KR100980379B1 - Process for the preparation of optically active 5-hydroxy-3-oxoheptanoate derivatives - Google Patents

Abstract

The present invention relates to a method for preparing a 5-hydroxy-3-oxoheptanoate derivative having optical activity useful for the preparation of a statin-based compound, wherein a variety of statins are prepared by using a ring opening reaction and a blaze reaction selective from an epoxy compound. The present invention relates to a method for manufacturing a core precursor.

Manufacturing method, statins, blaze reaction, ring opening reaction

Description

Process for the preparation of optically active 5-hydroxy-3-oxoheptanoate derivatives}

The present invention relates to a method for preparing a 5-hydroxy-3-oxoheptanoate derivative having optical activity useful for preparing a statin-based compound.

Cerivastatin (US Pat. No. 5,177,080), Fluvastatin (US Pat. No. 5,345,772), Pitavastatin (US Pat. No. 5,856,336), Rosevastatin (Rosuvastatin) Patent No. 5,260,440), Lovastatin (US Pat. No. 4,231,938), Simvastatin (US Pat. No. 4,444,784) and the like are well known, and various studies on their preparation have been continued.

Among the statin drugs, atorvastatin is particularly well known for treating hyperlipidemia due to its excellent HMG-Co A reductase inhibitory activity.

Many studies have been conducted on the preparation of atorvastatin (International Patent Publication No. WO98 / 04543, U.S. Patent 5,124,482, U.S. Patent 5,216,174, U.S. Patent 5,273,995). Scheme 1 below is a general method for preparing atorvastatin, using a (S) -3-hydroxy-butylactone represented by the following formula (I) as a starting material, a decyclization reaction, a cyanide introduction reaction, and t-butyl The target atorvastatin was prepared using an optically active intermediate represented by the following Formula V by performing a group introduction reaction.

<Scheme 1>

However, in the conventional method according to Scheme 1, the decyclization reaction yields a decyclization compound at a low yield of 41.5% in the presence of acetic acid, ethanol and hydrogen bromide, and the reaction of introducing a t-butyl group is used industrially. The following unsuitable process, ie t-butylacetate, is carried out for at least 20 hours at cryogenic conditions of -78 ° C using lithium diisopropylamide (LDA) base. Therefore, according to the conventional method according to Scheme 1, the production conditions are made so harsh that they are not suitable for industrial use, the production yield is low, and the purity of the targets is due to the production of a large amount of isomers having a stereoalignment different from the final target. It is pointed out that there is a problem such as lowering.

In addition, in order to synthesize an amine compound represented by the formula (V), in the preparation method represented by the following Reaction Scheme 2, the conversion from the hydroxy compound of the formula (VI) to a series of leaving groups proceeds through the intermediates represented by the formulas (VII) and (VIII) (European Patent No. 414,206). , International Patent Publication No. WO03 / 004459).

<Scheme 2>

However, in order to synthesize hydroxy compound VI, commercially unsuitable manufacturing processes such as ultra-low temperature reaction at -80 ° C or high pressure hydrogenation reaction are used (Japanese Patent No. 1992-173767, US Patent No. 5,155,251, Japanese Patent No. 1992-069355). In addition, there is a method of using microbial strains from inexpensive raw materials without using the harsh conditions as described above, which has limitations in the purification and synthesis of various derivatives because microbial strains are used in the preparation of the optically active compound, which is a core process. There are still significant restrictions on industrialization.

Therefore, there has been a need for a new method of production which is industrially available and obtains the desired compound in high purity and yield without generation of impurities.

Accordingly, the present inventors have studied the method for preparing a 5-hydroxy-3-oxoheptanoate derivative having optical activity using a commercially available material as a starting material to improve the problems of the prior art mentioned above. Was completed.

OBJECT OF THE INVENTION The present invention relates to a process for the preparation of 5-hydroxy-3-oxoheptanoate derivatives having optical activity.

Another object of the present invention relates to a novel compound used in the above production method.

In one embodiment, the present invention provides a method for preparing a 5-hydroxy-3-oxoheptanoate derivative having optical activity represented by the following Chemical Formulas 1a to 1c.

<Formula 1a>

<Formula 1b>

<Formula 1c>

At this time

R ¹ is hydrogen, C1 to C10 straight or branched alkyl or C1 to C10 alkylaryl, preferably t-butyl,

R ³ is azide or phthalimide,

Ar is phenyl unsubstituted or substituted with one group selected from the group consisting of C1 to C10 alkyl, C1 to C10 alkoxy and halogen.

In a preferred embodiment, formula (1a) of the present invention,

1) preparing an intermediate compound of Formula 5 through substitution reaction with cyanide without purification after the ring opening reaction of the compound of Formula 2 and nitromethane sodium salt,

Preparing an intermediate compound of Formula 5 through substitution reaction with nitromethane sodium salt without purification after the ring opening reaction of the compound of Formula 3 and cyanide, or

Preparing an intermediate of Chemical Formula 6 through the ring-opening reaction of the compound of Chemical Formula 4 and the nitromethane sodium salt; And

2) the intermediate of formula 5 or 6 prepared may be prepared by a step of reacting the blaze with the formula (7) in the presence of zinc.

<Scheme 3>

At this time,

R ¹ and R ² are hydrogen, C1 to C10 straight or branched chain alkyl or C1 to C10 alkylaryl,

X is a halogen atom.

As a specific embodiment, step 1) in Scheme 3 is a nitromethane sodium salt obtained in the presence of a base using (R) -Epichlorohydrin (Formula 2) having commercially available optical activity as a starting material (J) Chem. Soc. Perkin Trans II, 1988, 725-730), and then ring reaction with cyanide without purification.

Cyanide is first reacted with (S) -Epichlorohydrin (Formula 3) as a starting material, followed by ring opening, followed by substitution with nitromethane sodium salt without purification to synthesize formula (5). can do.

As cyanide used in the reaction, sodium cyanide, potassium cyanide or quaternary alkylammonium cyanide of C1 to C4 may be used. Preferably sodium cyanide or potassium cyanide can be used. The reaction solvent is preferably an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane and dimethyl sulfoxide (DMSO). The reaction temperature is carried out in the range of room temperature to reflux temperature, preferably at 45 ° C. to reflux temperature, more preferably at a temperature of 60 ° C.

Alternatively, the starting material may be an optically active epoxide compound represented by Chemical Formula 4, which is commercially available or easily obtained by the preparation method described in the literature (JACS, 2000, 1235-1236, Tetrahydron letters, 1986, 27, 5791). The intermediate compound of Chemical Formula 6 may be synthesized through a ring opening reaction with the nitromethane sodium salt. The solvent usable in the ring opening reaction is an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane, dimethylsulfoxide (DMSO) and tetrahydrofuran (THF). Is preferably. The reaction temperature is carried out in the room temperature to reflux temperature range, preferably at a temperature of 40 ℃ to 80 ℃, more preferably at 70 ℃.

Step 2) is to protect the hydroxy group of the intermediate of formula 5 or 6 prepared in step 1) as described above, and then performs a blaze reaction (synthesis 2004, 16, 2629-2632) with the formula (7) in the presence of activated zinc Formula 1a may be synthesized.

The hydroxy protecting group includes a SiR ⁴ R ⁵ R ⁶ group, ethoxyethyl, and tetrahydropyranyl, wherein R ⁴ is hydrogen, saturated alkyl of C1 to C4 or unsaturated alkyl of C2 to C4, and R ⁵ And R ⁶ represents hydrogen, saturated alkyl of C1 to C6, unsaturated alkyl of C2 to C6, or aromatic of C6 to C12, respectively. Preferred examples of the SiR ⁴ R ⁵ R ⁶ group include trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS) or t-butyldiphenylsilyl (TBDPS). The most preferred hydroxy protecting group in terms of purity and yield is trimethylsilyl.

As the zinc, zinc dust or zinc powder may be used, and zinc powder is preferably used. Zinc is activated before reaction and used as an organic acid or derivative thereof to activate R ⁷ CO ₂ H, R ⁷ SO ₃ H, R ⁷ CO ₂ TMS, R ⁷ SO ₃ TMS or (R ⁷ SO ₂ ) ₂ NH Wherein R ⁷ is hydrogen, C1 to C6 saturated alkyl, C2 to C6 unsaturated alkyl, halogen substituted C1 to C6 saturated alkyl, halogen substituted C2 to C6 unsaturated alkyl, C6 to C12 Aromatic or C6 to C12 substituted with halogen. Preferably methanesulfonic acid is used.

In another preferred embodiment of the general formula 1b of the present invention,

1) preparing an intermediate compound of Formula 9 through ring opening reaction with cyanide without purification after substitution reaction of Compound 8 with nucleophile; And

2) it can be prepared by the step of reacting the prepared intermediate of formula 9 with the formula (7) in the presence of zinc.

<Scheme 4>

At this time

R ¹ is hydrogen, C1 to C10 straight or branched alkyl or C1 to C10 alkylaryl,

R ³ is azide or phthalimide,

X is a halogen atom.

Step 1) in Reaction Scheme 4 is carried out by ring opening reaction with cyanide without purification after substitution reaction with nucleophile using Formula 8 as a starting material which can be synthesized by a known method (Helvetica Chemica Acta 1981, 64, 1467-1487). Formula 9, an intermediate compound, may be prepared.

The nucleophile represented by R ³ -M in the substitution reaction is azidotrimethylsilane, sodium azide, zinc azide, trimethyltin azide, tributyltin azide, phthalimide potassium, phthalimide sodium or phthalimide triethyl Amine salts may be used, preferably sodium azide or phthalimide potassium. The reaction solvent is preferably an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane and dimethyl sulfoxide (DMSO). The reaction temperature is carried out in the room temperature to reflux temperature range, preferably at a temperature of 35 ℃ to 70 ℃, more preferably at 60 ℃.

As cyanide used in the reaction, sodium cyanide, potassium cyanide or quaternary alkylammonium cyanide of C1 to C4 may be used. Preferably, sodium cyanide or potassium cyanide is used.

Step 2) may include formula (Ib) comprising the step of reacting the formula (7) and the blaze in the presence of the intermediate of formula (9) prepared in step 1) in the presence of zinc. It is the same as step 2) of the preparation method of Chemical Formula 1a.

In another preferred embodiment, Formula 1c of the present invention,

 1) preparing an intermediate of Chemical Formula 13 by ring-opening reaction with cyanide without purifying the compound of Chemical Formula 10 with Chemical Formula 11 or

Preparing an intermediate of Chemical Formula 13 by substituting the compound of Chemical Formula 3 with cyanide without purification after the ring opening reaction with Chemical Formula 12; And

2) The intermediate of Formula 13 may be prepared by the step of subjecting the compound of Formula 7 to the blaze reaction in the presence of zinc.

Scheme 5

At this time,

R ¹ is hydrogen, C1 to C10 straight or branched alkyl or C1 to C10 alkylaryl,

Ar is phenyl unsubstituted or substituted with one group selected from the group consisting of C1 to C10 alkyl, C1 to C10 alkoxy and halogen,

X is a halogen atom.

Step 1) in Scheme 5 may prepare an intermediate substance 13 by reacting commercially available formula 10 with formula 11 under basic conditions, and then performing ring opening reaction with cyanide without purification. At this time, the benzyl halide derivative of Formula 11 may be used, such as benzyl bromide, benzyl chloride or 4-methyl benzyl bromide, but is not limited thereto. The reaction solvent is preferably an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane and dimethyl sulfoxide (DMSO). The reaction temperature may be performed at room temperature to reflux temperature, preferably at a temperature of 70 ℃.

Alternatively, the reaction of Chemical Formula 3 with Chemical Formula 12 may be carried out by a known technique (Tetrahydron Asymmetry 2001, 12, 2543-2549, Tetrahedron Lett. 2004, 45, 3689-3691), without the purification process after the selective ring opening reaction under basic conditions. Substituted with nitrile to prepare the intermediate compound of formula (13).

In step 2), the compound of formula 13, which is the intermediate obtained in step 1), in the presence of zinc, may be prepared by chemically formulating the compound 1c. It is the same as step 2) of the preparation method of Chemical Formula 1a.

The 5-hydroxy-3-oxoheptanoate derivative having the optical activity prepared as described above may be easily converted into a core precursor of a statin-based drug through a conventional protection and deprotection process as shown in Scheme 6 below.

<Scheme 6>

When R ³ of Formula 1b is phthalimide, the carbonyl reduction and cyclization reaction are performed according to a known method, and then Chemical Formula 14 is subjected to an amine conversion reaction of a phthalimide group using a commonly used hydrazine. It can manufacture.

In addition, when R ³ of Formula 1b is an azide, the carbonyl reduction and the cyclization reaction are performed according to a known method, and then an amine conversion method of an azide substituent that is commonly used (for example, using Pd / C The compound of 14 can be manufactured using a hydrogenation reaction or an amine conversion reaction using triphenylphosphine, etc.).

According to the production process according to the invention, selective ring opening reaction is possible from the optically active epoxy compound which is commercially available or can be prepared by step 1), and the core intermediate compound is prepared without purification process such as column chromatography or recrystallization. The advantage is that you can.

It is also possible to prepare a 5-hydroxy-3-oxoheptanoate derivative having optical activity through the blaze reaction carried out in the presence of zinc without using a strong base such as LDA by step 2). The production method of the present invention has the advantage that it is easy for mass production and can be manufactured in high yield.

In another embodiment the invention also provides novel compounds represented by the formulas 5, 9-a, 9-b, 1-b-1 and 1-b-2.

<Formula 5>

<Formula 9-a>

<Formula 9-b>

<Formula 1-b-1>

<Formula 1-b-2>

At this time,

R ⁸ is methyl, ethyl, t-butyl and benzyl.

The novel compounds have the advantage that they can be usefully used in the preparation of key precursors of statin drugs.

The following examples illustrate the invention in more detail. These examples are only for illustrating the present invention, but the scope of the present invention is not limited to the following examples.

Preparation Example 1 Preparation of (R) -3-hydroxy-5-nitropentanenitrile-1

In a 250 ml round flask at room temperature, (R) -2- (chloromethyl) oxylane (18 g, 200 mmol) was dissolved in 100 ml of DMF, followed by adding nitromethane sodium salt (17.6 g, 220 mmol) and vigorously for 3 hours. After stirring, the temperature was raised and stirred at 60 ° C. for 2 hours. Potassium cyanide (14.3 g, 220 mmol) was dissolved in this solution in 20 ml of water, and then slowly added thereto, and the temperature was raised and stirred at 45 to 50 ° C. for 6 hours. After completion of the reaction, 300 ml of water and 300 ml of ethyl acetate were added and extracted. The organic layer was washed twice with 200 ml of water. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and the next reaction was carried out without purification. Yield: 78%

¹ H NMR (300 MHz, CDCl ₃ ): 4.45 (t, 2H, J = 7.2 Hz), 3.92 (m, 1H), 2.12-2.25 (m, 2H), 1.98-2.05 (m, 2H); Mass (M + H): 145

Preparation Example 2 Preparation of (R) -3-hydroxy-5-nitropentanenitrile-2

Dissolve (S) -2- (chloromethyl) oxylane (18g, 200mmol) in DMF 100ml in 250ml round flask at room temperature, add potassium cyanide (14.3g, 220mmol) and raise the temperature at 60 ℃. Stir for 6 hours. Nitromethanesodium salt (17.6g, 220mmol) was added slowly at the same temperature and stirred vigorously for 5 hours and then cooled to room temperature. After completion of the reaction, 300 ml of water and 300 ml of ethyl acetate were added and extracted. The organic layer was washed twice with 200 ml of water. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and the next reaction was carried out without purification. Yield: 75%

¹ H NMR (300 MHz, CDCl ₃ ): 4.45 (t, 2H, J = 7.2 Hz), 3.92 (m, 1H), 2.12-2.25 (m, 2H), 1.98-2.05 (m, 2H); Mass (M + H): 145

Preparation Example 3 Preparation of (R) -ethyl-3-hydroxy-5-nitropentanenitrile

(S) -ethyl-2- (oxirane-2-yl) -acetate (13.0 g, 100 mmol) was dissolved in 100 mL of DMF at room temperature in a 250 mL round flask, followed by nitromethane sodium salt (9.0 g, 110 mmol). After the addition was stirred vigorously for 3 hours, the temperature was raised and stirred at 40 ℃ for 2 hours. After completion of the reaction, 300 ml of water and 300 ml of ethyl acetate were added and extracted. The organic layer was washed twice with 200 ml of water. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and the next reaction was carried out without purification. Yield: 80%

¹ H NMR (300 MHz, CDCl ₃ ): 4.30-4.40 (m, 2H), 4.10-4.20 (q, 2H, J = 6.9 Hz), 3.82 (m, 1H), 2.15-2.30 (m, 2H), 1.98 -2.05 (m, 2H), 1.20-1.30 (t, 3H, J = 6.9 Hz); Mass (M + H): 192

Preparation Example 4 Preparation of (R) -tert-Butyl-5-hydroxy-7-nitro-3-oxoheptanoate-1

In a 250 ml round flask cooled to 0 ° C. under nitrogen, (R) -3-hydroxy-5-nitropentanenitrile (14.4 g, 100 mmol) prepared in Preparation Examples 1 and 2 was dissolved in 100 ml of THF, followed by triethyl. Amine (120 mmol) was added and stirred for 10 minutes. Trimethylsilyl chloride (TMSCl, 110 mol) was slowly added to the solution, stirred at room temperature for 12 hours, and the solvent was distilled off under reduced pressure. In another 250 ml round flask, Zn powder (7.8 g, <10 micron, Aldrich, 120 mmol) was added, dissolved in 150 ml of THF, and methanesulfonic acid (4 mg, 0.4 mmol) was added and refluxed for 20 minutes. The solution prepared above and t-butylbromoacetate (20.6 g, 114.4 mmol) were dissolved in 50 mL of THF and then added to a solution containing Zn. After raising the temperature to reflux for 5 hours and then cooled to 0-5 ℃ 200mL 3N HCl solution was slowly added and stirred for 3 hours. After extracting twice with 300 ml of ethyl acetate, the organic layer was washed twice with 50 ml of saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and then purified by column chromatography (ethyl acetate / n-hexane = 1/2) to give pure (R) -tert-butyl-5-hydroxy-. 7-nitro-3-oxoheptanoate was obtained. Yield: 77%

¹ H NMR (300 MHz, CDCl ₃ ): 4.42 (s, 2H), 3.28-3.53 (m, 3H), 3.01 (m, 1H), 2.80-2.90 (m, 2H), 2.02-2.10 (m, 2H) , 1.48 (s, 9 H); Mass (M + H): 262

Preparation Example 5 Preparation of (R) -tert-Butyl-5-hydroxy-7-nitro-3-oxoheptanoate-2

The same procedure as in Preparation Example 4 was performed except that (R) -ethyl-3-hydroxy-5-nitropentanenitrile was used instead of (R) -3-hydroxy-5-nitropentanenitrile. R) -tert-butyl-5-hydroxy-7-nitro-3-oxoheptanoate was obtained. Yield: 80%

¹ H NMR (300 MHz, CDCl ₃ ): 4.42 (s, 2H), 3.28-3.53 (m, 3H), 3.01 (m, 1H), 2.80-2.90 (m, 2H), 2.02-2.10 (m, 2H) , 1.48 (s, 9 H); Mass (M + H): 262

Preparation Example 6 Preparation of (R) -5-azido-3-hydroxypentanenitrile

(S) -2- (2-bromoethyl) oxylane (15 g, 100 mmol) was dissolved in 100 mL DMF at room temperature in a 250 mL round flask, and sodium azide (6.6 g, 105 mmol) was added thereto for 3 hours. After stirring vigorously, the temperature was raised and stirred at 35 to 40 ° C. for 1 hour. Potassium cyanide (7.2 g, 110 mmol) was dissolved in this solution in 20 ml of water, and then slowly added thereto. After completion of the reaction, 300 ml of water and 300 ml of ethyl acetate were added and extracted. The organic layer was washed twice with 200 ml of water. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and the following reaction was carried out without purification. Yield: 65%

¹ H NMR (300MHz, CDCl ₃ ): 4.08 (m, 1H), 3.60-3.70 (m, 2H), 3.17 (bs, 1H), 2.98-3.05 (m, 2H), 1.90-1.95 (m, 2H) ; Mass (M + H): 141

Preparation Example 7 Preparation of (R) -tert-butyl 7-azido-5-hydroxy-3-oxoheptanoate

Except for using (R) -5-azido-3-hydroxypentanenitrile (14.0g, 100mmol) instead of (R) -3-hydroxy-5-nitropentanenitrile in Preparation Example 4 Pure (R) -tert-butyl 7-azido-5-hydroxy-3-oxoheptanoate was obtained. Yield: 63%

¹ H NMR (300 MHz, CDCl ₃ ): 4.39 (s, 2H), 3.16-3.33 (m, 3H), 2.98 (m, 1H), 2.75-2.85 (m, 2H), 2.02-2.13 (m, 2H) , 1.49 (s, 9 H). Mass (M + H): 258

Preparation Example 8 Preparation of (R) -5- (1,3-dioxoisoindolin-2-yl) -3-hydroxypentanenitrile

Pure (R) -5- (1,3-dioxoisoindolin-2-yl) was prepared in the same manner except for using phthalimide potassium salt (19.0 g, 105 mmol) instead of sodium azide in Preparation Example 6. 3-hydroxypentanenitrile was obtained. Yield: 70%

¹ H NMR (300 MHz, CDCl ₃ ): 7.35-7.80 (m, 4H), 4.20-4.31 (m, 2H), 3.65 (m, 1H), 2.78-2.85 (m, 2H), 1.75-1.84 (m, 2H); Mass (M + H): 245

Preparation Example 9 Preparation of (R) -tert-butyl 7- (1,3-dioxoisoindolin-2-yl) -5-hydroxy-3-oxoheptanoate

(R) -5- (1,3-dioxoisoindolin-2-yl) -3-hydroxypentanenitrile was used instead of (R) -3-hydroxy-5-nitropentanenitrile in Preparation Example 4. Except for the same method, pure (R) -tert-butyl 7- (1,3-dioxoisoindolin-2-yl) -5-hydroxy-3-oxoheptanoate could be prepared. Yield: 55%

¹ H NMR (300 MHz, CDCl ₃ ): 7.32-7.78 (m, 4H), 4.35 (s, 2H), 3.15-3.38 (m, 3H), 3.01 (m, 1H), 2.73-2.83 (m, 2H) , 2.01-2.12 (m, 2H), 1.48 (s, 9H); Mass (M + H): 362

Preparation Example 10 Preparation of (S) -4- (benzyloxy) -3-hydroxybutanenitrile

(S) -2- (chloromethyl) oxylane (18 g, 200 mmol) was dissolved in DMF 100 mL in a 250 mL round flask at room temperature. Benzyl alcohol (195 mmol) and potassium carbonate (220 mmol) were added thereto, and the temperature was increased to 45. Stir for 6 hours at 50 ℃. Potassium cyanide (14.3 g, 220 mmol) was slowly added at the same temperature, the temperature was raised, vigorously stirred at 70 to 80 ° C. for 5 hours, and then cooled to room temperature. After completion of the reaction, 300 ml of water and 300 ml of ethyl acetate were added and extracted. The organic layer was washed twice with 200 ml of water. The organic layer was dried over magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and the next reaction was carried out without purification.

Preparation Example 11 Preparation of (S) -tert-butyl-6- (benzyloxy) -5-hydroxy-3-oxohexanoate

In Preparation Example 4, instead of (R) -3-hydroxy-5-nitropentanenitrile, (S) -4- (benzyloxy) -3-hydroxybutanenitrile was used and column chromatography (ethyl acetate / n-hexane was used. Pure (S) -tert-butyl-6- (benzyloxy) -5-hydroxy-3-oxohexanoate could be prepared in the same manner except that = 1/5) was used. Yield: 62%

¹ H NMR (300 MHz, CDCl ₃ ): 7.10-7.30 (m, 5H), 4.51 (s, 2H), 4.28 (m, 1H), 3.35-3.48 (m, 2H), 3.37 (s, 2H), 2.95 (bs, 1 H), 2.75 (d, 2H, J = 6.9 Hz), 1.48 (s, 9H); Mass (M + H): 309

According to the preparation method of the present invention, selective ring opening reaction is possible, and core intermediate compound can be prepared without purification process such as column chromatography or recrystallization, and strong base can be obtained through a blaze reaction performed in the presence of zinc. 5-hydroxy-3-oxoheptanoate derivatives having optical activity under mild conditions without use can be prepared. Therefore, the preparation method according to the present invention is useful for commercial mass production of 5-hydroxy-3-oxoheptanoate derivatives having optical activity for statin-based drug synthesis.

Claims (13)

1) preparing an intermediate compound of Formula 5 through substitution reaction with cyanide without purification after the ring opening reaction of the compound of Formula 2 and nitromethane sodium salt, Preparing an intermediate compound of Formula 5 through substitution reaction with nitromethane sodium salt without purification after the ring opening reaction of the compound of Formula 3 and cyanide, or Preparing an intermediate of Chemical Formula 6 through the ring-opening reaction of the compound of Chemical Formula 4 and the nitromethane sodium salt; And 2) subjecting the prepared intermediate of formula 5 or 6 to a blaze reaction with formula 7 in the presence of zinc, To prepare a formula (1a). <Formula 1a>

<Formula 2>

<Formula 3>

<Formula 4>

<Formula 5>

<Formula 6>

<Formula 7>

At this time, R ¹ and R ² are hydrogen, C1 to C10 straight or branched chain alkyl, or benzyl, X is a halogen atom. The method according to claim 1, wherein the cyanide of step 1) is sodium cyanide or potassium cyanide. The process according to claim 1, wherein the solvent used in step 1) is an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane and dimethyl sulfoxide (DMSO). . 1) preparing an intermediate compound of Formula 9 through ring opening reaction with cyanide without purification after substitution reaction of Compound 8 with nucleophile; And 2) subjecting the prepared intermediate of formula 9 to a blaze reaction with formula 7 in the presence of zinc, To prepare a formula (1b). <Formula 1b>

<Formula 8>

<Formula 9>

<Formula 7>

At this time R ¹ is hydrogen, C ¹ to C 10 straight or branched chain alkyl, or benzyl, R ³ is azide or phthalimide, X is a halogen atom. The method according to claim 4, wherein the nucleophile of step 1) is sodium azide or phthalimide potassium salt. The process according to claim 4, wherein the cyanide of step 1) is sodium cyanide or potassium cyanide. The process according to claim 4, wherein the solvent of step 1) is an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane and dimethylsulfoxide (DMSO). 1) preparing an intermediate of Chemical Formula 13 by ring opening reaction with cyanide without purifying the compound of Chemical Formula 10 with Chemical Formula 11 or Preparing an intermediate of Chemical Formula 13 by substituting the compound of Chemical Formula 3 with cyanide without purification after the ring opening reaction with Chemical Formula 12; And 2) subjecting the prepared intermediate of Formula 13 to a blaze reaction with Formula 7 in the presence of zinc, To prepare a formula (1c). <Formula 1c>

<Formula 10>

<Formula 3>

<Formula 11>

<Formula 12>

<Formula 13>

<Formula 7>

At this time, R ¹ is hydrogen, C ¹ to C 10 straight or branched chain alkyl, or benzyl, Ar is phenyl unsubstituted or substituted with one group selected from the group consisting of C1 to C10 alkyl, C1 to C10 alkoxy and halogen, X is a halogen atom. The method according to claim 8, wherein the cyanide of step 1) is sodium cyanide or potassium cyanide. The process according to claim 8, wherein the reaction solvent of step 1) is an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF), acetonitrile, 1,4-dioxane and dimethylsulfoxide (DMSO). A compound of formula 5 used as an intermediate according to claim 1. <Formula 5>

A compound of formula 9-a or 9-b used as an intermediate according to claim 4. <Formula 9-a>

<Formula 9-b>

A compound of formula 1-b-1 or 1-b-2 prepared according to claim 4. <Formula 1-b-1>

<Formula 1-b-2>

At this time, R ⁸ is methyl, ethyl, t-butyl or benzyl.