CZ292221B6 - Process for preparing (4R,6R) tert-butyl[6-(2-aminoethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate and intermediates for its preparation - Google Patents

Abstract

In the present invention there is disclosed a process for preparing (4R,6R) tert-butyl[6-(2-aminoethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate of the general formula I, wherein the preparation process comprises a) reacting (4R,6S) tert-butyl[6-formyl-2,2-dimethyl[1,3]dioxan-4-yl)]acetate of the general formula V with nitro methane in a suitable solvent, preferably in a lower alcohol under catalysis of suitable catalysts, preferably potassium fluoride and under suitable conditions, preferably under laboratory temperature, thus obtaining tert-butyl[6-(1-hydroxy-2-nitroethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate of the general formula VI; b) reaction the tert-butyl[6-(1-hydroxy-2-nitroethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate of the general formula VI with an anhydride of a corresponding carboxylic acid thus obtaining tert-butyl[6-(1-acyloxy-2-nitroethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate of the general formula VII, wherein R represents an unsubstituted or substituted alkyl group containing 1 to 5 carbon atoms; c) reducing the obtained tert-butyl[6-(1-acyloxy-2-nitroethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate of the general formula VII with sodium borohydride in a suitable medium, such as aqueous medium, water-alcoholic medium or alcoholic medium, thus obtaining tert-butyl[2,2-dimethyl-6-(2-nitroethyl)[1,3]dioxan-4-yl]acetate of the general formula VIII; d) subjecting the obtained tert-butyl[2,2-dimethyl-6-(2-nitroethyl)[1,3]dioxan-4-yl]acetate of the general formula VIII to hydrogenation under catalysis of hydrogenation catalyst such as Raney nickel, palladium, or platinum, and in suitable solvents such as lower alcohols, to obtain (4R,6R) tert-butyl[6-(2-aminoethyl)-2,2-dimethyl[1,3]dioxan-4-yl]acetate of the general formula I.

Description

The invention relates to a novel process for the preparation of (4R, 6R) tert-butyl [6- (2-aminoethyl) -2,2-dimethyl- [1,3] dioxan-4-yl] acetate and intermediates therefor. Said compound is a preferred intermediate for the convergent synthesis of hypolipidemic and hypocholesteric drugs, for example atorvastatin.

(47 R, 67 R) tert-Butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (I) serves as an important intermediate in the synthesis of atorvastatin. In the patent literature, e.g., US Pat. Nos. 5103024 and 5155251, several methods of its production are described, wherein the last step is always the catalytic hydrogenation of (47%, 67%) tert-butyl [6- (2-aminoethyl) -2,2]. -dimethyl [1,3] dioxan-4-yl] acetate (Π) carried out at room or slightly elevated temperature and at elevated hydrogen pressure of about 350 kPa in ammoniacal alcoholic solutions. The same procedure is described in Brower P.L., Butler D.E., Deering C.F. et al., Tetrahedron Letters 1992, 33: 2279-2282 and Baumann K.L., Butler D.E., Deering C.F. et al., Tetrahedron Letters 1992, 33: 2283-2284. Starting (47 R, 67 R) Zerc-Butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate is prepared in several ways. U.S. Pat. Nos. 5,130,224 and 5,155,251 disclose a process starting from (3 R) alkyl 3-hydroxy-4-cyanobutyrates, which have been converted in several steps to (7 R) tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate, whose diastereoselective reduction and subsequent protection of the primary dihydroxyester formed afforded the desired (47 R, 67 R) tert-butyl (6-cyanomethyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate. This procedure is also described in Brower P.L., Butler D.E., Deering C.F et al., Tetrahedron Letters 1992, 33: 2279-2282.

US Patent No. 5,248,793 starts from (45,65) tert-butyl (6-hydroxymethyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (ΙΠ), which, by reaction with a suitable arylsulfonyl chloride, affords the arylsulfonate (IV). If a sufficiently activated benzenesulfonyl group (for example 4-chlorobenzenesulfonyl or 4-nitrobenzenesulfonyl) is used as the arylsulfonyl group, the nitrile (Π) can be produced by reaction of these (IV) with an alkali cyanide. This procedure is also described in Brower P.L., Butler D.E., Deering C.F et al. Tetrahedron Letters 1992, 33: 2279-2282.

-1GB 292221 B6

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel, improved process for producing (4R, 6R) (47R, 67R) tert-butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate using (47 R, 65) tert -butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (V) using a new type of synthesis and novel hitherto not described intermediates. The starting (47 R, 65) tert -butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (V) is a known substance which can be prepared, for example, by the oxidation of alcohol (ΙΠ), as described in, for example, Wess G., Kessler K., Baader E. et al., Tetrahedron Letters 1990, 31: 2545-2548. Another amount of synthesis of this compound is the oxidation of isopropyl 3- (6-tert-butoxycarbonylmethyl-2,2). dimethyl [1,3] dioxan-4-yl) -2,3-dihydroxypropionate with sodium periodate, as described in JP 6107592 and in Minami T., Takahashi K, Hiyama T., Tetrahedron Letters 1993, 34 : 513 to 516.

For more than 100 years, the so-called Henry reaction has been known in which both aliphatic and aromatic aldehydes react with anitroalkanes under appropriate conditions; aliphatic nitroalkanes provide nitroalcohols. In 1978, Wollenberg and Miller (Wollenberg R. H., Miller S.J., Tetrahedron Letters 1978, 3219-3222) described the reaction of aliphatic aldehydes with nitromethane at room temperature under catalysis with potassium fluoride and leading to the corresponding nitroalcohols. The same publication describes the acetylation of a hydroxyl group and the subsequent reduction of an acetoxy derivative to a nitroalkane derivative.

It has been shown that the conditions are, after minor adjustments, also used to react with (47%, 65) tert-butyl

6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (V), which provided the nitroalcohol (VI) at room temperature. Acylation of the acid with the anhydride of the appropriate acid gave the corresponding acyloxy derivatives (VH), for example tert-butyl [6- (1-acetoxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate. Reduction of these substances with sodium borohydride at room temperature results in cleavage of the acyloxy group to give tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate (BUT). This material can then be easily hydrogenated at room temperature in conventional solvents such as alcohols to catalyze conventional hydrogenation catalysts such as Raney nickel, palladium on C, or platinum oxide without the need to apply a hydrogen overpressure to the desired (47?, 67?). tert-butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (I) (Scheme I).

-2GB 292221 B6

Scheme 1

Although this approach includes from (4R, 6S) tert-butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (V) to (4R, 6R) tert-butyl [ 6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (I) 4 reaction steps, the complexity is only apparent. All reaction steps are rapid, carried out at room temperature, and do not require expensive chemicals. They are simple to perform and no chromatographic purification is required at any stage. After the first reaction step, the nitroalcohol (VI) need not be isolated and potassium fluoride can also be left in the reaction mixture without appreciably reducing the yield. The crude product of the third reaction step, i.e. the corresponding tert-butyl [6- (1-acyloxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (VII), is contaminated with a small amount of of the corresponding elimination product, i.e. tert-butyl [2,2-dimethyl-6- (2-nitrovinyl) [1,3] dioxan-4-yl] acetate, but in the next step it is also hydrogenated to 15 (4, 6, 6A). tert-Butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (I). Hydrogenation of tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate (BUT) is particularly preferred. Unlike the hydrogenation of (4R, 6R) tert-butyl (6-cyanomethyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (Π), which requires the use of elevated pressure and must be carried out in a saturated alcoholic solution ammonia, which makes processing considerably more difficult, pressurized hydrogenation in conventional solvents, such as alcohols, is used in the process disclosed herein.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of (4R, 6R) tert-butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula I

-3GB 292221 B6 (1).

and intermediates therefor, in particular tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate of formula VHI

(vno, tert-butyl [6- (1-acyloxy-2-nitroethyl) -2,2-dimethyl] [1,3] dioxan-4-yl] acetate of formula VH, wherein R is methyl, ethyl, or propyl

and tert-butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula VI,

resting

a) in the conversion of (4S, 6S) tert-butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate of formula V

(V), by reaction with nitromethane to the compound of formula VI

b) converting VI to VH by treatment with the anhydride of the corresponding acid of formula (RCO) ₂ O-, wherein R is as defined above;

c) reducing the VH to the VIH, preferably using borohydride as the reducing agent;

-4GB 292221 B6

(d) converting VHI by hydrogenation to product I.

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives for the preparation of the compounds of the invention, are intended to be illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 tert-Butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (VI)

To a stirred mixture of (47 R, 65) tert-butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (9.7 g, 37.6 mmol) and anhydrous potassium fluoride ( 0.25 g) in isopropyl alcohol (50 ml) was added dropwise nitromethane (5 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then evaporated to dryness, dissolved in ether (250 mL), the insoluble material was filtered off with suction over kieselguhr and the filtrate was evaporated to dryness. 11.4 g (95%) of a GC purity of 98.86% were obtained. An analytical sample was crystallized from heptane-diethyl ether to give white crystals of mp 129-137 ° C. [α] _D ²⁰ = -3.08 °. 1 H-NMR (CDCl ₃ ): δ 1.28 (dt, 1H), 1.36 (bs, 3H), 1.43 (bs, 3H), 1.45 (s, 9H), 1.82 ( dt, 1H), 2.33 (dd, 1H), 2.45 (dd, 1H), 2.81 (bs, 1H), 3.90 (ddd, 1H), 4.13-4.33 (m) 2H, 4.45 (dd, 1 H), 4.63 (dd, 1 H). UV spectrum, (log, ε): 207.2 (3.6). IR spectrum (KBr): 1556 (NO ₂ ), 1722 [CC (= O) -O], 3566 (OH).

Example 2 tert-Butyl [6- (1-acetoxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (VIIa)

A) To a solution of tert-butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (3.2 g, 10 mmol) and 4-dimethylaminipyridine (0.05 g) in diethyl ether (50 ml) was added dropwise acetic anhydride (1.2 g) over 5 minutes and the mixture was stirred at room temperature for 1 hour. Then the mixture was shaken with brine and the solution was dried with magnesium sulfate. 3.5 g of a GC residue of 93% purity was obtained. An analytical sample was obtained by double crystallization from hexane, giving white crystals of mp 92-95 ° C. 1 H-NMR (CDCl ₃ ): δ 1.32 (dt, 1H), 1.38 (bs, 3H), 1.41 (bs, 3H), 1.43 (s, 9H), 1.66 (dt, 1H), 2.02 (s, 3H), 2.30 (dd, 1H), 2.42 (dd, 1H), 4.03 (ddd, 1H), 4.18 (ddd, 1H) 4.68 (m, 2H); 5.28 (m, 1H). UV spectrum, (loge): 206.0 (3.7). IR spectrum (KBr): 1228 [CC (O) -C], 1560 (NO ₂ ), 1724 [CC] = O-O], 1750 [CC (= O) -O].

B) To a stirred mixture of (47 R, 65) tert -butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate (9.7 g, 37.6 mmol) and anhydrous fluoride Potassium potassium (0.25 g) in isopropyl alcohol (50 ml) was added dropwise with nitromethane (5 ml) and the mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was evaporated to dryness, dissolved in diethyl ether (250 mL), and acetic anhydride (4.8 g, 47 mmol) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 1 hour. Then the mixture was shaken with brine and the solution was dried with magnesium sulfate. 12.1 g of a residue were obtained and a GC purity of 93%.

Example 3 tert-Butyl [6- (1-propionyloxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (VIIb)

-5GB 292221 B6

To a solution of tert -butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (0.32 g, 1 mmol) and 4-dimethylaminopyridine (0 0.01 g) in diethyl ether (5 ml) was added propionyl hydride (0.15 g) and the mixture was stirred at room temperature for 1 hour. Then the mixture was shaken with brine and the solution was dried with magnesium sulfate. 0.37 g of an oily residue having a GC purity of 95% was obtained and failed to crystallize.

Example 4

Tert-Butyl [6- (1-butyryloxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (Villa)

To a solution of tert-butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (0.32 g, 1 mmol) and 4-dimethylaminopyridine (0.01 g) butyrylamide (0.2 g) was added in diethyl ether (5 ml) and the mixture was stirred at room temperature for 1 hour. Then the mixture was shaken with brine and the solution was dried with magnesium sulfate. 0.30 g of an oily residue having a GC purity of 91% was obtained, which failed to crystallize.

Example 5 tert-Butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate (VIII).

A) To a stirred suspension of sodium borohydride (5 g) in ethanol (50 mL) was added dropwise a solution of tert-butyl [6- (1-acetoxy-2-nitroethyl) -2,2-dimethyl [1,3] while cooling in an ice bath. Dioxan-4-yl acetate (12.1 g, 33.5 mmol) in ethanol (100 mL) was stirred at room temperature for 1 hour. Then, the reaction mixture was poured into a 10% acetic acid solution (100 mL), and the mixture was extracted with diethyl ether, and the extract was dried with magnesium sulfate. 9.3 g of an oily substance (92%) with a GC purity of 98% were obtained. [α] _D ²⁰ + 18.17 °. 1 H-NMR (CDCl ₃ ): 81.22 (dt, 1H), 1.34 (d, 3H), 1.42 (d, 3H), 1.44 (s, 9H), 1.61 (d, 1H); dddd, 1H), 2.22 (dddd, 1H), 2.30 (dd, 1H), 2.42 (dd, 1H), 3.96 (dddd, 1H), 4.25 (dddd, 2H), 4.45 (ddd, 1 H), 4.54 (ddd, 1 H). UV spectrum, (log ε): 205.8 (3.7). IR spectrum (KBr): 1554 (NO ₂ ), 1721 [CCl = O-O].

B) To a stirred suspension of sodium borohydride (0.5 g) in ethanol (5 mL) was added dropwise a solution of tert-butyl [6- (1-propionyloxy-2-nitroethyl) -2,2-dimethyl [1], while cooling in an ice bath. 3] dioxan-4-yl] acetate (1.1 g, 2.9 mmol) in ethanol (10 mL) and the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was poured into a 10% acetic acid solution (10 mL), and the mixture was extracted with diethyl ether, dried over magnesium sulfate. 0.6 g of an oily substance (68%) was obtained.

C) To a stirred suspension of sodium borohydride (0.5 g) in ethanol (5 mL) was added dropwise a solution of tert-butyl [6- (1-butyryloxy-2-nitroethyl) -2,2-dimethyl [1] dropwise while cooling in an ice bath. 3] dioxan-4-yl] acetate (1.2 g, 3.1 mmol) in ethanol (10 mL) and the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was poured into a 10% acetic acid solution (10 mL), and the mixture was extracted with diethyl ether, dried over magnesium sulfate. 0.55 g of an oily substance (58%) was obtained.

Example 6 (4R, 6R) tert-Butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate (I)

A) To a solution of tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate (3 g, 10 mmol) in methanol (50 mL) was added Reney's nickel pre-washed several times

Methanol (0.5 g) and the mixture was hydrogenated under pressure without shaking under pressure for 4 hours. After the catalyst was filtered off through diatomaceous earth, the filtrate was evaporated to dryness. 2.6 g of a colorless oil having a GC content of 98% were obtained. [α] D ²⁰ = + 18.17 °. 1 H-NMR (CDCl 3): δ 1.23 (m, 1H), 1.37 (s, 3H), 1.47 (s, 3H), 1.47 (s, 9H), 1.56 (s) m, 1H), 1.60 (m, 2H), 2.24 (bs, 2H), 2.30 (dd, 1H), 2.43 (dd, 1H), 2.85 (m, 2H), 3.99 (m, 1H); 4.26 (m, 1H). GC-MS: 274 (M + 1), 202 (M-CH ₃ -C ₄ H ₈ , 200 (M-OC ₄ H ₉ ), 30 (CH ₂ NH ₂ ). UV spectrum, U (logs): 204.2 ( 2.6). IR spectrum (KBr): 1721 [CC (= O) -O], 3382 (NH _2). [β] _ο ²⁰ + 13.12 °.

Β) To a solution of tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate (0.3 g, 1 mmol) in methanol (5 mL) was added 10 % palladium on C (0.05 g) and the mixture was filtered through diatomaceous earth as catalyst, the filtrate was evaporated to dryness. 0.3 g of a colorless oil having a GC content of 91% was obtained.

C) To a solution of tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate (0.3 g, 1 mmol) in ethanol (5 mL) was added platinum dioxide (0.05 g) and the mixture was pressurized without hydrogen for 2 hours under magnetic stirring. After the catalyst was filtered off through diatomaceous earth, the filtrate was evaporated to dryness. 0.27 g of a colorless oil was obtained.

PATENT CLAIMS

Claims (7)

A process for the preparation of (47 R, 67 R) tert-butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula I (i). characterized in that: a) (47 R, 65) tert-Butyl (6-formyl-2,2-dimethyl [1,3] dioxan-4-yl) acetate of formula V (V), by reaction with nitromethane in a suitable solvent, preferably in a lower alcohol, under catalysis of suitable catalysts, preferably potassium fluoride, under suitable conditions, preferably at room temperature, affords tert-butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxane- 4yl] acetate of formula VI b) wherein tert-butyl [6- (1-hydroxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula VI by reaction with the corresponding carboxylic acid anhydride affords tert-butyl [6] - (1-acyloxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula VII, wherein R is unsubstituted or substituted C 1 -C 5 alkyl; c) tert-butyl [6- (1-acyloxy-2-nitroethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula VH by reduction with sodium borohydride in a suitable medium, e.g. aqueous, aqueous alcohol, or alcohol, to give tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate of formula VHI (VIII), d) wherein the tert-butyl [2,2-dimethyl-6- (2-nitroethyl) [1,3] dioxan-4-yl] acetate of formula VIII is hydrogenated to catalyze hydrogenation catalysts such as Raney nickel, palladium, or platinum in suitable solvents, for example lower alcohols, to (47 R, 6 R) tert-butyl [6- (2-aminoethyl) -2,2-dimethyl [1,3] dioxan-4-yl] acetate of formula I. 2. The process according to claim 1, wherein acetic anhydride is used as the acylating agent in step b). Process according to claim 1, characterized in that propionic anhydride is used as the acylating agents in step b). The process according to claim 1, characterized in that butyric anhydride is used as the acylating agent in step b). 5. A compound of formula VI A compound of formula VII wherein R is unsubstituted or substituted C 1 -C 5 alkyl. A compound of formula VIII