JP2002544207A - 2,2-Dimethyl-1,3-dioxane intermediate salt and method for producing the same - Google Patents

Abstract

(57) Abstract: The present invention provides a compound represented by the general formula (I): And (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate. The novel salts according to the invention are stable and are easily purified by recrystallization. The novel salts of the present invention are valuable pharmaceutical intermediates used, for example, in the manufacture of hyperlipidemic agents having the generic name (INN) "atorvastatin". The present invention further relates to a method for producing a novel salt of the compound represented by the general formula (I).

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel pharmaceutical intermediate and a method for producing the same.

More specifically, the present invention relates to (4R-cis)-(1,1-dimethyl-ethyl)-
The present invention relates to an organic acid salt of 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate.

The general formula (I)

Embedded image (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl
) -2,2-Dimethyl-1,3-dioxane-4-acetate is, for example, a compound of the general formula (II) having the general name (INN) "atorvastatin"

Embedded image Is a valuable pharmaceutical intermediate used in the production of the hyperlipidemic agent represented by

For the preparation of the compounds of the general formula (I), two methods are known from the prior art. The method disclosed in US Pat. No. 5,155,251 is illustrated in Reaction Scheme A below.

Embedded image

According to this patent, an aminoethyl derivative of the compound represented by the general formula (I) is produced by performing fractional distillation at 125 to 135 ° C./0.05 mmHg. The product purity is less than 96%. The disadvantage of this method is that the fractional distillation at high vacuum is a complicated purification method, which on an industrial scale can only be carried out in certain circumstances.

The process disclosed in US Pat. No. 5,103,024 and the corresponding Hungarian patent 213,731 is shown in Reaction Scheme B.

Embedded image

According to this patent, the compounds of the general formula (I) are purified by column chromatography. The disadvantage of this method is that not only is column chromatography expensive, but it is difficult to perform, especially on an industrial scale. The purity of the product obtained does not exceed 98.2%.

A disadvantage of the above two known methods is that neither fractional distillation nor column chromatography can give a product with a purity higher than 99%.

The object of the present invention is to overcome the disadvantages of the known processes and to provide a product which is preferably carried out on an industrial scale and has a purity of more than 99% (4R-cis)-(1,1) −
It is an object of the present invention to provide a simple method for producing (dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate.

The above object is achieved by the present invention.

(4R-cis)-(1,1-dimethyl-ethyl) -6- (2) represented by the general formula (I)
(-Aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate forms a salt with an organic acid, and it has been found that this salt is well crystallized, stable, and of high purity. Was done. The compounds of the invention of the general formula (I) in salt form are extremely pure and are advantageously converted to "atorvastatin" of the general formula (II) having a purity satisfying the requirements of the Pharmacopoeia. You. An advantage of the present invention is that it eliminates the fractional distillation and column chromatography performed at high vacuum used in prior art methods.

According to an aspect of the present invention, (4R-cis)-(1,1-dimethyl-ethyl) -6- (2
-Aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate is provided.

According to another aspect of the present invention, the compound represented by the general formula (I) is reacted with an organic acid in an organic solvent, and comprises (4R-cis)-(1,1-dimethyl) -Ethyl)
A process for the preparation of an organic acid salt of -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate is provided.

The present invention is based on the finding that the compound represented by the general formula (I) forms a stable salt with an organic acid. Such a finding is surprising because in the prior art, ketals are known to be unstable in the presence of acids. Two hydroxyl groups of the amine derivative represented by the general formula (I) are protected by a ketal ring. The ketal groups are not expected to be resistant to organic acids under the reaction conditions used. It is particularly surprising that the salts of the present invention are not only stable at room temperature, but also retain stability during recrystallization from organic solvents performed at higher temperatures.

According to the process of the invention, for the formation of salts, the following acids are used: aliphatic monocarboxylic acids, dicarboxylic acids or polycarboxylic acids, cycloalkanecarboxylic acids, aliphatic unsaturated carboxylic acids, aromatics Carboxylic, heterocyclic carboxylic or sulfonic acids are used.

According to one preferred embodiment of the invention, the following acids are used: acetic acid,
Butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, fumaric acid, maleic acid Benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo-benzoic acid,
4-tert-butyl-benzoic acid, benzenesulfonic acid, methanesulfonic acid, p-methyl-benzenesulfonic acid, p-bromo-benzenesulfonic acid, nicotinic acid, tetrahydrofuran-2-carboxylic acid or thiophen-3-carboxylic acid It is.

According to a particularly preferred embodiment of the present invention, pivalic acid is used.

The reaction is performed in a non-polar, polar, aprotic or protic solvent. As reaction medium, use is made of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, nitriles, alcohols or ethers. The following solvents: hexane, heptane, petroleum ether, toluene, benzene, xylene, dichloromethane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol,
1 of isopropanol, tetrahydrofuran, dioxane or diethyl ether
It is preferred to use one.

As reaction medium, it is also possible to use solvent mixtures. Heptane-toluene,
It is preferred to use a mixture of hexane-toluene, hexane-toluene-tetrahydrofuran, heptane-toluene-tetrahydrofuran, or hexane-diethyl ether.

According to a particularly preferred embodiment of the present invention, the compound of general formula (I) and the organic acid are reacted in the form of a solution prepared using the same solvents.

The compound represented by the general formula (I) and the organic acid are used in an amount of 0.5 to 5, preferably 0.5 to 5.
2, particularly preferably in a molar ratio of 0.5 to 1.2.

The compound represented by the general formula (I) and the organic acid are preferably mixed at room temperature, and the reaction is carried out under heating or at room temperature. Preferably, it can be operated at the boiling point of the reaction mixture.

The reaction of the reaction mixture can be terminated in a simple manner. One method is preferably carried out by allowing the reaction mixture to cool, isolating the precipitated salt of the compound of formula (I) by filtration or centrifugation, washing the salt with an organic solvent and drying. Let it. The salt can be purified by recrystallization.

According to one preferred embodiment of the process according to the invention, the starting material is a compound of general formula (I)
) Is used. In this case, expensive and complicated purification of the compound represented by the general formula (I) is excluded.

The advantages of the present invention are summarized as follows.

According to the invention, the compounds of the general formula (I) are clearly more readily available than fractional distillation and column chromatography carried out at high vacuum, as used in known methods. Purified by recrystallization performed.

The present invention can provide a product having a higher purity than the conventional method. After one recrystallization step, the purity of the product is> 99% (by gas chromatography)
After two recrystallizations, the purity is> 99.95%. The purity of the products obtained in known manner is less than 98%.

The process of the present invention is easily carried out on an industrial scale. Scale-up does not cause any problems. On the other hand, fractional distillation and column chromatography performed at a high vacuum not only require a great deal of expense, but are also difficult to implement on an industrial scale.

The compounds of the general formula (I) are stable and can be stored for a long time without decomposition in the form of salts formed with organic acids.

From the highly pure salts of the compounds of the general formula (I) according to the invention, "atorvastatin" which meets the requirements of the Pharmacopoeia is prepared.

Further details of the present invention will be found in the examples below. However, the scope of protection of the present invention is not limited to the embodiments.

[0032]

Example 1 Crude pivalate salt of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate 55 g of oily (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate in 4 parts of heptane-toluene : 1 mixture was dissolved in 500 ml. Also, 20.6 g (201 mmol) of pivalic acid was dissolved in 190 ml of a 4: 1 mixture of heptane-toluene. The two solutions were mixed and the reaction mixture was refluxed for 1 hour. The hot solution was filtered and the mixture was cooled with ice water under stirring. The precipitated crystals were collected by filtration, washed with a cold mixture of heptane-toluene and dried. Thus, 64.9 g of the desired compound
(172 mmol) were obtained. Yield: 86% Melting point: 131 ° C Elemental analysis: C% H% N% Theoretical 60.77 9.93 3.73 Found 60.77 9.88 3.81 TLC (propanol: ammonia = 7: 3): R _f = 0.63 IR (KBr): 2949, 1725, 1520, 1173 H NMR (DMSO, i400): 4.17 (m, 1H), 3.98 (m, 1H), 2.66 (m, 2H), 2.36 (d
d, J1 = 4.9 Hz, J2 = 15.0 Hz, 1H), 2.22 (dd, J1 = 8.1 Hz, J2 = 15.0 Hz, 1H), 1
.54 (m, 3H), 1.39 (s, 12H), 1.24 (s, 3H), 1.05 (s, 9H), 1.03 (~ t, J
= 12.0Hz, 1H) CNMR: 180.87, 169.77, 98.22, 79.85, 66.50, 66.12, 42.34, 38.26, 37.05, 3
6.44, 35.97, 30.11, 28.03, 27.92, 19.88 MS: 274 (3), 202 (57), 200 (47), 173 (44), 158 (50), 57 (100), 41 (48), 30 ( 96
) GC content:> 99% Diastereomeric contamination: <0.7%

[0033]

Example 2 Pivalate of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate 1 (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate pivalate 2
3.3 g were dissolved in 220 ml of a 4: 1 mixture of hexane-toluene. Heating the solution,
At reflux, the hot solution was filtered off and the mixture was cooled with ice water under stirring. The precipitated crystals were filtered, washed with cold diethyl ether and dried. In this way, 20.7 g of the desired product are obtained. Yield: 89% Melting point: 132-133 ° C GC content:> 99.95% Total impurities: <0.05%

[0034]

Example 3 Crude pivalate of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate 21 g of oil (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate in hexane-toluene-tetrahydrofuran Was dissolved in 116 ml of a 2: 2: 1 mixture. Also, 7.6 g (74 mmol) of pivalic acid were dissolved in 53 ml of a 1: 1 mixture of hexane-toluene. The two solutions were mixed and the reaction mixture was heated to the boil while refluxing. The hot solution was filtered off and the mixture was cooled with ice water under stirring.
The precipitated crystals were filtered, washed with cold diethyl ether and dried. In this way, 21.1 g of the desired product are obtained. Yield: 73% Melting point: 131 ° C

[0035]

Example 4 Crude pivalate salt of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate Oil (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (24 g, 87.8 mmol) in heptane 200 ml of a 4: 1: 1 mixture of toluene-tetrahydrofuran
Was dissolved. In addition, 9.0 g (88 mmol) of pivalic acid was dissolved in 100 ml of a 4: 1: 1 mixture of heptane-toluene-tetrahydrofuran. The two solutions were mixed and the reaction mixture was heated to boiling under reflux. The hot solution was filtered and the mixture was cooled with ice water under stirring. The precipitated crystals were collected by filtration, washed with cold diethyl ether and dried. In this way, 29.0 g of the desired product are obtained.
Yield: 88% Melting point: 131 ° C

[0036]

Example 5 Crude benzoate of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl)
0.6 g (2.19 mmol) of -2,2-dimethyl-1,3-dioxane-4-acetate was dissolved in 4 ml of ethyl acetate. Also, 0.26 g of benzoic acid was dissolved in 8 ml of a 1: 1 mixture of hexane-diethyl ether. The two solutions were mixed and stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuum. The residue was recrystallized from 5 ml of a 4: 1 mixture of hexane-toluene. After cooling, the precipitated crystals were collected by filtration, washed with cold hexane and dried. In this way 0.71 g of the desired compound is obtained. Yield: 82% Melting point: 113-114 ° C Chemical formula: C ₂₁ H ₃₃ NO ₆ Molecular weight: 395.500 Elemental analysis: C% H% N% Theoretical 63.78 8.41 3.54 Found 63.74 8.38 3.55 TLC (propanol: ammonia = 7: 3 ): R _f = 0.63 IR (KBr): 2979, 1722, 1519, 1370 H NMR (CDCl ₃ , g200): 8.39 (b, 3H), 7.98 (-d, J = 7.0 Hz, 2H), 7.39 (m,
3H), 4.13 (m, 1H), 3.79 (m, 1H), 2.97 (m, 2H), 2.23 (m, 2H), 1.70 (
m, 2H), 1.43 (s, 9H), 1.32 (s, 3H), 1.27 (s, 3H), 1.00 (m, 2H)

[0037]

Example 6 Crude maleate salt of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate Of oil (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (0.6 g, 2.19 mmol). Was dissolved in 6 ml of diethyl ether. In addition, maleic acid 0.25 g (2.19
Mmol) was dissolved in 4 ml of diethyl ether. The two solutions were mixed and stirred at room temperature. After cooling, the precipitated crystals were collected by filtration, washed with cold hexane and dried. In this way 0.80 g of the desired compound is obtained. Yield: 93% mp: 87-89 ° C. Chemical formula: C ₁₈ H ₃₁ NO ₈ molecular weight: 389.450 Elemental analysis: C% H% N% theoretical value 55.51 8.02 3.60 measurements 54.70 8.12 3.52 TLC (propanol: ammonia = 7: 3 ): R _f = 0.63 IR (KBr): 3430, 2980, 1722 HNMR (CDCl ₃ , i400): 7.97 (b, 3H), 6.25 (s, 2H), 4.28 (m, 1H), 4.10 (
m, 1H), 3.21 (m, 2H), 2.40 (m, 1H), 2.31 (m, 1H), 1.89 (m, 2H), 1.5
7 (m, 1H), 1.46 (s, 3H), 1.44 (s, 9H), 1.35 (s, 3H), 1.27 (m, 1H)

[0038]

Example 7 Crude fumarate of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate Of oil (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (0.6 g, 2.19 mmol). Was dissolved in 4 ml of absolute ethanol. Also, 0.25 g (2.19 mmol) of fumaric acid was dissolved in 10 ml of anhydrous ethanol. The two solutions were mixed and stirred at room temperature. The reaction mixture was evaporated and the residue was suspended in hexane. After cooling, the precipitated crystals were collected by filtration and recrystallized from 2-propanol. In this way 0.75 g of the desired compound is obtained. Yield: 85% Melting point: 145-148 ° C Chemical formula: C ₁₈ H ₃₁ NO ₈ Molecular weight: 389.450 Elemental analysis: C% H% N% Theoretical 55.51 8.02 3.60 Found 55.31 8.04 3.55 TLC (propanol: ammonia = 7: 3 ): R _f = 0.63 IR (KBr): 3430, 2988, 1736, 1157 H NMR (DMSO, g200): 8.52 (b, 3H), 6.44 (s, 2H), 4.17 (m, 1H), 3.98 (m
, 1H), 2.80 (m, 2H), 2.36 (m, 1H), 2.19 (m, 1H), 1.68 (m, 2H), 1.58
(M, 1H), 1.38 (m, 12H), 1.24 (m, 3H), 1.09 (m, 1H)

[0039]

Example 8 m-methyl- (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate 0.6 g of crude oil of benzoate (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate ( 2.19 mmol) was dissolved in 6 ml of diethyl ether. Also, 0.3 g (2.19 mmol) of meta-methyl-benzoic acid was dissolved in 3 ml of diethyl ether. The two solutions were mixed and stirred at room temperature. The reaction mixture was evaporated and the residue was recrystallized from a 5: 1 mixture of hexane-toluene. In this way 0.84 g of the desired compound is obtained. Yield: 92% mp: 95-96 ° C. Chemical formula: C ₂₂ H ₃₅ NO ₆ Molecular weight: 409.527 Elemental analysis: C% H% N% theoretical value 64.52 8.61 3.42 measurements 64.23 8.64 3.45 TLC (propanol: ammonia = 7: 3 ): R _f = 0.63 IR (KBr): 2977, 2200, 1722, 1367 H NMR (CDCl ₃ , i400): 8.86 (b, 3H), 7.79 (m, 1H), 7.77 (m, 1H), 7.24 (
m, 2H), 4.13 (m, 1H), 3.79 (m, 1H), 3.02 (m, 1H), 2.93 (m, 1H), 2.3
7 (s, 3H), 2.31 (m, 1H), 2.18 (m, 1H), 1.71 (m, 2H), 1.50 (m, 1H),
1.43 (s, 9H), 1.33 (s, 3H), 1.26 (s, 3H), 1.00 (m, 1H)

[0040]

Example 9 Benzenesulfonic acid salt of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate 0.6 g (2.19 mmol) of crude oily (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate Was dissolved in 5 ml of a 4: 1 mixture of hexane-toluene. Also, 0.34 g (2.19 mmol) of benzenesulfonic acid was dissolved in 5 ml of toluene. The two solutions were mixed. The reaction mixture was stirred at room temperature and evaporated in vacuo. The residue was recrystallized from a 5: 1 mixture of hexane-toluene. Thus, the desired compound
0.76 g was obtained. Yield: 80% mp: 96 to 98 ° C. Formula: C ₂₀ H ₃₃ NO ₇ S Molecular weight: 431.553 Elemental analysis: C% H% S% N % theoretical value 55.66 7.71 7.43 3.25 measurements 54.79 7.73 7.32 3.28 TLC (propanol: ammonia _{= 7: 3): R f} = 0.63 IR (KBr): 3430,2976,1737,1719,1165 HNMR (CDCl 3, i400): 7.90 (m, 1H), 7.63 (m, 2H), 7.40 (m , 2H), 4.13 (
m, 1H), 3.82 (m, 1H), 2.98 (m, 2H), 2.33 (m, 1H), 3.21 (m, 1H), 1.6
8 (m, 2H), 1.50 (m, 1H), 1.44 (s, 9H), 1.33 (s, 3H), 1.27 (s, 3H),
1.03 (m, 1H)

[0041]

Example 10 Preparation of crude acetate salt of (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 -dimethyl-1,3-dioxane-4-acetate 0.6 g (2.19 mmol) of oily (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate was obtained. It was dissolved in 6 ml of diethyl ether. In addition, 0.131 g (2.19 mmol) of acetic acid was dissolved in 5 ml of diethyl ether. The two solutions were mixed. The reaction mixture was stirred at room temperature. The crystals were collected by filtration, washed with hexane and dried in vacuo at room temperature. In this way 0.56 g of the desired compound is obtained. Yield: 76% Melting point: 76-77 ° C Chemical formula: C ₁₆ H ₃₁ NO ₆ Molecular weight: 333.429 Elemental analysis: C% H% N% Theoretical 57.64 9.37 4.20 Measurement 57.80 9.40 4.09 TLC (propanol: ammonia = 7: 3 ): R _f = 0.63 IR (KBr): 3430, 2986, 1731, 1157 H NMR (CDCl ₃ , i400): 8.18 (b, 3H), 4.26 (m, 1H), 3.97 (m, 1H), 2.93 (
m, 2H), 2.43 (m, 1H), 2.29 (m, 1H), 1.96 (s, 3H), 1.80 (m, 2H), 1.5
6 (m, 1H), 1.44 (s, 9H), 1.44 (s, 3H), 1.34 (s, 3H), 1.22 (m, 1H)

[0042]

Example 11 Bis- (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl)
-2,2-dimethyl-1,3-dioxane-4-acetate oxalate crude oil (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2 0.6 g (2.19 mmol) of -dimethyl-1,3-dioxane-4-acetate were dissolved in 6 ml of diethyl ether. Also, 0.19 g (2.19 mmol) of oxalic acid was dissolved in 3 ml of diethyl ether. The two solutions were mixed. The reaction mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with cold hexane and dried in vacuo at room temperature. In this way 0.56 g of the desired compound is obtained. Yield: 80% mp: 76-77 ° C. Chemical _{formula: C 30 H 56 N 2 O} 12 Molecular weight: 636.725 Elemental analysis: C% H% N% theoretical value 56.59 8.86 4.40 measurements 56.21 8.38 4.36 TLC (propanol: ammonia = 7 _{: 3): R f = 0.63} IR (KBr): 3430,2982,1739,1161 HNMR (CDCl 3, i400): 8.60 (b, 3H), 4.24 (m, 1H), 3.99 (m, 1H), 3.00 (
m, 2H), 2.32 (m, 2H), 1.90 (m, 2H), 1.54 (m, 1H), 1.44 (s, 9H), 1.4
1 (s, 3H), 1.32 (s, 3H), 1.21 (m, 1H)

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR , ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Josef Barcoczi Hungary Hah 1016 Budapest Silom Uzza 4-6b (72) Inventor Jura Simig Hungary Hah-1126 Budapest Holosui Esch Uzza 25 (72) Inventor Lathrow Barrage Hungary 1088 Budapest Budapest Uzza 38 (72) Inventor Imre Doman Hungary Ha-1035 Budapest Mocha チ ュ Uzza 18b (72) Inventor Zoltan Ratkai Har-1101 Budapest Monoli Uzza, Hungary 19 (72) Inventor Peter Selesh Hungary 1153 Budapest Reda Barnen Uzza 6 (72) Inventor Ferenc Barta Hungary Har-4440 Tisavasi vari Kaba バ イ u Uzza 3-5 / 5 Inventor Jorzey Veletskeine Donat Hungary Har-1036 Budapest Layosh Uzza 49be (72) Inventor Karman Naj Hungary Har-1025 Budapest Turishta Uzza 2A F-term (reference) 4C022 GA07

Claims (17)

[Claims] 1. A compound of the general formula (I) formed by an organic acid (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl
) -2,2-Dimethyl-1,3-dioxane-4-acetate salt. 2. An aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid,
The salt of the compound represented by the formula (I) according to claim 1, which is formed by a cycloalkanecarboxylic acid, an aliphatic unsaturated carboxylic acid, an aromatic carboxylic acid, a heterocyclic carboxylic acid or a sulfonic acid. 3. Acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid Acid, fumaric acid, maleic acid, benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo-benzoic acid, 4-tert-butyl-benzoic acid, benzenesulfonic acid,
Methanesulfonic acid, p-methyl-benzenesulfonic acid, p-bromo-benzenesulfonic acid, nicotinic acid, tetrahydrofuran-2-carboxylic acid or thiophene-
The salt of the compound represented by the formula (I) according to claim 2, which is formed by 3-carboxylic acid. 4. The salt of the compound represented by the general formula (I) according to claim 1, which is formed by pivalic acid. 5. The (4R-cis)-(1,1-dimethyl-) represented by the general formula (I)
Ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4
In a method for producing an acetate salt, (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl- represented by the general formula (I) A method for producing a salt, comprising reacting 1,3-dioxane-4-acetate with an organic acid in an organic solvent. 6. As the organic acid, an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkanecarboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulfonic acid is used. The method according to claim 5, wherein: 7. Acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid Acid, fumaric acid, maleic acid, benzoic acid, m-methyl-benzoic acid, 4-methoxy-benzoic acid, 4-bromo-benzoic acid, 4-tert-butyl-benzoic acid, benzenesulfonic acid,
Methanesulfonic acid, p-methyl-benzenesulfonic acid, p-bromo-benzenesulfonic acid, nicotinic acid, tetrahydrofuran-2-carboxylic acid or thiophene-
7. The method according to claim 6, wherein a 3-carboxylic acid is used. 8. The method according to claim 7, wherein pivalic acid is used. 9. The process according to claim 6, wherein a nonpolar, polar, aprotic or protic solvent is used as the reaction medium. 10. The method according to claim 9, wherein an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile, an alcohol or an ether is used as the organic solvent. 11. An organic solvent comprising hexane, heptane, petroleum ether, toluene, benzene, xylene, dichloromethane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or diethyl ether. The method according to claim 10, wherein 12. The process according to claim 9, wherein a solvent mixture is used as a reaction medium. 13. The method according to claim 12, wherein a mixture of heptane-toluene, hexane-toluene, hexane-toluene-tetrahydrofuran, heptane-toluene-tetrahydrofuran, or hexane-diethyl ether is used as a reaction medium. . 14. The process according to claim 5, wherein the compound represented by the general formula (I) and the organic acid are dissolved in the same solvent, and the two solutions are mixed. . 15. A compound represented by the general formula (I) and an organic acid,
The process according to any of claims 5 to 13, characterized in that it is used in a molar ratio of preferably 0.5 to 2, particularly preferably 0.5 to 1.2. 16. The process according to claim 5, wherein the reaction is carried out at room temperature or under heating, preferably at 20 to 90 ° C. 17. A raw material comprising crude (4R-cis)-(1,1-dimethyl-ethyl) -6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-
The method according to any one of claims 5 to 16, wherein 4-acetate is used.