31
CHAPTER – 2
Synthesis of valsartan, an antihypertensive drug
32
2.1 Introduction
The renin angiotensin system (RAS) produces angiotensin II (A-II),
a very potent vasoconstrictive and volume-retaining hormone, which
plays a critical role in the regulation of blood pressure.1 & 2 Prevention of
the formation of A-II, via inhibition of angiotension converting enzyme
(ACE),3 has confirmed the therapeutic benefit of inhibiting the RAS in
hypertension and congestive heart failure. Losartan is described as the
first non-peptide AT1 receptor antagonist, and coined group name as
sartans. Immediately thereafter, all major pharmaceutical companies
embarked on a fast followup program. Today, eprosartan, irbesartan,
candesartan, valsartan, tasosartan, telmisartan and olimersartan are all
established in the market.4 Valsartan (5), chemically known as (N-(1-
oxopentyl)-N-[[2`-(1H-tetrazol-5-yl)[1,1`-biphenyl]-4-yl]methyl]-L-valine),
is an orally active specific A-II receptor antagonist used as a hypotensive
drug.5 A-II receptor antagonists are safe and effective agents for the
treatment of hypertension, anxiety, glaucoma and heart failure, either
alone, or in conjunction with hydrochlorothiazide.6
Valsartan blocks the vasoconstrictor and aldosterone-secreting
effects of angiotensin II (A-II) by selectively blocking the binding of A-II to
the AT1 receptor in many tissues, such as vascular smooth muscle and
the adrenal gland. Its action is therefore independent of the pathways
33
for A-II synthesis.7 Valsartan contains a chiral carbon at valine moiety.
Valsartan is marketed as the free acid under the name DIOVAN®, and
has a unique structure compared to all other A II antagonists.4 The
structure of some of the established sartan compounds are as shown
below:
S.No. Name Structure
1 Ripisartan
NN
N
HN
O
(1)
NHNN
N
2 EprosartanN
NH3C COOH
S
O
OH
(2)
3 Tasosartan
N
NN NNH
O
N
N
CH3
H3C
(3)
34
4 Ellsartan
N
(4)
NCl
O
OO
OO
NHNN
N
5 Valsartan
OH3C N COOH
H3C CH3
NN NNH
(5)
6 Candesartan cilexetil
NNN N NHN
O
H3C
(6)
O
O
O
O
O
H3C
35
7Olmesartan
medoxomil
N
NN NNH
N CH3
H3CCH3HO
O
OO
O
CH3
O
(7)
8 Telmisartan
N
COOH
N CH3N
NCH3
CH3
(8)
2.2. Literature Background
Buhlmayer et al., reported the preparation of valsartan starting
from 2-(4′-bromomethylphenyl)benzonitrile (10) and L-valine methyl ester
hydrochloride (9) resulting in the formation of N-alkyl compound 11
which was then treated with n-valeryl chloride in the presence of N,N-
diisopropylethylamine (Hunig′s base) to produce N-acylated compound
12 and then treated with tri-n-butyltinazide to form valsartan methyl
ester (13). Valsartan methyl ester (13) on hydrolysis under alkaline
condition (Scheme 2.1) gave valsartan (5).8
36
Problems associated with this synthetic process have been (a) the
use of highly toxic tri-n-butyltinazide in the conversion of compound 12
to compound 139 & 10 at penultimate stage of valsartan, (b) contamination
of final product with traces of toxic tin metal, (c) racemisation of
valsartan up to 15% during hydrolysis under basic conditions,11 and (d)
low purity and an overall low yield of valsartan. To achieve acceptable
purity, chiral purity and acceptable limit of tin as per International
Conference on Harmonisation (ICH) guidelines to meet the
pharmaceutical compositions, a series of purifications are warranted
thereby resulting in low yield.
37
Br
H2N COOCH3
CH3H3CDIPEA,CH2Cl2
Valeryl chloride,TEA, CH2Cl2
Tributyltin azide
NaOH, Methanol
OH3C N COOCH3
H3C CH3
NN NNH
OH3C N COOCH3
H3C CH3
HN COOCH3
H3C CH3
OH3C N COOH
H3C CH3
NN NNH
+
CN
CN
.HCl
CN
(10) (9)(11)
(12) (13)
(5)
…..Scheme 2.1
Buhlmayer et al., reported8 another process for preparation of
valsartan starting from 1-trityl-5-[4′-(bromomethyl)biphenyl-2-yl]tetrazole
(14) and L-valine benzyl ester (15) prepared N-alkyl compound 16, which
38
was then treated with n-valeryl chloride in the presence of N,N-
diisopropylethylamine to yield N-acylated compound 17. Compound 17
was treated with acid for detritylation to yield valsartan benzyl ester (18),
which on catalytic Pd/C hydrogenation (Scheme 2.2) yielded valsartan
(5).
Some of the drawbacks of the approach are (a) isolation of
intermediates as an oily mass with low quality,12 (b) debenzylation of 18
with a large amount of Pd/C (~35% w/w) at high pressure H2 gas, (c)
purification of crude valsartan. The product synthesized by this
approach required multiple purifications to meet the regulatory
requirement, resulting in significant drop in yield.13 & 14
39
H2N COOCH2Ph
CH3H3C1,4-Dioxane
Valeryl chloride 1,4-Dioxane,1N-HCl
OH3C N COOCH2Ph
H3C CH3
NN NNH
OH3C N COOH
H3C CH3
NN NNH
+NN NN
Br
CPh3
HN COOCH2Ph
H3C CH3
NN NN
OH3C N COOCH2Ph
H3C CH3
NN NN CPh3
CPh3
Pd/C, H2,Methanol
(14)(15)
(16)
(17) (18)
(5)
DIPEA/DCM
…..Scheme 2.2
40
Bessa Bellmunt et al., reported15 the preparation of valsartan
(Scheme 2.3) starting from 4-bromobenzylbromide (19) and L-valine
methyl ester hydrochloride (9) obtained N-alkyl compound 20.
Compound 20 was hydrolysed in the presence of potassium hydroxide in
methanol and water mixture at reflux temperature to produce compound
21, which was then treated with n-valeryl chloride in the presence of
N,N-diisopropylethylamine to produce N-acylated compound 22.
Compound 22 was further coupled with phenyltetrazole (23) (Suzuki
coupling) in the presence of palladium tetrakistriphenylphosphine and
sodium hydroxide at reflux temperature to produced valsartan (5).
The drawbacks of this method are (a) use of large amount of
palladium tetrakistriphenylphosphine (b) isolation of valsartan by using
silica gel chromatography technique
41
H2N COOCH3
CH3H3C DIPA, DMF
Valeryl chloride,Sodium bicarbonate,
THF
OH3C
Br
N COOH
H3C CH3
OH3C N COOH
H3C CH3
NN NNH
+
Br
Br
Br
HN COOCH3
H3C CH3
Br
HN COOH
H3C CH3
(19)(9)
(20)
(5)
.HCl
KOH, Methanol,H2O
NN NNHB
HO
HO
(23)
(22)(21)
palladium tetrakistriphenylphosphine,sodium hydroxide
…..Scheme 2.3
.
42
2.3. Present work
In view of the above-mentioned problems and the need for the
simple and industrially viable, the following approaches were under
taken to prepare valsartan.
2.4. Results and Discussion
There were three different methods attempted to produce target
molecule. (L)-Valine-4-nitrobenzyl ester (24) was prepared according to
the method described in the literature.16
Method-I
Br
(14)
(26)
(25)
NNNN CPh3
(27)
OH3C N
H3C CH3
NN NNH
HN C
H3C CH3
NN NNCPh3
+ OO
NO2
H2N C
H3C CH3
OO
NO2
HN C
H3C CH3
NN NNH
OO
NO2COO
NO2
(24)
.PTSA
COOHCOOH
.
DIPEA,DMF,45-50°C
Methanol,IPA-HCl, RTOxalic acid
Aq.Na2CO3,Valeryl chloride,5-10°C, DIPEA,Toluene
…..Scheme 2.4
Compound 24 was N-alkylated with compound 14 in the presence
of N,N-diisopropylethylamine to produce N-[[2′-(1-
43
triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine-4-nitrobenzyl
ester (25), which was subsequently detritylated by treating with acid and
isolated N-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine-4-nitro
benzyl ester oxalate (26) as a white solid with good yield and purity
(Scheme 2.4). The product 25 was characterized by its spectral data.
Thus, its 1H NMR (300 MHz, DMSO-d6) spectrum showed signals at δ
0.86-0.91 (m, 6H, -CH(CH3)2), 1.87-1.92 (m, 1H, -CH(CH3)2), 3.01-3.03
(m, 1H, -NCHCO-), 3.51-3.75 (dd, 2H, -NCH2Ph-), 5.30 (s, 2H, -
CH2PhNO2), 6.82-8.25 (m, 27H, Ar-H) ppm.
The product 26 was characterized by its spectral data. Thus, its
1H NMR (300 MHz, DMSO-d6) spectrum showed signals at δ 0.86-0.95
(m, 6H, -CH(CH3)2), 2.01-2.08 (m, 1H, -CH(CH3)2), 3.27-3.29 (m, -
NCHCO- 1H), 3.67-3.90 (dd, 2H, -NCH2Ph-), 5.31 (s, 2H, -CH2PhNO2),
7.05-8.27 (m, 12H, Ar-H) ppm. The mass spectrum showed m/z 487 as
a molecular ion [M+H]+ in cation mode indicating its molecular mass is
486.
Compound 26 was neutralized with aqueous sodium carbonate
and extracted in toluene to obtained free base of compound 26. N-
acylation of amine function in valine moiety of compound 26 with n-
valeryl chloride in the presence of N,N-diisopropylethylamine resulted in
44
N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-
valine-4-nitrobenzylester 27 with lower purity. As expected, N-acylation
occurred at both NH functions of valine and tetrazole in compound 26
that was responsible for the low purity of 27 (Scheme 2.4). Further
conversion of impure 27 to valsartan on commercial scale is not
worthwhile. This synthetic approach was unsuccessful due to lack of
regioselective acylation at NH function of valine moiety.
The product 27 was characterized by its spectral data. Thus, its
1H NMR (300 MHz, DMSO-d6) spectrum showed signals at δ 0.74-0.95
(m, 9H, -CH2CH3 and -CH(CH3)2), 1.14-1.44 (m, 4H, -CH2CH2CH3 and -
CH2CH2CH3), 2.21-2.32 (m, 3H, -CH2CO- and, -CH(CH3)2), 4.15-4.65 (m,
3H, -NCHCO- and –NCH2Ph-), 4.71-4.97 (m, 2H, -CH2PhNO2), 6.97-8.24
(m, 12H, Ar-H) ppm. The mass spectrum showed m/z 571 as a
molecular ion +1 indicating its molecular mass is 570
45
Method-II
25
HN C
H3C CH3
NN NN
OO
NO2COOHCOOH
.
CPh3
Oxalic acid,Ethyl acetate
29
OH3C N
H3C CH3
NN NN
COO
NO2
Aq.Na2CO3,Valeryl chloride,DIPEA, Toluene
28
Methanol,IPA-HCl
CPh3
27
Pd/C, H2,Ethyl acetate
5
CH3
NH2
p-toluidine
…..Scheme 2.5
Alternatively, compound 25 (Scheme-2.5) was treated with oxalic
acid and corresponding oxalate salt 28 was isolated. Compound 28 was
neutralized with aqueous sodium carbonate and extracted in toluene to
obtained free base of compound 28. The NH function of valine moiety of
28 was acylated with n-valeryl chloride in the presence of N,N-
diisopropylethylamine and compound 29 was isolated with purity greater
than 95%. N-(1-oxopentyl)-N-[[2′-(1-triphenylmethyltetrazol-5-yl)[1,1′-
biphenyl]-4-yl]methyl]-L-valine-4-nitrobenzylester (29) was detritylated in
mild acidic conditions to yield 27, which was debenzylated with Pd/C to
afforded crude valsartan. Though, hydrogenation of 27 was successful
with commercially viable quantity of Pd/C (10% Pd/C, 50% wet), the
46
crude product was contaminated with by-product p-toluidine. Several
attempts made to remove p-toluidine from crude valsartan (5), were
unsuccessful to achieve required quality consistently.
The product 28 was characterized by its spectral data. Thus, its
1H NMR (300 MHz, DMSO-d6) spectrum showed signals at δ: 0.87-0.99
(m, 6H, -CH(CH3)2), 1.97-1.99 (m, 1H, -CH(CH3)2), 3.2-3.22 (m, 1H, -
NCHCO-), 3.78-4.06 (dd, 2H, -NCH2Ph-), 5.3 (s, 2H, -CH2PhNO2), 6.84-
8.26 (m, 27H, Ar-H) ppm.
The product 29 was characterized by its spectral data. Thus, its
1H NMR (300 MHz, DMSO-d6) spectrum showed signals at δ: 0.70-0.92
(m, 9H, -CH2CH3 and -CH(CH3)2), 1.14-1.62 (m, 4H, -CH2CH2CH3 and -
CH2CH2CH3), 2.212.32 (m, 3H, -CH2CO- and, -CH(CH3)2), 4.15-4.65 (m,
3H, -NCHCO- and –NCH2Ph-), 4.71-4.97 (m, 2H, -CH2PhNO2), 6.97-8.24
(m, 27H, Ar-H) ppm.
As the elimination of by-product p-toluidine from valsartan (5) was
unsuccessful, an alternative commercially viable process was developed,
which replaces the p-nitrobenzyl ester (29) with methyl ester (13)
(Scheme 2.6) for the preparation of valsartan (5) involved an inventive
hydrolysis of valsartan methyl ester (13) using barium hydroxide to
47
achieve chemical purity greater than 99.8% with enantiomeric purity
greater than 99.8% and high yield.
Method-III
Br
H2N COOCH3
CH3H3C
(14)
(33)
NNNN
(9)
CPh3
(13)
(5)
. HCl
OH3C N COOCH3
H3C CH3
NN NNH
HN COOCH3
H3C CH3
NN NNCPh3
OH3C N COOCH3
H3C CH3
NN NNCPh3
OH3C N COOH
H3C CH3
NN NNH
+
(31)
HN COOCH3
H3C CH3
NN NN
COOHCOOH.
CPh3
(34)
OH3C N COO
H3C CH3
NNNN
Aq.HCl,Ethyl acetate
.Ba2+
(30)
DIPEA,DMF
Oxalic acid,Ethyl acetate
Aq.Na2CO3, DIPEA,Valeryl chloride,Toluene, 5-10°C
Methanol,IPA-HCl,20-30°C
Aq.barium hydroxide,20-30°C
45-50°C 10-15°C
…..Scheme 2.6
48
2.4.1. Preparation of compound 31 from compound 14:
1-Trityl-5-[4′-(bromomethyl)biphenyl-2-yl]tetrazole (14) was reacted
with L-valine methyl ester hydrochloride (9) (Scheme 2.7) in the presence
of Hunig′s base in DMF. The product 30 was extracted with ethyl acetate
and treated with oxalic acid to form corresponding salt 31. N-[[2′-(1-
triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester
oxalate (31) was isolated with purity greater than 98% by HPLC and used
in the subsequent acylation reaction. The major impurity 32 was
eliminated into mother liquor during isolation of 31.
Br H2N COOCH3
CH3H3CNNNN CPh3
. HClHN COOCH3
H3C CH3
NN NNCPh3
+
HN COOCH3
H3C CH3
NN NN
COOHCOOH.
CPh3
DIPEA, DMF45-50°C
Oxalic acidEthyl acetate
(14) (9)
(30)
(31)
10-15°C
…..Scheme 2.7
49
The product 31 was characterized by its spectral data. Thus, its IR
(cm-1) spectrum showed peaks at 3443 (s, broad, -NH str.), 1759 (s, -C=O
str.), 1644 (s, -C=O str). 1H NMR (300 MHz, DMSO-d6) showed signals at
δ 0.86-0.97 (m, 6H, - CH(CH3)2 ), 1.96-2.03 (m, 1H, -CH(CH3)2), 3.26-
3.27 (m, 1H, -CHCH(CH3)2), 3.7 (s, 3H, -COOCH3), 3.82-3.90 (m, 2H, -
CH2NH-), 6.85-7.79 (m, 23H, Ar-H) ppm. Its 13C NMR (75 MHz, DMSO-
d6) showed signals at δ 19.1, 19.9 (two methyl carbon in valine), 30.9,
51.4, 52.7, 66.2, 83.2, 126.6, 128.7, 129.2, 129.5, 129.7, 130.4, 131.2,
131.4, 136.4,140.4, 141.7, 142.1 (phenyl carbons), 163.7, 164.4 (two
C=O oxalic acid), 173.0 (ester C=O) ppm.
HN COOCH3
H3C CH3
NN NNH
(32)
2.4.2. Preparation of compound 13 from compound 31:
Compound 31 was neutralized with aqueous sodium carbonate
and extracted in toluene as free base. The resulting free base of
compound 31 was acylated with n-valeryl chloride in the presence of
Hunig′s base and detritylated with isopropyl alcohol-hydrogen chloride in
anhydrous condition to yield compound 13 (Scheme 2.8). A robust
50
purification method has been developed to remove process impurities
and isolated compound 13 with purity greater than 97% by HPLC.
OH3C N COOCH3
H3C CH3
NN NNCPh3
HN COOCH3
H3C CH3
NN NN
COOHCOOH.
CPh3
Aq. Na2CO3,Valeryl chloride,DIPEA, toluene,5-10°C
OH3C N COOCH3
H3C CH3
NN NNH
Methanol, IPA-HCl,20-30°C
(31)(33)
(13)
…..Scheme 2.8
N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4yl]methyl]-
L-valine methyl ester (13) was characterized by its spectral data. Thus,
its IR (cm-1) spectrum showed peaks at 2959 (vs, -CH str.), 1737 (s, -C=O
str.), 1642 (s, -C=O str.). 1H NMR (300 MHz, DMSO-d6) showed signals at
δ 0.76-0.93 (m, 9H, -CH2CH3 and -CH(CH3)2), 1.18-1.46 (m, 4H, -
CH2CH2CH3 and -CH2CH2CH3), 2.25-2.33 (m, 3H, -CH(CH3)2 and -
COCH2-), 3.30 (s, 3H, COOCH3), 4.47-4.77 (m, 3H, -NCHCO- and -
NCH2Ph-), 6.98-7.63 (m, 8H, Ar-H) ppm. Its 13C NMR (75 MHz, DMSO-
d6) showed signals at δ 13.7, 18.1, 19.2 (three methyl carbons), 21.7,
51
27.0, 32.2 (methylene carbons), 44.5, 47.9, 51.4, 61.7, 64.6, 123.8,
124.0, 125.8, 126.8, 127.7, 128.4, 128.9, 130.6, 137.0, 137.4, 137.5,
138.0, 141.2, 141.4, 155.3 (phenyl carbons), 170.1, 170.5 (ester C=O),
173.4 (amide C=O) ppm. The mass spectrum showed m/z 450 as a
molecular ion +1 indicating its molecular mss is 449.
2.4.3. Preparation of compound 5 from compound 13:
Compound 13 can be hydrolysed with alkaline and alkaline earth
metal hydroxides. However, hydrolysis with bases such as lithium
hydroxide, sodium hydroxide, potassium hydroxide etc., resulted in
racemisation up to 15% (Table-1.1).
OH3C N COOCH3
H3C CH3
NN NNH
OH3C N COOH
H3C CH3
NN NNH
OH3C N COO
H3C CH3
NNNN
.Ba2+Aq. barium hydroxide,20-30°C
Aq. HCl,Ethylacetate
(13)
(34)
(5)
BaCl2
Barium chloride
…..Scheme 2.9
52
It was found in our hands that hydrolysis of compound 13 with
barium hydroxide (Scheme 2.9), however, resulted in N-(1-oxopentyl)-N-
[[2′-(1H-tetrazol-5yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine (5) with less
than 3% of racemization.
Table-1.1: Hydrolysis of compound 13 with different base.
S. No. base reaction time(h)
eea
5 (%)1 NaOH 9 88.00
2 LiOH 8 91.00
3 KOH 8 86.90
4 Ba(OH)2 10 99.95
5 Ca(OH)2 9 91.20aisolated product purity
Further, compound 34 was crystallized from the reaction mixture
with enantiomeric purity greater than 99.7% by HPLC. Barium
hydroxide is a suitable base to hydrolyse the compound 13 efficiently
and to produce compound 5 with minimum racemisation, which on
single crystallization resulted in compound 5 with higher purity and
enantiomeric purity with less than 20 ppm of barium content.
Another advantage in using barium hydroxide, valsartan barium
salt was neutralized with mineral acid to produce valsartan and by-
product barium chloride. The by-product barium chloride is freely
soluble in water than valsartan. After isolating valsartan, the effluent
53
was treated with sulfuric acid and recovered barium in the form of
barium sulfate.
The product 5 was characterized by its spectral data. Thus, its IR
(cm-1) spectrum showed peaks at 3441 (broad, -NH str.) 2964 (s, -
CHstr.), 1732 (s, -C=O str.), 1603 (s, -C=O str.). Its 1H NMR (300 MHz,
DMSO-d6) showed signals at δ 0.69-0.94 ((m, 9H, -CH2CH3 and -
CH(CH3)2), 1.08-1.56 (m, 4H, -CH2CH2CH3 and -CH2CH2CH3), 1.97-2.46
(m, 3H, -COCH2- and -CH(CH3)2), 4.06-4.62 (m, 3H, -NCHCO- and -
NCH2Ph-), 6.99-7.71 (m, 8H, Ar-H), 12.67 ((br, 1H, -NH (tetrazole), D2O
exchangeable), 16.20 (br, 1H, -COOH, D2O exchangeable) ppm. Its 13C
NMR (75 MHz, DMSO-d6) showed signals at δ 14.6, 19.2, 20.3 (three
methyl carbons), 21.0, 22.7, 27.0, 28.4 33.3 (methylene carbons), 49.6,
63.8, 66.6, 124.3, 127.7, 128.4, 128.6, 129.2, 129.7, 131.4, 131.5,
131.9, 138.0, 138.6, 139.1,142.2, 155.3 (phenyl carbons), 172.5, 172.8
(ester C=O), 174.3 (amide C=O) ppm. The mass spectrum showed m/z
436 as a molecular ion +1 indicating its molecular mass is 436.
54
2.5. Experimental Section
All the chemicals and reagents used were of LR grade. 1H NMR
and 13C NMR spectra were recorded on a Bruker 300 spectrometer at
300 MHz and 75 MHz, respectively and the chemical shifts were reported
as δ values in parts per million relative to TMS as an internal standard.
Infrared spectra were recorded in the solid state as KBr dispersion using
a Perkin-Elmer spectrophotometer. Mass spectra were recorded on API
2000 Perkin Elmer PE-SCIEX mass spectrometer..
1) Preparation of compound 25 from compound 14: L-Valine p-
nitrobenzyl ester 24 (19.2 g, 0.044 mol) was added to a mixture of 1-
triphenylmethyl-5-[4′-(bromomethyl)biphenyl-2-yl]tetrazole 14 (25 g,
0.044 mol) and N,N-dimethylformamide (75 mL) at 25-30°C and stirred
for 10 min. N,N-diisopropylethylamine (14.2 g, 0.11 mol) was added to
the reaction mass and heated to 45°C. The resulting reaction mixture
was maintained till completion of reaction at 45°C and cooled to 20-30°C.
The reaction mass was dissolved in methylene chloride (125 mL) and
washed successively with DM water (3x100 mL). The organic layer was
separated and concentrated completely at below 30°C under reduced
pressure to yield 25, (27.8 g, 85%).
2) Preparation of compound 26 from compound 25: Compound 25 (20
g, 0.027 mol) was added to a mixture of methanol (100 L) and 20% w/w
55
isopropyl alcoholic hydrogenchloride (0.79 g; 0.0054 mol) at 25°C and
stirred for 3 hr. The reaction mass was cooled, filtered off the solid by-
product, trityl methyl ether, and the filtrate was concentrated. The
resulting concentrated mass was dissolved in ethyl acetate (100 mL) and
treated with oxalic acid dihydrate (3.7 g, 0.0297 mol) at 20-30°C. The
reaction mixture was cooled to 0-5°C and the solid product was filtered,
washed with ethyl acetate (20 mL) and dried at 45-50°C to yield 26, (14
g, 90%).
3) Preparation of compound 31 from compound 9: L-Valine methyl
ester hydrochloride 9 (132.2 g, 0.789 mol) was added to a mixture of 1-
triphenylmethyl-5-[4′-(bromomethyl)biphenyl-2-yl]tetrazole 14 (400 g,
0.717 mol) and N,N-dimethylformamide (400 mL) at 25-30°C and stirred
for 10 min. N,N-diisopropylethylamine (231.7 g, 1.79 mol) was added to
the reaction mass and heated to 45-50°C. The resulting reaction mixture
was maintained till completion of reaction at 45-50°C. The reaction
mass was cooled to 10-15°C and quenched by pouring into a mixture of
ethyl acetate (2.0 L) and DM water (400 mL). The organic layer was
separated and washed successively with DM water (400 mL) followed by
10% w/w aqueous sodium chloride solution (200 mL). The ethyl acetate
layer was separated and treated with oxalic acid dihydrate (99.5 g, 0.789
mol) at 10-15°C. The reaction mixture was cooled to 0-5°C and the solid
product was filtered, washed with ethyl acetate (400 mL) and dried at 45-
50°C to yield 31, (420 g, 76%).
56
4) Preparation of compound 33 from compound 31: Compound 13
(150 g, 0.215 mol) was added to a mixture of toluene (450 mL) and DM
water (300 mL) and basified with 10% w/w aqueous sodium carbonate
solution (450 mL) at 20-30°C. The organic layer was separated and
washed with water (150 mL) followed by 10% w/w aqueous sodium
chloride solution. The organic layer was separated, dried over anhydrous
sodium sulfate and reacted with n-valeryl chloride (33.7 g, 0.23 mol) in
the presence of N,N-diisopropylethylamine (55.6 g, 0.43 mol) at 0-5°C.
The reaction mixture was stirred at 5-10°C for 3 hr and quenched into
DM water (150 mL). The organic layer was separated and washed with
10% w/w sodium carbonate solution (68 mL) followed by 10% w/w
aqueous oxalic acid solution (40 mL). The organic phase was separated
and concentrated completely at below 30°C under reduced pressure to
yield 33 as oily mass, (141.3 g, 95%).
5) Preparation of compound 13 from compound 33: Compound 33
(100 g, 0.1445 mol) was added to a mixture of methanol (1.0 L) and 20%
w/w isopropyl alcohol hydrogenchloride (2.756 g, 0.0143 mol) at 20-30°C
and stirred for 5 hr. The reaction mass was cooled, filtered off the solid
by-product (trityl methyl ether), and the filtrate was concentrated. The
resulting concentrated mass was dissolved in ethyl acetate (300 mL) and
treated with 2% w/w aqueous sodium carbonate solution (700 mL). The
aqueous layer was separated, pH adjusted to 7.0-8.0 with 10% w/w
aqueous acetic acid and washed with ethyl acetate (100 mL). The
57
aqueous layer was separated and acidified with 10% w/w aqueous acetic
acid to pH 4.0 to precipitate the product. The solid product was filtered,
washed with water and dried to yield 13, (47 g, 72.3%).
6) Preparation of compound 5 from compound 13: Compound 13 (45
g, 0.1 mol) was hydrolyzed with 15% w/v aqueous barium hydroxide
solution (528 mL) at 20-30°C for 10 hr. The precipitated solid was
filtered, treated with 10% w/v dilute hydrochloric acid to pH 0.5-1.5 in
DM water and isolated crude valsartan. The crude valsartan was
dissolved in 2.5% w/v aqueous sodium carbonate solution (460 mL) at
20-30°C and acidified to pH 5.0 with 10% w/v hydrochloric acid and
then washed with methylene chloride (90 mL). The aqueous layer was
further acidified to pH 1.0 with 10% w/v hydrochloric acid and the
product was extracted with ethyl acetate (495 mL). The organic layer was
separated and distilled completely under reduced pressure at 50-60°C.
The resulting solid mass was recrystallized from ethyl acetate (225 mL),
filtered at -15 to -20°C and dried at 45-50°C to yield 5, (28.5 g, 65%).
58
2.5. Spectral data
1H NMR spectrum (300MHz, DMSO-d6) of compound 26:
Mass spectrum of compound 26:
(26)
HN C
H3C CH3
NN NNH
OO
NO2
COOHCOOH
.
(26)
HN C
H3C CH3
NN NNH
OO
NO2
COOHCOOH
.
(26)
HN C
H3C CH3
NN NNH
OO
NO2COOHCOOH
.
(26)
HN C
H3C CH3
NN NNH
OO
NO2COOHCOOH
.
59
1H NMR spectrum (300MHz, DMSO-d6) of compound 28:
IR spectrum of compound 31:
HN C
H3C CH3
NN NN
OO
NO2COOHCOOH
.
CPh3
(28)
(31)
HN COOCH3
H3C CH3
NN NN
COOHCOOH.
CPh3
60
1H NMR spectrum (300MHz, DMSO-d6) of compound 31:
13C NMR spectrum (75MHz, DMSO-d6) of compound 31:
31
HN COOCH3
H3C CH3
NN NN
COOHCOOH.
CPh3
HN COOCH3
H3C CH3
NN NN
COOHCOOH.
CPh3
(31)
61
1H NMR spectrum (300MHz, DMSO-d6) of compound 13:
13C NMR spectrum (75MHz, DMSO-d6) of compound 13:
OH3C N COOCH3
H3C CH3
NN NNH
(13)
OH3C N COOCH3
H3C CH3
NN NNH
(13)
62
Mass spectrum of compound 13:
IR spectrum of compound 5:
OH3C N COOCH3
H3C CH3
NN NNH
(13)
OH3C N COOH
H3C CH3
NN NNH
(5)
63
1H NMR spectrum (300MHz, DMSO-d6) of compound 5:
13C NMR spectrum (75MHz, DMSO-d6) of compound 5:
OH3C N COOH
H3C CH3
NN NNH
(5)
OH3C N COOH
H3C CH3
NN NNH
(5)
64
Mass spectrum of compound 5:
OH3C N COOH
H3C CH3
NN NNH
(5)
65
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66
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