Safe and Alternate Process for the Reductions of Methanesulfonates: Application in the Synthesis of 1,2,3-Triacetyl-5-deoxy-d-ribofuranoside

Article abstract of DOI:10.1021/acs.oprd.5b00286

Diethylene glycol dimethyl ether, diglyme, and 1,2-bis(2-methoxyethoxy)ethane, triglyme, are found to be suitable and safe alternate solvents to DMSO for the reduction of methanesulfonate in sodium borohydride. Addition of anhydrous lithium chloride led to the complete reduction of methanesulfonate esters to the corresponding alkanes in the presence of sodium borohydride in these solvents (diglyme and triglyme). This protocol is useful in the preparation of 1,2,3-triacetyl-5-deoxy-d-ribofuranoside, 7, a key intermediate of Capecitabine, 1, on the commercial scale.

Full text of DOI:10.1021/acs.oprd.5b00286

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Full Paper
A safe and alternate process for the reductions of methanesulfonates:
Application in the synthesis of 1,2,3-triacetyl-5-deoxy-D-ribofuranoside
Nagaraju Mekala, Murthy V R K Moturu, Rao VLN Dammalapati, and Atchuta R. Parimi
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00286 • Publication Date (Web): 04 Feb 2016
Downloaded from http://pubs.acs.org on February 9, 2016
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A safe and alternate process for the reductions of methanesulfonates:
Application in the synthesis of 1,2,3ꢀtriacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside
7
8
9
*
$#Nagaraju Mekala, $Murthy VRK Moturu , $Rao VLN Dammalapati and #Atchuta R Parimi
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Oncology Division, Process Development Laboratories, Laurus Labs Private Limited, ICICI
Knowledge Park, Turkapally, Shameerpet, Hyderabadꢀ500 078, Telangana, India
Department of Organic Chemistry, Food, Drugs & Water, School of Chemistry, Andhra
University, Visakhapatnamꢀ 530 003, Andhra Pradesh, India
*Corresponding author. Telephone: +91 40 30413393. Fax: +91 40 23480481.
Email: murthy.moturu@lauruslabs.com
$Laurus Labs Private Limited, Hyderabadꢀ500 078
#Andhra University, Visakhapatnamꢀ 530 003
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ABSTRACT:
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Diethylene glycol dimethyl ether, diglyme and 1,2ꢀbis(2ꢀmethoxyethoxy)ethane, triglyme are
found to be suitable and safe alternate solvents to DMSO for the reduction of methanesulfonate
in sodium borohydride. Addition of anhydrous lithium chloride led to the complete reduction of
methane sulfonate esters to the corresponding alkanes in presence of sodium borohydride in
these solvents (diglyme and triglyme). This protocol is useful in the preparation of 1,2,3ꢀtriacetylꢀ
5ꢀdeoxyꢀDꢀribofuranoside, 7 a key intermediate of Capecitabine, 1 in the commercial scale.
Key words: Capecitabine; diethylene glycol dimethyl ether; reduction; methane sulfonates;
sodium borohydride; lithium chloride
INTRODUCTION:
Capecitabine, 1 (Trade name; Xeloda), 5′ꢀdeoxyꢀ5ꢀfluoroꢀNꢀ[(pentyloxy) carbonyl]ꢀcytidine, is a
fluoropyrimidine carbamate with antineoplastic activity.1 It is an orally administered systemic
prodrug of 5′ꢀdeoxyꢀ5ꢀfluorouridine, 3 (5′ꢀDFUR) which is converted to 5ꢀfluorouracil, 4 (5ꢀFU)
invivo (Schemeꢀ1).2 It was approved for the use as a secondꢀline therapy of metastatic breast,
gastric, colorectal, bladder cancers and other malignancies.
Schemeꢀ1: Metabolism of Capecitabine
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O
4
5
6
HN
O
F
NH2
F
N
N
Carboxyesterase
7
8
9
O
O
N
O
O
N
liver
OH
OH
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OH
Capecitabine,1
OH
Cyd
deaminase
2
(tumor, liver)
O
N
F
HN
O
F
dThdpase
(tumor)
O
O
HN
O
N
H
OH
OH
5I-DFUR, 3
5-Fluorouracil (5-FU), 4
The industrial preparation of capecitabine involves the use of 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀ
ribofuranoside, 7 as a key starting material in the process chemistry (Schemeꢀ2).1,3 This key unit
is generally synthesized by peracetylation of 6ꢀdeoxyꢀDꢀribofuranose, 14. Essentially, 6ꢀdeoxyꢀ
Dꢀribofuranose, 14 is procured by the reduction of methylꢀ5ꢀOꢀmesylꢀ2,3ꢀOꢀisopropylidineꢀDꢀ
ribofuranose 12a, or methylꢀ5ꢀOꢀtosylꢀ2,3ꢀOꢀisopropylidineꢀDꢀribofuranose 12b which in turn
could be obtained from Dꢀribose, 10 in two steps. In this protocol, reduction of methane
sulfonate or tosylate group to methyl is very significant step in the preparation of 1,2,3ꢀtriꢀOꢀ
acetylꢀ5ꢀdeoxyꢀDꢀribofuranoside, 7 (Schemeꢀ3).4 The transformation of methane sulfonate or
tosylate to methyl group is usually carried out with sodium borohydride, a versatile reagent in
organic synthesis which can be used in Lab or commercial scales for the reduction of a wide
variety of functional groups like aldehydes,5 esters6 and tosylates & methanesulfonates.7
Schemeꢀ2: Preparation of 5′ꢀdeoxyꢀ5ꢀfluoroꢀNꢀ [(pentyloxy) carbonyl]ꢀcytidine
(Capecitabine)
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O
OAc
4
5
6
7
NH2
N
F
NH2
OAc
N
NHTMS
F
AcO
F
N
HMDS, (NH4)2SO4
7
O
N
8
O
9
O
N
H
TMSO
N
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OAc
5-Fluorocytosine, 5
6
OAc
8
O
O
NH
N
O
NH
N
O
F
F
N
N
NaOH, Methanol
n-PCF, Pyridine
O
O
O
O
OH
OAc
OH
OAc
9
1
RESULTS AND DISCUSSION:
DMSO or DMF is used as the most common solvent system to affect reductions of alkyl halides,
esters, acyl chlorides and sulfonate esters such as methanesulfonates or tosylates, using sodium
borohydride. However, reductions in these solvents generate large amounts of heat and hydrogen
gases which need to be controlled. A violent exothermic reaction has been reported involving
saturated solutions of sodium borohydride in DMF.8a Presence of moisture and elevated
temperatures are also not suitable for the use of DMSO as solvent in scale.8b Hence, DMF and
DMSO are not suitable solvents for the reduction of above substrates at higher temperatures in
commercial scale due to this explosive nature. This necessitates the discovery of a safe and
alternate solvent system to be used in a commercial scale. Herein, we report an alternate and safe
solvent for the reduction of 2,3ꢀOꢀisopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀDꢀribofuranoside, 12a
with a combination of borohydride and lithium chloride in commercial scale.
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Schemeꢀ3: Preparation of 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside
5
6
7
8
9
O
Mesylation/
Tosylation
HO
HO
O
O
O
HO
RO
OH
OMe
OMe
Reduction
NaBH4
Protection
O
O
OH
O
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12a: R=Ms
12b: R=Ts
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11
O
O
O
O
OMe
OH
Acylation
Deprotection
OAc
O
HO
AcO
OH
14
OAc
1,2,3-tri-O-acetyl-5-deoxy-
D-ribofuranoside, 7
13
Reduction of sulfonates with sodium borohydride as a reducing agent in dipolar aprotic solvents9
(HMPA, Me2SO, sulfolane) and ethylene glycol oligomers (PEGs)9c under anhydrous conditions
has been reported in the literature. The title compound, 1,2,3ꢀtriacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside,
7 was achieved by borohydride reduction of mesylate 12a and tosylate 12b in DMSO4g and the
same reduction of 12b was carried out in a mixture of THF and ether with LAH2b. Due to the
explosive reactions involved with the use of DMSO, we have screened a number of protic,
aprotic and mixed solvent systems for the reduction of methanesulfonate, 12a to the
corresponding methyl compound 13. When compared with all aprotic solvents, our experiments
revealed that, diglyme and triglyme are adequate solvents for this transformation. We checked
the solubility of sodium borohydride and found almost insoluble in monoglyme and soluble in di
& triglymes10a at ambient temperatures. In the prior art, diglyme was used as solvent with a
borohydride for the reduction of alkyl halide and the reaction is slower than DMSO.10b To our
knowledge, diglyme and borohydride was not used for the reduction of either sulfonates or
tosylates in the preparation of 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside, 7. Primary
methanesulfonates are less reactive substrates; require higher temperature and catalyst for
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reduction. Without catalyst methanesulfonates are not converted to corresponding alkyl group
even though a large excess of borohydride is used.11
7
8
9
Schemeꢀ4: Reduction of 2,3ꢀOꢀisopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀDꢀribofuranoside
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O
O
O
O
MsO
OMe
OMe
Reduction
NaBH4
O
O
13
12a
s
Initially, the reduction of 2,3ꢀOꢀisopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀO-mesylꢀDꢀribofuranoside, 12a
(Schemeꢀ4) was effected in methanol with 0.5 eq of sodium borohydride at ambient temperature.
However, the reaction didn’t proceed at all under these conditions (Tableꢀ1; entry no.1). It was
also found that the reaction doesn’t occur with more equivalents of the reagent (4.5 eq.) and even
at higher temperatures (60ꢀ65°C) for prolonged time (entry no. 2). Conducting the reaction in a
mixture of solvents like THF and methanol (entry no. 3) also did not give the fruitful results.
Interestingly, the reaction proceeded (~50%) when a mixture of IPA and methanol was used
(entry no. 4) as solvent system under reflux conditions. The reaction also did not proceed in other
solvents like toluene and PEGꢀ400 (entry nos. 5&6) even at higher temperatures. But, a complete
conversion was observed using DMSO even in shorter time (entry no. 7) as reported in the
literature.2b,4a,4g
Tableꢀ1: Reduction of Methanesulfonate without catalyst
S.
Reagent Temp.
Time
(h)
Conversion
by TLC
Solvent
MeOH
MeOH
Remarks
No.
(Eq.)
(°C)
0.5
25ꢀ35
48
1
2
No product
formation observed
No conversion
4.5
60ꢀ65
72
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3
4
MeOH/THF 2.0
MeOH/IPA 4.0
60ꢀ65
80ꢀ90
5
5
Conversion
observed
is
~50% product
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formation observed
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9
5
6
Toluene
2.0
2.0
80ꢀ90
80ꢀ90
5
No conversion
No conversion
RM remains as is
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RM turns into sticky
mass.
PEGꢀ400
15
Complete
conversion
observed
7
DMSO
4.5
80ꢀ90
5
Product formed
Later, the influence of the catalyst for the conversion of methanesulfonate to corresponding
methyl group was investigated in different solvent systems with different catalysts, such as
MgCl2, TiCl4, AlCl3, and TOAB (Tetraoctyl ammonium bromide). The reaction was tried in
o
toluene from ambient temperature to elevated temperature up to 110 C but observed no
conversion at all by TLC (Tableꢀ2; entry no. 1ꢀ4) even after prolonged period of time (entry 5).
Though sodium borohydride is not soluble in toluene at ambient temperature, we thought
reaction may proceed at higher temperatures in presence of these solvents. Also, the reaction did
not proceed with sodium borohydride dissolved in a 2% aq. sodium hydroxide solution to the
substrate in toluene or diphenyl ether in presence of tetraoctylammonium bromide (TOAB)
catalyst (entry no. 5 &6). When the reaction was tried in polyethylene glycolꢀ400 (PEGꢀ400) in
presence of lithium chloride catalyst at ambient temperature, conversion was observed by TLC,
but reaction did not go to completion (entry no. 7). Similar result was obtained when the reaction
was tried in IPA at 60ꢀ65oC (entry no. 8) with LiCl as catalyst. Product decomposition was
observed when the reaction was carried out in a mixture of IPA and methanol with a 0.5 eq. of
LiCl as catalyst (entry no. 9).
Tableꢀ2: Reduction of Methanesulfonate with catalyst
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S.
Temp.
(°C)
Time
(h)
Conversion by
TLC
Solvent
Catalyst/Eq.
Remarks
No.
7
8
9
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
MgCl2/0.5
TiCl4/0.5
AlCl3/0.5
TOAB/0.2
108ꢀ110 10
108ꢀ110 10
108ꢀ110 10
Product
formation is not
observed
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No conversion
80ꢀ90
5
TOAB/0.1
TOAB/0.1
80ꢀ90
80ꢀ90
12
16
15
10
No conversion
No conversion
NaBH4 dissolved
in 2% aq. NaOH
solution
Diphenyl
ether
PEGꢀ400
25ꢀ35
60ꢀ65
Conversion
observed
ꢀꢀ
IPA
LiCl/0.5
Product
decomposition
observed
Less conversion
observed
9
IPA/MeOH
80ꢀ90
5
Having seen the progress of the reaction with LiCl, we planned to carry out the reactions in
presence of this catalyst by monitoring on a gas chromatograph (GC). These results are tabulated
in tableꢀ3. When the reaction was carried out in DMSO at 80ꢀ90°C it took 6 h for completion to
give 68% yield with 85% purity (entry no.1). When Nꢀmethylpyrrolidone (NMP) was used as a
solvent 65% yield was observed with 76% purity (entry no. 2). Interestingly, the yield was
improved substantially to 98% when the reaction was conducted in presence of 0.5 eq. of LiCl
(entry no. 3). Similar yield is observed with better purity (87%) when a mixture of toluene and
NMP were used as solvent again with catalytic amount of LiCl (entry no. 4). Due to the
difficulty in the removal of NMP by distillation at lower temperatures, the reaction was carried
out in mono, di and triglyme under similar reaction conditions. It was observed that the
conversion is poor (43.6%) in monoglyme (entry no. 5) and good (74.0%) in triglyme (entry
no.6). Since the boiling point is very high for triglyme hence, further experimentation is not
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carried out. To our good fortune, when diglyme was used as a solvent along with LiCl, high
purity product (92%) was observed with 90% yield, but the reaction is slow, took 16 h for
completion (entry no.7). An experiment was carried out without LiCl to check its effect in the
reaction and observed that reaction was not progressing to completion even for prolonged time
(entry no.8). It is also interesting to note that addition of NaBH4/ LiCl in four lots gave good
conversion rather than single lot addition (entry no 9). It is understood that the sodium
borohydride reacts with LiCl forming LiBH4 in situ which enhances the reactivity. The formation
of LiBH4 is well documented in the literature.10b This enhanced reductive reactivity of the
reagent system, NaBH4/ LiCl is highly applicable in commercial scale as the use of LiBH4 which
is expensive and unstable can be avoided. An additional experiment was carried out by using lot
wise addition of LiBH4 in diglyme that proceeded smoothly (entry no.10), further confirmed the
in situ formation of LiBH4 in our regular reactions (entry no. 9). Single lot addition of LiBH4
gave ~90% conversion observed by TLC. The process was optimized further and the required
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1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside, 7 was obtained in 81ꢀ87% yield and 97.66 to
97.90% purities. This technology was successfully transferred to the commercial scale and
compound 7 was obtained in 87ꢀ89% yield with 97.24 to 97.50 purities (Tableꢀ4).
Further, the process was optimized for the synthesis of precursor, 2,3ꢀOꢀisopropylideneꢀ1ꢀOꢀ
methylꢀ5ꢀOꢀmesylꢀDꢀribofuranoside, 12a (Schemeꢀ3), intermediate, 9 and 5′ꢀdeoxyꢀ5ꢀfluoroꢀ
Nꢀ[(pentyloxy) carbonyl]ꢀcytidine (Capecitabine, 1; Schemeꢀ2) in Lab and commercial scale.
Capecitabine was successfully manufactured at 75.0 Kg scale in 79% yield and 99.8% purity.
Tableꢀ3: Reduction of methanesulfonate with NaBH4 in presence of LiCl catalyst
S. No. Input
(g)
Solvent
Catalyst Time
(eq.) (h)
Yield
(%)
Purity
(%)
(Product/SM)
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1a
2a
3a
20.0
30.0
20.0
20.0
DMSO
NMP
ꢀ
6
6
4
4
68
65
98
98
85.45/0.5
76.55/0.11
78.62/0.28
87.62/0.57
ꢀ
NMP
LiCl/0.5
LiCl/0.5
4a
5a
6a
7a
8a
Toluene
+NMP
Monoglyme
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30.0
20.0
20.0
20.0
ꢀ
ꢀ
24
6
75
75
90
60
90
86
43.64/44.51
74.04/15.30
92.33/1.40
65.0/21.50
97.38/1.15
ꢀꢀ
Triglyme
Diglyme
Diglyme
Diglyme
Diglyme
LiCl/0.5 16
20
ꢀ
9b 20.0
LiCl/2.45 16
ꢀꢀ 12
10c 5.0
a2.0 eq NaBH4 and 0.5 eq LiCl was used in each reaction and carried out 80ꢀ90°C; 2.45 eq of
NaH4 and 2.45 eq of LiCl used; c2.45eq of LiBH4 used; NMP = NꢀMethylpyrrolidone
b
Tableꢀ4: Manufacturing details of 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside, 7
in the Plant
Input
Yield
Purity
GC
area)
by
(%
S.
Output
(Kg)
(2,3ꢀOꢀIsopropylidene
ꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀ
Dꢀribofuranoside; Kg)
No.
(w/w)
(%)
1
2
3
98.0
98.0
98.0
80.0
77.9
79.0
0.82
0.80
0.81
89
87
87
97.50
97.24
97.40
Experimental procedures:
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Preparation of 2,3ꢀOꢀisopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀDꢀribofuranoside, 12a
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To a mixture of acetone (200 mL) and methanol (150 mL) was added DꢀRibose (50 g; 0.33 mol),
cooled the solution to 0ꢀ5°C and slowly added sulfuric acid (5.3 mL; 0.20 mol) and maintained
for 1 h. The reaction mass was raised to ambient temperature and stir for 24ꢀ26 h. After
completion of the reaction which was monitored by TLC, the reaction mass was adjusted to
neutral pH with aq. 10% sodium carbonate solution and distilled out the solvent at below 50°C.
The obtained residue was diluted with DCM (400 mL) and water (100 mL) and stirred for 15ꢀ20
min. The two phases were separated, washed the dichloromethane phase with water followed by
sodium chloride solution. To the obtained DCM layer, triethylamine (83.1 mL; 0.61 mol) was
added, cooled to 0ꢀ5°C and methane sulfonyl chloride solution (27.07 mL; 0.35 mol dissolved in
25 mL DCM) was added over a period of 30ꢀ45 min. The reaction mass was raised to ambient
temperature and maintained for 1ꢀ2hrs. After completion of the reaction, which was monitored
by TLC, the reaction mass pH was adjusted to neutral with 5% aq. sodium bicarbonate solution.
The two phases were separated and the DCM layer washed with water followed by saturated
sodium chloride solution. The DCM was distilled and the product was precipitated by adding
water and stirred for 1h at 60ꢀ70°C followed by 2h at 5ꢀ10°C. The obtained material was filtered
and dried to obtain 71.0 g colorless white solids of 2,3ꢀOꢀisopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀ
Dꢀribofuranoside.1H NMR spectral data were identical with those reported in the literature.2b,4a,4g
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Preparation of 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside, 7: To a solution of 2,3ꢀOꢀ
isopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀDꢀribofuranoside 100g (0.35 mol) in diglyme (500 mL)
was added sodium borohydride (32.5g; 0.86 mol, 2.45eq.) and lithium chloride (36.5g; 0.86 mol,
2.45eq.) in four lots. After addition of first lot, (sodium borohydride; 9.3g and lithium chloride;
10.5g) slowly the temperature was raised to 80ꢀ90°C and maintained for 4.0h. The reaction mass
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was cooled to ambient temperature, added second lot reagents and slowly raised the temperature
to 80ꢀ90°C and maintained for 4.0h. After addition of 4th lot (sodium borohydride; 4.6g and
lithium chloride; 5.0g) reaction was maintained for 12.0h. After completion of the reaction which
was monitored by GC, the reaction mass is cooled to room temperature, quenched with 1.0L 5%
aq. acetic acid solution and stirred for 15 min. The product is extracted with dichloromethane up
to TLC shows no product in the aqueous layer. The combined DCM layer was washed with
water, concentrated to obtain a residue. To the residue was added 550 mL 0.1% aq. sulfuric acid
and maintained for 5ꢀ6h at 80ꢀ90°C. After completion of the reaction which was monitored by
TLC, adjusted the reaction mass pH to neutral with triethylamine and washed the reaction mass
with 2X150 mL DCM to remove organic impurities. The left over aq. phase is concentrated to
obtain a residue which was treated with TEA (75 mL; 0.54 mol) and DMAP (2.13 g; 0.017 mol)
and acetic anhydride (132 mL; 1.4 mol) at ꢀ5 to +5°C for 4h. After completion of the reaction
monitored by TLC the reaction mass was charged to cold water and adjusted the pH to neutral
with sodium carbonate. The obtained precipitate was maintained for 2ꢀ3h, filtered and dried to
obtain a colorless solid of 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside in 85ꢀ90% yield and >
95% purity, mp: 63ꢀ65oC (lit 63ꢀ64 oC)4a, 4g and 1H NMR spectral data2b were identical with those
reported in the literature.
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Preparation of 5'ꢀDeoxyꢀ5ꢀfluoroꢀ2′,3'ꢀOꢀacetylꢀNꢀpentyloxycarbonylꢀcytidine, 9
A suspension of 5ꢀfluorocytosine (52.0 g; 0.40 mol), hexamethyldisilazane (71.3 g; 0.44 mol),
and ammonium sulphate (1.0 g; 0.008 mol) in toluene (100 mL) was heated at reflux temperature
for 1.0ꢀ1.5h. Then the solvent was distilled at atmospheric pressure and cooled the reaction mass
to ambient temperature. The obtained residue was dissolved in dichloromethane (400 mL), added
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1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside (100.0 g, 0.38 mol), then cooled the reaction mass
to 5ꢀ10°C and added stannic chloride (105g; 0.24 mol, in 50mL of dichloromethane) solution at
5ꢀ10°C and maintained for 30ꢀ45 min at the same temperature. After completion of the reaction
which was monitored by TLC, solid sodium bicarbonate (200 g) was added and the obtained
salts were removed by filtration. The organic layer was washed with aq. sodium bicarbonate,
water followed by sodium chloride solution and distilled off DCM completely at atmospheric
pressure. The obtained residue was dissolved in fresh dichloromethane added pyridine (36g, 0.46
mol), cooled to ꢀ5 to +5 oC, added nꢀpentyl chloroformate solution (60.7g; 0.80 mol, in 50 mL
DCM) and maintained for 2ꢀ3 h. After completion of the reaction which was monitored by TLC,
methanol (5 mL) was added and DCM distilled completely. To the residue was added toluene
(400 mL) and the obtained salts were removed by filtration. The toluene layer washed with aq.
sodium bicarbonate, water followed by sodium chloride solution and stripped off completely
under reduced pressure and the product was isolated by adding diisopropyl ether (150 mL). The
obtained precipitate was maintained for 2ꢀ3 h, filtered and dried to obtain 120g of offꢀwhite color
solids of 5'ꢀdeoxyꢀ5ꢀfluoroꢀ2',3'ꢀOꢀacetylꢀN4ꢀpentyloxycarbonylꢀcytidine.1H NMR spectral data
were identical with those reported in the literature.2b,4g
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Preparation of 5′ꢀDeoxyꢀ5ꢀfluoroꢀNꢀ(pentyloxy carbonyl) cytidine (Capecitabine), 1
To a solution of acetyl protected capecitabine (120 g; 0.27 mol) in methanol (240 mL) at 0 to
5°C was added aq. sodium hydroxide solution (16 g; 0.40 mol, dissolved in 400mL water) and
maintained the reaction for 15ꢀ30 min. After completion of the reaction which was monitored by
TLC the reaction mass pH adjusted to neutral with aq. hydrochloric acid and the product was
extracted with dichloromethane. The DCM layer was separated, washed with water followed by
brine and dried over sodium sulphate. The DCM was distilled under reduced pressure and the
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product was isolated from ethyl acetate and nꢀheptane. The obtained precipitate was maintained
for 2ꢀ3 h, filtered and dried to obtain a white color solid of pure 5′ꢀDeoxyꢀ5ꢀfluoroꢀNꢀ(pentyloxy
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1
carbonyl) cytidine (capecitabine) in 78% yield. H NMR spectral data were identical with those
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reported in the literature2b,4g and all other impurities complies as per USP monograph.
CONCLUSION:
In summary, we have successfully developed a facile and safe alternate method for the reduction
of methanesulfonate with sodium borohydride/LiCl mixture in diglyme by avoiding DMSO.
Compared to triglyme, the boiling point of diglyme is low and convenient to handle at scale
during distillation. In addition to that the use of expensive LiBH4 was avoided. We optimized
this process in the Lab and demonstrated to produce 1,2,3ꢀtriꢀOꢀacetylꢀ5ꢀdeoxyꢀDꢀribofuranoside
7, in the commercial plant. Also the process was optimized for other intermediates, 2,3ꢀOꢀ
isopropylideneꢀ1ꢀOꢀmethylꢀ5ꢀOꢀmesylꢀDꢀribofuranoside and 5'ꢀDeoxyꢀ5ꢀfluoroꢀ2′,3'ꢀOꢀacetylꢀ
N4ꢀpentyloxycarbonylꢀcytidine along with capecitabine in the Lab. All this technology was
transferred to commercial plant and produced ICH quality capecitabine in consistent yields.
ACKNOWLEDGMENT:
The authors wish to thank Dr. Satyanarayana Chava, CEO, Laurus Labs Pvt. Ltd for his constant
encouragement and support. We also thank Process R&D Senior Management for their helpful
discussions in carrying out this work.
REFERENCES:
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