahydro-benzothiazol-2- il} -10 acetamide, [(Ie), R = -NH-CO-CH3]

A 500 ml reactor equipped with a mechanical stirrer, thermometer and condenser was charged with 10 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO -CH3] suspended in 146 ml of N, N-dimethylformamide and 4.65 g of triethylamine were added. A solution consisting of 12.52 g of diphenylphosphoryl azide (DPPA) dissolved in 10 ml of N, N-dimethylformamide was added therein in 2 hours. The reaction mixture 15 was gradually solubilized during the addition until complete dissolution. After 5 hours, the reaction mixture in 1.3 liters of an aqueous solution was added at 60 ° C. The mixture was allowed to cool, the separated solid was filtered, washing twice with 50 ml of water to obtain 5.9 g of a white solid.

1 H-NMR in DMSO: 1.72 ppm (m, 1 H); 1.86 ppm (m, 1 H); 2.07 ppm (s, 3H); 2.4 ppm (dd, 1 H); 2.59 ppm (m, 2H); 2.8 ppm (dd, 1 H); 3.93 ppm (m, 1H), 5.96 ppm (d, 1H), 11.84 ppm (s, 1H). twenty

13 C-NMR in DMSO: 22.30 ppm; 23.74 ppm; 26.55 ppm; 26.59 ppm; 44.36 ppm; 118.42 ppm; 144.02 ppm; 156.13 ppm; 157.98 ppm, 169.18 ppm.

Example 10 - N- (6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl) -amine dihydrochloride, [(VII), Ra = -NH2, R3 = -H].

A 1-liter reactor equipped with a mechanical stirrer, thermometer and condenser is charged with 70 g of N- {6- [3- (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl) -ureido ] -4,5,6,7-tetrahydro-benzothiazol-2-yl} -acetamide, [(Ie), R = -NH-CO-25 CH3] suspended in 500 ml of water, and 151 g of acid are added 37% hydrochloric. The mixture is refluxed for 40 hours, then allowed to cool. The aqueous phase is concentrated to a residue that crystallizes from i-propanol-water to obtain 53 g of a white solid.

According to the same procedure, starting from (S) -N- {6- [3- (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl) -ureido] -4,5,6, 7-tetrahydro-benzothiazol-2-yl} -acetamide, [(Ie), R = -NH-CO-CH3] with an enantiomeric purity of 96%, 30 (S) -N- (6-amino) dihydrochloride is obtained -4,5,6,7-tetrahydro-benzothiazol-2-yl) -amine, [(VII), Ra = -NH2, R3 = -H] with an enantiomeric purity> 97%.

1 H-NMR in DMSO: 1.91 ppm (m, 1 H); 2.17 ppm (s, 3H); 2.19 ppm (m, 1 H); 2.73 ppm (m, 3H); 3.07 ppm (dd, 1H); 3.49 ppm (s, width, 1H); 8.39 ppm (s, width, 2H),

13 C-NMR in DMSO: 22.50 ppm; 23.64 ppm; 26.49 ppm; 26.66 ppm; 46.56 ppm; 117.39 ppm; 142.89 ppm; 156.06 ppm; 35 168.28 ppm.

Example 11 - (S) N- (6-Propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl) -amine; [(IX) Ra = H]

A 1-liter reactor equipped with a mechanical stirrer, thermometer and nitrogen condenser is charged with 43.7 g of (S) N- (6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl) - amine and 220 ml of methyl ethyl ketone (MEK). It is heated to 28-32 ° C and approximately 33.6 g of propionic anhydride are added therein in 2 hours keeping the temperature at about 28-32 ° C. The solution is cooled to about 0-5 ° C and 109 g of 10% aqueous NaOH are added. The aqueous phase is separated; The organic phase is diluted with 60 ml of toluene and concentrated in vacuo at approximately 40-45 ° C. Under these conditions, the product begins to crystallize. The suspension is cooled to 0-5 ° C and left under stirring for one hour. The precipitate is filtered with suction and washed with 10 ml of toluene.

54.2 g of (S) N- (6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl) -amine are obtained. Four. Five

Example 12 - Intermediate product (VIII) Ra = H; pramipexole free base

A 2-liter reactor is charged under nitrogen with 53.3 g of, 33.0 g of (S) N- (6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl) -amine, 95% sodium borohydride and 260 ml of tetrahydrofuran (THF). A solution of 98.7 g of iodine in 160 ml of THF is added therein in about 3 hours, keeping the temperature at about 20-25 ° C. The reaction mixture is maintained with stirring for an additional 2 hours at about 20-25 ° C. The reaction mixture was poured into a solution of 60.0 g of 37% HCl in 260 ml of

Water. The mixture is heated to 50-55 ° C and left under stirring for one hour. The complete cleavage of the boron complexes is checked by HPLC. 250 g of 50% aqueous NaOH are added to the mixture, keeping the temperature at about 20-25 ° C. After that, 315 ml of toluene are added and the mixture is heated to about 30-35 ° C. Stirring is interrupted and the two phases are separated. The organic phase is washed, concentrated to a residue and dissolved in 420 ml of ethyl acetate. 5

The solution is concentrated in vacuo at a temperature below 50 ° C to a volume of approximately 150 ml. The resulting suspension is refluxed, then cooled to about 10-15 ° C, stirred for an additional 1-2 hours, then filtered with suction and the precipitate washed twice with 30 ml of ethyl acetate. The product is dried under vacuum at 40 ° C. 32 g of (S) -2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole are obtained.

Example 13 - (S) - (2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl) -isopropyl carbamate [(VII), Ra = -NH-CO-10 CH3, R3 = - CO-O-C3H7]

A 2000 ml reactor equipped with a mechanical stirrer, thermometer and condenser is charged with 100 g of (S) -2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid [(I), R = -NH-CO-CH3] with an enantiomeric purity of 97%, suspended in 700 ml of isopropanol; 84.16 g of triethylamine are added. The mixture is refluxed (approximately 80 ° C) and a solution consisting of 120.42 g of diphenylphosphoryl azide (DPPA) is added thereto in 2 hours. After 2 hours, the reaction mixture is cooled to 20-30 ° C and 500 ml of water and 1.6 g of sodium hydroxide are added. Isopropanol is removed by vacuum distillation, then 400 ml of ethyl acetate are added. The mixture is refluxed for 15 minutes, then the suspension is filtered hot through Celite. The solution is cooled to 20-30 ° C and 1800 ml of water is added. The phases are separated and the organic phase is concentrated to dryness. The residue is taken to 200 ml of acetonitrile. The suspension is heated at 50 ° C for 1 hour, then cooled to 20 ° C and filtered to obtain 75 g of (S) - (2-acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-yl) - Isopropyl carbamate, with an enantiomeric purity of 97%.

Claims (10)

1. Compound of formula (I) or of formula (II), as an individual enantiomer (S), or a salt thereof, wherein R is a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group; R1 is linear or branched C1-C6 alkyl optionally substituted with phenyl; and the asterisk * indicates the stereogenic carbon atom. 2. Compound of formula (I) or a salt thereof, according to claim 1, which is: (S) -2-Acetylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid; or (S) -2-Propionylamino-4,5,6,7-tetrahydro-benzothiazol-6-carboxylic acid. 3. Compound according to claims 1 or 2, with an enantiomeric purity of at least 96%. 10 4. Use of a compound of formula (I), or a salt thereof, according to claim 1, for the preparation of pramipexole or a pharmaceutically acceptable salt thereof, in a process comprising the alkylation of a compound of formula ( VII) as individual enantiomer (S) wherein Ra is a protected or free amino group, R3 is hydrogen or an R4-O-CO- group, wherein R4 is linear or branched C1-C4 alkyl and the asterisk * has the same meaning as in the claim 1, to obtain a compound of formula (VIII) wherein Ra, R3 and the asterisk * are as defined above, and, if necessary, the removal of the primary amino protecting group and / or the R4-O-CO- group from the secondary amino group and, if desired, its conversion to a pharmaceutically acceptable salt thereof, characterized in that: a) a compound of formula (VII), wherein Ra is a protected amino group and R3 is as defined above, as an individual enantiomer (S), is prepared by transposition of a compound of formula (I), as an enantiomer (S) individually, by formation of isocyanate, and subsequent addition of a nucleophilic solvent or subsequent extinction in water in the presence of an acidic agent; or 25 b) a compound of formula (VII), in which Ra is a free amino group and R3 is hydrogen, as an individual enantiomer (S), is prepared by transposition of a compound of formula (I), as an individual enantiomer (S) , by formation of isocyanate, and subsequent addition of water, to obtain a compound of formula (Ie) wherein R ’has the same meaning as R defined in claim 1, and subsequent hydrolysis. 30 5. Use according to claim 4, variant a), wherein the extinction in water in the presence of an acidic agent provides a compound of formula (VII), as defined in claim 4, wherein R3 is hydrogen. 6. Use according to claim 4, variant a), wherein the nucleophilic solvent is a C1-C4 alkanol, to obtain a compound of formula (VII), as defined in claim 4, wherein R3 is a group R4-O-CO-, wherein R4 is as defined in claim 4. 7. Use according to claim 4, variant a), wherein the transposition reaction is carried out according to Curtius in a nucleophilic solvent, by forming a compound of formula (Ia). in which Y is N3 and of a compound of formula (Id) wherein R5 is a linear or branched C1-C4 alkyl group, without recovery of intermediate products. 10 8. Use according to claim 4, wherein the transposition takes place by formation of an isocyanate of formula (Ic) wherein R is a protected amino, and subsequent addition of a nucleophilic solvent or subsequent extinction in water in the presence of an acidic agent. fifteen 9. Compound of formula (Ia), (Ic) or (Ie), as individual enantiomer (S), in which Y is NHOCOR4, N3 or NH2, in which R4 is linear or branched C1-C4 alkyl and R is a protected amino group in the form of an acylamino, carbamoyl, arylmethylamino, phthalimido or silylamino group. twenty