KR20080086629A - Process for preparing optically pure oxoribose derivatives - Google Patents

Abstract

A process for preparing optically pure oxoribose derivatives is provided to improve economical efficiency of preparation, reaction yield, preparation simplicity and purity of oxoribose derivatives by using a novel intermediate, so that enantiomers of oxoribose derivatives are selectively prepared. A process for preparing optically pure oxoribose derivatives represented by the formula(I-D) or (I-L) comprises the steps of: (1) reacting ethyl 3-hydroxy propionic acid ester compounds represented by the formula(V) with optically pure amine-based compounds to prepare optically pure 3S- or 3R-hydroxy propane amide derivatives represented by the formula(II-R) and the formula(II-S); (2) protecting the compounds represented by the formula(II-R) and the formula(II-S) with a hydroxyl group to prepare compounds represented by the formula(IV-R) and the formula(IV-S); (3) reacting the compounds represented by the formula(IV-R) and the formula(IV-S) with acid to prepare 5-hydroxy-1-oxo-ribose compounds having erythro or threo structure, represented by the formula(III-D) and the formula(III-L); and (4) protecting the compounds represented by the formula(III-D) and the formula(III-L) with 5-hydroxyl group, wherein R and R1 are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4-t-butylbenzoyl, [1,1'-biphenyl]-4-carbonyl, 1-naphtoyl or 2-naphtoyl group; R2 and R3 are each independently C1-C3 alkyl; R4 is methyl or ethyl group; and R5 is hydrogen, methyl, methoxy or Cl.

Description

Process for preparing optically pure oxoribose derivatives

The present invention relates to a D-erythro-2,2-difluoro-2-deoxy-1-oxoribose compound represented by the following formula (I-D) and L-threo-2,2-difluoro represented by the formula (I-L). It relates to a method for producing a rho-2-deoxy-1-oxoribose compound.

[Formula I-D]

[Formula I-L]

Wherein R and R ₁ are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4- as protecting groups t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group.

Stereochemically, the compound of the formula (I) has an erythro enantio oriented downward as shown in the formula (I-D) according to the positional orientation of the hydroxyl group in which the hydroxyl or protecting group is introduced as the substituent at the 3-position of the lactone ring as shown above. It can be divided into erythro enantiomer and threo enantiomer which is oriented upward as shown in Chemical Formula I-L, and the naturally occurring nucleoside having pharmaceutically excellent activity is generally an erythro structure. To provide.

As a representative drug, Gemcitabin, a non-small cell lung cancer treatment agent, is an erythro compound having a structure in which a hydroxyl group at position 3 or a hydroxyl group introduced with a protecting group is oriented downward as shown below. The compound of can be used as an important intermediate.

Therefore, in order to prepare gemcitabine, an erythro compound having a structure in which a hydroxyl group at position 3 or a hydroxyl group introduced with a protecting group is oriented downward can be effectively synthesized 1-oxoribose compound of Formula I-D. The development of methods is very important.

Looking at a known method for preparing a 1-oxo ribose compound having an erythro structure, US Pat. No. 4,526,988 discloses 3R-hydroxy enantiomer (1) and 3S-hydroxy enantiomer (2) Process for preparing an erythro compound through 2,2-difluoro-3-hydroxy-3- (2,2-dialkyldioxoran-4-yl) propanoic acid alkyl ester mixed in a ratio of about 3 to 1 This is described.

When the 3R-hydroxy enantiomer (1) is reacted with a strong acid, the dioxolane group, which is a protecting group, is hydrolyzed and the lactonation reaction proceeds so that the 3-hydroxy group is oriented downward as shown in Scheme 1 below. An erythro structure of 2,2-difluoro-2-deoxy-D-erythro-1-oxoribose (3) is produced, while 3S-hydroxy enantiomer (2) is reacted to 3 -Treo compound (4) of the above oriented structure with opposite hydroxyl groups is produced.

Wherein R ₆ and R ₇ are each independently C ₁ to C ₃ alkyl.

Therefore, the 3R-hydroxy enantiomer (1) must be separated in a pure state to proceed with hydrolysis and lactonation reaction to selectively prepare the 1-oxoribose compound (3) having a desired erythro structure.

In this process, only 3R-hydroxy enantiomer (1) which is stereochemically suitable from a mixture of 3R-hydroxy enantiomer (1) and 3S-hydroxy enantiomer (2) in a three-to-one manner is purely Silica gel column chromatography was used for separation. However, the column chromatography method is not suitable for large scale production due to the limited size of the column and the amount of material to be loaded. Especially, the silica gel, which is a column filler, is expensive, and the development solvent must also be used in an excessive amount. It has the disadvantage of being expensive. In addition, the method has a problem that the reaction must be carried out for a long time at room temperature for 4 days to complete the lactonation reaction.

Meanwhile, US Pat. Nos. 4,965,374, 5,223,608 and 5,434,254 disclose 3-benzoyloxypropionate esters in which 3R- and 3S- are mixed in a 3-1 ratio, as shown in Scheme 2 below. ) By hydrolysis with an acid, and then azeotropically distilling water to minimize reverse reaction with the precursor to prepare a lactone ring (6) in which erythro and treo are mixed, and protect 5-hydroxy group with benzoyl. Process of preparing 3,5-dibenzoyloxy compound (7) and then cooling only the desired erythro-enantiomer (8) from the erythro and threo mixtures as a precipitate by cooling in dichloromethane to a low temperature of -5 ° C to 10 ° C. This is described.

In the above formula, Bz means benzoyl group.

This method is characterized in that the 3-benzoyl oxypropionate ester (5) mixed with 3R- and 3S- is used directly for the lactone ring reaction without separation, particularly 3,5- with a mixture of erythro and treo. By dissolving dibenzyl-1-oxo ribose compound (7) in a solvent and lowering the temperature to low temperature, only 3,5-dibenzoyl enantiomer (8) having a desired erythro structure can be easily separated and obtained. There is a characteristic. However, this method is a highly corrosive acid used in the lactone ring reaction, and uses an excess of 3 equivalents or more of trifluoroacetic acid, an expensive and highly toxic reagent, and especially 3-benzoyl oxypropionate ester (5) as a starting material. As a result, the overall reaction yield of obtaining 3,5-dibenzoyl enantiomer (8) is very low, which is only about 25%, which is disadvantageous in that it is uneconomical.

On the other hand, looking at the manufacturing method of the 3R- enantiomer and 3S-enantiomer used as precursor of the 1-oxo ribose compound, as described above, US Patent Nos. 4,526,988, 4.965.374, 5,233,608 and No. 5,434,254 describes a process in which 3R-enantiomers (1) and 3S-enantiomers (2) are produced in a ratio of about 3 to 1 via Reformatsky reaction. US Pat. Nos. 5,428,176 and 5,618,951 also include 2,2-difluoroketene silyl acetal (9) as glyceraldehyde derivatives (10) and 1,3-dimethylpropylene urea (as shown in Scheme 3 below). Reacted in a specific solvent such as DMPU), to which the 3R-silylhydroxy enantiomer optionally contains a high proportion of 2,2-difluoro-β-silyloxy-1,3-dioxolane-4-propanoic acid ester ( The manufacturing method of 11) is described.

Wherein R ₈ , R ₉ , R ₁₀ and R ₁₁ are alkyl groups, and R ₁₂ and R ₁₃ are C ₁ to C ₃ alkyl groups.

According to the above method, when the reaction proceeds in a specific solvent, the ratio of the 3R-compound and the 3S-compound is 7 to 1 to 10: 1, which shows that the 3R-compound having a desired structure is greatly increased. However, this method is also a state in which 2,2-difluoro-β-silyloxy-1,3-dioxolane-4-propanoic acid ester (11) is stericly mixed with 3R- and 3S-, and is not a solid. In order to obtain a 1-oxo ribose compound having a desired erythro structure because it is obtained as a liquid, there is a problem in that the precursor 3R-propanoic acid ester enantiomer must be separated through column chromatography.

In addition, Korean Patent Application No. 10-2004-0057711 introduces a three-dimensionally large protecting group to a hydroxyl group (13), and then treats with a base to obtain a 3R-enantiomer (14) as an optically pure salt, which is locked under strong acid conditions. A method of obtaining an enantiomer (16) having an erythro structure by performing a toning reaction was shown in the following Scheme 4.

Wherein R ₁₄ , R ₁₅ and R ₁₆ are C1 to C3 alkyl groups, R ₁₇ is a phenyl group or a phenyl group with a substituent, and M is NH ₃ , Na or K.

According to the above method, the compound used as the protecting group is biphenyl-4-carbonyl chloride and the like, which is generally higher in price than the benzoyl or naphthoyl compound used as the protecting group, wherein 3R-carboxylic acid ester enan Separation of the thiomers is possible but has the disadvantage that it is not possible to obtain 3S-carboxylic acid ester enantiomers.

As described above, the conventionally known method mainly performs column chromatography of 3R-hydroxy enantiomers, which are precursors, in order to synthesize 1-oxoribose compounds having an erythro structure by hydrolyzing 3R-hydroxy group enantiomers. It is not suitable for mass production methods because it is obtained by separation via a chromatography method or by introducing expensive protecting groups, and it is difficult to obtain 3R- and 3S-hydroxy compounds selectively, and even though 3R- and 3S-hydroxy compounds are Even when the lactonation reaction is completed in the state of the mixed mixture, erythro and threo enantiomers are mixed, so that the yield of selectively separating only erythro enantiomers from the 1-oxo ribose mixture is very low, which is uneconomical.

It is therefore an object of the present invention to provide a process for the selective production of 1-oxoribose compounds of L-threo or D-erythro structure with improved reaction yields than conventional methods.

Another object of the present invention is to provide a simpler and higher reaction yield in synthesizing 1-oxoribose compounds of the treo or erythro structures using the novel 3R- or 3S-hydroxypropane amide derivatives as intermediates.

According to the above object, in the present invention, an alkyl 3-hydroxy propanoic acid ester mixture containing 3R- and 3S-hydroxy enantiomers in a predetermined ratio is used to prepare 3-hydroxy propane amide derivative using optically pure amine. Recrystallization is carried out to perform lactonation of 3R- or 3S-hydroxy propane amide derivatives to obtain 2,2-difluoro-2-deoxy-1-oxoribose compounds having an erythro or threo structure. Provided are methods for producing the process efficiently and selectively.

Specifically, in the present invention

(1) reacting the ethyl 3-hydroxy propanoic acid ester compound of Formula V with an optically pure amine based compound to prepare a compound of Formula II, which is an optically pure 3S- or 3R-hydroxy propane amide derivative;

(2) protecting the hydroxy group of the compound of formula II with a protecting group to produce a compound of formula IV;

(3) reacting a compound of Formula IV with an acid to prepare a 5-hydroxy-1-oxoribose compound of Formula III having an erythro or threo structure; And

(4) L-threo or D-erythro-2,2-difluoro-2-deoxy-1- of formula I, comprising protecting the 5-hydroxy group of the compound of formula III by conventional methods Provided is a method for preparing an oxo ribose compound.

[Formula I-D]

[Formula I-L]

[Formula II-R]

[Formula II-S]

[Formula III-D]

[Formula III-L]

[Formula IV-R]

[Formula IV-S]

 [Formula Ⅴ]

Wherein R and R ₁ are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4- as protecting groups t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group, R ₂ and R ₃ are each independently C ₁ to C ₃ alkyl and R ₄ Is a methyl or ethyl group, R ₅ is hydrogen, methyl, methoxy or Cl.

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

The preparation method for the purpose of the general formula (I-D) is an erythro compound according to the present invention as shown in Scheme 5 below.

In Scheme 5, R, R ₁ , R ₂ and R ₃ are as defined above, and the compound of Formula V is a mixture of 3R- and 3S-enantiomers mixed in a proportion.

Looking at the progress of the entire manufacturing process, the reaction of the ester compound of Formula (V) by heating and refluxing with an optically pure amine in the presence of sodium cyanide catalyst in a toluene solvent is a pure 3R- or 3S- hydroxy amide, respectively The generation of is optionally possible. The compound of formula (II) is a solid form of both the compound of 3R- or 3S- can be easily obtained by pure recrystallization method. In this case, depending on the stereoselectivity of the amine used as the reactant, the compound of Formula II may be selectively produced as 3R- (Formula II-R) or 3S-hydroxy amide derivative (Formula II-S). Since the 3-hydroxy group of the amide compound of formula (II) is a reactive functional group, it is preferentially protected, and when the protected amide compound of formula (IV) is reacted with an acid, the dioxolane group is first deprotected, water is removed at high temperature, and lac Protonation reaction yields 5-hydroxy-1-oxoribose compound of the erythro form of Formula III-D. Finally, the erythro (Formula I-D) or threo-2,2-difluoro-2-deoxy of Formula I, which is the final object of the present invention, is protected by protecting the 5-hydroxy group of the compound of Formula III in a conventional manner. The -1-oxo ribose compound (Formula I-L) is stereoselective and efficient production is possible.

As shown in the above scheme, the present invention reacts the enantiomeric mixture of formula (V) with an optically pure amine to give 3- (2,2-dialkyl-1,3-dioxolan-4-yl)-of formula (II)- 2,2-difluoro-3-hydroxy) propanamide can be selectively separated into 3R- (Formula II-R) or 3S-enantiomer (Formula II-S), and optically selective 3R-3- (2,2-dialkyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy) propanamide of formula II-R obtained purely as a precursor When used as an erythro 1-oxo ribose compound of the general formula (I-D) can be selectively prepared by a very simple route.

Compounds of formula II-R and formula II-S are 3R- or 3S- (2,2-dialkyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy) It is a novel compound that is a propanamide, which is obtained as a solid rather than a liquid.In this case, it can be obtained in a high purity state by simple recrystallization, and all compounds obtained in a subsequent process can also be formed as a solid, thereby avoiding column chromatography. This has the possible advantage. The compounds of formula II-R can be usefully used as pharmaceutical intermediates, and the compounds of formula II-S are also expected to be used as important chiral intermediates, which can be expected to expand the scope of application.

The (2,2-dialkyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy propane ester compound of formula V used as starting material in the process of the present invention is It can be manufactured according to the method described in patent 4,526,988, 4,965,374, 5,223,608 or 5,434,254. Specifically, as shown in Scheme 6, when the aldehyde ketonide (17) and the difluoro compound (18) are mixed and the lipomethsky reaction is carried out using zinc, 3R-enantiomer and 3S-enantio (2,2-dialkyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy propane ester compound of formula V in which mer is mixed at a ratio of about 3 to 1 Is generated.

Wherein R ₂ and R ₃ are as defined above.

Meanwhile, as shown in Scheme 7 below, (2,2-dialkyl-1,3-dioxolan-4-yl) -2,2-difluoro of Formula V in which R- and S-enantiomers are mixed. Reaction of the rho-3-hydroxy propane ester with optically pure amines yields amides, depending on the stereoselectivity of the amines, depending on the stereoselectivity of the amines, 3R- or 3S- (2,2-dialkyl-1,3-dioxoran-4-yl It is possible to obtain a compound of the formula (II), which is a) -2,2-difluoro-3-hydroxy propane amide derivative, as a solid, which is separated off in a pure state.

In which R ₂ , R _{3 and} R ₄ And R ₅ is as defined above.

In the present invention, the compound of formula (V) containing 3S- and 3R-enantiomers can be optically separated by reacting with an optically pure amine to form an amide, wherein the stereoselectivity of the resulting amide forms an amide. It has the advantage of being adjustable by the choice of amines. The optically active amines used here include a phenyl group in the molecule and thus have a structural size (R) or (S) -phenylethanamine, (R) or (S) -1- (4-methylphenyl). Ethaneamine, (R) or (S) -1-phenyl-1-propanamine, (R) or (S) -1- (4-methoxyphenyl) ethanamine, (R) or (S) -1- (4-chlorophenyl) ethanamine is used. Among them, (R) or (S) -phenylethanamine, (R) or (S) -1- (4-methylphenyl) ethanamine, (R) or (S) -1-phenyl-1-propanamine are preferred. .

Under the conditions of Scheme 7, the reaction solvent is possible even in a single solvent such as toluene, dichloromethane, ethyl acetate, etc., which has good solubility with respect to the compound of Formula V, and preferably shows high purity stereoselectivity under solvent conditions of toluene, dichloromethane. Compounds of formula (II) are produced in high yields.

As such, the amide produced by reacting the optical selectivity of the chiral amine represented by (R) or (S) with the compound of formula (V), which is an enantiomer mixture, can be stereoselectively separated and produced in a solid form for easy purification. . The hydroxyl group at position 3, which is a functional group of the compounds of Formula II, may be stabilized by introducing various protecting groups.

Wherein R, R ₂ , R _{3 ,} R ₄ And R ₅ is as defined above.

In the present invention, the 3-hydroxy group of the compound of formula (II) is capable of introducing a variety of protecting groups, wherein in the step of protecting, it is possible to neutralize using a base when an acid is generated, and as a usable base, pyridine, triethyl Amine, tributyl amine, diisopropylethyl amine, methylpiperidine and the like can be exemplified, of which triethylamine is most preferred.

According to the method of the present invention, the amide compound of formula (II) could be obtained in high yield of 80% or more, and analyzed by fluoro NMR showed one fluorine peak and confirmed that it had stereoselectivity of 99% or more. . In order to confirm this result more clearly, the analysis of the compound of formula (IV-R) incorporating a protecting group using an HPLC instrument showed that very high purity of 99.8% or more containing 0.2% or less of the compound of formula (IV-S), which is the opposite isomer. (As a result, 99.6% or more of the de value), it can be seen that the formula (II) having excellent stereoselectivity can be produced by the method of the present invention.

On the other hand, the compound of formula (IV) is a lactonation reaction to undergo a dehydration reaction under acidic conditions as shown in Scheme 9 Eritro-2,2-difluoro-2-deoxy-1 of the general formula III-D intermediate Oxoribose or threo-2,2-difluoro-2-deoxy-1-oxoribose of formula III-L. Incorporation of a protecting group into the hydroxy group at position 5 of this compound allows the production of more stable compounds of formula (I-D) or (I-L).

Wherein R, R ₁ , R ₂ And R ₃ is as defined above.

The acid used for the lactonation reaction is preferably a strong acid having a pka of about -10.0 to about 2.0, for example, inorganic acids such as 1 N--12 N-hydrochloric acid, 1 N--9 N-sulfuric acid, methanesulfonic acid, p Organic acids such as toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like can be used. Of these, 12 N-hydrochloric acid and trifluoroacetic acid are preferred, and 12 N-hydrochloric acid is most preferred.

The amount of acid used may be 1 to 2 molar equivalents based on the compound of formula IV-R, with 1.1 to 1.5 molar equivalents being preferred.

D-erythro or L-threo-2,2-difluoro- of formula (I) from the D-erythro or L-threo-5-hydroxy-1-oxoribose compound of formula (III), which is the final step of the process In the step of obtaining 2-deoxy-1-oxoribose, the 5-hydroxy group can be protected by a conventional method, and a protecting group having a hydrophobic benzene ring or a naphthalene ring can be used as the protecting group. For example, benzoyl, phenylbenzoyl, substituted benzoyl and the like 1-naphthoyl, 2-naphthoyl, substituted 1-naphthoyl, substituted 2-naphthoyl and the like can be used, and benzoyl, 1-naphthoyl, or 2-naphthoyl is preferred.

On the other hand, in the method for producing 2,2-difluoro-2-deoxy-1-oxo ribose of the general formula (I) from the compound of the general formula (IV) via the 5-hydroxy-1-oxo ribose compound of the general formula (III) There is also a method of preparing a 5-hydroxy-1-oxoribose compound of the formula (III) and then carrying out a protection reaction. The protection reaction is carried out directly in the same reactor without separating the compound of the formula (III). There is also a method of preparation (in situ). In the same reactor, the process of directly proceeding to the 5-hydroxy protection reaction, in the case of progressing step by step, the loss of yield arising from the process of separating and obtaining the 5-hydroxy-1-oxo ribose compound of Formula III Avoidable and more advantageous in total yield, which can be obtained by naturally separating the 2,2-difluoro-2-deoxy-1-oxoribose of formula (I) as a crystalline phase, Since there is no difference from the case proceeded, it can be said to be a more preferable method for the production of the yarn.

On the other hand, the erythro 2,2-difluoro-2-deoxy-1-oxoribose of the general formula (I-D) prepared according to the present invention is analyzed by high pressure liquid chromatography method iso iso treo compound of formula (I-L) Is not detected, and the 1-oxoribose compound of the desired erythro structure shows a very high purity of about 99%.

As described above, the present invention showed that the compound of the general formula (I-D), which is an erythro compound of D-form, can be produced with excellent yield and stereoselectivity compared to the conventional method by introducing more excellent stereoselectivity, and the opposite orientation Compounds of the general formula (I-L), which are shown as the treo compounds, can be produced with excellent yield and stereoselectivity. This not only allows the preparation of intermediates of gemcitabine, an important anticancer agent known in the art, but also the production of new chiral pools.

In addition, the reaction step is reduced and can be said to be an economically advantageous method.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to help the understanding of the present invention, but the scope of the present invention is not limited thereto.

Preparation Example: Ethyl 2,2-Difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxoran-4-yl) propionate

13 g (200 mmol) of zinc are added to 26 mL of tetrahydrofuran, 0.51 mL of 1,2-dibromoethane is added, followed by heating to 60 ° C. for 1 minute. 0.76 mL (6 mmol) of chlorotrimethylsilane are added at 40 ° C. After 10 minutes, the internal temperature was raised to 60 ° C., 25.5 mL (200 mmol) of ethyl bromodifluoroacetate, 30.8 g (237 mmol) of 2,2-dimethyl- [1,3] -dioxolane-4-carboaldehyde ) And 39 mL of tetrahydrofuran solution are added dropwise to react with heating under reflux. The reflux is further heated for 30 minutes after the drop is complete. 65 mL of diethyl ether was added to the reaction solution and poured into 260 g of ice. 260 mL of 1 N hydrochloric acid is added thereto and stirred until the ice is dissolved. The aqueous layer is extracted three more times with 90 mL of diethyl ether. The combined organic layers are washed with 65 mL of brine and 65 mL of saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate and filtration, the residue was distilled under vacuum of 10 Torr to obtain an organic layer separated at a temperature of 130 to 134 ℃ to give a colorless liquid 28.9 g (yield: 57%) of the title compound (R: S = 3: 1).

¹ H NMR (CDCl ₃ , 300 MHz): 1.31-1.52 (m, 9H), 2.67 (s, 1H, (R) -OH), 2.90 (d, 1H, (S) -OH), 3.7-4.4 ( m, 6H)

Example 1. 3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy-N-[(S) -1-phenylethyl Propaneamide (Formula II-R)

150 g of ethyl 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxoran-4-yl) propionate (R: S = 3: 1) Dissolve (590 mmol) in 750 mL of toluene, add a catalytic amount of sodium cyanide, and slowly add dropwise 75 mL (590 mmol) of (S)-(-)-1-phenylethanamine. The reaction solution is heated to reflux for one day. Ethyl acetate was added to the reaction solution, and the mixture was washed three times with 2,000 mL of water. It is dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain a brown solid compound. Recrystallization using hexane or a mixture of hexane and ethyl acetate gives 105 g (54% yield) of a pale off-white solid.

¹ H NMR (CDCl ₃ , 400 MHz): 7.39-7.28 (m, 5H), 6.66 (m, NH), 5.13 (m, 1H), 4.33-4.24 (m, 2H), 4.05-4.03 (m, 2H) , 1.56 (d, 3H, J = 6.9), 1.31 (s, 3H), 1.29 (s, 3H)

Example 1-1: 3- (2,2-dimethyl-1,3-dioxoran-4-yl) -2,2-difluoro-3-hydroxy-N-[(R) -1- Phenylethyl] propaneamide (Formula II-S)

150 g of ethyl 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxoran-4-yl) propionate (R: S = 3: 1) Dissolve (590 mmol) in 750 mL of toluene, add a catalytic amount of sodium cyanide, and slowly add dropwise 75 mL (590 mmol) of (R)-(-)-1-phenylethanamine. The reaction solution is heated to reflux for one day. Ethyl acetate was added to the reaction solution, and the mixture was washed three times with 2,000 mL of water. It is dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain a brown solid compound. Recrystallization using hexane or a mixture of hexane and ethyl acetate gives 33 g (yield 17%) of a pale off-white solid.

¹ H NMR (CDCl ₃ , 400 MHz): 7.35-7.23 (m, 5H), 6.63 (m, NH), 5.11 (m, 1H), 4.29-4.21 (m, 2H), 4.03-4.01 (m, 2H) , 1.54 (d, 3H, J = 6.9), 1.29 (s, 3H), 1.26 (s, 3H)

Example 2. (R) -1-((R) -2,2-Dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-oxo-3-(( S) -1-phenylethylamine) propyl 1-naphthoate (Formula IV-R)

3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy-N-[(S) -1-phenylethyl] propaneamide ( 50 g (152 mmol) of Formula II-R) are dissolved in 200 mL of methylene chloride, followed by addition of 32 mL (228 mmol) of triethylamine. 25 mL (167 mmol) of 1-naphthoyl chloride dissolved in 100 mL of methylene chloride are added to the reaction solution. After stirring for 2 hours at room temperature, the mixture was washed with 600 mL of 1N hydrochloric acid, 600 mL of 5% sodium bicarbonate solution and 600 mL of water. Anhydrous magnesium sulfate was added, dried, filtered and distilled under reduced pressure to obtain a white solid compound. The obtained solid was recrystallized with a hexane-ethyl acetate mixed solution to give 63.9 g (yield: 87%) of a white solid compound.

¹ H NMR (CDCl ₃ , 400 MHz): 8.93 (d, 1H, J = 8.67), 8.20 (dd, 1H, J = 1.15, 7.30), 8.06 (d, 1H, J = 8.21), 7.90 (d, 1H , J = 8.16), 7.66-7.61 (m, 1H), 7.58-7.54 (m, 1H), 7.51-7.47 (m, 1H), 7.30-7.27 (m, 5H), 6.08-6.04 (m, 1H) , 5.13-5.10 (m, 1H), 4.60-4.58 (m, 1H), 4.11-4.07 (m, 2H), 1.45 (d, 3H, J = 6.9), 1.29 (s, 3H), 1.23 (s, 3H)

Example 3: 2-deoxy-2,2-difluoro-D-erythropentofuranos-1-ulose-3- (1-naphtho) -5-benzoate (Formula I-D)

R) -1-((R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-oxo-3-((S) -1- 35 g (72 mmol) of phenylethylamine) propyl 1-naphthoate (Formula IV-R) is dissolved in 150 mL of acetonitrile, and 15 mL (180 mmol) of concentrated hydrochloric acid is added thereto, followed by heating to reflux for 4 hours. After the reaction is completed, toluene is added to the reaction mixture to remove the solvent and water by distillation. Toluene was added to the reaction mixture again, and the distillation was carried out, and the mixture was completely concentrated to give 2-deoxy-2,2-difluoro-D-erythropentopuranos-1-ulose-3- (1-naphtho) ate ( Formula III-D) is obtained. The reaction mixture is dissolved in 100 mL of methylene chloride and then 8.7 mL (108 mmol) of pyridine is added. 11 mL (72 mmol) of 1-naphthoyl chloride dissolved in 20 mL of methylene chloride are added to the reaction solution. After stirring for 3 days at room temperature, washed with 300 mL of 1N hydrochloric acid, 300 mL of 5% sodium bicarbonate solution, and 300 mL of water. It is dried over anhydrous magnesium sulfate, filtered and then distilled under reduced pressure. The obtained solid was recrystallized from a hexane-ethyl acetate mixed solution to obtain 20 g of a white solid compound (yield: 67%).

¹ H NMR (DMSO-d ₆ , 400 MHz): 8.93 (d, 1H, J = 8.67), 8.20 (dd, 1H, J = 1.15, 7.30), 8.06 (d, 1H, J = 8.21), 8.03-8.01 (m, 2H), 7.90 (d, 1H, J = 8.16), 7.66-7.59 (m, 2H), 7.58-7.54 (m, 1H), 7.51-7.43 (m, 3H), 5.11 (quintet, 1H, J = 7.24), 4.59 (q, 1H, J = 5.71), 4.13-4.05 (m, 2H)

The enantiomers of the amides of formula (II) can be selectively prepared in the (R)-or (S)-form by the process of the present invention, by using the 2,2-difluoro-2 of formula (I) The erythro or threoforms, each enantiomer of the -deoxy-1-oxoribose compound, can optionally be prepared in high purity and high yield.

Claims (5)

(1) reacting the ethyl 3-hydroxy propanoic acid ester compound of Formula V with an optically pure amine based compound to prepare a compound of Formula II, which is an optically pure 3S- or 3R-hydroxy propane amide derivative; (2) protecting the hydroxy group of the compound of formula II with a protecting group to produce a compound of formula IV; (3) reacting a compound of Formula IV with an acid to prepare a 5-hydroxy-1-oxoribose compound of Formula III having an erythro or threo structure; And (4) A process for preparing a compound represented by the following formula (I-D) or (I-L), which comprises protecting a 5-hydroxy group of the compound of formula (III). [Formula I-D]

[Formula I-L]

[Formula II-R]

[Formula II-S]

[Formula III-D]

[Formula III-L]

[Formula IV-R]

[Formula IV-S]

[Formula Ⅴ]

Wherein R and R ₁ are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4- as protecting groups t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group, R ₂ and R ₃ are each independently C ₁ to C ₃ alkyl and R ₄ Is a methyl or ethyl group, R ₅ is hydrogen, methyl, methoxy or Cl. The compound of claim 1, wherein the optically pure amine compound of step (1) comprises (R) or (S) -phenylethanamine, (R) or (S) -1- (4-, wherein the phenyl group is included in the molecule. Methylphenyl) ethanamine, (R) or (S) -1-phenyl-1-propanamine, (R) or (S) -1- (4-methoxyphenyl) ethanamine, (R) or (S)- A process for producing a compound represented by formula (I-D) or (I-L), characterized in that 1- (4-chlorophenyl) ethanamine. The process according to claim 1, wherein the protecting group used in step (4) is benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, Preparation of compound represented by formula (I-D) or (I-L), characterized in that 4-t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group Way. The process for preparing a compound represented by formula (I-D) or (I-L) according to claim 1, wherein step (4) is carried out in the same reactor without separating the compound of formula (III) in step (3). The compound represented by following formula (II-R) or (II-S). [Formula II-R]

[Formula II-S]

Wherein R ₂ and R ₃ are each independently C ₁ to C ₃ alkyl, R ₄ is a methyl or ethyl group, R ₅ is hydrogen, methyl, methoxy or Cl.