WO2000068221A1 - Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof - Google Patents

Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof Download PDF

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WO2000068221A1
WO2000068221A1 PCT/HU2000/000042 HU0000042W WO0068221A1 WO 2000068221 A1 WO2000068221 A1 WO 2000068221A1 HU 0000042 W HU0000042 W HU 0000042W WO 0068221 A1 WO0068221 A1 WO 0068221A1
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acid
dimethyl
carboxylic acid
formula
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PCT/HU2000/000042
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Péter KÓTAY NAGY
Zoltán Greff
József Barkóczy
Gyula Simig
László BALÁZS
Imre Domán
Zoltán RÁTKAI
Péter SERES
Ferenc Bartha
Györgyi VERECZKEYNÉ DONÁTH
Kálmán NAGY
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EGIS Gyógyszergyár Rt.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D319/00Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/041,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/061,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Abstract

The invention relates to salts of (4R-cis) -(1,1-dimethyl -ethyl) -6-(2-aminoethyl) -2,2-dimethyl -1,3-dioxane -4-acetate of formula (I) formed with organic acids. The new salts according to the invention are stable and can be easily purified by recrystallization. The new salts of the invention are valuable pharmaceutical intermediates which can be used e.g. in the preparation of the hypolipidemic agent having the generic (INN) name atorvastatin. The invention further relates to the preparation of the new salts of the compound of formula (I).

Description

WO 00/68221 PCTtHUOO/00042

SALTS OF 2 ,2-DIMETHYL-l ,3-DI0XANE INTERMEDIATES AND PROCESS FOR THE PREPARATION THEREOF

FIELD OF THE INVENTION

This invention relates to new pharmaceutical intermediates and a process for the preparation thereof.

The invention relates more particularly to salts of (4R- -cis)-(1 , 1 -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3- -dioxane-4-acetate formed with organic acids. TECHNICAL BACKGROUND

The (4R-cis)-(1 , 1 -dimethyl-ethyl)-6-(2-aminoethyl)-2,2- -dimethyl-1 ,3-dioxane-4-acetate of the Formula

Figure imgf000003_0001
is a valuable pharmaceutical intermediate which can be used e.g. in the preparation of the hypolipidemical agent of the Formula

Figure imgf000004_0001
having the international non-proprietary name (INN) atorvastatin.

Two methods are known from prior art for the preparation of the compound of the Formula I. The process disclosed in US patent No. 5,155,251 is disclosed on reaction scheme A.

Figure imgf000005_0001
According to this patent the aminoethyl derivative of the Formula I is prepared by fractionated distillation carried out at 125-135°C/0.05 Hgmm. The purity of the product is not higher than 96 %. The disadvantage of this process is that fractionated distillation in high vacuo is a complicated purification method which is only circumstantially feasible on industrial scale.

The process set forth in US patent No. 5,103,024 and the corresponding Hungarian patent No. 213,731 is shown on reaction scheme B.

Figure imgf000007_0001

\\/

Figure imgf000007_0002
According to this patent the compound of the Formula I is purified by column chromatography. The drawback of this process is that column chromatography requires large investments and is but difficultly feasible, particularly on industrial scale. The purity of the product obtained does not exceed 98.2 %.

The disadvantage of the above two known processes is that a product having a purity higher than 99 % can be prepared neither by means of fractional distillation nor by column chromatography. ESSENCE OF THE INVENTION

It is the object of the present invention to overcome the drawbacks of the known processes and to elaborate a simple process for the preparation of (4R-cis)-(1 ,1-dimethyl-ethyl)-6- -(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate which is preferably feasible on industrial scale too and provides a product having a purity above 99 %.

The above object is solved by the present invention.

It has been found that (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate of the Formula I forms with organic acids salts which can be excellently crystallized, are stable and of high purity. The invention compound of the Formula I being in salt form is extremely pure and can be advantageously converted into atorvastatin of the Formula II having a purity which meets the requirements of Pharmacopoeia. The advantage of the present invention is that fractionated distillation carried out in high vacuo and column chromatography used in prior art methods are eliminated.

According to an aspect of the present invention there are provided salts of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate formed with organic acids.

According to a further aspect of the invention there is provided a process for the preparation of salts of (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate formed with organic acids which comprises reacting the compound of the Formula I with an organic acid in an organic solvent. DETAILS OF THE INVENTION

The present invention is based on the recognition that the compound of the Formula I forms stable salts with organic acids. This recognition is so much the more surprising as it is known from prior art that ketales are instable in the presence of acids. The two hydroxy groups of the amine derivative of the Formula I are protected by a ketale ring. It was unforeseen that said ketale group would 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 remain stable even during recrystallization from an organic solvent carried out at higher temperature.

According to the process of the present invention the following acids may be used for salt formation: an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.

According to a preferred embodiment of our 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, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic 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, nicotic acid, tetrahydrofurane-2- -carboxylic acid or tiophen-3-carboxylic acid.

According to a particularly preferred embodiment of our invention pivalic acid is used.

The reaction may be carried out in an apolar, dipolar aprotic or protic solvent. As reaction medium an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, nitrile, alcohol or ether may be used. It is preferred to use one of the following solvents: hexane, heptane, petrolether, toluene, benzene, xylene, dichloro methane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofurane, dioxane or diethyl ether.

A solvent mixture may also be used as reaction medium. It is preferred to use a mixture of heptane and toluene; hexane and toluene; hexane, toluene and tetrahydrofurane; heptane, toluene and tetrahydrofurane; or hexane and diethyl ether.

According to a particularly preferred embodiment of our invention the compound of the Formula I and the organic acid are reacted in the form of solutions formed with the same solvent.

It is preferred to use the compound of the Formula I and the organic acid in a molar ratio of 0.5-5, preferably 0.5-2, particularly preferably 0.5-1.2.

The compound of the Formula I and the organic acid are admixed preferably at room temperature and the reaction may be performed under heating or at room temperature. One may preferably work at the boiling point of the reaction mixture.

The reaction mixture may be worked up by simple methods. One may proceed preferably by cooling the reaction mixture, isolating the precipitated salt of the compound of the Formula I by filtration or centrifugation, washing the salt with an organic solvent and drying. The salt may be purified by recrystallization.

According to a preferred embodiment of the process according to the present invention as starting material a crude compound of the Formula I is used. In this case the expensive and complicated purification of the compound of the Formula I is eliminated.

The advantages of the present invention may be summarized as follows: According to the present invention the compound of the Formula I is purified by simple recrystallization which can be carried out significantly easier than fractionated distillation performed in high vacuo and column chromatography used in the known methods.

The present invention provides a product of higher purity than the prior art methods. After a single recrystallization step the purity of the product is > 99 % (according to gas chromatography), after two-fold recrystallization the purity amounts to > 99.95 %. The purity of the product obtained by known methods is lower than 98 %.

The process of the present invention can be easily carried out on industrial scale too. The scaling-up causes no problems. On the other hand the fractionated distillation performed in high vacuo and column chromatography requires considerable investments and is but difficultly feasible on industrial scale.

The compound of the Formula I is stable and can be stored for a long period of time without decomposition in the form of salts formed with organic acids.

From the high purity salts of the compound of the Formula I according to the present invention atorvastatin meeting the requirements of Pharmacopoeia can be prepared.

Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples. Example 1

Pivalate of (4R-cisH1 ,1-dimethyl-ethylV6-.2-aminoethyl)-2.2- -dimethyl-1 ,3-dioxane-4-acetate

55 g of crude oily (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate are dissolved in 500 ml of a 4:1 mixture of heptane and toluene. 20.6 g (201 millimoles) of pivalic acid are dissolved in 190 ml of a 4:1 mixture of heptane and toluene. The two solutions are admixed and the reaction mixture is refluxed for an hour. The hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with a cold mixture of heptane and toluene and dried. Thus 64.9 g (172 millimoles) of the desired compound are obtained, yield 86 %, mp.: 131 °C.

Elementary analysis: for C% H% N% calc: 60.77 9.93 3.73 found: 60.77 9.88 3.81

TLC propanol/ammonia = 7:3, Rf = 0.63 IR (KBr): 2949, 1725, 1520, 1173.

HNMR (DMSO, i400): 4.17 (m, 1 H), 3.98 (m, 1 H), 2.66 (m, 2H), 2.36 (dd, J1=4.9 Hz, J2=15.0 Hz, 1 H), 2.22 (dd, J1=8.1 Hz, J2=15.0 Hz, 1 H), 1.54 (m, 3H), 1.39 (s, 12H), 1.24 (s, 3H), 1.05 (s, 9H), 1.03 (~t, J=12.0 Hz, 1 H).

CNMR: 180.87, 169.77, 98.22, 79.85, 66.50, 66.12, 42.34, 38.26, 37.05, 36.44, 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%, diastereomer contamination < 0.7%.

Example 2

Pivalic acid salt of ,4R-cisH1.1-dimethyl-ethyl)-6-(2-

-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

23.3 g of one recrystallized (4R-cis)-(1 ,1-dimethyl- -ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate pivalic acid salt are dissolved in 220 ml of a 4:1 mixture of hexane and toluene. The solution is heated to reflux, the hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with cold diethyl ether and dried. Thus 20.7 g of the desired product are obtained, yield 89 %, mp.: 132-133°C. GC content > 99.95 %; total impurities < 0.05 %. Example 3

Pivalic acid salt of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

21 g of crude oily (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate are dissolved in 116 ml of a 2:2:1 mixture of hexane, toluene and tetrahydrofurane. 7.6 g (201 millimoles) of pivalic acid are dissolved in 53 ml of a 1 :1 mixture of hexane and toluene. The two solutions are admixed and the reaction mixture is heated to boiling under reflux. The hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with cold diethyl ether and dried. Thus 21.1 g of the desired product are obtained. Yield 73 %, mp.: 131 °C. Example 4

Pivalic acid salt of (4R-cisV(1 ,1-dimethyl-ethvh-6-(2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

24 g (87.8 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 200 ml of a 4:1 :1 mixture of heptane, toluene and tetrahydrofurane. 9.0 g (88 millimoles) of pivalic acid are dissolved in 100 ml of a 4:1 :1 mixture of heptane, toluene and tetrahydrofurane. The two solutions are admixed and the reaction mixture is heated to boiling under reflux. The hot solution is filtered and the mixture is cooled with icecold water under stirring. The precipitated crystals are filtered, washed with cold diethyl ether and dried. Thus 29.0 g of the desired compound are obtained, yield 88 %, mp.: 131°C. Example 5

Benzoic acid salt of (4R-cis)-(1.1-dimethyl-ethylV6-,2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

0.6 g (219 millimoles) of crude (4R-cis)-(1 ,1-dimethyl- -ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate are dissolved in 4 ml of ethyl acetate. 0.26 g of benzoic acid are dissolved in 8 ml of a 1 :1 mixture of hexane and diethyl ether. The two solutions are admixed and stirred at room temperature for an hour. The reaction mixture is evaporated in vacuo. The residue is recrystallized from 5 ml of a 4:1 mixture of hexane and toluene. After cooling the precipitated crystals are filtered, washed with cold hexane and dried. Thus 0.71 g of the desired compound are obtained, yield 82 %, mp.:

113-114°C.

Formula: C2-|H33NO6

Molecular weight: 395.500

Elementary analysis: for C% H% N% calc: 63.78 8.41 3.54 found: 63.74 8.38 3.55

TLC propanol/ammonia =7:3 Rf =0.63

IR (KBr): 2979, 1722, 1519, 1370.

HNMR (CDCI3, g200): 8.39 (b, 3H), 7.98 (~d, J=7.0 Hz, 2H),

7.39 (m, 3H), 4.13 (m, 1 H), 3.79 (m, 1 H), 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).

Example 6

Maleic acid salt of (4R-cisH1.1-dimethyl-ethyl)-6-(2-

-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.25 g (219 millimoles) of maleic acid are dissolved in 4 ml of diethyl ether. The two solutions are admixed and stirred at room temperature. After cooling the precipitated crystals are filtered, washed with cold hexane and dried. Thus 0.80 g of the desired compound are obtained, yield 93 %, mp.: 87-89°C. Formula: Cι8H31N08 Molecular weight: 389.450 Elementary analysis: for C% H% N% calc: 55.51 8.02 3.60 found: 54.70 8.12 3.52

TLC propanol/ammonia =7:3 Rf =0.63

IR (KBr):3430, 2980, 1722.

HNMR (CDCI3, i400): 7.97 (b, 3H), 6.25 (s, 2H), 4.28 (m, 1 H),

4.10 (m, 1 H), 3.21 (m, 2H), 2.40 (m, 1 H), 2.31 (m, 1 H), 1.89

(m, 2H), 1.57 (m, 1 H), 1.46 (s, 3H), 1.44 (s, 9H), 1.35 (s, 3H),

1.27 (m, 1 H).

Example 7

Fumaric acid salt of (4R-cis)-(1 ,1-dimethyl-ethvD-6-(2-

-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 4 ml of anhydrous ethanol. 0.25 g (219 millimoles) of fumaric acid are dissolved in 10 ml of anhydrous ethanol. The two solutions are admixed and stirred at room temperature. The reaction mixture is evaporated and the residue is suspended in hexane. After cooling the precipitated crystals are filtered and recrystallized from 2- propanol. Thus 0.75 g of the desired compound are obtained, yield 85 %, mp.: 145-148°C. Formula: CιβH3ιNθ8 Molecular weight: 389.450

Elementary analysis: for C% H% N% calc: 55.51 8.02 3.60 found: 55.31 8.04 3.55 TLC propanol/ammonia =7:3 Rf =0.63

IR (KBr): 3430, 2988, 1736, 1157.

HNMR (DMSO, g200): 8.52 (b, 3H), 6.44 (s, 2H), 4.17 (m, 1 H),

3.98 (m, 1 H), 2.80 (m, 2H), 2.36 (m, 1 H), 2.19 (m, 1 H), 1.68

(m, 2H), 1.58 (m, 1 H), 1.38 (m, 12H), 1.24 (m, 3H), 1.09 (m,

1 H).

Example 8

Meta-methyl-benzoic acid salt of (4R-cis)-, 1 ,1-dimethyl-ethvD-

-6-(2-aminoethyl)-2l2-dimethyl-1 ,3-dioxane-4-acetate

0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.3 g (219 millimoles) of meta-methyl-benzoic acid are dissolved in 3 ml of diethyl ether. The two solutions are admixed and stirred at room temperature. The reaction mixture is evaporated and the residue is crystallized from a 5:1 mixture of hexane and toluene. Thus 0.84 g of the desired compound are obtained, yield 92 %, mp.: 95-96°C. Formula: C22H3δN06 Molecular weight: 409.527 Elementary analysis: for C% H% N% calc: 64.52 8.61 3.42 found: 64.23 8.64 3.45

TLC propanol/ammonia =7:3 Rf =0.63 IR (KBr): 2977, 2200, 1722, 1367.

HNMR (CDCI3, i400): 8.86 (b, 3H), 7.79 (m, 1 H), 7.77 (m, 1 H), 7.24 (m, 2H), 4.13 (m, 1 H), 3.79 (m, 1 H), 3.02 (m, 1 H), 2.93 (m, 1H), 2.37 (s, 3H), 2.31 (m, 1 H), 2.18 (m, 1H), 1.71 (m,

2H), 1.50 (m, 1 H), 1.43 (s, 9H), 1.33 (s, 3H), 1.26 (s, 3H), 1.00

(m, 1H).

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 (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 5 ml of a 4:1 mixture of hexane and toluene. 0.34 g (219 millimoles) of benzenesulfonic acid are dissolved in 5 ml of toluene. The two solutions are admixed. The reaction mixture is stirred at room temperature and evaporated in vacuo. The residue is recrystallized from a 5:1 mixture of hexane and toluene. Thus 0.76 g of the desired compound are obtained, yield 80 %, mp.: 96-98°C. Formula: C2oH33NO S Molecular weight: 431.553 Elementary analysis: for C% H% s% N% calc: 55.66 7.71 7.43 3.25 found: 54.79 7.73 7.32 3.28

TLC propanol/ammonia =7:3 Rf =0.63 IR (KBr): 3430, 2976, 1737, 1719, 1165. HNMR (CDCI3, i400): 7.90 (m, 1H), 7.63 (m, 2H), 7.40 (m, 2H), 4.13 (m, 1 H), 3.82 (m, 1 H), 2.98 (m, 2H), 2.33 (m, 1 H), 3.21 (m, 1H), 1.68 (m, 2H), 1.50 (m, 1 H), 1.44 (s, 9H), 1.33 (s, 3H), 1.27 (s, 3H), 1.03 (m, 1 H). Example 10

Acetic acid salt of .4R-cisH1 ,1-dimethyl-ethyl)-6-,2- -aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate

0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.131 g (219 millimoles) of acetic acid are dissolved in 5 ml of diethyl ether. The two solutions are admixed. The reaction mixture is stirred at room temperature. The crystals are filtered, washed with hexane and dried at room temperature in vacuo. Thus 0.56 g of the desired compound are obtained, yield 76 %, mp.: 76- 77°C.

Formula: Ci6H3ιNO6 Molecular weight: 333.429 Elementary analysis: for C% H% N% calc: 57.64 9.37 4.20 found: 57.80 9.40 4.09

TLC propanol/ammonia =7:3 Rf =0.63 IR (KBr): 3430, 2986, 1731 , 1157.

HNMR (CDCI3, i400): 8.18 (b, 3H), 4.26 (m, 1 H), 3.97 (m, 1 H), 2.93 (m, 2H), 2.43 (m, 1 H), 2.29 (m, 1 H), 1.96 (s, 3H), 1.80 (m, 2H), 1.56 (m, 1 H), 1.44 (s, 9H), 1.44 (s, 3H), 1.34 (s, 3H), 1.22 (m, 1 H). Example 11

Bis-(4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl- -1.3-dioxane-4-acetate oxalic acid salt

0.6 g (219 millimoles) of crude oily (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate are dissolved in 6 ml of diethyl ether. 0.19 g (219 millimoles) of oxalic acid are dissolved in 3 ml of diethyl ether. The two solutions are admixed. The reaction mixture is stirred at room temperature. The precipitated crystals are filtered, washed with cold hexane and dried at room temperature in vacuo. Thus 0.56 g of the desired compound are obtained, yield 80 %, mp.: 76-77°C. Formula: C30H56N2O12 Molecular weight: 333.429 Elementary analysis: for C% H% N% calc: 56.59 8.86 4.40 found: 56.21 8.38 4.36

TLC propanol/ammonia =7:3 RF =0.63 IR (KBr): 3430, 2982, 1739, 1575, 1161. HNMR (CDCI3, i400): 8.60 (b, 3H), 4.24 (m, 1 H), 3.99 (m, 1 H), 3.00 (m, 2H), 2.32 (m, 2H), 1.90 (m, 2H), 1.54 (m, 1 H), 1.44 (s, 9H), 1.41 (s, 3H), 1.32 (s, 3H), 1.21 (m, 1 H).

Claims

What we claim is,
1. Salts of (4R-cis)-(1 ,1-dimethyl-ethyl)-6-(2-amino- -ethyl)-2,2-dimethyl-1 ,3-dioxane-4-acetate of the Formula
Figure imgf000022_0001
formed with organic acids.
2. Salts of the compound of the Formula I according to Claim 1 formed with an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
3. Salts of the compound of the Formula I according to Claim 2 formed with acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic 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, nicotic acid, tetrahydrofurane-2-carboxylic acid or tiophen-3- -carboxylic acid.
4. Salt of the compound of the Formula I according to Claim 1 formed with pivalic acid.
5. Process for the preparation of salts of (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate of the Formula I which comprises reacting (4R-cis)- -(1 ,1-dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate of the Formula I with an organic acid in an organic solvent.
6. Process according to Claim 5 which comprises using as organic acid an aliphatic monocarboxylic acid, dicarboxylic acid or polycarboxylic acid, cycloalkane carboxylic acid, aliphatic unsaturated carboxylic acid, aromatic carboxylic acid, heterocyclic carboxylic acid or sulphonic acid.
7. Process according to Claim 6 which comprises using acetic acid, butyric acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malic acid, succinic acid, malonic acid, citric acid, cyclopropane carboxylic acid, cyclobutane carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic 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, nicotic acid, tetrahydrofurane-2- -carboxylic acid or tiophen-3-carboxylic acid.
8. Process according to Claim 7 which comprises using pivalic acid.
9. Process according to any of Claims 6-8 which comprises using as reaction medium an apolar, dipolar, aprotic or protic solvent.
10. Process according to Claim 9 which comprises using as organic solvent an aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, nitrile, alcohol or ether.
11. Process according to Claim 10 which comprises using as organic solvent hexane, heptane, petrolether, toluene, benzene, xylene, dichloro methane, chloroform, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofurane, dioxane or diethyl ether.
12. Process according to any of Claims 9-11 which comprises using as reaction medium a solvent mixture.
13. Process according to Claim 12 which comprises using as reaction medium a mixture of heptane and toluene; hexane and toluene; hexane, toluene and tetrahydrofurane; heptane, toluene and tetrahydrofurane; or hexane and diethyl ether.
14. Process according to any of Claims 5-13 which comprises dissolving the compound of the Formula I and the organic acid in the same solvent and admixing the two solutions.
15. Process according to any of Claims 5-14 which comprises using the compound of the Formula I and the organic acid in a molar ratio of 0.5-5, preferably 0.5-2, particularly preferably 0.5-1.2.
16. Process according to any of Claims 5-15 which comprises carrying out the reaction at room temperature or under warming, preferably at 20-90°C.
17. Process according to any of Claims 5-16 which comprises using as starting material crude (4R-cis)-(1 ,1- -dimethyl-ethyl)-6-(2-aminoethyl)-2,2-dimethyl-1 ,3-dioxane-4- -acetate.
PCT/HU2000/000042 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof WO2000068221A1 (en)

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HU9901526A HU227840B1 (en) 1999-05-06 1999-05-06 Intermediates of atorvastatin synthesis and process for producing them

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CA 2373077 CA2373077A1 (en) 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
AU4600200A AU4600200A (en) 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
PL35114500A PL351145A1 (en) 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
JP2000617201A JP2002544207A (en) 1999-05-06 2000-05-05 Salts and their preparation of 2,2-dimethyl-1,3-dioxane intermediates
SK15842001A SK15842001A3 (en) 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
KR20017014104A KR20020033617A (en) 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
EP20000927612 EP1178980A1 (en) 1999-05-06 2000-05-05 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
HRP20010846A2 HRP20010846A2 (en) 1999-05-06 2001-11-16 Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof

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WO2003106447A1 (en) * 2002-06-17 2003-12-24 Dsm Ip Assests B.V. Process for the preparation of dioxane acetic acid esters
US6870059B2 (en) 2000-07-19 2005-03-22 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives
US7157255B2 (en) 2000-05-09 2007-01-02 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
EP1861364A1 (en) 2005-03-14 2007-12-05 Pfizer Science and Technology Ireland Limited Preparation of an atorvastatin intermediate using a paal-knorr condensation
US7692034B2 (en) 2001-07-06 2010-04-06 Teva Pharmaceutical Industries Ltd. Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives
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US7157255B2 (en) 2000-05-09 2007-01-02 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7888083B2 (en) 2000-05-09 2011-02-15 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7732171B2 (en) 2000-05-09 2010-06-08 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7416865B2 (en) 2000-05-09 2008-08-26 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US6870059B2 (en) 2000-07-19 2005-03-22 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives
US7989643B2 (en) 2000-07-19 2011-08-02 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US7642363B2 (en) 2000-07-19 2010-01-05 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US6867306B2 (en) 2001-01-19 2005-03-15 Biocon Limited Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds
WO2002057274A1 (en) * 2001-01-19 2002-07-25 Biocon India Limited A process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds
US7692034B2 (en) 2001-07-06 2010-04-06 Teva Pharmaceutical Industries Ltd. Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives
US7718812B2 (en) 2001-12-27 2010-05-18 Astrazeneca Uk Limited Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
US7442811B2 (en) 2002-06-17 2008-10-28 Astrazeneca Uk Limited Process for the preparation of dioxane acetic acid esters
JP2005533065A (en) * 2002-06-17 2005-11-04 アストラゼネカ・ユーケイ・リミテッド Method for producing a dioxane acetates
EP1375493A1 (en) * 2002-06-17 2004-01-02 Dsm N.V. Process for the preparation of an dioxane acetic acid ester
WO2003106447A1 (en) * 2002-06-17 2003-12-24 Dsm Ip Assests B.V. Process for the preparation of dioxane acetic acid esters
EP1861364A1 (en) 2005-03-14 2007-12-05 Pfizer Science and Technology Ireland Limited Preparation of an atorvastatin intermediate using a paal-knorr condensation
WO2012032035A1 (en) 2010-09-09 2012-03-15 Dsm Sinochem Pharmaceuticals Netherlands B.V. Salts of 7-amino-3,5-dihydroxyheptanoic acid esters
US20130197243A1 (en) * 2010-09-09 2013-08-01 Dsm Sinochem Pharmaceuticals Netherlands B.V. Salts of 7-amino-3,5-dihydroxyheptanoic acid esters

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