KR20060008051A - Process for preparation of chiral 4-hydroxy-2-piperidinone - Google Patents

Abstract

The present invention relates to a novel and efficient process for the preparation of stereoselective 4-hydroxy-2-piperidinone, wherein a hydroxy ester obtained by high-pressure hydrogenation of a nitrogen-substituted betaketopentanoic acid derivative under ruthenium catalyst according to the present invention The method for preparing 4-hydroxy-2-piperidinone, which comprises a step of first deprotection reaction under an acid catalyst and a cyclization reaction, is economical and has excellent stereoselectivity and reaction yield, thereby treating hyperlipidemia, anticancer agents, antibiotics, and antiviral agents. It can be usefully used in the development of a number of drugs, including.

Description

Process for producing stereoselective 4-hydroxy-2-piperidinone {PROCESS FOR PREPARATION OF CHIRAL 4-HYDROXY-2-PIPERIDINONE}

The present invention relates to a method for the stereoselective preparation of 4-hydroxy-2-piperidinone for use as a key intermediate of several drugs, including hyperlipidemia, antibiotics, antivirals and anticancer agents.

4-hydroxy-2-piperidinone represented by the following formulas (1a) and (1b) is atorvastatin, cis-trans-4-hydroxy pipecolic acid, alkaloids SS 20,846A, powerful HIV inhibitor palinavir, anticancer agent CHIR 200,131 Key intermediates such as derivatives are in great demand.

Wherein Q represents hydrogen, C _1-4 straight or branched alkyl or benzyl.

Looking at the existing preparation methods for the compounds of Formula 1a and 1b, as shown in Scheme 1, 1) synthesized from substituted glutaronitrile through several steps of enzymatic and chemical reaction (Reference: Author Mei- Xiang Wang et al., Tetrahedron Lett , 41, 8549-8552, 2000; author Timothy Beard et al., Tetrahedron Asymmetry , 4, 1085-1104, 1993, etc.), 2) synthesized from epichlorohydrin by chemical and enzymatic methods ( REFERENCES: JACS, 122, 168-169, 2000; US 4,705, 572), 3) Piperidinone was synthesized by enzymatic reaction (Reference JOC 2002. 67. 7869-7871).

However, the reactions according to Scheme 1 have difficult reaction conditions, low stereoselectivity, and are uneconomical.

It is therefore an object of the present invention to provide a more efficient process for the preparation of stereoselective 4-hydroxy-2-piperidinone.

In order to achieve the above object, in the present invention, the beta keto pentanoic acid ester of the following formula (2) is a bi-substituted beta keto pentanoic acid ester in the presence of a ruthenium catalyst to a high pressure hydrogenation of the nitrogen of the formula (3a) Synthesis of hydroxy pentanoic acid ester, followed by a deprotection reaction and a cyclization reaction, a method for preparing 4-hydroxy-piperidinone of formula 1a or 1b having nitrogen-substituted high stereoselectivity to provide.

<Formula 1a>

<Formula 1b>

Where

P and P ¹ each independently represent benzyl, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl, acetyl, and the like,

R represents a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, t-butyl, isopropyl,

Q represents hydrogen, linear or branched alkyl or benzyl having 1 to 4 carbon atoms.

Hereinafter, the present invention will be described in more detail.

The method according to the invention can be represented as in Scheme 2 below.

In the above scheme, P, P ¹ , R and Q are as described in the above formula definition.

Reaction Scheme 2 may be represented by Reaction Schemes 2a to 2c more specifically.

In the above scheme, P, P ¹ , R and Q are as described in the above formula definition.

Nitrogen-disubstituted beta ketopentanoic acid ester of Chemical Formula 2 used as starting material in Scheme 2 may be synthesized in the same manner as in Korean Patent Application No. 2003-51360 of the same applicant as the present application. As an organic solvent such as alcohol such as methanol, ethanol, isopropanol, butanol, tetrahydrofuran, acetonitrile, dimethylformamide or the like, it can be obtained by hydrogenation reaction under a ruthenium catalyst at a pressure of 30 to 100 atm.

For example, according to Schemes 2a and 2b, after nitrogen-desubstituted beta hydroxypentanoic acid ester obtained by the high-pressure hydrogenation reaction is deprotected by a conventional method in t-butyl group in the presence of an acid, the ring is present in the presence of a base. When the reaction is carried out, N-benzyl-4-hydroxy-piperidin-2-one can be obtained in a good yield of 90% or more.

Further, for example, as shown in Scheme 2c, betahydroxy pentanic acid ester in which nitrogen is substituted with benzyl and benzyloxy carbonyl group is subjected to high-pressure hydrogenation as in Scheme 2a or 2b, and then deprotection and ring Hydrogenation of the benzyloxycarbonyl group with a short time (e.g., 30 minutes) at normal pressure in the presence of 5% Pd / C without the polymerization reaction yields a substance free of benzyloxycarbonyl groups. Benzyl-4-hydroxy-piperidin-2-one is obtained, which is then hydrogenated again for a long time (e.g., 10 hours) to form 4-hydroxy-piperidin-2-one with N-benzyl removed. Good yield can be obtained. At this time, the cyclization reaction and the subsequent hydrogenation reaction may be carried out by changing the order.

Examples of ruthenium catalysts that can be used in the hydrogenation reaction include (R) Ru ₂ Cl ₄ (BINAP) NEt ₃ (dichloro [R (+)-2,2'-bis (diphenylphosphino) -1,1'- Vinaphthyl] rutheniumtriethylamine) _, (S) Ru ₂ Cl ₄ (BINAP) NEt ₃ (dichloro [S (-)-2,2'-bis (diphenylphosphino) -1,1'-binaf Tyl] rutheniumtriethylamine) _, (R) Ru ₂ Cl ₂ (BINAP) ₂ (dichloro [R (+)-2,2'-bis (diphenolylspino) -1,1'-binafthyl] ruthenium ), (S) Ru ₂ Cl ₂ (BINAP) ₂ (dichloro [S (-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] ruthenium), (R) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ (dichloro [R (+)-2,2'-toluyl-bis (diphenylphosphino) -1,1'-binafthyl] rutheniumtriethylamine) _, And (S) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ (dichloro [S (-)-2,2'-toluyl-bis (diphenylspino) -1,1'-binafthyl] rutheniumtriethyl Amines).

As for the temperature in the said hydrogenation reaction, the range of 0 degreeC-100 degreeC is suitable, and about 30 degreeC is preferable. Preferred solvents include organic solvents such as tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl ether, ethyl acetate, acetone, chloroform, methanol, ethanol, isopropanol, butanol and the like.

As the acid used in the deprotection reaction, a solution of saturated hydrochloric acid gas in alcohol, toluenesulfonic acid, oxalic acid, trifluoroacetic acid, 6N HCl, and other inorganic acids may be used. Inorganic salts such as potassium carbonate, calcium carbonate, sodium carbonate, sodium hydride, tert-butoxide, potassium methoxide, sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo Organic salts such as [5,4,0] -7-undecene (DBU).

Hereinafter, the present invention will be described in detail with reference to Examples, and these Examples are merely illustrative of the present invention, and the present invention is not limited to these Examples.

Preparation Example 1 Synthesis of 5- (benzyl, t-butoxycarbonylamino) -3-oxo-pentanoic acid ethyl ester

  20 g (0.07 mol) of 3- (benzyl-t-butoxycarbonylamino) -propionic acid and 400 mL of acetonitrile were added to a 1 L reactor, followed by stirring under nitrogen for 15 minutes, followed by 13 g of 1.1'-carbonyl diimidazole (0.084). mol) and further stirred for 30 minutes, the temperature was lowered to 10 ℃, 18.4 g (0.105 mol) of potassium malonate ethyl ester and 7.5 g (0.077 mol) of magnesium chloride were added and stirred for 1 hour. After stirring for 2 hours at 58 ° C., the reaction was completed. After cooling to room temperature and distilling under reduced pressure to remove the solvent, the mixture was extracted and adjusted to pH = 4 with ethyl acetate and 6N hydrochloric acid solution, and the organic layer was dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 21 g (85%) of a yellow oil.

¹ H NMR (CDCl ₃ , ppm): δ 7.54-7.23 (m, 5H), 4.44 (s, 2H), 4.17 (q, 2H), 3.45-3,36 (m, 4H), 2.81-2.71 (m , 2H), 1.45 (s, 9H), 1.28 (t, 3H)

Preparation Example 2 Synthesis of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester

  Into a 1 L reactor, 28 g (0.09 mol) of 3- (benzyl, benzyloxycarbonylamino) -propionic acid and 500 mL of acetonitrile were stirred under nitrogen for 15 minutes, after which 15.9 g of 1,1'-carbonyldiimidazole (0.108) was added. mol) and further stirred for 30 minutes, the temperature was lowered to 10 ℃, 22.7g of potassium malonate ethyl ester and 9.4g of magnesium chloride were added and stirred for 1 hour. After further stirring at 50 ° C. for 2 hours, when the reaction was completed, the reaction mixture was cooled to room temperature, distilled under reduced pressure, and the solvent was removed. The mixture was extracted with ethyl acetate and 6N hydrochloric acid, adjusted to pH = 4, and the organic layer was dried over anhydrous magnesium sulfate. Then, the mixture was concentrated under reduced pressure to give 29.3 g (85%) of a yellow oil.

¹ H NMR (CDCl ₃ , ppm): δ 7.36-7.25 (m, 5H), 5.16 (s, 2H), 4.51 (s, 2H), 4.14 (q, 4H), 2.84-2.70 (m, 2H), 1.24 (t, 3 H)

Preparation Example 3 Synthesis of 5- (benzyl, benzyloxycarbonylamino) -3 (R) -hydroxypentanoic acid ethyl ester

20 g (0.052 mol) of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester obtained in Preparation Example 2 and dichloro [R (+)-2,2'-bis (diphenolphosphino) 10 mg of -1,1'-binafthyl] ruthenium was added to 100 mL of anhydrous ethanol and reacted at room temperature at 70 atm in a high pressure hydrogen reactor for 24 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove ethanol, extracted with ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 17.2 g of yellow oil. (85%, ee98-99%) were obtained.

¹ H NMR (CDCl ₃ , ppm): δ 7.36-7.18 (m, 5H), 5.18 (s, 2H), 4.58-4.37 (m, 2H), 4.14 (q, 2H), 4.09-3.90 (m, 1H ), 3.63 (br, 1H), 3.39-3.01 (m, 2H) 2.47-2.36 (m, 2H) 1.79-1.45 (m, 2H), 1.25 (t, 3H)

HPLC: column: Chiralcel-OD, mobile phase: hexane: isopropanol = 90:10, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 21.97 minutes

Preparation Example 4 Synthesis of 5- (benzyl, benzyloxycarbonylamino) -3- (S) -hydroxypentanoic acid ethyl ester

The ruthenium catalyst was used in the same manner as in Preparation Example 3, and dichloro [S (-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] ruthenium was used. (Yield 89%, ee 98% or more)

¹ H NMR (CDCl ₃ , ppm): δ 7.36-7.18 (m, 5H), 5.18 (s, 2H), 4.58-4.37 (m, 2H), 4.14 (q, 2H), 4.09-3.90 (m, 1H ), 3.63 (br, 1H), 3.39-3.01 (m, 2H), 2.47-2.36 (m, 2H), 1.79-1.45 (m, 2H), 1.25 (t, 3H)

HPLC: column: Chiralcel-OD, mobile phase: hexane: isopropanol = 90: 10, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 31.00 min

Preparation Example 5 Synthesis of 5- (benzyl, t-butoxycarbonylamino) -3- (R) -hydroxy acid ethyl ester

  10 g of 5- (benzyl, t-butoxycarbonylamino) -3-oxo-pentanoic acid ethyl ester and dichloro [R (+)-2,2'-bis (diphenolphosphino)-obtained in Preparation Example 1 1,1'-binafthyl] ruthenium and 5 mg were reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove ethanol, extracted with ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 9.1g of yellow oil. Got it.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.21 (m, 5H), 4.58-4.20 (m, 2H), 4.12 (q, 2H), 4.02-3.92 (m, 1H), 3.70 (br, 1H ), 3.27-2.98 (m, 2H), 2.55-2.38 (m, 2H), 1.80-1.48 (m, 2H) 1.80-1.48 (m, 2H), 1.46 (s, 9H), 1.26 (t, 3H)

HPLC: column: Chiralcel-OD, mobile phase: hexane: isopropanol = 90:10, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 11.78 minutes

Preparation Example 6 5- (Benzyl, t-butoxycarbonylamino) -3- (S) -hydroxy acid ethyl ester

The ruthenium catalyst was used in the same manner as in Preparation Example 5, and dichloro [S (-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] ruthenium was used. (Yield: 90%, ee 98% up)

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.21 (m, 5H), 4.58-4.20 (m, 2H), 4.58-4.20 (m, 2H), 4.12 (q, 2H), 4.02-3.92 (m , 1H), 3.70 (br, 1H), 3.27-2.98 (m, 2H), 2.55-2.38 (m, 2H) 1.80-1.48 (m, 2H), 1.46 (s, 9H), 1.26 (t, 3H)

HPLC: column: Chiralcel-OD, mobile phase: hexane: isopropanol = 90:10, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 16.11 minutes

Preparation Examples 7 to 10

Ester materials were synthesized using Ru BINAPCl ₂ · Et ₃ N as the Ru catalyst in the reaction process according to Preparation Examples 3 to 6, which are summarized in Table 1 below.

Example 1: Synthesis of N-benzyl-4- (R) -hydroxy piperidin-2-one

5 g of 5- (benzyl, t-butoxycarbonylamino) -3- (R) -hydroxypentanoic acid ethyl ester obtained in Preparation Example 5 were added to a 100 ml reactor, 50 ml of ethanol was added, and 10 ml of 10% HCl / MeOH was added thereto. After stirring at room temperature for 5 hours. After confirming that the t-butyl group was removed by TLC, the solvent was distilled under reduced pressure to obtain 5-benzylamino-3 (R) -hydroxy acid ethyl ester hydrochloride, which was placed in 50 mL of ethanol without purification and sodium ethoxide 1.5 g was added and refluxed for 2 hours. After distilling the solvent under reduced pressure, silica gel column chromatography was performed with Hex: EA = 1: 1 to obtain 3 g of the target compound. (Yield 85%)

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H), 1.96-1.91 (m, 1H), 1.85-1.79 (m, 1H)

HPLC: column: Chiral PAK AS, mobile phase: hexane: isopropanol = 75: 25, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 12.12 minutes

Example 2: Synthesis of N-benzyl-4- (S) -hydroxy piperidin-2-one

5 g of 5- (benzyl, t-butoxycarbonylamino) -3- (S) -hydroxyethyl ester obtained in Preparation Example 6 were added to a 100 mL reactor, 50 mL of ethanol was added, and 10 mL of 10% HCl / MeOH was added thereto. Stirred for 5 hours. After confirming that the t-butyl group was removed by TLC, the solvent was distilled under reduced pressure to obtain 5-benzylamino-3- (S) -hydroxy acid ethyl ester hydrochloride, which was then purified without addition of ethane to 50 mL of sodium ethoxylate. Add 1.45 g of side and reflux for 2 hours. After distilling off the solvent under reduced pressure, silica gel column chromatography with Hex: EA = 1: 1 gave 3.1 g of the desired compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H), 1.96-1.91 (m, 1H), 1.85-1.79 (m, 1H)

HPLC: column: Chiral PAK AS, mobile phase: hexane: isopropanol = 75: 25, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 19.62 minutes

Example 3: Synthesis of N-benzyl-4- (R) -hydroxy piperidin-2-one

5 g of 5- (benzyl, benzyloxycarbonylamino) -3- (R) -hydroxypentanoic acid ethyl ester obtained in Preparation Example 3 were placed in a 100 mL reactor, 50 mL of methanol was added, and 100 mg of 5% Pd / C was added. Was carried out for 30 minutes at room temperature and atmospheric pressure. 5% Pd / C was filtered off using Celite, and then sodium ethoxide was added to the reaction solution and refluxed for 2 hours. After distilling off the solvent under reduced pressure, silica gel column chromatography was performed with Hex: EA = 1: 1 to obtain 2.26 g of the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H), 1.96-1.91 (m, 1H), 1.85-1.79 (m, 1H)

HPLC: column: Chiral PAK AS, mobile phase: hexane: isopropanol = 75: 25, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 12.12 minutes

Example 4: Synthesis of N-benzyl-4- (S) -hydroxy piperidin-2-one

Under the conditions similar to Example 3, 5 g of 5- (benzyl, benzyloxycarbonylamino) -3- (S) -hydroxypentanoic acid ethyl ester obtained in Preparation Example 4 was reacted to obtain 2.2 g of the target compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.34-7.22 (m, 5H), 4.57 (dd, 2H), 4.18-4.15 (m, 1H), 3.62-3.45 (br, 1H), 3.43-3.38 (m , 1H), 3.15-3.10 (m, 1H), 2.69 (dd, 1H) 2.48 (dd, 1H), 1.96-1.91 (m, 1H), 1.85-1.79 (m, 1H)

HPLC: column: Chiral PAK AS, mobile phase: hexane: isopropanol = 75: 25, flow rate: 1 mL / min, detection wavelength: 254 nm, retention time: 19.62 minutes

Determination of Structure by Mosher Method

The ester was prepared by reacting N-benzyl-4- (R) -hydroxy-piperidine-2-non and R (+)-α-methyl-α-trifluoromethyl-phenyl acetic acid obtained in Example 1 or 3 above. Synthesized.

¹ H NMR (CDCl ₃ , ppm): δ 7.18-7.47 (m, 10H), 4.61 (s, 2H), 4.23 (brs, 1H), 3.58-3.44 (m, 1H), 3.45 (s, 3H), 3.19-3.13 (m, 1H), 2.81-2.75 (dd, J = 1.85, 6.05 Hz, 1H) 2.74-2.52 (dd, J = 1.9, 10.25 Hz, 1H), 2.17-1.84 (m, 1H), 1.85 -1.79 (m, 2H)

¹⁹ F NMR 500 MHz (CDCl ₃ , δ ppm) 71.88 (3F, S, OCF ₃ )

An ester was prepared by reacting N-benzyl-4- (S) -hydroxy-piperidine-2-non and R (+)-α-methyl-α-trifluoromethyl-phenyl acetic acid obtained in Example 2 or 4 above. Synthesized.

¹ H NMR (CDCl ₃ , ppm): δ 7.18-7.47 (m, 10H), 4.61 (s, 2H), 4.23 (brs, 1H), 3.58-3.44 (m, 1H), 3.45 (s, 3H), 3.19-3.13 (m, 1H), 2.81-2.75 (dd, J = 1.85, 6.05 Hz, 1H) 2.74-2.52 (dd, J = 1.9, 10.25 Hz, 1H), 2.17-1.84 (m, 1H), 1.85 -1.79 (m, 2H)

¹⁹ F NMR 500 MHz (CDCl ₃ , δ ppm) 72.16 (3F, S, OCF ₃ )

According to the present invention, 4-hydroxy-2-piperidinone can be economically obtained in a short time and simply in high purity and high yield under mild reaction conditions than conventional methods.

Claims (6)

Comprising a high pressure hydrogenation of the beta keto pentanoic acid ester of the formula (2) in the presence of a ruthenium catalyst to synthesize the beta hydroxy pentanoic acid ester of the formula (3a) or 3b, and then deprotection and cyclization reaction, Process for preparing 4-hydroxy-piperidinone of formula 1a or 1b: <Formula 1a>

<Formula 1b>

<Formula 2>

<Formula 3a>

<Formula 3b>

Where P and P ¹ each independently represent benzyl, benzyloxycarbonyl, t-butyloxycarbonyl, benzoyl or acetyl, R represents a linear or branched alkyl group having 1 to 4 carbon atoms, Q represents hydrogen, linear or branched alkyl or benzyl having 1 to 4 carbon atoms. The method of claim 1, And when Q is hydrogen, further comprising hydrogenating at atmospheric pressure in the presence of a Pd / C catalyst after the cyclization reaction. The method of claim 1, Ruthenium catalyst is (R) Ru ₂ Cl ₄ (BINAP) NEt ₃ (dichloro [R (+)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] rutheniumtriethylamine) _, (S) Ru ₂ Cl ₄ (BINAP) NEt ₃ (dichloro [S (-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] rutheniumtriethylamine) _, ( R) Ru ₂ Cl ₂ (BINAP) ₂ (dichloro [R (+)-2,2'-bis (diphenolylspino) -1,1'-binafthyl] ruthenium), (S) Ru ₂ Cl ₂ (BINAP) ₂ (dichloro [S (-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl] ruthenium), (R) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ (dichloro [R (+)-2,2'-toluyl-bis (diphenylphosphino) -1,1'-binafthyl] rutheniumtriethylamine) _, or (S) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ (dichloro [S (-)-2,2'-toluyl-bis (diphenylspino) -1,1'-binafthyl] rutheniumtriethyl Amines). The method of claim 1, Wherein the hydrogenation reaction is carried out in one or more solvents selected from the group consisting of tetrahydrofuran, toluene, benzene, acetonitrile, dimethylformamide, dimethylether, ethyl acetate and alcohol. The method of claim 1, The deprotection reaction is carried out in the presence of an inorganic or organic acid catalyst. The method of claim 1, The cyclization reaction is carried out in the presence of an organic or inorganic base.