|Title of Invention||
PREPARATION OF NUCLEOSIDES RIBOFURANOSYL PYRIMIDINES
|Abstract||The present process provides an improved method for the preparation of 4- amino-l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahydro-furan-2-yl)-lH-pyrimidin-2-one of the formula (IV) which is a potent inhibitor of Hepatitis C Virus (HCV) NS5B polymerase.|
|Full Text||This application is being filed on October 5,2007, as a PCT International Patent application in the name of PHARMASSET, INC., a U.S. national corporation, and F. HOFFMANN LA-ROCHE AG, a Swiss national corporation, applicants for the designation of all countries except the US, and Steven D. Axt, .5 U.S. citizen; Keshab Sarma, U.S. citizen; Justin Vitale, a U.S. citizen; Jiang Zhu, a Canadian citizen; Bruce Ross, a U.S. citizen; Suguna Rachakonda, an Indian citizen; Qingwu Jin, a Chinese citizen; and Byoung-Kwon Chun, a Korean citizen; applicants for the designation of the US only, and claims priority to U.S. Provisional patent application Serial No. 60/850,962, filed October 10,2006. 10 The present invention relates to an improved process for the preparation of 4-
amino-1 -((2R,3 R,4R, 5R)-3 -fluoro-4-hydroxy-5-hy droxymethyl-3 -methyl- . tetrahydrofuran-2-yl)-1 H-pyrimidin-2-one of the formula
which is a potent inhibitor of Hepatitis C Virus (HCV) NS5B polymerase.
The PCT Publication WO 2006/012440 discloses a process according to the scheme below. The process requires the burdensome separation of the anomers 14 and 16.
Object of the present invention is to provide an improved and scalable 5 process for the preparation of 4-amino-l-((2R>3R,4R,5R)-3-fluoro-4-hydroxy-5-
hydroxymethyl-3-methyl4eti£ihydro-furan-2-yl)-lH-pyrimidm-2-one of the formula
10 which avoids the drawbacks known in the art.
The process of the present invention comprises a) transforming an (aryl)alkanoic acid (2R,3R,4R)-2- (aiyI)alkanoyloxymethyl-4-fIuoro-4-methyl-5-oxo-tetrahydro-furan-3 -yl ester of formula II
wherein R is aryl or alkyl
into an (aryl)alkanoic acid (2RJ3R,4R)-2-(atyl)alkanoyloxy methyl-5-chIoro- 4-fluoro-4-methyl-tetrahydro-fura,n-3-yl ester of formula III
wherein R is aryl or alkyl;
b) converting the (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl ester of formula HI into 10 an(aryl)alkanoic acid (2RJ3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamino-2-
oxo-2Hpyrimidin-l-yl)-4-fluoro-4-methyl-tetrahydro-furaii-2-ylmethyI ester of formula I
15 wherein R is aryl or alkyl and Bz is benzoyl and
c) hydrolyzing the (aryl)alkanoic acid (2R,3RJ4R,5R)-3-(aryl)alkanoyloxy-5- (4-betxzoylamino-2-oxo-2H-pyrimidin-l-yl)-4-fluoro-4-methyl-tetrahydro-furan- ylmethyl ester of formula I to afford the 4-amino-l-((2R,3R,4R,5 5 R)-3-fluoro-4- hydroxy-5 -hydroxymethyl-3 -methyl-tetrahydro-furan-2-yl) -1 H-pyrimidin-2-one of 20 formula IV.
The term (aryl)alkanoic acid as used herein refers to a group RCO2H wherein R is either alkyl or aryl as those terms are defined herein. Correspondingly the term (aryl)alkanoic ester refers to a group RCO2R' where R is either alkyl or aiyl. Most typically the R' represents the 3' and/or 5' position(s) of a ribose ring. The terms 25 "(aryl)alkanoyl" and "(ajyl)alkanoyloxy" refer to the groups RCO- and RCOO- respectively, where R is as described previously. The term
"(aryl)alkanoyloxymethyl" group refers a group RCOOCH2- where R is as described previously.
The terra "alkyl" as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
5 The term "aryl" as used herein refers to phenyl group.
In a preferred embodiment of the present invention R has the meaning of
In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of 10 IUPAC systematic nomenclature. If there is a discrepancy between a depicted
structure, and a name given that structure, die depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. 15 The transformation in step a) comprises a reduction in the presence of a
reducing agent and a subsequent chlorination in the presence of chlorinating agent.
Suitable reducing agent is sodium W,y-(2-methoxyethoxy) (2,2,2- trifluoroethoxy) aluminum hydride which is commercially available under the tradename RedAl® as a solution in toluene. 20 The reduction usually takes place in an organic solvent such as in a
halogenated hydrocarbon like dichloromethane at a reaction temperature of below 0°C, preferably below-5°C.
After completion of the reduction the reaction mixture is subjected to the chlorination reaction.
25 The chlorinating agent is as a rule selected from sulfuryl chloride, thionyl
chloride or phosphorus oxychloride.
Preferably sulfuryl chloride in the presence of catalytic amounts of tetrabutyl ammonium bromide is used.
The chlorination is expediently performed at a reaction temperature between 30 0°C and 40°C.
The (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4- fluoro-4-methyI-tetrahydro-furan-3-yl ester of formula III can be separated from the reaction mixture applying techniques known to the skilled in the art.
The conversion in step b) comprises reacting the (aryl)alkanoic acid
(2R,3R,4R)-2-(aiyl)aIkanoyloxy methyl-5-chloro-4~fluoro-4-methyl-tetrahydro- furan-3-yl ester of formula III with O-trimethyl silyl-N4-benzoylcytosin in the presence of a Lewis acid.
The O-trimethyl silyl-N4-benzoylcytosin may be prepared in situ by reacting 5 N-benzoyl cytosine with hexamethyldisilazan in the presence of ammonium sulfate in chlorobenzene under reflux conditions.
Common Lewis acids known in the art are suitable for the conversion in step b). Good results have been achieved with stannic chloride.
The reaction is usually performed at elevated temperature, for instance at 10 about 70°C until the coupling is complete.
The (aryl)alkanoic acid (2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4- , benzoylamino-2-oxo-2H-pyrimidin-l-yl)-4-fluoro-4-methyl-tetrahydro-furan-2- ylmethyl ester of formula I so obtained can be separated from the reaction mixture applying techniques known to the skilled in the art. 15 The hydrolysis in step c) is performed in. the presence of a base.
Suitable bases are organic bases like alkali metal alkoxides. Preferably sodium methoxide in methanol as solvent is used.
The reaction is performed at elevated temperature, for instance at about 50°C until the hydrolysis is complete. 20 The 4-amino-l-((2R,3RJ4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-
methyltetrahydro-furan-2-yl)-lH-pyrimidin-2-one of the formula IV can be isolated following methods known to the skilled in the art.
In a further embodiment of the present invention a process for the preparation of the starting product, the (aryl)alkanoic acid (2R,3R,4R)-2- 25 (aryl)alkanoyloxymethyl-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl ester of formula II
wherein R is phenyl has been developed. The process comprises the steps
al) transforming the (E)-3-((S)-2,2-dimethyl-[lJ3]dioxolan-4-yl)-2-methyl- aciylic acid ethyl ester of formula V
into the (2S,3R)-3-((R)-2,2-dimethyl-[ 1,3]dioxolan-4-yl)-2s3-dihydroxy-2- 10 methyl propionic acid ethyl ester of formula VI
bl) converting the (2S,3R)-3-((R)-2,2-dimethyl-[lJ3]dioxolan-4-yl)-2!3- 15 dihydroxy-2-methyl-propionic acid ethyl ester of formula VI into the sulfite of
20 cl) further reacting the sulfite of formula VH to the sulfate of formula VIII
dl) transforming the sulfate of formula VIII into the fluorohydrin sulfate of 5 formula IX
el) decomposing the fluorohydrin sulfate of formula IX into the lactone of 10 formula X
15 fl) acylating the lactone of formula X to form the end product gf formula II
wherein R is phenyl.
The present process can be described with SCHEME A below:
(al) acetone-NaMnC>4 (aq), ethylene glycol, NaHC03, -10 to 0°C; aq.
5 NaHS03 (quench); (bl) i-PrOAc, MeCN, TEA, SOCI2; (cl) f-PrOAc,
MeCN, NaOCl; (dl) TEA-3HF, TEA; (el) HC1 (aq)-BaCl2-aq; (fl) (PhCO) zO, DMAP, MeCN.
The asymmetric hydroxylation in step al) was discovered to be best carried out with sodium permanganate in the presence of ethylene glycol, 10 sodium bicarbonate in acetone at a temperature of -20 to 0° C which afforded
the diol in 60-64% on pilot plant scale. Starting compound (V) can be obtained from (1 S,2S)-1,2-bis-((R)-2,2-dimethyl-[l33]dioxolan-4-yl)-ethane- 1,2-diol (C. R. Schmid arid J. D. Bryant, Jerry D., Org. Syn. 1995 72:6-13) by oxidative cleavage of the diol and treating the resulting aldehyde with 2- 15 (triphenyl-X5-phosphanylidene)-propionic acid ethyl ester.
The cyclic sulfate (VHI) can be prepared by eyclization of the vicinal diol with e.g. thionyl chloride in step bl) and oxidation of the resulting cyclic sulfite (VII) in step cl) to the corresponding sulfate (VIII) with NaOCl in the presence of MeCN. It has been found that the cyclic sulfates can be 20 stabilized during processing by the addition of a trialkylamine such as TEA
or DIPEA at 2-10 mole % relative to the cyclic sulfote. Differential scanning calorimetry (DSC) showed a shift in the onset of decomposition from
approximately 110 to 180 °C when 3.5 mole % of DIPEA was added to (VHI). Contacting (VIII) with triethylamine-trihydrofluoride/TEA in step dl) affords the sulfated fluorohydrin (IX) which in the presence of water affords the fluorohyrin (X) An improved yield of (X) can be obtained in step dl) when BaCl2 is incorporated in the reaction mixture to scavenge the liberated sulfate. Under the acidic conditions concomitant hydrolysis of the acetonide liberates a triol which spontaneously cyclizes to the y-lactone (X). Contacting (X) with benzoic anhydride and DMAP in step fl) affords the dibenzoate of the lactone (IIb) which is used in the glycosylation step.
While the benzoyl protecting group (R=phenyl) is preferred, other potential protecting groups selected from methoxymethyl, methoxyethyl, benzyloxymethyl, ethoxymethyl, trityl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, acyl including acetyl, pivaloyl, benzoyl, toluoyl, 4-phenyl benzoyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, other substituted benzoyl may be applied. The base used for step fl) includes, but is not limited to the following list: imidazole, pyridine, DMAP, TEA, DIPEA, l,4-diazabicyclo[2,2,2]octane. The solvent used for step fl) includes, but is not limited to acetonitrile, pyridine, DCM, chloroform, DCE, THF.
The abbreviations used include: 1,2-dichloroethane (DCE), dichloromethane (DCM), di-iso-propylethylamine (DIPEA), N,N-dim ethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), ethanol (EtOH), ethylacetate (EtOAc), methanol (MeOH), methyl (Me), ethyl (Et), isopropanol (IPA), acetonitrile 5 (MeCN), phenyl (Ph), room temperature (rt or RT), triethylamine (TEA or Et3N), tetrahydrofuran (THF). Example 1
Benzoic acid 3-benzoyloxy-5-(4-benzoyIamino-2-oxo-2H-pyrimidin- l-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-yhnethyl ester (14)
Trifluoroethanol (4.08 kg) is added slowly to a cold solution (-15°C) of RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at or below -10°C. After wanning up to ambient 5 temperature (ca. 20°C), the modified RED-AL reagent mixture (30.1 kg out
of the 37.6 kg prepared) is added slowly to a pre-cooled solution (-15°C) of fluorolactone dibenzoate 10 (10 kg) in DCM (94.7 kg) while maintaining reaction temperature at or below -10°C. After reduction of the lactone (monitored by in-process HPLC), catalytic amounts of tetrabutylammonium 10 bromide (90 g) is added to the reaction mixture. Sulfuryl chloride (11.86 kg)
is then added while maintaining reaction temperature at or below 0°C. The reaction mixture is then heated to 40°C until formation of the chloride is complete (ca. 4 h) or wanned to ambient temperature (20-25°C) and stirred over night (ca. 16 h). The reaction mixture is cooled to about 0°C, and water
15 (100 L) is added cautiously while maintaining reaction temperature at or
below 15°C. The reaction mixture is then stirred at ambient temperature for ca. 1 h to ensure hydrolytic decomposition of excess sulfuryl chloride and the phases are separated. The organic layer is washed with a dilute solution of citric acid (prepared by dissolving 15 .5 kg of citric acid in 85 L of water) and
20 then with dilute KOH solution (prepared by dissolving 15 kg of 50% KOH in
100 L of water). The organic phase is then concentrated and solvents are replaced with chlorobenzene (2 x 150 kg) via atmospheric replacement distillation. The resulting solution containing 30 is dried azeotropically.
A suspension of N-benzoyl cytosine (8.85 kg), ammonium sulfate 25 (0.07 kg) and hexamethyldisilazane (6.6 kg) in chlorobenzene (52.4 kg) is
heated to reflux (ca. 135°C) and stirred (ca. 1 h) until the mixture becomes a clear solution. The reaction mixture is then concentrated in vacuo to obtain the O-trimethyl silyl-N4»benzoylcytosin as a syrupy liquid. The anhydrous solution of 30 in chlorobenzene (as prepared) and stannic chloride (28.2 kg)
are added to this concentrate. The reaction mixture is maintained at about 70°C until the desired coupling reaction is complete (ca. 10 h) as determined by in process HPLC. Upon completion, the reaction mixture is cooled to ambient temperature and diluted with DCM (121 kg). This solution is added 5 • to a suspension of solid NaHCOj (47 kg) and CELITE® (9.4 kg) in DCM
(100.6 kg). The resulting slurry is cooled to 10-15°C, and water (8.4 kg) is added slowly to quench the reaction mixture. The resulting suspension is very slowly (caution: gas evolution) heated to reflux (ca. 45°C) and maintained for about 30 min. The slurry is then cooled to ca 1S0C, and
10 filtered. The filter cake is repeatedly reslurried in DCM (4 x 100 L) and
. filtered. The combined filtrate is concentrated under atmospheric pressure (the distillate collected in the process is used for reslurrying the filter cake) until the batch temperature rises to about 90°C and then allowed to cool slowly to about -5°C. The resulting slurry is aged for at least 2 h at -5°C.
15 The precipitated product is filtered and washed with IPA (30 kg + 20 kg),
and oven-dried in vacuo at about 70°C to afford 8.8 kg (57.3%) of l-(2- deoxy-2-fluoro-2-methyl-3-5-Odibenzoyl-0-D-ribofuranosyl)-N-4- benzoylcytosine (14, CAS Reg No. 817204-32-3) which was 99.3% pure.=
20 Example 2
4-Amino-l -(3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl- tetrahvdro-furaa-2-yl)-lH-pyrimidin- 2-one (18)
ca 50 L. The resulting slurry is heated to ca. 80°C and then cooled slowly to ca. 5°C and aged (ca. 2 h). The precipitated product is isolated by filtration, washed with EPA (16.8 kg) and dried in an oven at 70°C in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure
(2S,3R)-3-[(4R)-2,2-dimethyl-[l,3]dioxolan-4-yl]-2,3-dihydroxy-2- methyl-propionic acid ethyl ester (24)
10 A suspension of 22 (10 kg, CAS Reg. No. 81997-76-4), ethylene
glycol (11.6 kg), solid NaHC03 (11.8 kg) and acetone (150 L) is cooled to ca. -15° C. A solution of 36% aqueous NaMn04 (19.5 kg) is charged slowly (over 4 h) to the suspension maintaining reaction temperature at or below -10°C. After stirring for 0.5 h at -10° C, an aliquot of the reaction mixture 15 (ca. 5 mL) is quenched with 25% aqueous sodium bisulfite (ca. 15 ml). A
portion of resulting slurry is filtered and submitted for GC analysis to check the progress of the reaction. When the reaction is complete, the reaction mixture is quenched by slow (over 40 min) addition of cooled (ca 0°C) 25% aqueous NaHSO3 (60 L). The temperature of the reaction mixture is allowed 20 to reach 4°C during the quench. CELITE® (ca. 2.5 kg) is then slurried in
acetone (8 kg) and added to the dark brown reaction mixture. The resulting slurry is aged at ambient temperature to obtain light tan slurry. The slurry is filtered, and the filter cake is washed with acetone (3 x 39 kg); The combined filtrate is concentrated by vacuum distillation (vacuum approximately 24 25 inches of Hg (ca. 810 mbar); max pot temperature is 32°C) to remove the
acetone. The aqueous concentrate is extracted with EtOAc (3 x 27 kg), and the combined organic extracts were washed with water (25 L). The organic phase is then concentrated by atmospheric distillation and EtOAc is replaced with toluene. The volume of the batch is adjusted to ca. 20 L. Heptane (62 30 kg) is added and the batch cooled to ca. 27° C to initiate crystallization. The
batch is then cooled to -10° C. After aging overnight at -10° C, the product is filtered, washed with 10% toluene in heptane and dried at 50°C under vacuum to afford 6.91 kg (59.5%) of 24 (CA RN 81997-76-4) as a white crystalline solid.
(3R,4R,5R)-3-Fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-dihydro- furan-2-one (10)
Steps 1 & 2 - A dry, clean vessel was charged with 24 (6.0 kg), isopropyl acetate (28.0 kg), MeCN (3.8 kg) and TEA (5.4 kg). The mixture was cooled to 5-10°C, and thionyl 10 chloride (3.2 kg) was added slowly while cooling the solution to maintain the temperature below 20°C. The mixture was stirred until no starting material was left (GC analysis). The reaction was typically complete within 30 min after addition is complete. To the mixture was added water (9 kg) and after stirring, the mixture was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a mixture of water (8 kg) and saturated NaHCC>3 (4 kg ) solution. To the remaining organic phase containing 36 was added MeCN (2.5 kg ) and solid NaHC03 (3.1 kg). The resulting slurry was cooled to ca 10°C. Bleach (NaOCl solution, 6.89 wt% aqueous solution, 52.4 kg, 2 eq.) was added slowly while cooling to- maintain temperature below 25°C. The mixture was aged with stirring over 90-120 min at 20-25°C, until the reaction was complete (GC analysis). After completion of the reaction, the mixture was cooled to ca 10°C and then quenched with aqueous Na2SC>3 solution (15,1% w/w, 21 kg) while cooling to maintain temperature below 20°C. The
quenched reaction mixture was filtered through a cartridge filter to remove inorganic solids. The filtrate was allowed to settle, and phases are separated and the aqueous phase is discarded. The organic layer was washed first with a mixture of water (11 kg) and saturated NaHC03 solution (4.7 kg), then 5 , with of saturated NaHC03 solution (5.1 kg). DIPEA (220 mL) was added to
the organic phase and the resulting solution was filtered through CELITE® (bag filter) into a clean drum. The reactor was rinsed with isopropyl acetate (7 kg) and the rinse is transferred to the drum. The organic phase was then concentrated under vacuum ca. 850-950 mbar while maintaining reactor 10 jacket temperature at 45-50°C to afford 26 as an oil (~10 L). Additional
DIPEA (280 mL) .was added and the vacuum distillation was continued (jacket temperature 50-55°C) until no more distillate was collected. (Batch volume ca 7 L).
15 Step 3 - To the concentrated oil from step 2 containing 26 was 5 added TEA
(2.34 kg )and TEA-trihydrofluoride (1.63 kg). The mixture was heated to 85°C for 2 h. The batch was sampled to monitor the progress of the reaction by GC. After the reaction was complete conc. HC1 (2.35 kg) was added to the mixture and the resulting mixture heated to ca 90° C (small amount of 20 distillate collected). The reaction mixture was stirred at ca. 90° C for 30 min
and then saturated aqueous BaCU solution (18.8 kg) was added. The resulting suspension was stirred at about 90°C for 4 h. The resulting mixture was then azeotropically dried under a vacuum (9-10 inches of Hg) by adding slowly n-propanol (119 kg ) while distilling off the azeotropic mixture 25 (internal batch temperature ca. 85-90°C). To the residual suspension was
added toluene (33 kg ) and vacuum distillation was continued to distill off residual n-propanol (and traces of water) to a minimum volume to afford 28.
Step 4 - To the residue from step 3 containing 28 was added MeCN (35 kg) 30 andca. 15L was distilled out under atmospheric pressure. The reaction
mixture was cooled to ca. 10°C and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 40°C. The batch was aged at ca. 20°C and the progress of the benzoylation is monitored by HPLC.
After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE® pad (using a nutsche filter) to remove inorganic salts. The solid cake was washed with EtOAc (38 kg). The 5 combined filtrate and washes were washed successively with water (38 kg),
saturated NaHC03 solution (40 kg) and saturated brine (44 kg). The organic phase was polish-filtered (through a cartridge filter) and concentrated under modest vacuum to minimum volume. IPA (77 kg) was added to the concentrate and ca. 25 L of distillate was collected under modest vacuum 10 allowing the internal batch temperature to reach ca 75°C at the end of the
distillation. The remaining solution was then cooled to ca. 5°C over 5 h and optionally aged overnight. The precipitate was filtered and washed with of cold (ca. 5°C) IPA (24 kg). The product was dried under vacuum at 60-70°C to afford 6.63 kg (70.7% theory of 10 which was 98.2% pure by HPLC.
1. A process for the preparation of 4-amino-l-((2R,3R,4Rs5R)-3-fluoro-4- hydroxy-5-hydroxymethyl-3-methyl4etrahydro-furan-2-yl)-1H-pyrimidin-2-one of
a) transforming an (aryl)alkanoic acid (2R,3R,4R)-2- (aryl)alkanoyloxymethyl-4- fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl ester of formula II
wherein R is aryl or alkyl
into an (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro- 4-fluoro-4-methyl-tetrahydro-furan-3-yl ester of formula HI
wherein R is aryl or alkyl;
b) converting the (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl ester of formula III into an (aryl)alkanoicacid(2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamino-2-oxo-
2H-pyriraidin-l-yl)-4-fluoro-4-mefhyl-tetrahydro-furan-2-ylmethyl ester of formula I
wherein R is aryl or alkyl and Bz is benzoyl and
c) hydrolyzing the (aryl)alkanoic acid (2R>3R,4R35R)-3-(aiyl)alkanoyloxy-5- (4-benzoylamino-2-oxo-2H-pyrimidin-l-yl)-4-fluoro-4-methyl-tetrahydro-furan-2- ylmethyl ester of formula I to afford the 4-amino-l-((2R,3R,4R,5 5 R)-3-fluoro-4- hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1 H-pyrimidin-2-one of formula IV
2. Process according to claim 1, characterized in that R has the meaning of
3. Process according to claim 1 or 2, characterized in that the transformation in step a) comprises a reduction in the presence of a reducing agent and a subsequent chlorination in the presence of chlorinating agent.
4. Process according to claim 3, characterized in that the reducing agent is sodium bis-(2-methoxyethoxy)(2,2,2-trifluoro-ethoxy)aluminum hydride
5. Process according to claim 3, characterized in that the chlorinating agent is selected form sulfuryl chloride, thionyl chloride or phosphorus oxychloride
6. Process according to claim 5, characterized in that the chlorinating agent is sulfuryl chloride in the presence of catalytic amounts of tetrabutylammonium bromide.
7. Process according to claim 1 or 2, characterized in that the conversion in step b) comprises reacting the (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl ester of formula HI with O-trimethyl silyl-N4-benzoylcytosin in the presence of a Lewis acid.
8. Process according to claim 1 or 2, characterized in that the hydrolysis in step c) is performed in the presence of a base.
9. Process according to claim 1, comprising the preparation of an (aiyl)alkanoic acid (2RJ3R,4R)-2-(aryl)alkanoyloxymethyl-4-fluoro-4-methyl-5- oxo-tetrahydro-furan-3-yl ester of formula II
wherein R is phenyl, comprising the steps of
al) transforming the (E)-3-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-2-methyl-acrylic acid ethyl ester of formula V
into the (2S,3R)-3-((R)-2,2-dimethyl-[l,3]dioxolan-4-yl)-2,3-dihydroxy-2- methylpropionic acid ethyl ester of formula VI
bl) converting the (2S53R)-3-((R)-2,2-dimethyl-[l,3]dioxolan-4-yl)-2,3-dihydroxy- 2-methyl-propionic acid ethyl ester of formula VI into the sulfite of formula VII
cl) further reacting the sulfite of formula VII to the sulfate of formula VIII
dl) transforming the sulfate of formula VIII into the fluorohydrin sulfate of formula IX
el) decomposing the fluorohydrin sulfate of formula IX into the lactone of formula X
f1) acylating the lactone of formula X to form the end product of formula II wherein R is phenyl
10. Process according to claim 9, characterized in that the transformation in step a1) is performed with sodium permanganate in the presence of ethylene glycol and sodium bicarbonate.
11. Process according to claim 9, characterized in that the transformation in step b1) is performed with thionylchloride.
12. Process according to claim 9, characterized in that the transformation in step c1) is performed with sodium hypochlorite.
13. Process according to claim 9, characterized in that the transformation in step d1) is performed with a trialkylamine.
14. Process according to claim 13, characterized in that triethylamine together with triethylamin-trihydrofluoride is used.
15. Process according to claim 9, characterized in that the decomposition in step e1) is performed with barium chloride in water.
16. Process according to claim 9, characterized in that the acylation 5 in step f1) is performed with benzoic anhydride.
17. The process as hereinbefore described.
|Indian Patent Application Number||817/MUMNP/2009|
|PG Journal Number||20/2012|
|Date of Filing||27-Apr-2009|
|Name of Patentee||PHARMASSET, INC.|
|Applicant Address||303A COLLEGE ROAD EAST, PRINCETON, NEW JERSEY 08540.|
|PCT International Classification Number||C07H 19/06|
|PCT International Application Number||PCT/US2007/021548|
|PCT International Filing date||2007-10-05|