KR19990069272A - (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one and its intermediates - Google Patents

Abstract

The present invention relates to a process for producing (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1) used as a core intermediate in the synthesis process of a taxane- .

(One)

The production method of the present invention is a process for producing (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) by reacting as a starting material a trans- (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of the general formula (8) is reacted with a base to give a compound of the formula (X) N-substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one compound of the formula (11) (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1).

Description

(3R, 4S) -3-hydroxy-4-phenylazetidin-2-one and its intermediates

The present invention relates to a novel process for producing (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the following general formula (1) and intermediates thereof.

(One)

The compound of the general formula (1) is a precursor of the (2R, 3S) -3-phenylisoserine of the N-substituted form of the general formula (3), which is a side chain substituent group of the taxane anticancer drug represented by the general formula Is an intermediate required for the synthesis of the compound of formula (2).

(2)

The taxane-based compound represented by the general formula (2) is known as an anticancer agent. When R is a phenyl group and R 'is an acetyl group, it is called Paclitaxel or Taxol, and R is tert- BuO) group and R 'is a hydrogen atom, it is called docetaxel or taxotere.

(3)

(Wherein R is a phenyl group or a t-BuO group)

Of the taxanes listed in the general formula (2), which exhibit excellent efficacy in ovarian cancer or breast cancer, paclitaxel, which is useful as an anticancer agent, is obtained from the bark of Pacific yew tree. However, the yield of the extract is so low that it can not be supplied in large quantities, and serious mass destruction is expected when mass production is made. On the other hand, 10-deacetyl-baccatin-III (represented by the general formula (4)) having both skeletal and functional groups of paclitaxel was obtained from leaves and twigs of European yew tree ) Is extracted, which is advantageous in that the yield of the extract is relatively high, and that the recoverable leaf or twig is used as a raw material. Recently, a newly developed anticancer agent docetaxel is prepared through a pure synthetic route from 10-diacetyl-bacatin-III represented by the general formula (4).

Therefore, up to now, the use of 10-diacetyl-bacactin-III represented by the general formula (4) and paclitaxel starting from the N-substituted (2R, 3S) -3-phenylisoserine of the general formula (3) The semisynthetic process of docetaxel is known to be the most practical and economical.

(4)

However, the known process for semi-synthesis of a taxane-based anticancer drug represented by the general formula (2) using 10-diacetyl-bacatin-III as a starting material represented by the general formula (4) Pat. Appl. 1990; EP 400,971; J. Org. Chem., 56, 1681, (1991); Tetrahedron, 48, 6985, (1992); Tetrahedron Lett., 32, 3151 (1991); Synlett., 1992, 761; J. Am. Chem. Soc., 110, 5917 (1988 )] according to the general formula (1) of the (3R, 4S) -3- hydroxy-4-phenyl-azetidin-2-one and 10-D in the general formula (4) acetyl Benzoyl (2R, 3S) -3-phenylisoserine of the formula (3) and a compound of the formula (4) ) Of 10-diacetyl-bacatin-III as starting materials, it is known that the yield and the optical purity of the product are much higher than those of the semi-synthetic process. (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of the general formula (1) is used instead of the (2R, 3S) -3-phenylisoserine of the N- Diacetyl-bacactin-III in the general formula (4) is high and the part of the carbon position (C-2 'position) of the compound of the general formula (2) The optical purity of the product is greatly improved.

However, the preparation of (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1) 3) have been used.

In fact, due to the availability of (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1) As follows.

In European Patent Application EP 400,971 para-methoxyphenylbenzaldimines and acetoxy e cetyl chlorides are 2,2-cyclized in the presence of a base to give the racemic mixture of cis-para-methoxyphenyl-3-acetic acid (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1) was prepared from the racemic mixture These were subjected to optical resolution using optically pure methoxy-2- (trifluoromethyl) -phenylacetyl chloride.

On the other hand, another known method [ J. Org. Chem., 56 , 1681 (1991); Tetrahedron, 48 , 6985 (1992); Tetrahedron Lett., 32 , 3151 (1991)), a chiral enolate compound having N-trimethylsilylbenzaldimine and a chiral auxiliary bonded thereto was reacted with 2,2'- (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of the general formula (1) was prepared.

However, the first method uses an inefficient optical resolution method, which requires a complicated manufacturing process, can not yield a yield of 50% or more, requires several purification steps, and the second method is extremely sensitive to moisture in the atmosphere There is a problem in that the reaction temperature is too low and an expensive chiral auxiliary is used in an amount of 1 equivalent or more. Thus, these known methods may be useful on a laboratory scale, but it is difficult to produce (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of the general formula (1) there was.

Accordingly, the present invention has been made to solve the problems of the prior art as described above, and to provide an optically pure (3R, 4S) -3-hydroxy-4-phenyl Azetidin-2-one. ≪ / RTI >

The present invention relates to a novel process for preparing (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1) and intermediates thereof.

As described above, the present invention is a core intermediate required for the semi-synthetic step of paclitaxel useful as an anticancer agent in the taxane system represented by the general formula (2) showing excellent efficacy in ovarian cancer or breast cancer. (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one is reacted with an N-substitution of the general formula (3) at the C13-position side chain of the taxane compound represented by the general formula Is the precursor of (2R, 3S) -3-phenylisoserine. The present invention also relates to novel intermediates for preparing (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1).

The production method of the present invention,

(2R, 3S) -2,3-dihydroxy-3-phenylpropionamide represented by the general formula (6) by subjecting the trans-cinnamamide derivative of the general formula (5) A first step of preparing a derivative;

(2S, 3R) -2,3-dihydroxy-3-phenylpropionamide derivative of general formula (6) prepared in the first step is halocarboxylated to obtain (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative;

(2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of general formula (8) prepared in the second step is reacted with a base in an aprotic organic solvent to obtain N -Substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound;

(11) by reacting the N-substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound of the general formula (10) prepared in the third step with an oxidizing agent in an organic solvent, (4R) -3-carboxy-4-phenylazetidin-2-one derivative of formula (I); And

(3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative of the general formula (11) prepared in the fourth step is hydrolyzed to obtain the (3R, 4S ) -3-hydroxy-4-phenylazetidin-2-one;

.

(5)

Wherein R is para-methoxyphenyl or 3,4-dimethoxyphenyl group.

(6)

Wherein R is as defined above.

(7)

In the formula, R 'is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a phenyl group, and R' 'is a methyl, ethyl or propyl group.

(8)

Wherein R and R 'are as defined above and X is chlorine, bromine or iodine.

(9)

Wherein R and R 'are as defined above and R " is a methyl, ethyl or propyl group.

(10)

Wherein R and R 'are as defined above.

In general formula (11)

In the formula, R 'is the same as defined above. In the production method of the present invention, each step will be described in detail as follows.

Step 1: The catalyst used in the reaction of the first step is a mixture of osmium tetroxide (OsO ₄ ) or potassium osmate dihydrate (K ₂ OsO ₄ .2H ₂ O) (9-O-dihydroquininyl) phthalazine, 3,6-bis (9-O-dihydroquininyl) pyridazine, dihydroquinine 4-chlorobenzoate, or 1,4- -O-quininyl) phthalazine or 3,6-bis (9-O-quininyl) pyridazine as a chiral monomer, or a compound obtained by chemically bonding these monomers to silica gel as a chiral ligand do. (2R, 3S) -2,3-dihydroxy-3- (2-methoxyphenyl) propane represented by the general formula (6) in the presence of the catalyst thus prepared, Phenylpropionamide derivative.

(9-O-dihydroquininyl) phthalazine, 3,6-bis (9-O-di (tert-butoxycarbonyl) (K ₃ Fe (CN) ₆ ) and potassium carbonate, for the asymmetric dihydroxylation reaction of tertiary alcohols such as pyridazine, dihydroquinine 4-chlorobenzoate and the like, - Mix in a mixed solvent of butanol and water for a period of time. At this time, it is preferable to use 0.002 to 0.10 equivalents of synuclein or alkaloid ligand, 2 to 4 equivalents of potassium ferricyanide and 2 to 4 equivalents of potassium carbonate. The tertiary butanol and water used as a solvent are preferably mixed in a volume ratio of 1: 1 to 2: 1, and the stirring is preferably performed for 5 to 60 minutes.

After the stirring, an aqueous solution of osmium tetroxide or potassium osmate (preferably, 0.002 to 0.02 equivalents) was added, and the mixture was stirred again for a certain period of time. Then, the trans-cinnamamide derivative of general formula (5) and methanesulfonamide Preferably about 1 equivalent) is added, and the reaction is carried out at 0 ° C to 30 ° C for about 12 to 30 hours. Then, the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) is isolated through a conventional separation process such as a recrystallization method or chromatography.

Optically pure compound of the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) by a simple recrystallization purification method using a solvent such as toluene, methanol, ethanol, isopropanol, Can be easily obtained.

In addition, the asymmetric dihydroxylation catalysis of the trans-cinnamamide derivative of the general formula (5) can be carried out by reacting 1,4-bis (9-O-quininyl) Syncone alkaloid polymers using thalazine or 3,6-bis (9-O-quininyl) pyridazine as chiral monomers, or synuclear alkaloid derivatives in which these monomers are bonded to silica gel as non-homologous chiral ligands, (Song, CE, Roh, EJ, Lee, SG, Kim, IO, Tetrahedron: Asymmetry, 6 , 2687 (1995); Song, CE, Yang, JW, Ha, HJ, Lee, SG, Tetrahedron: Asymmetry, 7 , 645 (1996); Song, CE, Yang, JW, Ha, HJ, Tetrahedron: Asymmetry, 8 , 841 (1997)].

The non-homogeneous cinchona alkaloid derivatives prepared by the present inventors exhibited the activity and optical selectivity of the catalysts such as the above-mentioned homogeneous catalysts in the asymmetric dihydroxylation catalysis of the trans-cinnamamide derivatives of the general formula (V) The complex of osmium tetroxide and alkaloid ligand, which is expensive and toxic, is easily separated from the reaction solution after completion of the reaction, and the efficacy of the catalyst, especially the enantioselectivity of the catalyst, Do.

In the first step, the compound of the general formula (6) is produced in a yield of 90% or more.

Step 2: In the second step, the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) prepared in the first step is halocarboxylated to give the general formula ) Of (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative is prepared.

As a first method for halocarboxylating the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) (2S, 3R) -2-carboxy-3-methylpropionamide derivative represented by general formula (8) by reacting 2,3-dihydroxy-3-phenylpropionamide derivative with bromic acid (HBr) in an acidic solvent (for example, 3-halo-3-phenylpropionamide derivative. At this time, it is preferable to use 2 to 10 equivalents of bromic acid, and the reaction time is preferably about 1 to 2 hours at 20 to 50 캜, and the yield is 80% or more.

Of course, in order to halocarboxylate the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6), the compound of the general formula (6) is reacted with? -Acetoxyisobutyl Reibromide or acetyl salicyloyl bromide may be directly reacted, but it is more preferable to react with bromic acid in an acidic solvent (preferably acetic acid) in consideration of economical aspects.

Another process for the preparation of the (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of the general formula (8) is carried out in the presence of an acid catalyst in a dichloromethane or acetonitrile solvent (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) and the trialkyl orthocarboxylate represented by the general formula (7) And reacted at about 0 캜 to room temperature to prepare the orthoester of the cyclized general formula (9). Examples of the trialkylorthocarboxylate represented by the general formula (7) include trimethyl orthoacetate, trimethyl orthoformate, trimethyl ortho butyrate, trimethyl ortho valerate, trimethyl orthoformate, trimethyl ortho Benzoate, triethylorthoacetate, triethylorthophosphonate, triethylorthobutyrate, triethylorthosalvalate, triethylorthoformate, or triethylortho benzoate, and the like.

Only the produced alcohol and solvent are removed by distillation and the residue containing the cyclized orthoester of the general formula (9) is directly isolated in a solvent such as dichloromethane, acetonitrile or benzene, Is reacted with a mixture of iodotrimethylsilane, sodium iodide (NaI) and acetyl chloride, acetyl bromide, bromotrimethylsilane, chlorotrimethylsilane, or acetyl chloride at a temperature of 40 ° C to 0 ° C for a certain time, For 6 hours to prepare a (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative represented by the general formula (8).

Step 3: In the third step, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dichloromethane, dimethylformamide, dimethyl sulfoxide (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of general formula (8) with one equivalent of sodium hydride, potassium hydride, n-butyl (3R, 4S) - (3R, 4S) - (3R, 4S) -2,6-dicarboxylic acid represented by the general formula (10) by reacting a base such as lithium, tetra-n-butylammonium fluoride, or a mixture of cesium fluoride and a catalytic amount of tetraalkylammonium chloride. 3-carboxy-4-phenylazetidin-2-one derivative is prepared. The base is preferably used in an amount of 1 equivalent, and the reaction time is preferably 1 to 3 hours at a temperature of 0 to 30 ° C.

Step 4: in the acetonitrile solvent, serik ammonium nitrate ((NH _{4) 2} Ce (NO _{3) 6)} and substituted N- (3R, 4S) of the general formula (10) prepared in Step 3 as an oxidizing agent (3R, 4S) -3- (4-fluorophenyl) -3-carboxy-4-phenylazetidin- Carboxy-4-phenylazetidin-2-one < / RTI > With a yield of about 80% or greater. Alternatively, instead of reacting with seric ammonium nitrate in an acetonitrile solvent, an N-alkyl substituted compound of general formula (10) is reacted at 0 ° C to 15 ° C using ozone as an oxidizing agent in a dichloromethane solvent , The (3R, 4S) -3-carboxy-4-phenylazetidin-2-one compound of formula (11) can be prepared with a yield of about 50% or more.

Step 5: To a solution of (3R, 4S) -3-carboxy-4-phenylacetate of general formula (11) prepared in the fourth step in a saturated sodium bicarbonate aqueous solution and a methanol solvent, 2-one derivative (preferably at 10 to 30 占 폚 for about 1 to 3 hours) to hydrolyze the carboxy group at the 3-position of the compound of formula (11) (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1).

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

Example 1

Preparation of N- (4-methoxyphenyl) -cinnamamide

Para-Anisidine (81 g, 659 mmol) was dissolved in dry methylene chloride (500 mL) and the temperature was cooled to 0 < 0 > C. Cinnamoyl chloride (50 g, 299 mmol) was slowly added dropwise, and after the reaction was completed, the solvent was distilled off, and 2N hydrochloric acid solution was added to the remaining residue, followed by thorough stirring and filtration. The white solid filtrate was washed with water, dried and then washed again with diethyl ether to give the product (75.3 g) as a white solid.

Melting point: 155 ℃

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 7.74 (d, 1H, J = 15.6Hz), 7.56~7.35 (m, 7H), 6.88 (d, 2H, J = 8.9Hz), 6.57 (d, 1H, J = 15.6 Hz), 3.79 (s, 3H);

¹³ C NMR (75 MHz, CDCl 3) ?: 164.9, 157.1, 142.4, 135.4, 132.0, 130.4, 129.5, 128.6, 122.6, 121.8, 114.8, 56.1

IR (KBr): 1661 cm ^-1

Example 2

(2R, 3S) -N- (4-methoxyphenyl) -2,3-dihydroxy-3-phenylpropionamide

(0.384 g, 0.494 mmol), potassium ferricyanide (19.50 g, 59.22 mmol), potassium carbonate (8.18 g, 59.22 mmol), methanesulfone Amide (1.88 g, 19.74 mmol) was dissolved in a solvent (t-BuOH: H2O = 1: 1, 150 mL) at 0 ° C and stirred for 30 minutes. Osmethyl tetroxide (0.050 g, 0.197 mmol) was added and stirred for 1 hour.

After stirring, N- (4-methoxyphenyl) -cinnamamide (5.0 g, 19.74 mmol) was added and vigorously stirred. When the reaction is complete (about 17 hours), sodium metasulfide (5.63 g, 29.61 mmol) is added, stirred for 30 minutes and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was recrystallized in ethanol to obtain a white solid (5.30 g).

Melting point: 199 ~ 201 ℃

[?] _D = +81.2 (c 0.13 MeOH)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 9.44 (S, 1H), 7.58 (d, 2H, J = 9.0Hz), 7.42~7.22 (m, 5H), 6.87 (d, 2H, J = 9.0Hz) , 5.52 (d, 1H, J = 6.5 Hz), 5.39 (d, 1H, J = 6.5 Hz), 4.97 (dd, J = 4.8 Hz, J = 2.8 Hz), 4.07 = 2.8 Hz), 3.72 (s, 3H)

¹³ C NMR (75 MHz, d ⁶ -DMSO)?: 174.6, 159.3, 147.0, 135.7, 131.6, 130.7, 130.6, 125.0, 117.7, 80.3, 77.4, 59.1

IR (KBr): 1644 cm ^-1

Example 3

(2S, 3R) -N- (4-methoxyphenyl) -2-acetoxy-3-bromo-3-phenylpropionamide

3-phenylpropionamide (5.0 g, 17.4 mmol) was dissolved in acetonitrile (100 ml) and para-toluenesulfonic acid ((2R, 0.045 g, 0.26 mmol) and trimethyl orthoacetate (5.62 mL, 44.0 mmol) were added, and the mixture was stirred for 1 hour. The solvent was distilled off, acetonitrile (100 ml) was added again, and the temperature was cooled to minus 15 ° C. Acetyl bromide (2.68 mL, 33.1 mmol) was slowly added dropwise and stirred for 3 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. And recrystallized in a mixed solvent of benzene and hexane at a volume ratio of 2: 1 to obtain a target compound (6.47 g) as a white solid.

Melting point: 148 ℃

[?] _D = -18.3 (c 1.13, CHCl3)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 7.38~7.26 (m, 5H), 7.16 (d, 2H, J = 8.7Hz), 6.75 (d, 2H, J = 8.7Hz), 5.73 (d, 1H, J = 6.6Hz), 5.45 (d, 1H, J = 6.6Hz), 3.71 (s, 3H), 2.05

¹³ C NMR (75 MHz, CDCl ₃ )?: 170.1, 165.1, 158.0, 137.3, 130.0, 129.7, 129.3, 129.2, 114.9, 77.3, 56.1, 51.1, 21.3

IR (KBr) cm ^-1 : 1755, 1601

Example 4

(3R, 4S) -N- (4-methoxyphenyl) -3-acetoxy-4-phenyl-2-azetidinone

(2S, 3R) -N- (4-methoxyphenyl) -2-acetoxy-3-bromo-3-phenylpropionamide (11.10 g, 28.30 mmol) was dissolved in dry tetrahydrofuran. A tetrahydrofuran solution (29.60 mL, 113.2 mmol) of 1 M tetrabutylammonium fluoride was added and stirred for 3 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Recrystallization from methanol gave the desired compound as a white solid (7.82 g).

Melting point: 144 ~ 145 ℃

_{[α] D = +10.8 (c} 0.74, CH 2 Cl 2)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 7.35~7.26 (m, 7H), 6.81 (d, 2H, J = 9.0Hz), 5.94 (d, 1H, J = 4.9Hz), 5.34 (d, 1H, J = 4.9 Hz), 3.75 (s, 3H), 1.68 (s, 3H)

¹³ C NMR (75 MHz, CDCl ₃ )?: 170.0, 162.0, 157.3, 133.0, 131.0, 129.5, 129.2, 128.6, 119.5, 115.1, 77.1, 62.1, 56.1, 20.5

IR (KBr) Cm ^-1 : 1760, 1730 cm ^-1

Example 5

(3R, 4S) -3-acetoxy-4-phenyl-2-azetidinone (oxidizing agent: ceric ammonium nitrate)

To a solution of (3R, 4S) -N- (4-methoxyphenyl) -3-acetoxy-4-phenyl-2-azetidinone (2.10 g, 7.11 mmol) in acetonitrile (10 mL) Lt; / RTI > An aqueous solution (30 mL) of seric ammonium nitrite (11.6 g, 21.33 mmol) was slowly added dropwise. The mixture was stirred for 1 hour while taking care not to change the temperature when added dropwise. It was diluted with 20 mL of water and extracted with ethyl acetate. The organic layer was wiped once with water, and the aqueous layer was extracted once more. The combined organic layers were washed with 10% sodium sulfite, dried over anhydrous magnesium sulfate and the solvent was evaporated. Recrystallization from methanol gave the desired compound as a white solid (78%).

Example 6

(3R, 4S) -3-acetoxy-4-phenyl-2-azetidinone (oxidizing agent: ozone)

(3.10 g, 10.5 mmol) was dissolved in dry dichloromethane and ozone was injected at 10 < 0 > C. Respectively. After the reaction was completed, dimethyl sulfide (1.16 mL, 15.8 mmol) was added and stirred for 3 hours. The reaction mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated by silica gel chromatography (EtOAc: Hexane = 2: 1) to obtain the target compound as a white solid (1.3 g).

Melting point: 181 ℃

[[alpha]] _D = -15.7 (c 1.04, MeOH)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 7.65 (br, 1H), 7.32 (d, 5H, J = 5.8Hz), 5.84 (m, 1H), 4.99 (d, 1H, J = 4.6Hz), 1.66 (s, 3 H)

¹³ C NMR (75 MHz, CDCl 3)?: 169.6, 166.2, 135.5, 128.8, 128.0, 78.7, 58.1, 20.3

IR (KBr) cm ^-1 : 1760, 1726

Example 7

Preparation of (3R, 4S) -hydroxy-4-phenyl-2-azetidinone

(0.70 g, 3.41 mmol) was dissolved in methanol (10 mL), and a saturated sodium bicarbonate aqueous solution (5 mL) and sodium carbonate ( 0.036 g, 0.34 mmol) at room temperature, and the mixture was stirred for 4 hours. When the reaction was completed, sodium carbonate was removed by filtration, and the solvent was distilled off to obtain the target compound as a white solid (0.51 g).

Melting point: 187 ℃

[[alpha]] _D = +180.2 (c 1.04, MeOH)

^{1 H NMR (300MHz, d 6} -DMSO) δ: 8.47 (br, 1H), 7.35~7.24 (m, 5H), 5.82 (d, 1H, J = 6.8Hz), 4.95 (br, 1H), 4.70 ( d, 1 H, J = 4.5 Hz)

IR (KBr) cm ^-1 : 1728

(3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of the present invention represented by the general formula (I) of the present invention is optically pure with high yield as well as industrially useful by the present invention , It can be widely used as an anticancer drug raw material.

The present invention is extremely industrially advantageous in that not only all intermediates and final products can be obtained at high yields by very simple reaction conditions and simple purification methods, but also all reaction conditions are very simple processes suitable for large-scale production.

Claims (17)

(2R, 3S) -2,3-dihydroxy-3-phenylpropionamide represented by the general formula (6) by subjecting the trans-cinnamamide derivative of the general formula (5) A first step of preparing a derivative; (2S, 3R) -2,3-dihydroxy-3-phenylpropionamide derivative of general formula (6) prepared in the first step is halocarboxylated to obtain (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative; (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of general formula (8) prepared in the second step is reacted with a base in an aprotic organic solvent to obtain 3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound; (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound of general formula (10) prepared in the third step is reacted with an oxidizing agent in an organic solvent, , 4S) -3-carboxy-4-phenylazetidin-2-one derivative; And (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative of the general formula (11) prepared in the fourth step is hydrolyzed to obtain the (3R, 4S ) -3-hydroxy-4-phenylazetidin-2-one; (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1). (I) (5) In the formula, R represents para-methoxyphenyl or 3,4-dimethoxyphenyl group. (6) Wherein R is as defined above. (8) In the formula, R is as defined above, R 'represents a hydrogen atom, a C1-12 alkyl group or a phenyl group, and X represents a chlorine atom, a bromine atom or an iodine atom. (10) Wherein R and R 'are as defined above. (11) Wherein R 'is as defined above. The method of claim 1, wherein the catalyst of the first step is selected from the group consisting of osmium tetroxide (OsO ₄ ) or potassium osmate dihydrate (K ₂ OsO ₄ .2H ₂ O) (9-O-dihydroquininyl) pyridazine, dihydroquinine 4-chlorobenzoate or 1, 3-bis (9-O-dihydroquininyl) phthalazine, A polymer polymer using 4-bis (9-O-quininyl) phthalazine or 3,6-bis (9-O-quininyl) pyridazine as a chiral monomer, or a compound in which these monomers are chemically bonded to silica gel, ≪ / RTI > is used as a ligand. 3. The process according to claim 2, wherein the chiral ligand is stirred with potassium ferricyanide and potassium carbonate in a mixed solvent of tertiary butanol and water for a certain period of time. The process according to claim 1, wherein the second step is a step of reacting a compound of formula (6) with bromic acid in acetic acid. (6) Wherein R is as defined in claim 1. The process according to claim 1, wherein the second step is a step of reacting a compound of the general formula (6) with a trialkyl orthocarboxylate in a solvent selected from the group consisting of dichloromethane or acetonitrile . (6) Wherein R is as defined in claim 1. 6. The process according to claim 5, wherein said second step is carried out in the presence of para-toluenesulfonic acid catalyst. 6. The method of claim 5, wherein the trialkyl orthocarboxylate is selected from the group consisting of trimethyl orthoacetate, trimethyl orthoformate, trimethyl ortho butyrate, trimethyl ortho valerate, trimethyl orthoformate, trimethyl orthobenzoate, tri Is at least one member selected from the group consisting of ethyl orthoacetate, triethyl orthoformate, triethyl ortho butyrate, triethyl ortho valerate, triethyl orthoformate and triethyl ortho benzoate. Gt; 6. The process according to claim 5, wherein the second step is carried out by adding sodium iodide, iodotrimethylsilane and a mixture of acetyl chloride, acetyl bromide, chlorotrimethylsilane, bromotrimethylsilane or acetyl chloride. The method according to claim 1, characterized in that a mixture of sodium hydride, potassium hydride, n-butyl lithium, tetrabutylammonium fluoride or cesium fluoride and a catalytic amount of tetraalkylammonium chloride is used as the base in the third step . The method according to claim 1, wherein as the non-magnetic solvent in the third step, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dichloromethane, dimethyl ≪ / RTI > wherein the solvent is formamide or dimethylsulfoxide. The production method according to claim 1, wherein acetonitrile is used as the organic solvent in the fourth step and ceric ammonium nitrate is used as the oxidizing agent. The production method according to claim 1, wherein dichloromethane is used as the organic solvent in the fourth step and ozone is used as the oxidizing agent. The process according to claim 1, wherein the fifth step is carried out in a saturated sodium bicarbonate aqueous solution and methane in a solvent. A novel (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative represented by the following general formula (6). (VI) Wherein R is as defined in claim 1. A novel (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative represented by the following general formula (8). (8) Wherein R, R 'and X are as defined in claim 1. A cyclized orthoester derivative represented by the following general formula (9). (9) Wherein R and R 'are as defined above and R " is a methyl, ethyl or propyl group. A novel N-substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative represented by the following general formula (10) (10) Wherein R and R 'are as defined in claim 1.