Title of Invention

"METHOD FOR THE PREPARATION OF D-ERYTHRO-2,2-DIFLUORO-2-DEOXY-1-OXORIBOSE DERIVATIVE"

Abstract A method for preparing a 2,2-difluoro-2-deoxy-1 -oxoribose derivative of formula (I), comprising the steps of reacting a compound of formula (V) with a biphenylcarbonyl derivative to obtain a compound of formula (IV) having the 3-hydroxy group protected by a biphenylcabonyl group; reacting the compound of formula (IV) with a base in a mixed solvent essentially comprising water to obtain a 3R-carboxylate enantiomer of formula (III) by filtration; reacting the compound of formula (III) with an acid to obtain a 5-hydroxy-1-oxoribose derivative of formula (II); and protecting the 5-hydroxy group of the compound of formula (II) with R3.
Full Text METHOD FOR THE PREPARATION OF
D-ERYTHRO-2,2-DIFLUORO-2-DEOXY-l-OXORIBOSE DERIVATIVE
FIELD OF THE INVENTION
The present invention relates to a method for preparing highly pure
D-erythro-2,2-difluoro-2-deoxy-1 -oxoribose derivatives.
BACKGROUND OF THE INVENTION
D-erythro-2,2-difluoro-2-deoxy-l -oxoribose is an important intermediate used in the
preparation of gemcitabine of formula (A), an agent for treating non-small cell lung cancer.
OH F (A)
Since gemcitabine is an erythro enantiomer having the 3-hydroxy moiety oriented
down (opposite to the 5-hydroxy group with respect to the place of the tetrahydrofuran ring),
it is important in the preparation of gemcitabine to develop a method for preparing
1-oxoribose erythro compounds having the 3-hydroxy group oriented down.
US Patent No. 4,526,988 discloses a method for preparing an erythro 1-oxoribose
compound via alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxoran-4-yl)propionate, a 3:1
mixture of 3R-hydroxy enantiomer of formula (B) and 3S-hydroxy enantiomer of (Figure Removed)
R4 and R5 are each independently Q.3 alkyl.
However, such a method involves an uneconomical step of isolating only the
3R-hydroxy enantiomer of formula (B) from the mixture of the compounds of (B) and (B1) in
order to selectively prepare the desired erythro 1-oxoribose derivative, because the
compounds of (B) and (B1) produce an erythro compound of formula (C) and a threo
compound of formula (C), respectively, as shown in Reaction Scheme A and B.
Further, the method also has the problem that it takes a long reaction time, almost
four days at room temperature.
Meanwhile, US Patent Nos. 4,965,374; 5,223,608; and 5,434,254 disclose a method
for obtaining an erythro enantiomer of formula (D), as shown in Reaction Scheme C, by (i)
hydrolyzing and azeotropically distilling a 3-benzoyloxypropionate ester of formula (E) (a
3:1 mixture of 3R- and 3S-enantiomers) to obtain a lactone compound of formula (F); (ii)
protecting the 5-hydroxy group of the compound of formula (F) with benzoyl to obtain a
3,5-dibenzoyloxy compound of formula (G); and (iii) cooling the compound of formula (G)
to -5 ~10°C to precipitate only the erythro enantiomer of formula (D).
However, the above method is uneconomical due to its overall low yield of about
25% and the use of an expensive and toxic trifluoroacetic acid in an excess amount in the
hydrolyzing process.
Further, US Patent Nos. 5,428,176 and 5,618,951 teach a method of preparing a
2,2-difluoro-p-silyloxy-l,3-dioxolane-4-propionic acid ester of formula (H) having a high
3R-silylhydroxy enantiomer content by reacting a 2,2-difluoroketene silyl acetal with a
glyceraldehyde derivative in a solvent such as 1,3-dimethylpropylene urea (DMPU), as
shown in Reaction Scheme D.
Reaction Scheme D
R F
OSiR6R7R8
wherein, R6 to R9 are alkyl; and R10 and R11 are d.3 alkyl.
However, this method also requires an uneconomical column chromatography
process for isolating the 3R-enantiomer from the mixture of the enantiomers.
Accordingly, the present inventors have endeavored to develop an efficient method
for selectively preparing 1-oxoribose compounds having an erythro structure, and have
unexpectedly found an efficient, novel method for preparing highly pure
2,2-difluoro-2-deoxy- 1-oxoribose having an erythro structure.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an efficient method
for selectively preparing 2,2-difmoro-2-deoxy- 1-oxoribose derivatives having an erythro
structure.
It is another object of the present invention to provide a 3R-enantiomer compound
which can be used as an intermediate in said method.
In accordance with one aspect of the present invention, there is provided a method
for preparing a 2,2-difluoro-2-deoxy-l-oxoribose derivative of formula (I), comprising the
steps of (i) reacting a compound of formula (V) with a biphenylcarbonyl derivative to obtain
a compound of formula (TV) having the 3-hydroxy group protected by a biphenylcabonyl
group; (ii) reacting the compound of formula (IV) with a base in a mixed solvent essentially
comprising water to obtain a 3R-carboxylate enantiomer of formula (El); (iii) reacting the
compound of formula (III) with an acid to obtain a 5-hydroxy-l-oxoribose derivative of
formula (n); and (iv) protecting the 5-hydroxy group of the compound of formula (II)
R3 is benzoyl or
R4 is phenyl or substituted phenyl; and
M is ammonium (NHU), sodium or potassium.
In accordance with another aspect of the present invention, there is provided a
3R-carboxylate enantiomer of formula (HI):
(Figure Removed)
water to obtain a 5-hydroxy-1-oxoribose of formula (H) having an erythro structure; and
protecting the 5-hydroxy of the compound of formula (If) according to a conventional
method.
The inventive method is characterized in that it is possible to selectively obtain the
3R-carboxylate enantiomer of fonnula (DDT) by protecting the 3-hydroxy group of the
compound of formula (V) with a biphenylcarbonyl group, and obtaining the 1-oxoribose
derivative of formula (I) having a desired erythro structure therefrom.
Since the compound of formula (HI) can be obtained selectively as a solid in the
inventive method, it can be easily isolated using a simple filtering process without
conducting an uneconomical column chromatography or other purification processes.
Accordingly, the use of the compound of formula (II) as an intermediate is the unique
feature of the inventive method which is suitable for a large-scale production of the
1-oxoribose derivative.
The compound of formula (V) used as a starting material in the inventive method
may be prepared by a conventional method described in US Patent Nos. 4,526,988;
4,965,374; 5,223,608; and 5,434,254, as shown in Reaction Scheme H.
Reaction Scheme H
wherein, R, R1 and R2 have the same meanings as defined above.
In Reaction Scheme n, the compound of formula (V), a 3:1 mixture of 3R- and 3Senantiomers,
may be prepared by mixing an aldehyde ketonide of formula (VII) with a
difluoro compound of formula (VI), and allowing the mixture to undergo Reformatsky
reaction using zinc.
Further, a 3R-carboxylate of formula (III) can be prepared from the compound of
formula (V), as shown in Reaction Scheme HI.
Reaction Scheme ffl
wherein, R, R1, R2 and M have the same meanings as defined above.
hi Reaction Scheme HI, the 3R-carboxylate of formula (ET) can be obtained as a
solid by; (i) protecting the 3-hydroxy group of the compound of formula (V) with a
biphenylcarbonyl protecting group to obtain the compound of formula (TV); and (ii)
hydrolyzing the compound of formula (TV) with a base.
hi the inventive method, the protecting group used in step (i) may be a
biphenylcarbonyl group which is a benzoyl group substituted with benzene ring optionally
the benzene ring is substituted with one or more substituents selected from the group
consisting of hydrogen, cyano, halo, carboalkoxy, toluoyU nitro, alkoxy, alkyl and
dialkylamino. Representative examples of biphenylcarbonyl include such as
2-phenylbenzoyl (2-biphenylcarbonyl), 4-phenylbenzoyl (4-biphenylcarbonyl) and
substituted 2-(or 4-) phenylbenzoyl, preferably 2-phenylbenzoyl and 4-phenylbenzoyl.
Increased hydrophobicity due to the two benzene ring of biphenylcarbonyl group
makes it possible to separate 3R-carboxylate of formula (HI) as a solid even in the water
water containing mixed solvent
On the other hand, in case of using a conventional benzoyl group as a hydroxy
protecting group, it is impossible to get a 3R-carboxylate salt as a solid in the water or water
containing mixed solvent.
In contrast, in case of introducing a conventional hydroxy protecting group such as
1-naphtoyl, 2-naphtoyl, pivaloyl or acetyl for the 3-hydroxy group of the compound of
formula (V), it is very difficult to selectively isolate the 3R-carboxylate of formula (HI) as a
solid from the resulting reaction mixture.
The biphenylcarbonyl-based compound used in step (i) may be selected from the
group consisting of biphenylcarbonyl (or substituted biphenylcarbonyl) chloride, bromide,
cyanide or azide, which may be commercially obtained or chemically synthesized in
accordance with conventional methods.
Also, the base used in the neutralization process of step (i) may be selected from the
group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and
methylpiperidine, preferably triethylamine; a catalyst used in the acylation may be
4-dimethylaminopyridine or 4-pyrolidinopyridine; and the acylation may be conducted at
-25 to 50°C.
In the hydrolysis of step (ii), the base may be selected from the group consisting of
gaseous ammonia, aqueous ammonia, sodium carbonate, sodium bicarbonate, sodium
hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and a mixture
thereof, preferably potassium bicarbonate, which may be employed in an amount of 1
equivalent or more, preferably ranging from 1.5 to 5 equivalents based on the compound
Also, the mixed solvent essentially comprising water may be a mixture of water and
an organic solvent selected from the group consisting of tetrahydrofuran, dioxane,
acetonitrile, acetone, methylisobutylketone, methylethylketone, methanol, ethanol, propanol,
isopropanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethyl acetate and a
mixture thereof, preferably a mixture of tetrahydrofuran and methanol; and the water may be
employed in an amount ranging from 3 to 15 ml, preferably from 5 to 11 ml, and the organic
solvent, from 3 to 30 ml, preferably from 6 to 18 ml, based on 1.0 g of the compound of
formula (IV). The hydrolysis may be conducted at 5 to 50°C, preferably 10 to 30°C for min to 2 hours.
The compound of formula (ID) may be isolated easily from the reaction mixture
obtained in step (ii), by removing the organic solvent under a reduced pressure, and filtering
the resulting mixture; or by extracting the reaction mixture with an organic solvent, and
recrystallizing the product in a mixed solvent essentially comprising water.
In the inventive method, the 3R-carboxylate of formula (IH) may be obtained from
the compound of formula (V) in a high yield of 60 to 70% via a potassium or sodium salt, or
about 40% when an ammonium salt is used as a base in step (ii). Further, the compound of
formula (III) obtained in the inventive method has a 3R-carboxylate content of more than
99.7% while the 3S-carboxvlate content is less than 0.3% (consequently, e.e value over
99.4%).
The compound of formula (I) having the erythro structure may be obtained from the
compound of formula (ID) in a highly enantioselective manner, as shown in Reaction
(Figure Removed)
wherein, R, R, R3 and M have the same meanings as defined above.
In Reaction Scheme IV, the compound of formula (I) may be prepared by (iii)
reacting the compound of formula (HI) with an acid in a solvent to obtain the compound of
formula (II) having the erythro structure as a result of conducting the cascade of reactions
comprising the neutralization of the carboxylate, removal of the isoalkylidene protecting
group to produce a diol carboxylic acid of formula (VHI), and lactonization of the compound
of formula (VET); and (iv) protecting the 5-hydroxy group of the compound of formula (IT)
with a protecting group containing a hydrophobic benzene ring.
The acid used in the inventive step (iii) may be a strong acid having a pka value
ranging from -10.0 to 2.0, which may be selected from the group consisting of an inorganic
acid such as 1 to 12 N HC1 and 1 to 9 N HaSO-t, and an organic acid such as methanesulfonic
acid, p-toluenesulfom'c acid, trifluoroacetic acid and trifluoromethanesulfonic acid,
preferably 12 N HC1 and trifluoroacetic acid, more preferably 12 N HC1; employed in an
amount ranging from 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents based on the
compound of formula (HI).
Meanwhile, the reaction product of step (iii) may be regulated so as to comprise 1 to
10 equivalents, preferably 2 to 5 equivalents of water based on the compound of formula
(HI), for instance, by adding an aqueous solution thereto, e.g., an aqueous inorganic acid
having an appropriate concentration, or an aqueous solvent such as 95% ethanol, in order to
effectively remove the isoalkylidene group. The solvent used in step (iii) may be selected
from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethanol, methanol
10
and isopropanol, preferably acetonitrile.
Step (iii) may be carried out at a refluxing temperature of the solvent for 4 to 8 hours
to remove the isoalkylidene group; and the resulting mixture may be mixed with a solvent
such as benzene and toluene, and azeotropically distilled to remove water from the reaction
mixture to obtain the lactonized compound of formula (IT).
In step (iv), the protecting group may be selected from the group consisting o f
benzoyl, phenylbenzoyl and substituted benzoyl, preferably 2-phenylbenzoyl,
4-phenylbenzoyl and substituted 2- (or 4-) phenylbenzoyl.
Also, step (iv) may be conducted after isolating the compound of formula (II)
obtained in step (iii), or conducted without such an isolating process in situ. The in situ
process is preferred.
The compound of formula (I) obtained in the inventive method exhibits a high purity
of about 99% of the 1-oxoribose compound having the desired erythro structure.
Further, the inventive method has a total yield of 45 to 50%, which is improved more
than 20% relative to the conventional methods.
The following Examples are intended to further illustrate the present invention
without limiting its scope.
Preparation 1: Preparation of
2-difluoro-3-hydrox7-3-(2,2-dimethyl-[l,3]dioxoran-4-yl)propionate (compound of
(Figure Removed)
100 g of d-mannitol was mixed with 160 ml of 2,2-dimethoxypropane, 240 ml of
1,2-dimethylethanediol and 0.1 g of anhydrous SnClo, the mixture was heated until a
homogeneous solution was obtained, and refluxed for 30 min, and 0.2 ml of pyridine was
added thereto. The reaction mixture was cooled to room temperature, and distilled under
reduced pressure to remove the solvent. 700 ml of methylchloride was added to the residue
and refluxed for 1 hour. The resulting mixture was. filtered through 10 g of cellite at room
temperature, and the filtrate was distilled under a reduced pressure to remove the solvent.
The residue was recrystallized from 1 L of hexane, filtered, and dried to obtain 72.4 g (yield
50%) of the title compound as a white solid.
NMR (300 MHz, CDC13): 1.30(s, 6H), 1.36(s, 6H), 2.52(d, 2H), 3.67(t, 2H), 3.91(m,
2H), 4.04-4.14(m,4H)
Melting point (m.p.): 119~121°C
Step 2: Preparation of 2,2-dimethyl-[l,3]-dioxorane-4-carboaldehyde
72.4 g of the compound obtained in Step 1 was dissolved in 724 ml of
methylchloride, and 30 ml of saturated sodium bicarbonate was added thereto. The mixture
was cooled in a water bath, and 118 g of sodium methaperiodate was added in small portion
thereto over a period of 20 min while keeping the temperature at under 25°C. The reaction
mixture was stirred at room temperature for 2 hours. After confirmng the completion of the
reaction by thin layer chromatography (TLC), 36 g of anhydrous magnesiumsulfate was
added to the reaction mixture, and stirred for 20 min. The resulting mixture was filtered
and distilled under a reduced pressure at 30°C to remove the solvent, and the residue was
further subjected in distillation under an atmospheric pressure at 55°C to completely remove
the solvent. The reacting residue was distilled at 10 torr, about 40°C to obtain 61.6 g (yield
86%) of the title compound as a colorless liquid.
(Figure Removed)
13 g of zinc was added to 26 ml of tetrahydrofuran, 0.51 ml of dibromoethane was
added thereto, and the mixture was kept at 60°C for 1 min. 0.76 ml of
chlorotrimethylsilane was added thereto at 40°C, and the mixture was allowed to react for 10
min. The reaction mixture was heated to 60°C, a solution made of 25.5 ml of ethyl
bromodifluoroacetate, 30.8 g of the compound obtained in step 2 and 39 ml of
tetrohydrofuran was added dropwise thereto, and the mixture was refluxed for 30 min.
After adding 65 ml of diethyl ether and 260 g of ice thereto, 260 ml of 1 N HC1 was added
thereto and stirred until the ice was completely melted. The aqueous layer was extracted
three times with 90 ml portion of diethyl ether, the combined organic layer was washed
successively with 65 ml portion of Nad and sodium bicarbonate, dried over anhydrous
magnesiumsulfate, and filtered.. After removing the solvent, the residue was distilled at 10
torr to obtain 28.9 g (57%) of the title compound (R:S=3:1) at 130~134°C as a colorless
liquid.
NMR (300 MHz, CDC13): 1.31~1.52(m, 9H), 2.67(s, 1H, (R)-OH), 2.90(d, 1H,
(S)-OH), 3.7~4.4(m, 6H)
In the following Examples, the term "-OCOBiPh" or "BiPhOCO-" refers to
HPLC analyses of the compounds of formulas (I) and (HI) were performed with a
YMC pack pro CIS RS (4.6x150 mm, 5 urn) column using a mixture of a buffer and
acetonitrile (65:35, v/v) (for the compound of formula (HI)) or 80% acetonitrile (for the
compound of formula (I)) as an eluent. The buffer was prepared by mixing 7.0 g of
NaClO4,1.74 g of K2HP04 and 1 L of water, and adding EfePCthereto until pH 2.75.
50.0 g of the compound obtained in Preparation 1 was added to 500 ml of
methylene chloride, 42 ml of triethylamine and 51.1 g of 4-biphenylcarbonyl chloride
were added thereto, and the mixture was kept at room temperature for 6 hours. After
adding 360 ml of 1N HC1 thereto, the organic layer was successively washed with 180 ml
portion of water, saturated sodium bicarbonate and NaCl, and dried over magnesiumsulfate.
The residue was filtered, and distilled under a reduced pressure to obtain 83.7 g (yield 98%)
of the title compound as a cream-color liquid.
NMR (300 MHz, CDC13): 1.25~1.74(m, 9H), 4.11~4.19(m, 2H), 4.30-^.36(m, 2H),
4.56~4.58(m, 2H), 5.72~5.83(ddd, lHxl/3), 5.88~6.02(ddd, !Hx2/3), 7.42~7.53(m, 3H),
7.63~7.73(dd, 4H), 8.15~8.17(d, 2H)
Example 2: Preparation of potassium
2,2-difluoro-3R-(4-biphenylcarbonyl)oxy-3-(2,2-dimethyl-[l^]dioxoran-4-yl)propionat
(Figure Removed)
83.8 g of the compound obtained in Example 1 was added to 1.4 L of a mixture of
tetrahydrofuran and methanol (2:3, v/v), and 107 g of potassium carbonate dissolved in ml of water was added thereto. The mixture was stirred for 30 min, and kept under a
reduced pressure to remove the organic solvent After filtering, the solid was added to 100
ml of ether, stirred, filtered, washed with ether, and dried to obtain 60.1 g (yield 70 %) of the
title compound as a white solid.
HPLC: R-isomer 99.86%, S-isomer 0.11%
NMR (300 MHz, DMSO): 1.07(s, 3H), 1.22(s, 3H), 3.99(t, 1H), 4.11(t, 1H), 4.49(t,
14
1H), 5.88(ddd, 1H), 7.38~7.54(m, 3H), 7.75(d, 2H), 7.85(d, 2H), 8.07(d, 2H)
Method B
94.0 g of the compound obtained in Example 1 was added to 600 ml of a mixture of
tetrahydrofuran and methanol (1:1, v/v), and 54.4 g of potassium carbonate dissolved in 500
ml of water was added thereto. The mixture was stirred for 1 hour, washed twice with 500
ml portion of hexane, extracted with 500 ml of ethyl acetate, and kept under a reduced
pressure to remove the solvent. The resulting solid was mixed with 100 ml of water and
300 ml of i-propyl alcohol, heated until it dissolved, and 700 ml of i-propyl alcohol was
added thereto. The resulting mixture was kept at room temperature for 2 hours to allow the
recrystallization of solids, which were filtered, washed with i-propyl alcohol, and dried to
obtain 62.5 g (yield 65%) of the title compound as a white solid.
HPLC: R-isomer 99.91%, S-isomer 0.06%
NMR (300 MHz, DMSO): 1.07(s, 3H), 1.22(s, 3H), 3.99(t, 1H), 4.1 l(t, 1H), 4.49(t,
1H), 5.88(ddd, 1H), 7.38~7.54(m, 3H), 7.75(d, 2H), 7.85(d, 2H), 8.07(d, 2H)
Example 3: Preparation of
D-erythro-2-deoxy-2,2-difluoro-pentofuranos-l-ulose-5-benzoyl-3-(4-phenyl)benzoate
(the compound of formula (I); R=4-biphenylcarbonyI, R3=benzoyl)
Method A: Preparation by isolating each product of each step
Step 1: Preparation of
D-erythro-2-dexoy-2,2-difluoro-pentofuranos-1 -ulnose-3-(4-phenyl)benzoate (the
10 g of the compound obtained hi Example 2 was dispersed in 60 ml of acetonitrile,
2.5 ml of 12 N HC1 was added thereto, and the mixture was refluxed for 6 hours. 60 ml
toluene was added thereto, and the reaction mixture was distilled to remove the solvent.
This procedure was repeated twice. 100 ml of ether was added to the residue, filtered to
remove KC1, and distilled under a reduced pressure to remove the solvent. The resulting
residue was added to 50 ml of ether, and 100 ml of hexane was added thereto to induce
recrystallization of a solid. The solid was recovered by filtration (the first batch of solid);
and the filtrate was distilled under a reduced pressure, and subjected to a second
recrystallization step using 20 ml of ether and 50 ml of hexane to obtain a second batch solid. The solids were cobined, and dried under a vacuum to obtain 5.9 g (yield 75%) of
the title compound as a white solid.
NMR (300 MHz, CDC13): 1.8~2.4(brd s, 1H), 3.78~4.02(dd, 1H), 4.11~4.13(dd, 1H),
4.7173(m, 1H), 5.79~5.87(m, 1H), 7.44~7.54(m, 3H), 7.64~7.66(d, 2H), 7.21~7.75(d,
2H)
Melting point (m.p.): 107-111 °C
OCOBiPh OCOBiPh
15.0 g of the compound obtained in Step 1 was added to 150 ml of methylene
chloride, 6.9 ml of pyridine was added dropwise thereto with stirring at room temperature,
and 7.4 ml of benzoyl chloride dissolved in 40 ml of methylene chloride was added thereto
slowly while maintaining the temperature at 5 to 10°C. The reaction mixture was kept at
room temperature for 7 hours, 105 ml of 1N HC1 was added thereto to neutralize pyridine in
the mixture, and water added thereto to induce the separation of an orgainic layer. The
organic layer was separated, washed successively with 100 ml portion of saturated sodium
bicarbonate and NaCl, dried over magnesium sulfate, and filtered. The remaining solution
was kept under a reduced pressure to obtain a cream-color solid. The solid was
recrystallized from a mixture of ether and hexane (5:1, v/v) to obtain 16.8 g (yield 86%) oi
the title compound.
(Figure Removed)

232 ml of acetonitrile was mixed with 38.8 g of the compound obtained in Example
2 and 9.2 ml of 12 N HC1, and the mixture was refluxed for 6 hours. After adding 464 ml
of toluene thereto, the reaction mixture was distilled to remove water and acetonitrile until
the temperature became over 100°C. The resulting concentrate was filtered and kept under
a reduced pressure to obtain a foam-shaped solid. The solid was dissolved in 300 ml of
ethyl acetate, 14 ml of pyridine was added thereto with stirring, and 15 ml of benzoyl
chloride dissolved in 75 ml of ethyl acetate was added thereto. The mixture was kept at
room temperature for 6 hours, and 210 ml of 1 N HC1 was added thereto to neutralize
pyridine. The organic layer was separated, washed successively with 150 ml portion of
water, saturated sodium bicarbonate and NaCl, dried over magnesium sulfate, and kept
under a reduced pressure to obtain a cream-color solid. The solid was recrystallized from a
mixture of ether and hexane (5:1, v/v) to obtain 28.4 g (yield 72%) of the title compound as
a white solid.
NMR (300 MHz, CDC13): 4.90~4.75(ddd, 2H), 5.10(dd, 1H), 5.87(ddd, 1H),
7.65~7.50(m, 5H), 7.78~7.67(m, 3H), 7.81(d, 2H), 8.13(d, 2H), 8.23(cL 2H)
Melting point (m.p.): 130-131°C
HPLC purity: 99.05% (No threo isomer was detected)
(Figure Removed)
OCOBPh OCOBiPh
20 g of the compound obtained in Step 1 was added to 300 ml of chloroform, 9.5 ml
of pyridine was added thereto with stirring at room temperature, and 10.1 ml of benzoyl
chloride dissolved in 55 ml of chloroform was added thereto. The mixture was kept at
room temperature for 6 hours, and the remaining pyridine was neutralized using 140 ml of
IN HC1. The organic layer was separated, successively washed with 150 ml portion of
water, saturated sodium bicarbonate and NaCl, dried over magnesium sulfate, and kept
under a reduced pressure to obtain a cream-color solid. The solid was recrystallized from
mixture of acetate and hexane (3:1, v/v) to obtain 21.8 g (yield 72%) of the title compound
as a white solid.
NMR (300 MHz, CDC13): 4.72~4.79(m, 2H), 5.03(q, 1H), 5.84~5.76(m, 1H),
7.48~7.44(m, 6H), 7.72~7.60(m, 8H), 8.15~8.07(m, 4H)
Melting point (m.p.): 137~139°C
18
HPLC purity: 98.95% (No threo isorner was detected)
Method B: In situ preparation
40.0 g of the compound obtained in Example 2 was added to 240 ml of acetonitrile,
10 ml of 12 N HC1 was added thereto, and the mixture was refluxed for 6 hours. After
adding 250 ml of toluene thereto, the reaction mixture was distilled to remove water and
acetom'trile, cooled to room temperature, filtered, and kept under a reduced pressure to
obtain 5-hydroxy-l-oxoribose as an intermediate. The intermediate was dissolved in 480
ml of ethyl acetate, a mixture of 21.8 ml of pyridine and 39 g of 4-biphenylcarbonyl chloride
was added thereto, and allowed to react at room temperature for 12 hours. 320 ml of 1 N
HC1 was added to the reacting mixture to neutralize the remaining pyridine; the organic layer
was separated, washed successively with 160 ml portion of water, saturated sodium
bicarbonate and NaCl, dried, and filtered. The filtrate was kept under a reduced pressure to
remove the solvent, and the residue was recrystallized from a mixture ethylacetate and
hexane (3:1, v/v) to obtain 31.9 g (yield 65%) of the title compound as a white solid.
NMR (300 MHz, CDC13): 4.72~4.79(m, 2H), 5.03(q, 1H), 5.84~5.76(m, 1H),
7.48~7.44(m, 6H), 7.72~7.60(m, 8H), 8.15~8.07(m, 4H)
Melting point (m.p.): 137~139°C
HPLC purity: 98.33 (No threo isomer was detected)
While the invention has been described with respect to the above specific
embodiments, it should be recognized that various modifications and changes may be made
to the invention by those skilled in the art which also fall within the scope of the invention as






We claim:
1. A method for preparing a 2,2-difluoro-2-deoxy-1 -oxoribose derivative of formula (I),
comprising the steps of:
(i) reacting a compound of formula (V) with a biphenylcarbonyl derivative to obtain a
compound of formula (IV) having the 3-hydroxy group protected by a biphenylcabonyl group;
(ii) reacting the compound of formula (IV) with a base in a mixed solvent essentially
comprising water to obtain a 3R-carboxylate enantiomer of formula (III) by filtration;
(iii) reacting the compound of formula (III) with an acid to obtain a 5-hydroxy-1-oxoribose
derivative of formula (II); and
(iv) protecting the 5-hydroxy group of the compound of formula (II) with R3:
wherein,

(Formula Removed)
R1 is methyl or ethyl; R2 is C1-3 alkyl; R3 is benzoyl or
(Formula Removed)
R4 is phenyl or substituted phenyl; and M is sodium or potassium.
2. The method as claimed in claim 1, wherein the biphenylcarbonyl group of step (i) is 2-biphenylcarbonyl or 4-biphenyIcarbony I.
3. The method as claimed in claim 1, wherein the mixed solvent essentially comprising water used in step (ii) is a mixture of water and an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, acetone, methylisobutylketone, methylethylketone, methanol, ethanol, propanol, isopropanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethylacetate and a mixture thereof.
4. The method as claimed in claim 1, wherein the base used in step (ii) is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and a mixture thereof.
5. The method as claimed in claim 4, wherein the base used in step (ii) is potassium carbonate.
6. The method as claimed in claim 1, wherein the acid used in step (iii) is selected from the group consisting of 1 to 12 N HCI, 1 to 9 N H2SO4, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and trifiuoromethanesulfonic acid.
7. The method as claimed in claim 6, wherein the acid used in step (iii) is 12 N HCI.
8. The method as claimed in claim 1, wherein the acid used in step (iii) is employed in an amount ranging from 1.1 to 1.5 equivalents based on the compound of formula (II).

Documents:

1175-DELNP-2007-1-Correspondence Others-(27-10-2011)..pdf

1175-DELNP-2007-Abstract-(06-03-2012).pdf

1175-DELNP-2007-Abstract-(27-10-2011).pdf

1175-delnp-2007-abstract.pdf

1175-delnp-2007-Assignment-(21-07-2011).pdf

1175-delnp-2007-assignments.pdf

1175-DELNP-2007-Claims-(06-03-2012).pdf

1175-DELNP-2007-Claims-(27-10-2011).pdf

1175-delnp-2007-claims.pdf

1175-DELNP-2007-Correspondence Others-(06-03-2012).pdf

1175-DELNP-2007-Correspondence Others-(10-06-2011).pdf

1175-DELNP-2007-Correspondence Others-(19-10-2011).pdf

1175-delnp-2007-Correspondence Others-(21-07-2011).pdf

1175-DELNP-2007-Correspondence Others-(27-10-2011).pdf

1175-delnp-2007-correspondence-others-1.pdf

1175-DELNP-2007-Correspondence-Others.pdf

1175-delnp-2007-description (complete).pdf

1175-delnp-2007-Form-1-(21-07-2011).pdf

1175-DELNP-2007-Form-1-(27-10-2011).pdf

1175-delnp-2007-form-1.pdf

1175-delnp-2007-form-18.pdf

1175-delnp-2007-Form-2-(21-07-2011).pdf

1175-DELNP-2007-Form-2-(27-10-2011).pdf

1175-delnp-2007-form-2.pdf

1175-DELNP-2007-Form-3-(19-10-2011).pdf

1175-DELNP-2007-Form-3-(27-10-2011).pdf

1175-DELNP-2007-Form-3.pdf

1175-delnp-2007-form-6.pdf

1175-delnp-2007-GPA-(21-07-2011).pdf

1175-delnp-2007-pct-101.pdf

1175-delnp-2007-pct-210.pdf

1175-delnp-2007-pct-237.pdf

1175-delnp-2007-pct-308.pdf

1175-delnp-2007-pct-409.pdf

1175-delnp-2007-pct-notification.pdf


Patent Number 251827
Indian Patent Application Number 1175/DELNP/2007
PG Journal Number 15/2012
Publication Date 13-Apr-2012
Grant Date 10-Apr-2012
Date of Filing 13-Feb-2007
Name of Patentee HANMI HOLDINGS CO., LTD
Applicant Address #893-5,HAJEO-RI, PALTAN-MYEON, HWASEONG-GUN, KYUNGKI-DO 445-910, REPUBLIC OF KOREA
Inventors:
# Inventor's Name Inventor's Address
1 LEE JAEHEON XI 1-CHA APT., 101-405, SINBONG-DONG, YONGIN-SI, KYUNGKI-DO 449-150,KOREA
2 PARK GHA-SEUNG SINJEONGMAEUL IDANJI 107-1003, POONGDUKCHEON 2-DONG,YONGIN-SI, KYUNGKI-DO 449-756,KOREA
3 LEE MOONSUB #72-9, DEOKAM-DONG, DAEDEOK-GU, DAEJEON 306-200, KOREA
4 KIM CHEOL-KYONG SINNAMUSIL SINMYEONG APT., 634-1003,#968, YOUNGTONG-2-DONG, PALDAL-GU, SUWON-SI, KYUNGKI-DO 442-470 KOREA
5 LEE JAE-CHUL KYUNGWONYEONLIP RA-DONG 101, #781, JOWON-DONG, JANGAN-GU, SUWON-SI, KYUNGKI-DO 440-200, KOREA
6 CHANG YOUNG-KIL #34-4, SAMJEON-DONG, SONGPA-GU, SEOUL 138-838,KOREA
7 LEE GWAN-SUN 3-304, OKEUM-DONG, SONGPA-GU, SEOUL 138-130, KOREA
PCT International Classification Number C07H 3/08
PCT International Application Number PCT/KR2005/001955
PCT International Filing date 2005-06-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10-2004-0057711 2004-07-23 Republic of Korea