KR100275785B1 - Preparation method of (3r,4s)-hydroxy-4-phenylazetidine-2-one and intermediates thereof - Google Patents

Abstract

PURPOSE: Provided are a preparation method of (3R,4S)-hydroxy-4-phenylazetidine-2-one and its intermediate, represented by formula(1), wherein the intermediate is a vital intermediate in the synthesis of taxane based anti-cancer agents. The method provides optically pure compound of the formula(1) in high yield. CONSTITUTION: The method of preparation comprises: reacting trans-cinnamamide derivatives(formula 5) with unsymmetric dihydroxy catalyst to obtain (2R,2S)-2,3-dihydroxy-3-phenylpropionamide derivative(formula 6); halocarboxylating the above compound(formula 6) to prepare (2R,2S)-2-carboxy-3-halo-3-phenylpropionamide derivative(formula 8); reacting the above compound(formula 8) with base in a non protonic solvent to manufacture (3R,4S)-3-carboxy-4-phenylazetidine-2-one derivative(formula 10); reacting the above compound(formula 10) with oxidant in the organic solvent to manufacture (3R,4S)-3-carboxy-4-phenylazetidine-2-one derivative(formula 11); and hydrolyzing number 3 carbon atom of the above compound(formula 11) to manufacture the title compound(formula 1).

Description

Method for preparing (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one and intermediates thereof

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

Since the compound of Formula (1) is a precursor of N-substituted (2R, 3S) -3-phenylisoserine of Formula (3), which is a side chain substituent of the taxane-based anticancer agent represented by the following Formula (2), It is an intermediate required for the synthesis | combining process of the compound of Formula (2).

The taxane-based compound represented by 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 (TaXOl), and R is a tert-butoxide (t- BuO) group and when R 'is a hydrogen atom, it is called docetaxel or taxotere.

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

Among the taxanes represented by the general formula (2) showing excellent efficacy on ovarian cancer and breast cancer, paclitaxel, which is useful as an anticancer agent, is obtained from the bark of the Pacific yew tree. However, the yield of the extract is so low that it cannot be supplied in large quantities, and moreover, serious natural damage is expected when producing in large quantities. On the other hand, from the leaves or twigs of the European yew tree, 10-deacetyl-baccatin-III represented by the general formula (4) having both the skeleton and functional groups of the ring of paclitaxel. ) Is extracted, which has the advantage that the yield of the extract is relatively high, as well as renewable leaves or twigs as raw materials. The newly developed anticancer agent docetaxel is prepared through a pure synthetic route from 10-diacetyl-baccatin-III represented by the general formula (4).

Therefore, paclitaxel starting from 10-diacetyl-baccatin-III represented by the general formula (4) and 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.

However, a well-known document relating to the semisynthetic step of the taxane-based anticancer agent of the general formula (2) using 10-diacetyl-baccatin-III represented by the general formula (4) [Eur. 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)], (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1) and 10-diacetyl of formula (4) A semisynthetic step for preparing the compound of formula (2) using the baccatin-III compound as a starting material is obtained by using N-benzoyl (2R, 3S) -3-phenylisoserine of formula (3) and formula (4). It is known that the yield and the optical purity of the product are much higher than those of the semi-synthesis process prepared using the 10-diacetyl-baccatin-III compound of) as a starting material. (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1) may be used in place of N-substituted (2R, 3S) -3-phenylisoserine of formula (3) In case of not only high yield of binding to 10-diacetyl-baccatin-III of general formula (4) but also partial isomerization reaction of some carbon position (C-2 'position) of compound of general formula (2) This rarely occurs because the optical purity of the product is greatly improved.

However, until now, the preparation of (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1) was not easy, and instead of the compound of the general formula (1) The compound of 3) has been used.

In fact, due to the usefulness of (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by the general formula (1), a lot of research has been conducted on the preparation method thereof. As follows.

European Patent Application EP 400,971 discloses cis-para-methoxyphenyl-3-acetase of racemic mixtures by the addition of para-methoxyphenylbenzaldehyde and acetoxyethylchloride in the presence of a base. Toxoxy-4-phenylazetidin-2-one was prepared from which (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1) was prepared as a racemic mixture. They were used to optically divide using optically pure methoxy-2- (trifluoromethyl) -phenylacetylchloride.

Meanwhile, another known method [J. Org. Chem., 56, 1681 (1991); Tetrahedron, 48, 6985 (1992); Tetrahedron Lett., 32, 3151 (1991)], describes the reaction of chiral enolate compounds with N-trimethylsilyl benzaldimine and chiral adjuvant at 2,2'-cyclic addition reaction (2,2 ') at -78 ° C. -(cycloaddition) to prepare (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of the general formula (1).

However, the first method uses an inefficient optical splitting method, which is complicated in the manufacturing process, the yield cannot be more than 50%, and requires several purification processes. The second method is extremely sensitive to the minute moisture in the atmosphere. There is a problem in that the reaction temperature is used to hydrolyze, and in the industrial aspect, the reaction temperature is too cryogenic and an expensive chiral adjuvant must be used in one equivalent or more. Thus, these known methods may be useful on a laboratory scale, but there are many difficulties to produce on an industrial scale of (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1). there was.

Accordingly, the present invention solves the problems of the prior art as described above, and is (3R, 4S) -3-hydroxy-4-phenyl of formula (1) which is optically pure with industrial yield as well as high yield. It is intended to provide a new and advanced process for preparing azetidin-2-ones.

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.

The present invention is a key intermediate required for the semi-synthesis process of paclitaxel useful as an anticancer agent in the taxane system represented by the general formula (2) showing excellent efficacy for ovarian cancer and breast cancer as described above, which is represented by the general formula (1) N-substituted by the general formula (3) wherein (3R, 45) -3-hydroxy-4-phenylazetidin-2-one represented is the side chain of the C13-position of the taxane-based compound represented by the general formula (2) This is because it is a precursor of (2R, 3S) -3-phenylisoserine. The present invention also relates to new intermediates in the preparation of (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one represented by formula (1).

The manufacturing method of the present invention,

In the presence of a catalyst, (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide represented by the general formula (6) by carrying out an asymmetric dihydroxy catalysis of the trans-cinnaamide derivative of the general formula (5) A first step of preparing a derivative;

The (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) prepared in the first step was halocarboxylated to (2S, 3R) of the general formula (8). A second step of preparing a 2-carboxy-3-halo-3-phenylpropionamide derivative;

The (2R, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of formula (8) prepared in the second step was reacted with a base in an aprotic organic solvent to give N of formula (10). A third step of preparing a substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound;

The N-substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative of general formula (10) prepared in the third step was reacted with an oxidizing agent in an organic solvent to give general formula (11) A fourth step of preparing a (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative of; And

Hydrocarbon number 3 of the (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative of the general formula (11) prepared in the fourth step was hydrolyzed to (3R, 4S of the general formula (1) A fifth step of preparing) -3-hydroxy-4-phenylazetidin-2-one;

It consists of.

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

Wherein R is as defined above.

In formula, R 'is a hydrogen atom, a C1-C12 alkyl group, a phenyl group, and R "represents a methyl, ethyl or a propyl group.

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

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

Wherein R and R 'are as defined above.

Wherein R 'is as defined above. In the manufacturing method of the present invention, each step is described in detail as follows.

Step 1: The catalyst used in the reaction of the first stage / osmium tetroxide (OsO ₄₎ or potassium formate trehalose dihydrate _{(K 2 0s0 4 .2H 2 O} ) in the metal component of the catalyst, 1,4- Bis (9-0-dihydroquininyl) phthalazine, 3,6-bis (9-0-dihydroquininyl) pyridazine, dihydroquinine 4-chlorobenzoate, or 1,4-bis (9 Prepared using chiral ligand, a polymer polymer using -0-quinynyl) phthalazine or 3,6-bis (9-0-quinynyl) pyridazine as chiral monomer or a compound chemically bonded to silica gel with these monomers do. In the presence of the catalyst thus prepared, (2R, 3S) -2,3-dihydroxy-3- represented by the general formula (6) by reacting a trans-cinnaamide derivative of the general formula (5) with an asymmetric dihydroxy catalyst reaction It consists of making phenylpropionamide derivatives.

1,4-bis (9-0-dihydroquininyl) phthalazine, 3,6-bis (9-O-di, in order to catalyze the trans-cinnaamide derivatives of the general formula (5) Conventional synconal alkaloid ligands for asymmetric dihydration reactions such as hydroquininyl) pyridazine and dihydroquinine 4-chlorobenzoate, together with potassium ferricyanide (K ₃ Fe (CN) ₆ ) and potassium carbonate, are tertiary Stir for a certain period of time in a mixed solvent of butanol and water. In this case, it is preferable to use 0.002 to 0.10 equivalents for the cinnacoalkaloid ligand, 2 to 4 equivalents for potassium ferricyanide and 2 to 4 equivalents for potassium carbonate. The tert-butanol and water used as the solvent are preferably used in a volume ratio of 1: 1 to 2: 1, and the stirring is preferably performed for 5 to 60 minutes.

After stirring was completed, an aqueous solution of osmium tetroxide or potassium osmate (preferably 0.002 to 0.02 equivalents) was added and stirred for a while, followed by trans-cinnamamide derivative of general formula (5) and methanesulfonamide (preferably Add about 1 equivalent) and react for about 12-30 hours between 0 ° C and 30 ° C. Thereafter, the (2R, 3S) -2,3-dihydroxy-3-phenylopionamide derivative of the general formula (6) is separated through a conventional separation process such as recrystallization or chromatography.

The optically pure compound of the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) is easily prepared by a simple recrystallization purification method using a solvent such as toluene methanol, ethanol or isopropanol. You can get it.

In addition, the asymmetric dihydroxide catalysis of the trans-cinnaamide derivatives of the general formula (5) was carried out by the present inventors in addition to the conventional cinnaconalkaloid derivatives described above. Cinconal alkaloid polymers using tallazine or 3,6-bis (9-0-quinynyl) pyridazine as chiral monomers or cinnaconaloid derivatives in which these monomers are bonded to silica gel are used as non-uniform chiral ligands. Can be advanced by the method [Song, CE, ROh, EJ, Lee, SG, Kim, IO, Tetrahedron: asymmetry, 6, 2687 (1995); Song, C. E., Yang, J. W., Ha, H. J., Lee, S. G., Tetrahedron: Asymmetry, 7, 645 (1996); Song, C. E., Yang, J. W., Ha, H. J., Tetrahedron: Asymmetry, 8, 841] (1997).

The heterogeneous cinnacoalkaloid derivatives prepared by the present inventors exhibited the activity and optical selectivity of the same catalysts as the above-mentioned homogeneous catalysts in the asymmetric dihydroxide catalyst reaction of the trans-cinnaamide derivatives of general formula (V). However, the complex of the expensive and highly toxic osmium tetroxide and alkaloid ligand was easily filtered off from the reaction solution after the completion of the reaction, and the efficiency of the catalyst, in particular, the enantioselectivity of the catalyst was almost maintained, allowing reuse of these catalyst systems. Do.

In one step, the compound of formula (6) is prepared in a yield of 90% or more.

Second step: 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 a general formula (8). To (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative.

As a first method of halocarboxylating the (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6), (2R, 3S)-of the general formula (6) The 2,3-dihydroxy-3-phenylpropionamide derivative and bromic acid (HBr) are reacted in an acidic solvent (for example, acetic acid) to give (2S, 3R) -2-carboxy- of formula (8). There is a method of preparing 3-halo-3-phenylpropionamide derivatives. At this time, it is preferable to use bromic acid in 2 to 10 equivalents, and the reaction time is preferably about 1 to 2 hours at 20 to 50 ° C., which is prepared in a yield of 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 α-acetoxyisobuty Although it may be directly reacted with reyl bromide or acetylsalicyloyl bromide, in consideration of economics, a method of reacting with bromic acid in an acidic solvent (preferably acetic acid) is more preferable.

Another method for preparing the (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of the general formula (8) is in the presence of an acid catalyst in dichloromethane or acetonitrile solvent (e.g., para -Toluenesulfonic acid, etc.), (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) and the trialkyl orthocarboxylate represented by the general formula (7) The reaction is carried out at about 0 ° C. to room temperature to prepare orthoester of generalized formula (9).

Examples of the trialkyl orthocarboxylate represented by the general formula (7) include trimethyl ortho acetate, trimethyl ortho propionate, trimethyl ortho butyrate, trimethyl ortho valerate, trimethyl ortho formate, and trimethyl ortho Benzoate, triethyl ortho acetate, triethyl ortho propionate, triethyl ortho butyrate, triethyl ortho valerate, triethyl ortho formate, triethyl ortho benzoate and the like.

Instead of distilling off only the resulting alcohol and solvent and not subjecting to separate separation and purification, a residue containing cyclized orthoester of general formula (9) is immediately added in a solvent such as dichloromethane, acetonitrile, or benzene. A mixture of iodotrimethylsilane or sodium iodide (NaI) and acetylchloride, acetylbromide, bromotrimethylsilane, chlorotrimethylsilane, or acetylchloride at a temperature between 40 ° C. and 0 ° C. for a period of time, preferably 2 It is made to react for 6 hours, and the (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative represented by General formula (8) is manufactured.

Third Step In the third step, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dichloromethane, dimethylformamide, dimethylsulfoxide and the like In the aprotic organic solvent of (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of the general formula (8), 1 equivalent of sodium hydride, potassium hydride, n-butyllithium N-substituted (3R, 4S) -3 represented by general formula (10) by reacting a base such as tetra-n-butylammonium fluoride, or a mixture of cesium fluoride and a catalytic amount of tetraalkylammonium chloride. To prepare a carboxy-4-phenylazetidin-2-one derivative. At this time, the base is preferably used in one equivalent, the reaction time is preferably 1 to 3 hours at a temperature of 0 ~ 30 ℃.

Step 4: In acetonitrile solvent, ceric ammonium nitrate ((NH ₄ ) ₂ Ce (N0 ₃ ) ₆ ) as oxidant and N-substituted compound of formula (10) prepared in step 3 (3R, 4S) )-3-carboxy-4-phenylazetidin-2-one derivatives are reacted (preferably for about 1 to 2 hours at between 0 ° C and 5 ° C) to (3R, 4S) -3 of general formula (11) -Carboxy-4-phenylazetidin-2-one compound is prepared. At this time, the yield is about 80% or more. Alternatively, instead of reacting with ceric ammonium nitrate in an acetonitrile solvent, the N-alkyl substituted compound of the formula (10) is reacted at 0 ° C. to 15 ° C. using ozone as the oxidant in a dichloromethane solvent. Even in this case, the (3R, 4S) -3-carboxy-4-phenylazetidin-2-one compound of the general formula (11) may be prepared at a yield of about 50% or more.

5th step: (3R, 4S) -3-carboxy-4-phenylase of the general formula (11) prepared in the 4th step in a saturated sodium bicarbonate aqueous solution and methanol solvent which are the usual hydrolysis reaction conditions. A thidin-2-one derivative is reacted (preferably for about 1 to 3 hours at 10 to 30 DEG C) to undergo a hydrolysis reaction of the 3-position carboxyl group of the compound of the general formula (11) to give the general target compound (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1) is prepared.

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) -cinnaamide

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

Melting Point: 155 ℃

Example 2

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

1,4-bis (9-0-dihydroquininyl) phthalazine (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: H 2 O = 1: 1, 150 mL) at 0 ° C and stirred for 30 minutes. Osmium tetroxide (0.050 g, 0.197 mmol) was added and stirred for 1 hour.

After stirring, N- (4-methoxy phenyl) -cinnamid (5.0 g, 19.74 mmol) was added and stirred vigorously. When the reaction was terminated (about 17 hours), sodium metabisulfide (5.63 g, 29.61 mmol) was added, stirred for 30 minutes and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off and recrystallized from ethanol to give a white solid product (5.30g).

Melting Point: 199 ~ 210 ℃

[α] _D = +81.2 (c 0.13 MeOH)

Example 3

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

(2R, 3S) -N- (4-methoxyphenyl) -2,3-dihydroxy-3-phenylpropionamide (5.Og, 17.4 mmol) was dissolved in acetonitrile (100m1) and para-toluenesulfonic acid (0.045 g, -0.26 mmol) and trimethylorthoacetate (5.62 mL, 44.0 mmol) were added and stirred for 1 hour. The solvent was distilled off and acetonitrile (100m1) was added thereto, 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 complete, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Recrystallized from a mixed solvent of benzene and hexane in a volume ratio of 2: 1 to obtain the title compound (6.47g) as a white solid.

Melting Point: 148 ℃

Example 4

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

(25,3R) -N- (4-methoxyphenyl) -2-acetoxy-3-bromo-3-phenylpropionamide (11.10 g, 28.30 mmol) was dissolved in dried tetrahydrofuran. A tetrahydrofuran solution (29.60 mL, 113.2 mmol) of 1 M tetrabutylammonium pullolide was added and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Recrystallization from methanol gave the target compound as a white solid (7.82 g).

Melting Point: 144 ～ 145 ℃

Example 5

Preparation of (3R, 4S) -3-acetoxy-4-phenyl-2-azetidinone (oxidizing agent: Ceric ammonium nitriate)

(3R, 4S) -N- (4-methoxyphenyl) -3-acetoxy-4-phenyl-2-azetidinone (2.10 g, 7.11 mmol) was dissolved in acetonitrile (10 mL) and the temperature was -5 ° C. Cooled to. Aqueous solution of ceric ammonium nitrate (11.6 g, 21.33 mmol) (30 mL) was slowly added dropwise. The mixture was stirred for 1 hour while being careful not to change the temperature at the time of dropping. Diluted with 20mL of water and extracted with ethyl acetate. The organic layer was washed 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 in methanol gave the desired compound as a white solid (78%).

Example 6

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

Dissolve (3R, 4S) -N- (4-methoxyphenyl) -3-acetoxy-4-phenyl-2-azetidinone (3.10 g, 10.5 mmol) in dried dichloromethane and inject ozone at 10 ° C. It was. Upon completion of the reaction, dimethyl sulfide (1.16 mL, 15.8 mmol) was added and stirred for 3 hours. Extracted with dichloromethane, dried over anhydrous magnesium sulfate and distilled off the solvent. Separation by silica gel chromatography (EtOAc: Hexane = 2: 1) afforded the target compound as a white solid (1.3 g).

Melting Point: 181 ℃

[α] _D = -15.7 (c 1.04, MeOH)

Example 7

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

(3R, 4S) -3-acetoxy-4-phenyl-2-azetidino (0.70 g, 3.41 mmol) was dissolved in methanol (10 mL), followed by saturated aqueous sodium bicarbonate solution (5 mL) and sodium carbonate ( 0.036 g, 0.34 mmol) was added at room temperature and stirred for 4 hours. After the reaction was completed, the resultant was filtered to remove sodium carbonate and the solvent was distilled off to obtain the title compound as a white solid (0.51 g).

Melting Point: 187 ℃

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

The present invention not only obtains all intermediates and end products in high yields by very simple reaction conditions and simple purification methods, but also is very industrially advantageous because all reaction conditions are made in a very simple process suitable for large scale production.

Claims (17)

In the presence of a catalyst, (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide represented by the general formula (6) by carrying out an asymmetric dihydroxy catalysis of the trans-cinnaamide derivative of the general formula (5) A first step of preparing a derivative; The (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative of the general formula (6) prepared in the first step was halocarboxylated to (2S, 3R) of the general formula (8). A second step of preparing a 2-carboxy-3-halo-3-phenylpropionamide derivative; (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative of the general formula (8) prepared in the second step was reacted with a base in an aprotic organic solvent to A third step of preparing a 3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound; The (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative compound of the general formula (10) prepared in the third step was reacted with an oxidizing agent in an organic solvent to give (3R) of the general formula (11) A fourth step of preparing a 4S) -3-carboxy-4-phenylazetidin-2-one derivative; And hydrolyzing the carbon atom 3 of the (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative of the general formula (11) prepared in the fourth step to obtain (3R, A fifth step of preparing 4S) -3-hydroxy-4-phenylazetidin-2-one; A method for producing (3R, 4S) -3-hydroxy-4-phenylazetidin-2-one of formula (1), comprising: In the formula, R represents a para-methoxyphenyl or 3,4-dimethoxyphenyl group. Wherein R is as defined above. Wherein R is as defined above, R 'represents a hydrogen atom, an alkyl group or phenyl group of C1-12, and X represents a chlorine atom, bromine atom or iodine atom, respectively. Wherein R and R 'are as defined above. Wherein R 'is as defined above. The method of claim 1, wherein the catalyst of the first stage is the one selected from the group consisting of osmium tetroxide (OsO ₄₎ or potassium formate trehalose dihydrate _{(K 2 0s0 4 .2H 2 0} ) to the metal component of the catalyst 1,4-bis (9-0-dihydroquininyl) phthalazine, 3,6-bis (9-0-dihydroquininyl) pyridazine, dihydroquinine 4-chlorobenzoate or 1, Chiral polymers using 4-bis (9-0-quininyl) phthalazine or 3,6-bis (9-0-quininyl) pyridazine as chiral monomers or compounds in which these monomers are chemically bonded to silica gel Method for producing, characterized in that used as a ligand. The method according to claim 2, wherein the chiral ligand is stirred in a mixed solvent of tertiary butanol and water together with potassium ferricinide and potassium carbonate for a predetermined time. The method of claim 1, wherein the second step is reacting the compound of formula (6) with bromic acid in acetic acid. Wherein R is as defined in claim 1. The process according to claim 1, wherein the second step is a reaction of the compound of formula (6) with trialkyl orthocarboxylate in one solvent selected from the group consisting of dichloromethane or acetonitrile. . Wherein R is as defined in claim 1. 6. A process according to claim 5, wherein said second step is carried out in the presence of a para-toluenesulfonic acid catalyst. The method of claim 5, wherein the trialkyl ortho carboxylate is trimethyl ortho acetate, trimethyl ortho propionate, trimethyl ortho butyrate, trimethyl ortho valerate, trimethyl ortho formate, trimethyl ortho benzoate, tri At least one selected from the group consisting of ethyl ortho acetate, triethyl ortho propionate, triethyl ortho butyrate, triethyl ortho valerate, triethyl ortho formate and triethyl orthobenzoate Manufacturing method. The method of claim 5, wherein the second step is reacted by adding a mixture of sodium iodide or iodine trimethylsilane and acetyl chloride, acetyl bromide, chlorotrimethylsilane, bromotrimethylsilane, or acetyl chloride. The method of claim 1, wherein a mixture of sodium hydride, potassium hydride, n-butyllithium, tetrabutylammonium fluoride or cesium fluoride and a catalytic amount of tetraalkylammonium chloride is used as the base of the third step. Manufacturing method. The method of claim 1, wherein the aprotic solvent of the third step is diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dichloromethane, dimethyl. A process characterized by using formamide or dimethyl sulfoxide. The method according to claim 1, wherein acetonitrile is used as the organic solvent of the fourth step and ceric ammonium nitrate is used as the oxidizing agent. The process according to claim 1, wherein dichloromethane is used as the organic solvent of the fourth step and ozone is used as the oxidizing agent. The method of claim 1, wherein the fifth step is carried out with a saturated aqueous sodium bicarbonate solution and methane in a solvent. The novel (2R, 3S) -2,3-dihydroxy-3-phenylpropionamide derivative represented by following General formula (6). Wherein R is as defined in claim 1. The novel (2S, 3R) -2-carboxy-3-halo-3-phenylpropionamide derivative represented by following General formula (8). Wherein R, R 'and X are as defined in claim 1. The cyclized orthoester derivative represented by the following general formula (9). Wherein R and R 'are as defined above and R " is a methyl, ethyl or propyl group. The novel N-substituted (3R, 4S) -3-carboxy-4-phenylazetidin-2-one derivative represented by the following general formula (10). Wherein R and R 'are as defined in claim 1.