A NOVEL PROCESS FOR PREPARING 3.AMINO-5-FLUORO-4-DIALKOXYPENTANOIC ACID ESTER
FIELD OF THE INVENTION
The present invention relates to a novel process for the production of 3-amino-5-fluoro-4-dialkoxypentanoic acid ester represented by the following formula 1: [Formula 1]

wherein R and R" are as defined below.
BACKGROUND ART
Revesz group reported a process for the production of 3-amino-5-fluoro-4-oxopentanoic acid derivative which is well known in the art to play an important role in caspase inhibitor (Revesz et aL, Tetrahedron Lett. 1994 35, 9693). However, this process used an intermediate 2-fluoroacetaldehyde that is volatile, and its aldol reaction requires a large amount of organic solvent. Moreover, die purification of the product is difficult since there is no intermediate obtained as the form of solid. To overcome these problems, the present inventors developed a process of Reaction Scheme 1 for preparing the compound of formula 1 which is practical and provides good yield (see: KR 10-2005-016203). [Reaction Scheme 1 ]


Although significant improvement was made compared to the Revesz' s process, there is still room for further refinements in removing a very low temperature condition in preparing a compound of formula 2 by condensation between lithium anion of tiimethylsihi a::et\"Iene and ethylfluoro^etate. and in piepaiiiig a compexmd of formula 5

from the above Reaction Scheme could not be purified easily, and so the above method was difficult to be used for synthesizing the compounds in a large scale. Therefore, there has been a need for a new method which does not require the very low temperature condition, and has an easy purification process.
SUMMARY OF THE INVENTION
The present invention relates to a novel process for the production of 3-amino-5-fluoro-4-dialkoxypentanoic acid ester used in the precursor of 3-amino-5-fluoro-4-oxopentanoic acid, represented by the following formula 1: [Formula 1]


wherein R' and R" are as defined in the Description.
DETAILED DESCRIPTION OF THE LWTINTION
The object of the present invention is to provide a process for preparing a compound of formula 1 which does not require a very low temjjerature condition, and is suitable for a large scale of synthesis in which intermediates can be easily purified.
The present invention relates to a process for producing a compound of formula 6. v^iiich comprises the following steps:

(b) preparing a compound of formula 9 by reacting the compound of formula 4 with
R'0C(=0)0R^ and,
(c) reacting the compound of formula 9 with NHiR XR^):



in which,
R and R" independently represent alkyl group;
R independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane or dioxane;

Also, the present invention relates to a method for producing the compound of formula L including the above method When using the process of the present invention, the very low temperature condition is not required, and the purification process is simple. The reaction mechanism of the present invention can be depicted in the following Reaction Scheme 2:
[Reaction Scheme 2]


In the Reaction Scheme 2, the method for producing the compound of formula 2 by using the condensation reaction between an amide compound of formula 8 and trimethylsilyl acetylene, and the method for preparing a compound of formula 6 from a compound of formula 9 via the compound of fonmila 4 do not require a very low temperature condition. Also, the crystallized solid form of compounds of formulae 6, 10a, and I Ob can be obtained by the above process, and so the compound of formula 1 can be obtained in high purity. Furthermore, the compound of formula 9 is a new compound.
The present invention may be explained in light of the following examples in more detail. However, they are set forth for the purpose of illustration, and cannot be construed to limit the present invention in any manner.

Definitions
In describing the compounds and methods of the present invention, main terms have the following meanings unless indicated otherwise.
The term. "alkvL" means Ci.s-hydrocarbon radicals, or C;.,c-cyclic hydrocarbon radicals which may be linear or branched, and so may be methyl, ethyl, propyl, isopropyl, but>l, isobutyl, sec-butyl, r^rr-butyl, pent\'l, isopentyL hexyi. isohexyl. heptyl. octyl. 2,2,4-trimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyL cyclooctyl and the like, but are not limited thereto.
The term, "aryl," means aromatic group, heteroaromatic group, or partially reduced derivatives thereof. Aromatic group refers to 5-15 membered, unsaturated hydrocarbons which may be unfused ring or fused ring. Aromatic group includes benzene, biphenyl, naphthalene and the like, but are not limited thereto. The above heteroaromatic

imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, p}Tidazine, pyrimidine, pyrazine and the like, but are not limited thereto. Bicyclic heteroaromatic group includes indole, benzothiophene, benzofiiran, benzimidazole. benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine and the like, but are not limited thereto.
The term, "heterocycle," means a saturated 4-8 membered ring or 4-8 membered ring having 1 or 2 double bonds which may be fused with benzo or Cs-Cs-cycloalkyl, and includes 1 or 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen. Heterocycle includes piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine and the like, but are not limited thereto.

Here, one or more hydrogen of the alkyl group and aryl gi-oup can be substituted by other substituents, including acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryl, aryloxy, sulfoxy and guanido group, but are not limited thereto.


In the step (i), the amide compound of formula 8 is obtained by condensation between fluoroacetic acid and NH(R^)(R^), preferably A^, 0-dimethylhydroxyamine or morpholine. It is desirable that the condensation reaction is carried out after activating A-OC(=0)CH;F by dicyclohexyl carbodiimide or -V-O-dimethylaminopropyD-.V-ethylcarbodiimide hydrochloride (EDC).
In case the condensation uses morpholine, the compound of formula 8 can be easily obtained by reacting morpholine with an ester of fluoroacetic acid comprising ethyl fluoroacetate and methyl fluoroacetate without condensation reagent. The amount of NH(R )(R ) used in the reaction is 1.5 to 5 equivalents, preferably 1.5 to 3 equivalents, with respect to the A-0C(=0)CH2F. If the amount of NH(R^)(R^) is below 1.5 equivalents, the reaction speed slows down, and if the amount is excess 5 equivalents, the removal of excess amine is difficult. Preferably, the condensation reaction is conducted

temperature is preferably 60 to 100 , more preferably 65 _ to 90 . If the reaction temperature is below 60 , the reaction speed is slow, and if it is over 100 , the yield is rediKed by side reaction.
For the step (ii), the compound of formula 8 can be used without Imiitation. However, in a large scale of synthesis, it is preferable to use the compound of formula 8 which includes morpholine ring together with the nitrogen atom to which R and R' are attached, in terms of stability and economy. The amount of trimethyisilylacetyiene is 1 to 3 equivalents, preferably 1.1 to 1.5 equivalents, with respect to the compound of formula 8. If the amount of trimethyisilylacetyiene is over 3 equivalents, a large amount of by¬product reacting with 2 molecules of trimethyisilylacetyiene is synthesized. It is

preferable to use lithium trimethylsilylacetylide that is converted from trimethylsilylacetylene by using alkyllithium, preferably methyl lithium, n-hexyl lithium, or n-butyl lithium. The reaction is preferably carried out under the presence of one or more solvents selected from the group consisting of tetrahydrofitran. diethvlether, t-buiylmeihylether and 1,2-dimethoxyethane, though not specially limited thereto, as long as there is no negati\'e effect to the reaction. The reaction temperamre is -30 to 20 . preferably-10 to 20 .


carbonate and sodium hydrogen carbonate, wherein M' represents aDcali metal, M' represents alkaline earth metal. The amount of the base used in the deprotecting reaction is 1 to 2 equivalents with respect to the compound of formula 2.
Also, it is preferable to carrv^ out the deprotecting reaction in Ci-Cs ajcohol. such as methanol or ethanol; dichloromethane; or a mixture of chloroform aiiu water.


is 0.05 to 1.5 equivalent, preferably 0.1 to 0.5 equivalent, with respect to the compound of formula 4. If the amount of the base used is below 0.05 equivalent, the reaction speed slows down, and if it is over 1.5 equivalents, two (2) molecules of the compound of formula 4 react with one molecule of R'0C(=0)0R\ to obtain unwanted by-Dtoduct.
The preferable compound of R'0C(=0)0R' is one thai R' and R^ are independently selected from the group consisting of methyl, ethyl, propyl, buiyl and isopropyl. The more preferable compound of R'OC(=0)OR' is dimethyl carbonate, diethyl carbonate, dipropyl carbonate, dibutyl carbonate or diisopropyl carbonate, but is not limited thereto. The amount of R'OC(=0)OR^used is 1 to 5 equivalents, preferably 1 to 2.5 equivalents, more preferably 1.05 to 1.15 equivalents, with respect to the compound of formula 4. If the amount of R'0C(=0)0R^ used is over 5 equivalents, the reaction slows down, and carmot be completed.

thereof with tetrahydrofuran. However, it is not preferable to use tetrahydrofuran alone as the reaction solvent in terms of the reaction speed. The amount of reaction solvent is not specially lin:rited, but is more than 5 times, preferably iO times, based on tie amount of R'OC(=0)OR^ If the amount of the reaction solvent is less than 5 times, tte reaction speed slows down.
The reaction temperature is -20 ; to 50.:, preferably -5 to 30 . If the temperature is over 50 , the yield decreases.
The compound of formula 9 obtained from the Reaction Scheme 2 is a mixture of E and Z, and the ratio of E and Z is varied depending on the reaction condition. However, both of these isomers can be reacted with amine to obtain the compound of formula 6, and


amino group by reduction, but preferably arylmethylamine such as ammonia or benzylamine; primary amine including 1-arylethylamine, such as 1-phenylethylamine or 1-naphthylethylaraine, or protected trialkylsiiyl form thereof, and secondar}- amine including di(arylmethyl)amine, such as dibenzylamine, or di(arylethyl)amine such as diphenylethylamine. The amount of NHCR'^XR^) is 1 to 20 equivalents, preferably 3 to 8 equivalents. If die amount of NH(R'*)(R"'') is less than 1 equivalent, the reaction speed slows down. If it is over 20 equivalents, it is disadvantageous in that an excess amount of acid should be used to remove amine produced after the reaction.

The reaction is not specially limited, as long as the solvent has no negative effect to the reaction, but preferably is carried out under the presence of the solvent selected from the group consisting of t-butylmethylether, toluene, dimethylformamide and acetonitrile. It is more preferable to be carried out in the absence of solNent in terms of reaction speed. The reaction temperature is from. 30 to 150 , preferably from 80 to 110 . If the reaction temperature is below 30 , it is disadvantageous In terms of tbie reaction rate. If it is over 150 , the side reaction is problematic.


wherein.
R independently represents alkyl group;
R'independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane or dioxane;
R" and R' independently represent hydrogen, trialkylsilyl group, aryhnethyl group or 1-
arylethyl group.
As long as the reducing agent has no negative effect to the reduction reaction, conventional reducing agent capable of selectively reducing the double bond between carbon and nitrogen can be used in the reaction. Preferably, (i) sodium triacetoxyborohydride; (ii) acetic acid and sodium cyanoborohydride; or (iii) acetic acid and sodium borohydride, can be used, but is not limited thereto. The amount of reducing agent is from 1 to 5 equivalents, preferably 1.5 to 3 equivalents, with respect to the

quenched by water. In case of using acetic acid and sodium borohydride as the reducing agent, it is preferable to use each of them from 1 to 20 equivalents and from 1 to 5 equivalents, resf)ectively. It is also preferable to conduct the reaction unckr tbs: rs^sence of one or nwre solvents selected from the group consisting of ethylacetate, tetrahydrofuran, diethylether and t-butylmethylether.
Synthesis of a compound of formula 1
The compound of formula 1 is prepared by hydrogenating the compound of formula 7 as shown in the following Reaction Scheme 8 below.

[Reaction Scheme 8]

wherein,
R' independently represents alicyl group;
R'independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane or dioxane;
R and R" independently represent hydrogen, triallcylsilyl group, arylmethyl group or 1-
arylethyl group.

or Raney nickel based catalyst having nickel loading range of more than I weight% can be used in an amount of from 0.01 to 13 weight% to the compound of formula 7, based on the metal component, wherein said catalysts are in a loaded form into tte siippoTt selected from the group consisting of carbon, silica, and alumina. The hydrogenation reaction is not limited but preferably is conducted under the presence of one or more solvents selected from the group consisting of acetic acid, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dimethoxyethane, dioxane, ethylacetate and dichloromethane. Also, the hydrogenation reaction is preferably conducted under from 0 to 50 , and 1 to 100 atmospheres of hydrogen pressure.
Synthesis of a compound of formula 10. and purification and optical resolution of

the compound of formula 10 used thereof
A compound of formula 10 (isomers of formula 10a, stereoisomers of formula 10b, or racemates of formula 10a and formula 10b) is prepared by reacting the compound of formula I with tartaric acid derivatives (if necessan'. racemates or optical isc>mers), as shown in the Reaction Scheme 9 below. The resulting compourKl of formula iO can be used for the purification and optical resolution process of the compound of foTmuIa i.

R' independendy represents alkyl group:
R^ independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane or dioxane;
R^represents hydrogen, alkyl group or acyl group, wherein acyl has the form of RC(=0)-,
wherein R is alkyl group or aryl group.
The compound of formula 1 reacts with tartaric acid derivatives in the presence of water, and or« or more solvents selected from C!-C5-alcohoL preferably, selected from, the group consisting of methanol, ethanol and isopropanol, to obtain the compound of formula 10 (stereoisomers of formula 10a, stereoisomers of formula 10b, or racemic mixture of formula 10a and formula 10b). The reaction is conducted preferably in the temperature range of from 40 to 80 . After the reaction is completed, if the

temperature of the reactant cools down to a low temperature, preferably below ambient temperature, the compound of formula 10 is crystallized. The resulting precipitates include the compound of formula 10 having sufficient purity. However, if necessary, the compound of formula 10 having higher purit>' can be obtained from recn stallizarion in the presence of water and one or more solvents selected from Ci-Cs-alcohoi group, preferably selected from the group consisting of methanol, ethanol and isopropanol.
The amount of tartaric acid derivatives used is 0.9 to 1.5 equivalents with respect to the compound of formula 1.
Tartaric acid derivatives used in the reaction preferably include tartaric acid, O.O'-dibenzoyltartaric acid and the like, but are not limited thereto.
The compound of formula 10 can be easily isolated to the compound of formula 1 and tartaric acid derivatives by using the conventional method which isolates salt from the

formula 10b are prepared by selectively using racemic tartaric acid derivatives or tartaric acid derivatives having optica! activity. In particular, in case of using tartaric acid derivatives having optical activity, the compound of formula 1 can be optically divided since one enantiomer of the compound of formula 1 can form diastereomeric salt of formula 10a or lOb. The tartaric acid derivatives having opticai activity used in the reaction include optically active tartaric acid such as D,L-tartaric acid, 0,0'-dibenzoylxaitsnic acid, but are not limited thereto.
Better understanding on the present invention may be obtained in light of the following examples which are set forth to for the purpose of illustration, which however cannot be construed to limit the present invention in any way.

[Advantageous Effects]
The present invention provides advantages over the known prior arts since it the does not require a very low temperature condition, and the intermediate 6 is easily purified via crystallization to provide high purity^ of the compound of formula 1.



[Mode for Invention]
Example 1: 2-Fluoro-l-morpbolin-4-yI-ethanone{8)
A mixture of ethyl fluoroacetate (50 g, 472 mmol) and morpholine (82 g, 944 mmol) was heated at 70 for 20 h. After cooling to ambient temperature, the mixture was added to a stirred mixture of 2 N HCl (240 mL) and methylene chloride (200 mL) over 20 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 mL x 2). The combined organic phase was dried over anhydrous MgS04 and concentrated in vacuo to give 51.7 g (74.6%) of the title compound. 'H NMR (400 MHz, CDCI3) 5 4.96 (d, J = 47.2 Hz, 2H), 3.70 (bs, 4H), 3.64 (bs, 2H), 3.47 (bs, 2H).

Example 2: l-Fluoro-4-tr{methyIsilanyl-but-3-yn-2-one (2)
A 0 solution of trimethylsilylacetylene (42.0 g, 429 mmo!) in THF (400 mL) •A'as treated -Aiih n-BuU. (2J M in n-hexane; 171 raL. 428 minol; OMT 20 min maintaining the internal temperature below 10 using dry ice-acetone bath (—20 ). After stirring for 30 min at 0 .the mixture was treated with a solution of 2-fiuoro-i-morpholin-4-yl-ethanone (8, 48.4 g, 329 mmol) in THF (50 mL + 10 mL for wash), and stirring was continued for further Ih at 0 . The reaction was quenched by adding to a 0 mixture of acetic acid (250 mL) and water (150 mL) over 1 h maintaining the internal temperature below 5 Z. After addition of more water (150 mL), the organic layer was separated, washed with water (200 mL), and dried over anhydrous MgS04, and concentrated in vacuo. The residue was evaporated again with toluene (200 mL) to

Example 3: 4-Fluoro-3y3-dimetboxy-but-l-yne (4. R" = metiiyl)
A solution of l-fluoro-4-trimethylsilanyl-bat-3-yn-2-one (2, 50.0 g, 316 mmol) in methanol (260 mL) was treated with trimethyl ordtofoimate (33.6 g, 316 mmol) and p-TSOH-H2O (6.0 g, 31.5 mmol), and refluxed (bath temperature: 80 °C) for 6 h. After evaporation of about 130 raL of solvent under reduced pressure, the residue was diluted with dichloromethane (260 mL) and 10% NaHCOs solution (130 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (130 mL). The organic phases were combined and concentrated under reduced pressure to give a crude

compound of formula 3 (59.0 g, 92%). The compound was used as such for the next reaction, 'H NMR (500 MHz, CDCI3): S43S (d, i = 47.1 Hz, 2H), 3.40 (s, 6H), 0.20 (s, 9H).
To a soiuiion of a crude compound of formula 3 (59.0 g. 2S9 mmol) in dichloromethane (280 mL) was added tetra-77-but\lammonrjm bromide (59 mg, 0.1 S3 mmol) and 1 N NaOH (347 mL, 347 rmnol). The mixture was stirred at ambient temperature for 2 h. The organic layer was separated and the aqueous layer was extracted with dichloromethane (110 mL). The combined organic phase was washed with brine (110 mL) and concentrated under reduced pressure to give a crude the tide compound (4, R- = methyl, 40.9 g, 107 %). 'H NMR (500 MHz, CDCI3); 5 4.42 (d, 7 = 47.1 Hz, 2H), 3.42 (s, 6H), 2.64 (s, IH). '-^C NMR (125 MHz, CDCI3) 5 96.1 (d, 7= 20.3 Hz), 82.9 (d, J = 180 Hz), 77.5,75.5, 51.0.

A mixture of 4-fluoro-3,3-dimethoxy-but-l-yne (4, R" = methyl, 20.0 g, 152 mmol) and diediyl carbonate (20.1 mL, 167 mmul) in DMF (150 mL) was cooled to 0 ""C,
and treated with potassium ethoxide (3.8 g, 45.2 mmol). After stirring at 0 °C for4 h, the
solution was charged with a 1:1 mixture of saturated aqueous NH4CI and water (200 mL) and extracted with t-butylmethylether (200 mL x2). Tbe combined organic phase was washed with water (100 mL) and dried over anhydrous MgSO^ to give a crude ti^ titie compound (9, R' and R^= ethyl, R-= methyl, 37.8 g, 99.7%, Z:E= 6.5:1). (Z)-isoraen 'H NMR (400 MHz, CDCI3) 5 5.84 (s, IH), 4.48 (d, J = 46.8 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.17 (q, i = 7.2 Hz, 2H), 3.26 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). '^C NMR (100 MHz, CDCI3) 5 164.9, 162.5, 100.7, 99.2 (d, 7 = 30 Hz), 78.5 (d, 7 =

180 Hz), 70.7, 59.7, 48.9, 15.3, 14.0. (£)-isomer: 'H NMR (400 MHz. CDCl.) 5 5.21 fs. IH), 4.59 (d, J = 46.8 Hz. 2H). 4.16 (q, 7 = 7.2 Hz, 2H), 3.82 (q, J = 7.2 Hz, 2H), 3.29 (s. 6H), 1.35 (t, J = 7.2 Hz, 3H), 1.29 (t, / = 7.2 Hz, 3H). ''^C NMR (100 MHz, CDCl-,) 5 167.2. 157.3. 99.8 (d. / = 20 Hz). 97.6. 80.6 (d. J = 1 SO Hz), 64.0. 60.2. -9.4. 14.0.
Example 5: (Z)-ethyI 3-b€nz5iaraino-5-fluoro-4,4-dimeth0xypeiit-2-enoate (6, R'= ethyl, R^= methyl, R'*= benzyl, R^= hydrogen)
A mixture of ethyl 3-ethoxy-5-fluoro-4,4-dimethoxypent-2-enoate (9. R' and R'= ethyl, R:^= methyl, 37.8 g, 151 mmol) and benzylamine (99 mL, 907 mmol) was heated to 100 °C for 20 h. After cooling to 0 °C, the mixture was diluted with ethyl acetate (300 mL), and treated with 1 N HCl (360 mL) over 30 min maintaining the internal temperature below 20 °C. The separated organic layer was treated with 1 N HCl (330 mL),

with water (70 mL). After removal of oil bath, the mixture was stirred for 4 h at ambient temperature and for more 1 h at 0 °C. The resulting precipitate was filtered, washed with a 2:1 mixture of ethanol and water (120 mL), and dried over nitrogen purge to give tbe tide compound (6, R'= ethyl, R^= methyl, R''= benzyl, R-^= hydrogen, 30.2 g. 64.0% for two steps from the compound formula 4). 'H NMR (500 MHz, CDCI3) 5 8.53 (bs, IH), 733 (m, 5H), 5.07 (s, IH), 4.64 (d, J = 5.5 Hz, 2H), 4.48 (d, J = 46.5 Hz, 2H), 4.10 (q, / = 7.4 Hz, 2H), 3.30 (s, 6H), 1.25 (t, J = 7.4 Hz, 3H).
Example 6: Ethyl 3-(benzylamino)-5-fluoro-4,4-dimethoxypentanoate (7, R^= ethyl, R^= methyl, R''= benzyl, R^= hydrogen)

To a cooled solution of (Z)-ethyl 3-benzylamino-5-fluoro-4,4-dimethoxypent-2-enoate (6, R'= ethyl R'= methyl, R'^= benzyl R^= hydrogen; 30.2 g, 97 mmol) in t-butylmethylether (97 mL) was added sodium borohydride (NaBRj; 7.34 g, 194 mmol) and acetic acid (58 g, 970 mmol) for 30 minutes maintaining the temperature of the mixture below 0 . After 50 min,aqueous 3 N NaOH solution (194 mL. 582 mmol) was added thereto slowly for 30 min. The organic layer was separated, washed with brine i97 mL), and concentrated under reduced pressure to give the tide compound (7, R'= ethyl, R'= methyl, R'^= benzyl, R'= hydrogen, 32.1 g, 106 %), which was used in the next reaction. 'H NMR (400 MHz, CDCl.O 5 7.35-7.21 (m, 5H), 4.53 (2dd, J = 46.8. 10.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.80 (2d, / = 12.8 Hz, 2H), 3.53 (dd, J = 8.4, 4.0 Hz, IH), 3.30 (s, 3H), 3.22 (s, 3H), 2.79 (dd, / = 15.6, 3.6 Hz, IH), 2.40 (ddd, J = 15.6, 8.0, 1.6 Hz, IH), 1.25 (t, 7 = 7.2 Hz, 3H).
Exampie 7: Ethyl 3-amiiH)-5-^iKM-o-4.4Himietii<)XTpemanoaie ;1. R^= airrL R^= methyl
A solution of ethyl 3-(benzylamino)-5-fluoro-4,4-dimelhoxypentanoate (7, R' = ethyl. R^= methyl R'*= benzyl R^= hydrogen, 32.1 g, 103 mmol) in methanol (32] mL) was treated with 10% palladium catalyst (10% Pd/C) under hydrogen atinosptere (l atm) for 4 h. The crude maxture was filtered through a pad of Celite® (% g), washed with methanol (160 mL), and the filtrate was concentrated under reduced pressure to give the title compound (1, R'= ethyl, R'= methyl, 21.4 g, 94 %), which was used in the next reaction.
'H NMR (500 MHz, CDCI3) 5 4.53 (2dd, J = 46.5, 10.4 Hz, 2H), 4.14 (q, / = 7.3 Hz, 2H), 3.57 (dd, 7= 11.0, 1.9 Hz, IH), 3.29 (d, 7 = 11.7 Hz, 6H), 2.73 (dd, 7= 16.5, 2.5 Hz, IH), 2.36 (ddd, 7= 16.5, 10.4, 2.5 Hz, IH), 1.25 (t, 7= 7.3 Hz, 3H).

Example 8: l-ethoxy-5-fluoro-4,4-dimethoxy-l-oxopentan-3-aminium tartarate (10. R^= ethyl, R^= methyl, R*=H)

a solution of D,L-tartaric acid (2.91 g, 19.4 mmor) in water (6.6 mL). The oil bath was removed and the mixture was stirred at ambient mixture for 2 h. The resulting suspension was diluted with a mixture of isopropanol (47 m.L) and water (2 mL), and stirring was continued for further 2 h. Tlie precipitate was filtered, washed with isopropanol (18 mL) and dried over N2 purge to give the title compound (10, R'= ethyl,

INDUSTRIAL APPLICABIUTY
The present invention relates to a method of producing a compound of forrnula 1. The method synthetic procedure does not require a very low temperature condition, and the intermediate 6 is easily purified via crystallization to provide high purit>' of the compound of formula 1 to render it to be more viable for a large scale of synthesis.

CLAIMS
1. A process for producing a compound of formula 6, which comprises the following
steps:
(a) preparing a compound of formula 4 by depjrotecting a compound of formula 3:
(13) preparing a compound of formula 9 by reacting the compound of formula 4 with
R'OC(=0)OR^ and
(c) reacting the compound of formula 9 with NH(R'')(R^):


R' and R' independently represent alkyl gi"oup;
R' independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane or dioxane;
R" and R" indepen'Ocndy represent hvdrogen. nialkyisilv'I group. ar>imeth>i group or I -
arylethyl group, and P represents protecting group.
2. The process according to claim 1, wherein the step (a) is carried out in the presence of one or more bases selected from the group consisting of M'OH, M"(0H)2, (M')2C03, l group, or together with the oxygen atom to which the}' are attached may form a dioxolane or dioxane;
R^ and R independently represent alkyl group or alkoxy group, or together with the nitrogen atom to which they are attached may form a 4-8 membered heterocycie; and, P represents protecting group.

12. A process for producing a compound of formula 1, which comprises the following steps:
(e) preparing a compound of formula 7 by reducing the compound of formula 6 obtained
from the process according to claim 1 in the presence of a reducing agent capable of
selectively reducing the double bond between carbons; and
(f) hydrogenating the compound of formula 7:



R' represents alkyl group;
R independently represents alkyl group, or together with the oxygen atom to which they
are attached maj. forin a dioxolane or dioxane: aixL

13. The process according to claim 12, wherein the reducing agent of step (e) is selected
from the group consisting of (i) sodium triacetoxyborohydride; (ii) aceric acid and sodiurn
cyanoborohydride; or (iii) acetic acid and sodium borohydride.
14. The process according to claim 12, wherein the hydrogenation process is carried out
under the presence of a metal catalyst in the step (f).
15. A process for producing a compound of formula 10, which comprises reacting the
compound of formula 1 produced according to claim 12 with tartaric acid derivatives:
[Formula 1]


wherein,
R' represents alkyl group;

RC(=0)-, and,
R is alkyl group or aryl group.
16. The process according to claim 15, wherein the amount of tartaric acid derivatives is
0.9 to 1.5 equivalents with respect to the compound of formula 1.
17. The process according to claim 15, wherein the tartaric acid derivative is tartaric acid.
18. The process according to claim 15, wherein one type of stereoisomer in the
compound of formula 10 is prepared by using optically active tartaric acid or 0,0'-
dibenzoyltartaric acid as the tartaric acid derivatives.

19. A compound of formula (6): [Formula 6]

wherein.
R' represents alkyl group;
R" independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane; and,
R"* and R"''independently represent hydrogen, trialkylsilyl group, arylmethyl group or 1-
arylethyl group.

wherein,
R' and R^ independently represent alkyl group; and
R' independently represents alkyl group, or together with the oxygen atom to which they
are attached may form a dioxolane.