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31 CHAPTER – 2 Synthesis of valsartan, an antihypertensive drug

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Page 1: CHAPTER – 2 Synthesis of valsartan, an …shodhganga.inflibnet.ac.in/bitstream/10603/8438/10/10_chapter 2.pdf · TEA,CH2Cl2 Tributyltinazide NaOH,Methanol O H3C N COOCH3 H3C CH3

31

CHAPTER – 2

Synthesis of valsartan, an antihypertensive drug

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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

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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)

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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

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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

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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.

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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

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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

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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

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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

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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

.

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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-

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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

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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

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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

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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

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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

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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

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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

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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,

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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

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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

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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.

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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

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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%).

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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

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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%).

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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

.

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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

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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)

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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)

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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)

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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)

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Mass spectrum of compound 5:

OH3C N COOH

H3C CH3

NN NNH

(5)

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2.7. References

1. Duncia, J. V., Chiu, A. T., Carini, D. J., Gregory, G. B., Johnson,

A. L., Price, W. A., Wells, G. J., Wong, P. C., Calabrese, J. C.,

Timmermans, P. B. M. W. M. J. Med. Chem. 33, 1990, 1312.

2. Sealey, J. E., Laragh, J. H., Hypertension: Pathophysiology,

Diagnosis and Management; Laragh, J. H., Brenner, B. M., Eds,

Raven, New York, 1990, 1287.

3. Wyvratt, M. J., Patchett, A. A. Med. Res. Rev. 5, 1985, 483.

4. Buhlmayer, P., Furet, P., Criscione, L., De Gasparo, M.,

Whitebread, S., Schmidlin, T., Lattmann, R., Wood, J. Bioorg.

Med. Chem. Lett. 4, 1994, 29.

5. Schmidt, B., Schieffer, B. J. Med. Chem. 46, 2003, 2261.

6. Cocolas, G. H., Delgado, J. N., Remers, W. A., Eds. Textbook of

Organic Medicinal and Pharmaceutical Chemistry, 10th Ed,

Lippincott-Raven, Philadelphia, New York, 1998, 603.

7. Wexler, W. A., Greenlee, W. J., Irvin, J. D., Goldberg, M. R.,

Prendergast, K., Smith, R. D., Timmermans, P. B. M. W. M. J.

Med. Chem. 39, 1996, 625.

8. Buhlmayer, P., Ostermayer, F., Schmidlin, T. US Patent

5,399,578, 1995.

9. Wittenberger, S. J., Donner B. G. J. Org. Chem. 58, 1993, 4139.

10. Chen Z., Guojun Z., Lijing F., Yulin Li. Synlett. 2006, 477.

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66

11. Boojamra, C. G., Burow, K. M., Thompson, L. A., Ellman, J. A. J.

Org. Chem. 62, 1997, 1240.

12. Ashok K., Manmohan M. N., Sanjay G. B., Dattatray S. M., Rahul

S. K., Bharat D. S., Larkesh D. K. US Patent Appl. Publ. US

2006/0281801, 2006.

13. Cepanec, I., Litvic, M., Koretic, S., Bartolinlic, A., Druskovic, V.,

Sporec, A. PCT Int. Appl. WO 2005/049586, 2005.

14. Soni, R. R., Vasoya, S. L., Gotikar, R. C., Pandey A. K., Shah, H.

R. PCT Int. Appl. WO 2007/032019, 2007.

15. Bessa, B. J., Huguet C. J., Perez Andres, J. A., Dalmases, B. P.

PCT Int. Appl. WO 2005/102987, 2005.

16. Tagami, Y., Katsura, T., Itaya, N. EP 985,658, 2004.

17. Erwin E. M. US Patent 6,869,970, 2005.