KR101073978B1 - Manufacturing Process of Optically Active [6-2-(Aminoethyl)-(4R,6R)-2,2-dimethyl-[1,3]dioxan-4-yl]acetic acid Derivative as Intermediate of Atorvastatin - Google Patents

Abstract

The present invention relates to optically active [6- (2-aminoethyl)-of formula (4), which is known as a useful key intermediate of Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA). A method for producing a (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative. In the present invention, the alcohol compound, which is a conventional starting material, undergoes two steps when converted into a nitrile compound or a nitro compound, requires a cryogenic reaction, and shows a low yield of about 50 to 70%. It is also very high at 90%. In addition, the conventional method for preparing the final compound from the nitrile compound or nitro compound has the disadvantage of using a high-pressure hydrogenation reaction or an explosive reducing agent, the present invention is economical and workability to safety by using easy and inexpensive reactants It has the advantage of significantly improved.

[Formula 4]

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

Atorvastatin, Intermediates

Description

Method for preparing optically active [6-2- (aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivatives as intermediates of atorvastatin {Manufacturing Process of Optically Active [6-2- (Aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid Derivative as Intermediate of Atorvastatin}

The present invention relates to optically active [6- (2-aminoethyl)-of formula (4), which is known as a useful key intermediate of Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA). (4R, 6R) -2,2-Dimethyl- [1,3] dioxan-4-yl] acetic acid derivative was prepared by the following formula (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) of the formula (2) from [1,3] dioxan-4-yl) acetic acid derivative An acetic acid derivative or a (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative represented by the following Chemical Formula 3 is used.

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

Optically active [6- (2-aminoethyl)-(4R, 6R), known as a useful key intermediate of Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) Conventional preparation methods for the -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivatives are as shown in Schemes 1 and 2. Specifically, from the (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 1 obtained by a known method in two steps (6-Cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Formula 2 or (3) in a yield of approximately 50 to 70% Obtain a 6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative and then hydrogenate it under high pressure in the presence of Ni or Pd, which is known to have a strong reducing effect. [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxane-4 of formula 4 by reaction or by using lithium aluminum hydride (LiAlH ₄ .LAH) A method for obtaining a -yl] acetic acid derivative has been known.

However, the preparation methods shown in Scheme 1 and Scheme 2 may be a (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl-acetic acid derivative of Formula 2 or In order to obtain the (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of 3, the reaction proceeds in a relatively low yield in two steps. However, there is a disadvantage of requiring an ultra low temperature reaction near −80 ° C. Also, in order to obtain an amine compound of formula 4 from a nitrile compound of formula 2 or a nitro compound of formula 3, a high-pressure hydrogenation reaction or an explosive compound may be used. By using LAH as a reducing agent, which is not easily available, there is a problem in that it is not an effective method for commercial production because it requires a special reaction device or causes operational difficulties when applied to industrial production.

The present invention has been made to solve the above problems, the formula [4] which is a useful key intermediate of Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) [6 -(2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivatives can be prepared in high yields by a simple method without special equipment It aims to provide a manufacturing method.

In addition, the present invention provides a chemical formula of the (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the formula (1) without undergoing a cryogenic difficult reaction. (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of 2 or (6-nitroethyl- (4R, 6R) of formula 3 Another object is to provide a process for producing -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivatives in high yield.

In addition, the present invention provides a (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxane-4 of formula 2 without undergoing a high pressure reaction or a difficult reaction using an explosive reducing agent. -Yl) acetic acid derivative or (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 3 to [6- (2 It is another object of the present invention to provide a process for producing a -aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative in high yield. .

The preparation method of the [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of the formula 4 of the present invention is as described above. To achieve the same purpose,

(A) The triphenylphosphine (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the following formula (1) in an organic solvent (triphenylphosphine.PPh ₃ ), 2,3-dichloro-5,6-dicyano-parabenzoquinone (2,3-dichloro-5,6-dicyano-p-benzoquinone.DDQ) and tetrabutylammonium cyanide (tetrabutyl ammonium cyanide) to give a (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the formula (2), or PPh ₃ , DDQ and nitromethane sodium salt (NaCH ₂ NO ₂ ) to react with (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) Obtaining an acetic acid derivative; And

(B) (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula (2) or (6-nitroethyl of formula (3) -(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative is reacted with a hydrate of iodine, a chloride of Ni or Co, and NaBH _{4 in an} organic solvent to Obtaining a [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of formula 4

Characterized in that it includes:

[Formula 1]

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

[Formula 2]

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

(3)

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

[Formula 4]

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

On the other hand, the preparation method of the (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Chemical Formula 2 of the present invention is (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative was converted into triphenylphosphine (triphenylphosphine.PPh ₃ ) in an organic solvent, Obtained by reaction with 2,3-dichloro-5,6-dicyano-parabenzoquinone (2,3-dichloro-5,6-dicyano-p-benzoquinone.DDQ) and tetrabutyl ammonium cyanide Characterized in that.

Meanwhile, the preparation method of (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Chemical Formula 3 of the present invention is represented by The 6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative is reacted with PPh ₃ , DDQ and nitromethane sodium salt in an organic solvent It is characterized by obtaining.

On the other hand, the production method of the [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of Chemical Formula 4 of the present invention is (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 2 or (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative obtained by reacting with a hydrate of iodine, a chloride of Ni or Co, and NaBH ₄ in an organic solvent It is done.

Further, (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Chemical Formula 2 or (6-nitroethyl- of Chemical Formula 3) Organic solvents used in the preparation of (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivatives include acetonitrile, 1,4-dioxane, dimethylformamide, toluene, 1 Preference is given to those selected from the group consisting of, 2-dichloroethane and mixtures thereof.

In addition, the Ni or Co used in the preparation of [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of Chemical Formula 4 The hydrate of the chloride of is preferably NiCl ₂ · 6H ₂ O or CoCl ₂ · 6H ₂ O.

Further, (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Chemical Formula 2 or (6-nitroethyl- of Chemical Formula 3) [6- (2-aminoethyl)-(4R, 6R) -2,2 of formula (4) from (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative The organic solvent used in the preparation of the -dimethyl- [1,3] dioxan-4-yl] acetic acid derivative is preferably tetrahydrofuran or methanol.

Further, (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Chemical Formula 2 or (6-nitroethyl- of Chemical Formula 3) The reaction temperature in preparing the (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative may be room temperature to reflux temperature, more preferably 40 to 55 ° C.

Further, (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Chemical Formula 2 or (6-nitroethyl- of Chemical Formula 3) [6- (2-aminoethyl)-(4R, 6R) -2,2 of formula (4) from (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative The reaction temperature in preparing the -dimethyl- [1,3] dioxan-4-yl] acetic acid derivative may be from room temperature to reflux temperature, more preferably reflux temperature.

The present invention relates to [6- (2-aminoethyl)-(4R, 6R) of Formula 4, which is a useful key intermediate of Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA). Solving the problems of the conventional method for preparing a) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative, there is an advantage that it can be manufactured in a high yield even by a simple method without a special device. .

Specifically, the conventional method is a (6-cyano of formula 2 from (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 1 Methyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative or (6-nitroethyl- (4R, 6R) -2,2-dimethyl- of formula 3 In the preparation of the [1,3] dioxan-4-yl) acetic acid derivative, not only two steps were required but the cryogenic reaction of about 80 ° C. was required, and the yield was as low as 50 to 70%. And the reaction is made even at room temperature, the yield is up to 90% and the efficiency is very high.

Further, (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula (2) or (6-nitroethyl- (4R) of formula (3) , 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- of formula (4) Conventional methods for preparing [1,3] dioxan-4-yl] acetic acid derivatives have disadvantages in that economic efficiency, workability and safety are remarkably deteriorated by the use of high-pressure hydrogenation reactions or explosive reducing agents, but the present invention is easy to handle. By using low-cost reactants, there is an advantage that the economics and workability to safety is significantly improved.

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings. In addition, in the following description there are shown a number of specific details such as specific components, which are provided only to help a more comprehensive understanding of the present invention, it is common in the art that the present invention may be practiced without these specific details. It is self-evident to those who have knowledge of the world. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

First, the term 'reflux temperature' as used herein refers to the boiling point of the solvent used.

The present invention relates to [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- of formula 4, which is a useful key intermediate of atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme. An improved process for producing [1,3] dioxan-4-yl] acetic acid derivatives economically and simply.

To this end, the present invention provides (A) a (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of Formula 1 in an organic solvent, Triphenylphosphine (PPh ₃ ), 2,3-dichloro-5,6-dicyano-parabenzoquinone (2,3-dichloro-5,6-dicyano-p-benzoquinone.DDQ) and tetrabutylammonium Reacted with cyanide (tetrabutyl ammonium cyanide) to obtain a (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula (2), or Reacting with PPh ₃ , DDQ and nitromethane sodium salt to obtain a (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 3 step; And (B) a (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 2 or (6-nitroethyl- of formula 3 The (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative is reacted with a hydrate of iodine, a chloride of Ni or Co, and NaBH _{4 in an} organic solvent to give formula (4). It consists of two steps of obtaining a [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of.

First, step (A) may be represented by the following Scheme 3 or Scheme 4.

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

R ₁ in the above scheme represents hydrogen, alkyl, or alkylaryl.

Triphenylphosphine (triphenylphosphine. PPh ₃ ), 2,3-dichloro-5,6-dicyano-parabenzoquinone (2), which are readily available from the alcohol compound of Formula 1, which is a starting material in Scheme 3 or 4 In the presence of, 3-dichloro-5,6-dicyano-p-benzoquinone.DDQ), a combination of tetrabutyl ammonium cyanide or nitromethane sodium salt is a common organic solvent acetonitrile genus The nitrile compound of Formula 2 or the nitro compound of Formula 3 is obtained in high yield in one step. At this time, the molar ratio of the alcohol compound of Formula 1: PPh ₃ : DDQ: tetrabutylammonium cyanide or nitromethane sodium salt is preferably 1: 1 to 3: 1 to 3: 1. In addition, the reaction temperature is effective from room temperature to reflux temperature, and shows the best yield, especially at 40 to 55 ℃. Acetonitrile is effective as a solvent, and 1,4-dioxane, dimethylformamide (DMF), toluene and 1,2-dichloroethane, which are known as alternative solvents of conventional acetonitrile, can be used. desirable.

The present invention also includes the steps of Scheme 5 to obtain an amine compound of formula 4 from a nitrile compound of formula 2 or a nitro compound of formula 3.

Sodium borohydride (NaBH ₄ ), which is relatively easy to handle and inexpensive, is replaced with other inorganic reducing agents instead of the high-pressure hydrogenation reaction or the industrially difficult reducing agent LAH, which has been conventionally performed to obtain the amine compound represented by the formula ( ₄ ). It is economical and workability and safety by further reacting with the high yield of [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxane-4 -Yl] acetic acid derivatives can be obtained.

As the inorganic reducing agent, a hydrate of iodine (I ₂ ) or a chloride of Ni or Co may be used, and the hydrate of the chloride of the metal may be nickel chloride hexahydrate (NiCl ₂ · 6H ₂ O), or cobalt chloride hexahydrate ( CoCl ₂ .6H ₂ O) is more preferred. At this time, the molar ratio of the nitrile compound of formula (2) or the nitro compound of formula (3): hydrate of iodine or metal chloride: sodium borohydride is 1: 1 to 2: 2-3. And, the solvent used here is mainly tetrahydrofuran (THF) or methanol, the reaction temperature is effective from room temperature to reflux temperature, but most preferably reacted at reflux temperature.

The advantage of the process according to the invention is that the (6-cyanomethyl- (4R, 6R)-of the conventional formula (II), which yielded only 50 to 70% of yield, using the cryogenic reaction near -80 ° C in the first two steps. 2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative or (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxane- The production of 4-yl) acetic acid derivatives can be carried out in a high yield of 90% with only one step. Second, it is a relatively inexpensive and effective reduction method without using an explosive reducing agent or a high-pressure hydrogenation reaction. [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivatives can be obtained.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited only to the following Examples.

Example

Example  1-1: (6- Cyanomethyl -(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) Acetic Acid -t-butyl Easter  Produce

In a 250 mL round flask at room temperature, 2,3-dichloro-5,6-dicyano-parabenzoquinone (40 mmol, 10.08 g) and triphenylphosphine (40 mmol, 10.50 g) were acetonitrile (100 mL) After dissolving in, tetrabutylammonium cyanide (40 mmol, 10.72 g) was added and stirred for 5 minutes. 5.2 g (20 mmol) of (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid-t-butyl ester were added and the mixture was heated at 50 deg. Stir for 8 hours. After completion of the reaction, acetonitrile was removed, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and then purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to give (6-cyanomethyl- (4R, 6R) -2, 4.8 g of 2-dimethyl- [1,3] dioxan-4-yl) acetic acid-t-butyl ester (Formula 5) were obtained (yield: 90%).

¹ H NMR (300 MHz, CDCl ₃ ) 4.20-4.30 (m, 1 H), 4.11-4.16 (m, 1 H), 2.40-2.50 (m, 3 H), 2.34 (dd, 1 H, J = 15.6 , 6.00 Hz), 1.75 (dt, 1 H, J = 13.2, 2.24 Hz), 1.55 (s, 3 H), 1.46 (s, 9 H), 1.38 (s, 3 H).

Example  1-2: t-butyl-2-[(4R, 6R) -2,2-dimethyl-6- (2- Nitroethyl ) -1,3-dioxan-4-yl] acetate

Nitromethane sodium salt (NaCH ₂ NO ₂ , 3.32 g, 40 mmol, J. Chem. Soc. Perkin Trans II, 1988, 725 instead of tetrabutylammonium cyanide (40 mmol, 10.72 g) in Example 1-1 T-butyl-2-[(4R, 6R) -2,2-dimethyl-6- (2-nitroethyl) -1,3-dioxan-4-yl in the same manner except that ] 11.02 g of acetate (Formula 6) were obtained (yield: 91%).

¹ H NMR (300 MHz, CDCl ₃ ) 4.54 (ddd, J = 6.5, 8.1, 13.4 Hz, 1 H), 4.45 (ddd, J = 5.7, 7.0, 13.4 Hz, 1 H), 4.25 (dddd, J = 2.5, 6.1, 7.0, 11.4 Hz, 2 H), 3.96 (dddd, J = 2.5, 3.3, 9.1, 11.4 Hz, 1 H), 2.30 (dd, J = 6.1, 15.2 Hz, 1 H), 2.42 (dd , J = 7.0, 15.2 Hz, 1 H), 2.22 (dddd, J = 3.3, 6.5, 7.1, 14.6 Hz, 1 H), 2.02 (dddd, J = 5.7, 8.1, 9.1, 14.6 Hz, 1 H), 1.61 (dt, J = 2.5, 12.7 Hz, 1 H), 1.44 (s, 9 H), 1.42 (d, J = 0.7 Hz, 3 H), 1.34 (d, J = 0.7 Hz, 3 H), 1.22 (dt, J = 11.4, 12.7 Hz, 1 H).

Example  2-1: [6- (2- Aminoethyl )-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl]- Acetic Acid -t-butyl Easter  Produce ( NaBH ₄ , Yod  use)

(6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxane-4- obtained in Example 1-1 in a 1000 mL round flask cooled to 0 ° C. under nitrogen. (I) 300 ml of tetrahydrofuran was added to 27 g (100 mmol) of acetic acid-t-butyl ester and sodium borohydride (8.8 g, 230 mol), followed by stirring for 10 minutes. Iodine (25.4 g, 100 mmol) was dissolved in 200 mL of tetrahydrofuran and slowly added dropwise to the solution containing the starting material. After stirring for 20 minutes at the same temperature, the temperature was raised to reflux for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, 200 ml of water was added thereto, and the mixture was refluxed for 1 hour. After cooling to room temperature, sodium hydroxide 10 g was added thereto, stirred for 30 minutes, and extracted with 300 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and purified by column chromatography (methylene chloride: methanol = 7: 1) using pure [6- (2-aminoethyl)-(4R, 6R) -2. 18.0 g of, 2-dimethyl- [1,3] dioxan-4-yl] acetic acid-t-butyl ester (Formula 7) was obtained (yield: 66%).

¹ H NMR (300 MHz, CDCl ₃ ) 4.10-4.15 (m, 1 H), 3.80-3.84 (m, 1 H), 2.65 (t, 2 H, J = 6.6 Hz), 2.28 (dd, 1 H, J = 15.1, 7.00 Hz), 2.14 (dd, 1 H, J = 15.1, 7.00 Hz), 1.34-1.45 (m, 3 H), 1.28-1,31 (m, 12 H), 1.21 (s, 3 H), 1.08-1.16 (m, 1H)

Example  2-2: [6- (2- Aminoethyl )-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] Acetic Acid Preparation of t-butyl ester ( NaBH ₄ , NiCl ₂ 6 H ₂ O  use)

In a 100 ml round flask cooled to 0 ° C. under nitrogen, (6-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxane-4- obtained in Example 1-1 I) 30 ml of methanol was added to 2.7 g (10 mmol) of acetic acid-t-butyl ester and nickel chloride hexahydrate (2.37 g, 10 mol), followed by stirring for 10 minutes. Sodium borohydride (0.88 g, 23 mol) was added slowly to the solution containing the starting material. After stirring for 20 minutes at the same temperature, the temperature was raised to reflux for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, 200 ml of water was added thereto, and the mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was filtered through Celite and extracted twice with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and purified by column chromatography (methylene chloride: methanol = 7: 1) using pure [6- (2-aminoethyl)-(4R, 6R) -2. 1.64 g of, 2-dimethyl- [1,3] dioxan-4-yl] acetic acid-t-butyl ester (Formula 7) were obtained (yield: 60%).

¹ H NMR (300 MHz, CDCl ₃ ) 4.10-4.15 (m, 1 H), 3.80-3.84 (m, 1 H), 2.65 (t, 2 H, J = 6.6 Hz), 2.28 (dd, 1 H, J = 15.1, 7.00 Hz), 2.14 (dd, 1 H, J = 15.1, 7.00 Hz), 1.34-1.45 (m, 3 H), 1.28-1,31 (m, 12 H), 1.21 (s, 3 H), 1.08-1.16 (m, 1H)

Example  2-3: [6- (2- Aminoethyl )-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] Acetic Acid Preparation of t-butyl ester ( NaBH ₄ , CoCl ₂ 6 H ₂ O  use)

Pure [6- (2-aminoethyl)-(4R) in the same manner using cobaltchloride hexahydrate (2.37 g, 10 mol) instead of nickel chloride hexahydrate (2.37 g, 10 mol) in Example 2-2 above 1.50 g of, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid-t-butyl ester (Formula 7) was obtained (yield: 55%).

¹ H NMR (300 MHz, CDCl ₃ ) 4.10-4.15 (m, 1 H), 3.80-3.84 (m, 1 H), 2.65 (t, 2 H, J = 6.6 Hz), 2.28 (dd, 1 H, J = 15.1, 7.00 Hz), 2.14 (dd, 1 H, J = 15.1, 7.00 Hz), 1.34-1.45 (m, 3 H), 1.28-1,31 (m, 12 H), 1.21 (s, 3 H), 1.08-1.16 (m, 1H)

Example  2-4: [6- (2- Aminoethyl )-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] Acetic Acid preparation of -t-butyl ester (nitro compound, NaBH4 , NiCl ₂ 6 H ₂ O  use)

2.7 g (10-cyanomethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid-t-butyl ester in Example 2-2 above mmol) instead of t-butyl-2-[(4R, 6R) -2,2-dimethyl-6- (2-nitroethyl) -1,3-dioxan-4-yl obtained in Example 1-2 ] Pure [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxane-4 in the same manner except for using acetate (3.03 g, 10 mol) 1.41 g of -yl] acetic acid-t-butyl ester (Formula 7) were obtained (yield: 50%).

¹ H NMR (300 MHz, CDCl ₃ ) 4.10-4.15 (m, 1 H), 3.80-3.84 (m, 1 H), 2.65 (t, 2 H, J = 6.6 Hz), 2.28 (dd, 1 H, J = 15.1, 7.00 Hz), 2.14 (dd, 1 H, J = 15.1, 7.00 Hz), 1.34-1.45 (m, 3 H), 1.28-1,31 (m, 12 H), 1.21 (s, 3 H), 1.08-1.16 (m, 1H).

Although the above has been illustrated and described with respect to preferred embodiments of the present invention, the present invention is not limited to the specific embodiments described above, those skilled in the art without departing from the gist of the present invention various It is a matter of course that the modification is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.

Claims (10)

(A) The triphenylphosphine (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the following formula (1) in an organic solvent (triphenylphosphine.PPh ₃ ), 2,3-dichloro-5,6-dicyano-parabenzoquinone (2,3-dichloro-5,6-dicyano-p-benzoquinone.DDQ) and nitromethane sodium salt (NaCH ₂ NO ₂ ) to obtain a (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of formula 3; And (B) (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative represented by the following formula (3) in iodine, Ni or Co A hydrate of a chloride of and reacted with NaBH ₄ [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid of the formula Obtaining a derivative Method for preparing a [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of Formula 4 comprising: [Formula 1]

R ₁ in the above scheme represents hydrogen or alkyl. (3)

R ₁ in the above scheme represents hydrogen or alkyl. [Formula 4]

R ₁ in the above scheme represents hydrogen or alkyl. delete Obtained by reacting (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the formula (3) with iodine and NaBH _{4 in an} organic solvent: A process for preparing [6- (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative of the general formula (4): (3)

R ₁ in the above scheme represents hydrogen or alkyl. [Formula 4]

R ₁ in the above scheme represents hydrogen or alkyl. The method according to claim 1, The hydrate of the chloride of Ni or Co is NiCl ₂ .6H ₂ O or CoCl ₂ .6H ₂ O. [6- (2-aminoethyl)-(4R, 6R) -2,2 Process for the preparation of -dimethyl- [1,3] dioxan-4-yl] acetic acid derivative. The method according to claim 1, The organic solvent of step (A) is selected from the group consisting of acetonitrile, 1,4-dioxane, dimethylformamide, toluene, 1,2-dichloroethane, and mixtures thereof. Process for the preparation of (2-aminoethyl)-(4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl] acetic acid derivative. The method according to claim 1 or 3, [6- (2-aminoethyl)-(4R, 6R) -2,2 of formula 4, wherein the organic solvent of step (B) of claim 1 or the organic solvent of claim 3 is tetrahydrofuran or methanol. Process for the preparation of -dimethyl- [1,3] dioxan-4-yl] acetic acid derivative. delete delete (6-hydroxymethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the following formula (1) was dissolved in organic solvents with PPh ₃ , DDQ and nitromethane. A process for preparing (6-nitroethyl- (4R, 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative of the formula (3), which is obtained by reacting with a sodium salt. : [Formula 1]

R ₁ in the above scheme represents hydrogen or alkyl. (3)

R ₁ in the above scheme represents hydrogen or alkyl. The method according to claim 9, The organic solvent is selected from the group consisting of acetonitrile, 1,4-dioxane, dimethylformamide, toluene, 1,2-dichloroethane, and mixtures thereof of (6-nitroethyl- (4R) , 6R) -2,2-dimethyl- [1,3] dioxan-4-yl) acetic acid derivative.