CHAPTER 3 CONDENSATION OF SUBSTITUTED 4...

102

CHAPTER 3

CONDENSATION OF SUBSTITUTED 4-QUINOLYLOXY DERIVATIVES

WITH -HYDROXY CARBOXYLIC ACIDS

3.1. INTRODUCTION:

Hepatitis C virus (HCV) disease is a main health difficulty that

directs to chronic liver disease in a considerable number of infected

individuals, now approximate to be more than 1.70 lakh universal.[1] For

numerous patients the existing therapies which occupy treatment with

PEGylated interferon in amalgamation with the nucleoside analogue

ribavirin, giving a constant virological response of ~50% in genotype 1

infected patients.[2] The present therapies are associated with significant

side effects requiring discontinuation of treatment in certain patient

inhabitants. The high occurrence of infection together with the side

effects and the limited efficacy of current therapies highlight there is

subsequently vital need for the development of novel, specific and more

effective treatment strategies against this viral infection.

The synthesis of the quinoline ring system has been widely studied

since its discovery by Gerhardt in 1842. [3] The quinoline ring system is

found in a diversity of compounds including dyes, organic materials, and

pharmaceuticals.

103

Amongst the pharmaceuticals, quinoline derivatives have been in

use for treatment of parasitic infections such as malaria [4] and

leishmaniasis [5] as well as being present in antitumor agents such as

streptonigrin [6] luotonin A [7] dynemicin A [8] and camptothecin. [9] In

addition, natural product isolations and biological activity assays

continue to identify new, potentially useful quinoline alkaloids from both

plant and marine animal sources. [10]

In particular halogen containing quinolines are of considerable

interest because the halogen atom sometimes plays a pivotal role in the

compound’s bioactivity, and such compounds provide a further

possibility for structural elaboration. [11]

Table 3.1

Tetra peptide Inhibitors of the HCV NS3 Protease [12, 13]

S. No Compound IC50 / activity

01 N

O

O NH

OH

O

O

NH

ONH

O

70

4 M

104

02 N

O

O NH

OH

O

O

NH

ONH

O

NO2

71

4 M

03 N

O

O NH

OH

O

O

NH

ONH

O

Br

72

52 M

04 N

O

O NH

OH

O

O

NH

ONH

O

N

CF3

73

8 M

05 N

O NH

ONHO

O

CO2H

O

74

25 M

06 N

O NH

O

OBocNH

Ph OMe

CO2H

75

20 M

105

3.2. LITERATURE REPORTED METHODS:

Kappe, T et al., [14] have been prepared quinalinone (78) in one

step by the reaction of an equal molar quantity of m-anisidine (76) and

malonic acid (77) with excess of phosphorus oxychloride.

NH2

MeOO O

OH OH

NH

O

OH

MeONH

O

OHOMe

NH

MeO

O

NH

O

OMe

+

POCl3reflux + +

76 77 78 79

80

………Scheme 3.1

The above process suffers from a high exothermic and the

formation of thick, sticky suspensions during the addition of POCl3 as

well as an exothermic work-up during the addition of water. Secondly,

the reaction conditions provide a regioisomeric mixture of 78 and the

corresponding 5-methoxy derivative 79 in roughly a 4:1 ratio. In

addition, N1,N3-bis(3-methoxyphenyl)malonamide (80) is also produced

in the reaction. Isolated yields for the formation of 78 have been about

30%. The formation of the regioisomer & impurity impacts the yield of

the product.

Shanmugam, P et al., [15] have been prepared 4-hydroxyquinoline-

2-ones (81) by the condensation of diesters of malonic acid. Scheme 3.2

106

& 3.3 shows two literature examples from diethyl malonate (82) and

diphenyl esters of malonic acid (83 or 84) with substituted anilines

(85/76)

NH2

R O O

EtO OEt

NH

O

OH

R

+200°C

85 82 81

R=Cl,Me,CF3

………Scheme 3.2

NH2

MeO O O

O O

Cl Cl

X

Cl Cl

X

NH

O

OH

MeO

+

toluenereflux

X= H, Cl

76 83, 84 78

………Scheme 3.3

Although the diethyl malonate route is a cost-effective process to

78 and liabilities include the use of relatively high temperatures (200°C)

and the lack of a solvent for the condensation. While the diphenyl

malonate route appears to be more amenable since the process occurs

readily toluene at reflux, unfortunately esters 83 or 84 are not readily

available and therefore these will have to be prepared to execute this

process. Another liability with the phenol ester route is the removal the

phenol by-products which could prove difficult in the presence of the

hydroxyl group in quinalinone.

107

Kappe Oliver. C et al., [16] have been reported the formation of 4-

hydroxydichloroquinolin-2(1H)-one (85) and similar products using a

step-wise process. The most common of these routes is exemplified by

the generation of bis (anilide) 86 by condensation of diethyl malonate

(82) under high temperatures (200-220°C) followed by cyclization of 86

with POCl3 or Eaton’s reagent (P2O5 in methanesulfonic acid). The latter

reagent was shown to be superior to other dehydrating agents (AlCl3 or

P2O5) in the cyclization of malonamide containing aromatic rings with

electron-withdrawing groups (Scheme 3.4)

NH2

Cl

Cl

N O

OH

Cl

Cl

O O

EtO OEt

NH

O

O

NH

Cl

Cl

Cl

Cl

+

10% P2O5

in CH3SO3H

150-170°C220°C

87 82 86 85

......…Scheme 3.4

Blackburn et al., [17] has reported a step-wise approach involves

the formation of amides derived from the condensation of monoesters of

malonic acid (88) and the aniline (89) followed by cyclization to the target

compound 90 under the conditions mentioned previously (Scheme 3.5)

108

NH2

Cl

O O

O OH

NH

O

OH

ClNH

O

O

O

Cl

+

10% P2O5 in

CH3SO3H

150-170°CEDCCH2Cl2

89 88 90

………Scheme 3.5

A variant of the step-wise approach involves the formation of

amides derived from the condensation monoesters of malonic acid and

the aniline, followed by cyclization to the target compound under the

conditions mentioned previously, although the route is less attractive in

context of the added cost of the coupling agent.

Sheibani et al., [18] have established below methodology involves

the reaction of chlorocarbonyl ketene with anilides (91) as

dinucleophiles. At 80°C malonyl dichloride (92) loses hydrogen chloride

to form chloro carbonyl ketene which is more reactive than malonyl

dichloride. Liabilities with this scheme are the stability issues of malonyl

dichloride reagent and highly exothermic and runaway during reaction

(Scheme 3.6)

NHR O O

Cl Cl

NH

O

OH

+

reflux

R=Me,Ph

91 92 81

………Scheme 3.6

109

Youla & Tsantrizos et al., [20] has been carried out coupling

reaction starting with hydroxy proline methyl ester (93) with 4-hydroxy-

7-methoxy quinoline (78) via a Mitsunobu reaction in presence of diethyl

azodicarboxylate (DEAD) and triphenylphosphine (TPP) and resulting

ester is hydrolyzed to the acid (Scheme 3.7)

N

OH

MeO

N

OH

O

OMe

boc

N

O

O

OMe

boc

N

MeO

+

DEAD/TPP

78 93 94

………Scheme 3.7

3.3. PRESENT WORK:

The present work describes the practical and efficient synthesis of

(2S)-2-{[((2S, 4R)-1-[(2S)-2-hydroxy-3-phenylpropanoyl)-4-{[7-methoxy-2-

(1H-1-pyrazolyl)-4-quinolyl]oxy}tetrahydro-1H-2-pyrrolyl)carbonyl] amino}

-3-phenylpropanoic acid (95) and its enantiomerically pure tripeptide

quinoline analogues using standard coupling procedures in presence of

commercially available and inexpensive coupling agent O-(7-

azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate

(HATU) and triethylamine in dichloromethane at room temperature. The

core compound can built in a convergent manner using four building

110

blocks. The preparation and ultimate assembly of these building blocks

are disclosed in this chapter.

N

O NH

O

O

OH

NNN

OMe

OH

O

Ph

Fig 3.1 (95)

A retro synthetic analysis of Fig 3.1 (acyclic tripeptide) suggests be

assembled using standard solution peptide coupling procedures.

Introduction of quinoline derivative on to proline can be accomplished

early in the synthetic sequence by reaction with a 4-Chloro-7-methoxy-2-

pyrazol-1-yl quinoline and 4-hydroxy proline as the electrophile. Then

coupling is carried with methyl (S)-2-amino-3-phenyl propionate using

standard peptide coupling reaction procedures with HATU (Scheme). The

resulting dipeptide coupled with corresponding -hydroxy acid give

acyclic tripeptide 95.

111

3.4. Retro synthesis:

N

O

O NH

O

OH

O

OH

Ph

N N

N

MeO

NOCH

3

N

N

Cl

NH

OH

O OH

NH2

O

OH

OH

O

OH

NH

O

O

N N

N

MeO

OH

NH

O

O NH

O

OHPh

N N

N

MeO

+

quinoline derivative hydroxy proline

L-Phenyl alanine

2-hydroxy-3-phenyl propionic acid

+

+

dipeptide

acyclic tripeptide

Fig 3.2

112

3.5. RESULTS AND DISCUSSION:

These analogues were prepared using protecting groups which are

suitable for the direct introduction of these amino acids into synthetic

peptides. For the present work, (R) & (S) Phenylalanine is selected based

on combination of natural, commercially available, inexpensive, stable in

aqueous solution, and possess high specific activity.

O NH2 CO

2Et

CO2Et

NH

O

OH

O N

Cl

O Cl N

Cl

O N

N

+

i ii iii

76 82 78 96 97

O

N

O OH

boc

N

N

MeO

O

N

O NH

boc

O

O

Ph

N

N

MeO

O

NH

O NH

O

O

Ph

N

N

MeO

O

N

O NH

OH

O

O

OHPh

Ph

N

N

MeO

O

N

O NH

O

O

O

OHPh

Ph

N

N

MeO

HCl

98, iv 100, v vi

35a,vii

99 101102

viii

95103

(S)(S)

(S)(S)

(S) (S)

………Scheme 3.8

113

Conditions: i) Neat, >200°C ii) POCl3, reflux iii) Pyrazole, xylene, reflux

iv) trans-1-tert-butyloxy carbonyl-4-hydroxy-L-proline (98), KOBut, DMF,

rt; v) L-Phenylalanine methyl ester (100), HATU, DIPEA, DMF, rt; vi)

methanolic HCl (15% w/v),rt; vii) (S)-2-hydroxy-3-phenylpropionic acid

(35a), HATU, DIPEA, DMF, rt; viii) LiOH/THF/H2O/rt

3.5.1. Synthesis of quinoline derivative:

There has been continued interest in the synthesis of 4-hydroxy-2-

quinolones as it is starting materials for target molecules. In this way we

explored several routes to prepare quinolines from aniline derivative.

A recent publication reports the use of both POCl3 and zinc

chloride (ZnCl2) with aniline and malonic acid in the preparation of 4-

hydroxy-2-quinolones to provide the target compound in 72% yield. [22]

Unfortunately, the procedure does not describe the specific quantities of

POCl3 and Lewis acid that were employed so that some investigation of

the optimum quantities of these reagents will be needed to develop these

reaction conditions. We want to utilize the above method to prepare 7-

methoxy-2, 4-dyhydroxy quinolone (78) from 3-methoxy aniline (76). The

process suffers from highly exothermic and the formation of thick, sticky

suspensions during the addition of POCl3 as well as an exothermic work-

up during the addition of water. Secondly, the current reaction

conditions provide a regioisomeric mixture of 7-methoxy (78) and the

corresponding 5-methoxy derivative (79) in roughly a 9:1 ratio.

114

O NH2 COOH

COOH

NO

OH

OH N

OH

OH

OMe

+

Lewis acidPOCl3

+

76 77 78 79

………Scheme-3.9

To address above issues the present work explored the reaction with

use of several Lewis acids to prepare 7-methoxy-2, 4-dihydroxy quinolone

with following changes in existing process

1. Use of Lewis acids in combination of solvents

2. Cyclization of Diesters of Malonic acids

1. Use of Lewis acid in combination of solvents

Use of a Lewis acid catalyst in addition to phosphorus oxychloride

may provide improved yields and reduced regioisomer formation. Lewis

acid-mediated conditions described above essentially utilize POCl3 as

both a reagent and solvent. The corrosive nature of this reagent and its

reactivity to water and alcohols are partially responsible for the

difficulties observed in the synthesis 78. Secondly, these processes

require an excess of reagent which also serves as a solvent for the

reaction. Therefore, identification of a co-solvent may eliminate the

need for the use of large quantities of POCl3. Some options for a suitable

solvent include chlorobenzene, toluene or xylene for the conversion to 78

115

using POCl3 with or without the assistance of a Lewis acid.

Chlorobenzene will afford the lowest potential for side reactions by the

acylium ion intermediates, although the electron-rich 3-methoxyphenyl

ring of the substrate should minimize these side reactions.

Table-3.2:

Entry Lewis acid

(eq)

POCl3

(eq) Solvent

Temp

(°C)

Time

(h)

Yield

(%)

01 ZnCl2 (1.1) 1.1 NMP 70-75 2.5 8

02 BF3 etherate (1.1) 1.1 DCM reflux 5 6

03 AlCl3 1.1 NMP 70-75 2.5 5

04 SnCl4 1.1 DMF 70-75 2.5 5

05 Titanium isopropoxide 1.1 NMP 70-75 2.5 5

06 ZnCl2 (1.1) 1.1 DMSO 70-75 2.5 7.0

07 BF3 Et2O (1.1) 1.1 ACN reflux 5 5

08 - 1.1 - 70-75 0.5 85

Reaction of m-anisidine with malonic acid/POCl3 in presence of

various Lewis acids no product formation was observed in any

conditions (Table-3.2, entries 1-7) at the same time the reaction precede

without use any Lewis acid in presence of POCl3 provide a regioisomeric

mixture of 78 and the corresponding 5-methoxy derivative 79 in roughly

a 9:1 ratio. (Table 3.2, entry 8)

116

2. Cyclization of Diesters of Malonic acids

We observed that the reaction of m-anisidine (76) with diethyl

malonate (82) at higher temp initially mono ester was formed with

elimination of ethanol as by-product. As soon as elimination of ethanol

completed reaction-mass temp gradually increases and reached to

200°C. Cyclization was completed after losing another mole of ethanol at

this temp.

O NH2 COOEt

COOEt

NH

O

OH

ONH

O O

OEtO+

200°C

76 7882

………Scheme-3.10

The diethylmalonate condensation with aniline at higher temperature

is a cost-effective process with improved yields (Table 3.2, entry 1) than

Scheme-3.10 process. Advantage with this method is no formation of

regio isomer. Cyclization did not progress at less than 200°C temperature

(Table-3.3, entry 2)

Table 3.3:

Entry Temp (°C)

Time (h)

Yield (%)

78 79

1 >200 1.0 80 100 Nil

2 <200 12.0 0 0 0

117

7-methoxy-4-hydroxyquinoline-2-one (78) was treated with POCl3 in

reflux for 5-6 hours and followed by simple isolation to give 2, 4-dichloro-

7-methoxy quinoline (96). Compound 96 treated with pyrazole and

heated to >120°C resulted 4-Chloro-7-methoxy-2-pyrazol-1-yl quinoline

(97a) and 7-methoxy-2,4-pyrazol-1-yl quinoline (97b) mixture of

compounds with 6:4 ratio was formed (Table 3.4, entry 1). The process

suffers from the formation of thick, sticky suspensions during the

reaction as well as poor mixing of reagents due to lack of solvent in

reaction. Secondly, the current reaction conditions provide a mixture

mono (97a) di (97b) in roughly 6:4 ratio. To address this issue the

reaction studied in combination with solvents and issues were addressed

like formation of thick, sticky suspension but did not resolve the

formation of mono & di mixture. Certainly the formation of di compound

was reduced when reaction carried out at high temperature. Results are

mentioned in Table 3.4

Table 3.4

Entry Solvent Temp (°C) Time (h)

Yield (%)

97a 97b

1 Neat 130-140 2.0 100 60 40

2 Toluene reflux 24.0 50 50 50

3 Xylene reflux 4.0 85.0 85 15

4 acetonitrile reflux 24.0 - - -

Reaction in toluene resulted incompletion and un-reacted starting

material was observed at a level of 50% (Table 3.4, entry 2), good to

118

excellent yields achieved when reaction conducted in xylene as solvent

and formation 97b also decreased to 15% (Table 3.4, entry 3). Low

boiling solvents like in acetonitrile reaction did not progress (Table 3.4,

entry 4).

Compound 97a was condensed with commercially available Boc

protected trans (2S, 4R) hydroxy proline (98) in presence of potassium

tert-butoxide in DMSO as solvent give (2S, 4R)-(7-methoxy-2-pyrazol-1-

yl-quinolin-4-yloxy)-pyrrolidine-1, 2-dicarboxylic acid-1-tert butyl ester

(99) with good yields. Reaction gave poor yields when sodium hydride as

reagent in THF or DMSO (Table 3.5, entry 1 & 3) and reaction is

proceeded in BuLi but impurities generated along with product, probably

very strong reagent for this coupling reaction (table 3.5, entry 2).

Reaction was very smooth when potassium tert-butoxide used as reagent

in combination of DMF/DCM or DMSO as solvents (Table 3.5, entries 4-

5). Surprisingly reaction was not initiated when solvent switched to

dichloromethane (DCM) presumably poor solubility nature of reactants

(Table 3.5, entry 6).

Table 3.5

Entry Base Solvent Temp Time Yield

1 NaH THF RT to reflux 12.0 35

2 n-BuLi THF RT 15.0 30

3 NaH DMSO RT – 50°C 15.0 25

119

4 KOBut DMF:DCM RT 15.0 55

5 KOBut DMSO RT 5.0 90

6 KOBut DCM RT 24.0 0

Peptide coupling reactions were typically carried out in CH2Cl2 or DMF,

using HATU or TBTU as the coupling agent and DIPEA or NMM as the

base. (2S, 4R)-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1,

2-dicarboxylic acid-1-tert butyl ester (99) and methyl (S)-2-amino-3-

phenyl propionate (100) were coupled to give the (2S, 4R)-tert-butyl-2-

((R)-1-(methoxycarbonyl)-2-phenylethylcarbamoyl)-4-(7-methoxy-2-(1H-

pyrazol-1-yl) quinoline-4-yloxy) pyrrolidine-1-carboxylate (101) with

excellent yields of >95%. The coupling was initially tried with O-(7-

azabenzotriazol-1-yl)-N, N, N’, N’ –tetramethyluronium hexafluoro phos-

phate (HATU) as the coupling reagent in large excess of DCM at 25°C

gave coupled product 101. This coupling agent was tried first, and the

reaction complete in ten hours. The product was isolated in greater than

quantitative yield with good quality (Table 3.6, entry 1). The major focus

of this present work was to try to replace HATU with a cheaper coupling

reagent and find a solvent system that would improve the solubility and

product isolation. The other coupling reagents that were tested in this

reaction were HBTU [O-(benzotriazole-1-yl)-N, N, N’, N’ –

tetramethyluronium hexafluorophosphate)], BOP [(benzotriazol e-1-

yloxy)tris(dimethylamino) phosphonium hexafluorophosphate], EDC [N-

120

ethyl-N’-(3-dimethylaminopropyl) carbodiimide], HOBt

(hydroxybenzotriazol), and CDI (1,1-carbonyldiimidazole). The alternate

solvents tried were ethyl acetate, methyl isobutylketone (MIBK),

dichloromethane, dimethylsulfoxide and mixtures of dichloromethane

and DMF. All the coupling agents tried worked moderately well in the

coupling, but the quality of product and conversion were best with HATU

(Table 3.6, entry 5, 11). For a time, it appeared the CDI in MIBK (Table

3.6, entry 8) would be competitive with the HATU coupling. However,

when this reaction was tried with a new lot of the CDI, the reaction

produced a number of new impurities (Table 3.6, entry 10). Therefore,

HATU was chosen as the coupling reagent for this work (Table 3.6, entry

5). Also the solvent system was changed to DMSO from DCM as it is

using large excess (40 vol) in reaction. The downside of the HATU

coupling was that an impurity appeared as a singlet at 2.7 ppm in the 1H

NMR spectrum of the crude product that would not wash out. Based on

the chemical shift, the impurity was thought to be tetramethylurea, a by-

product from the HATU reagent. The work up of the HATU coupling

involved addition of water to the reaction mass and back extracted in to

ethyl acetate. The ethyl acetate solution was then washed with dilute

acid to remove diisopropylethylamine and azabenzotriazole by-products.

This usually gave crude compound that had 80-90% pure based on 1H

NMR, it had residual diisopropylethylamine and ethyl acetate in addition

to a small amount of the tetramethylurea by-product. However this was

121

washed off during the crude product recrystalized from diisopropylether

as solvent.

Hydrolysis of Boc group in compound 101 was successfully

achieved using with methanolic hydrogen chloride (8-10% w/w) at room

temperature, these conditions are superior than traditional conditions

like 4M hydrogen chloride in dioxane is due to removal of high boiling

solvent like dioxane & crystallization of product with addition co-solvent

is unlike, where as in methanolic HCl conditions product is precipitated

as its HCl salt of 102 after addition of anti-solvent.

Finally the dipeptide (102) converts to tripeptide by coupled with

(S)-2-hydroxy-3-phenyl propionic acid (35a) in presence of HATU &

DIPEA in DMSO to give methyl (2S)-2-{[((2S, 4R)-1-[(2S)-2-hydroxy-3-

phenylpropanoyl)-4-{[7-methoxy-2-(1H-1-pyrazolyl)-4-quinolyl]oxy} tetra-

hydro-1H-2-pyrrolyl) carbonyl] amino}-3-phenylpropionate (103) with

excellent yields (> 90%)

Table-3.6

entry Equiv of

6:10

Coupling

agent (equiv)

Solvent

(vol)

Temp

(°C)

Time

(h)

Yield

(%)

1 1:1.1 HATU (1.5) DCM (40) RT 16.0 80

2 1:1.1 HBTU (1.5) DMF (10) RT 12.0 85

3 1:1.1 EDC (1.3)

HOBt (1.4)

EtOAc (25) RT-50°C 24.0 50

4 1:1.1 BOP (1.5) DMF (10) RT-50°C 8.5 55

5 1:1.1 HATU (1.5) DMF (10) RT 12.0 100

6 1:1.1 CDI (1.6) DCM (40) RT 8.0 80

7 1:1.1 EDC (1.5) HOBt (1.5)

DMF (10) RT-50°C 48.0 75

122

8 1:1.1 CDI (1.6) MIBK (25) RT-50°C 24.0 90.0

9 1:1.1 CDI (2.0) DMF (10) RT 24.0 10.0

10 1:1.1 CDI (1.6) MIBK (25) RT-50°C 24.0 45.0

10 1:1.1 HATU (1.5) DCM (10) DMF (1.0)

RT 15.0 90.0

11 1:1.1 HATU (1.5) DMSO (10) RT 12.0 100.0

Compound 103 ester was hydrolyzed in lithium hydroxide in THF

& water medium to give (2S)-2-{[((2S, 4R)-1-[(2S)-2-hydroxy-3-

phenylpropanoyl)-4-{[7-methoxy-2-(1H-1-pyrazolyl)-4-quinolyl]oxy} tetra-

hydro-1H-2-pyrrolyl) carbonyl] amino}-3-phenylpropanoic acid (95) as a

white solid after recrystalized in diisopropylether and characterized by

IR, 1H NMR, 13C NMR and Mass spectral analysis. The major peaks in IR

(KBr) cm-1 3422.46, 1727.47, 1622.98. The major resonances in 1H-NMR

spectra in CDCl3 are 2.1-2.35 (m, 1H, Proline), 2.7-2.8 (m,1H, Proline),

2.85-3.00 (dd, 2H, CH2), 3.18-3.20 (d, 2H, Proline), 3.68-3.80 (dd, 2H,

CH2), 3.92 (s, 3H, OCH3), 3.95 (d, 1H, Proline),4.40-4.45 (t, 1H, Proline),

4.7-4.9 (m, 1H, CH & 1H, CH), 6.51-6.52 (d, 1H, Pyrazole), 7.06-7.28 (m,

13H, Ar-H), 7.83-7.86 (d, 2H, Ar-H & Pyrazole), 8.73-8.74 (d, 1H,

Pyrazole); the major resonances in 13C NMR are 31.60, 34.55, 37.21,

54.00, 55.88, 58.61, 71.10, 77.62, 107.22, 108.97, 114.89, 117.68,

123.53, 126.30, 127.61, 128.24, 128.50, 129.68, 129.87, 137.74,

138.73, 142.60, 149.42, 151.74, 161.68, 161.89, 171.11, 171.31,

172.20, 172.87, 173.00, 173.13; Mass m/z: 650 (M++1).

123

In the similar way compound 101 coupled with other hydroxy

acids namely (R)-2-hydroxy-3-phenylpropionic acid (104) and (S)-2-

hydroxy-2-phenylacetic acid (35b) in presence of HATU,

diisopropylethylamine in dimethyl sulfoxide to give corresponding

coupled products 105 & 107. Hydrolysis of methyl ester using with

lithium hydroxide in THF/water medium give (2S)-2-{[((2S, 4R)-1-[(2R)-2-

hydroxy-3-phenylpropanoyl)-4-{[7-methoxy-2-(1H-1-pyrazolyl)-4-quinolyl]

oxy} tetrahydro-1H-2-pyrrolyl) carbonyl]amino}-3-phenyl propionic acid

(106) & (2S)-2-{[((2S, 4R)-1-[(2S)-2-hydroxy-2-phenylacetic)-4-{[7-

methoxy-2-(1H-1-pyrazolyl)-4-quinolyl]oxy} tetrahydro-1H-2-pyrrolyl)

carbonyl] amino}-3-phenyl propionic acid (108) and products were

characterized by spectral analysis (Scheme 3.11)

N

N N

O

NH

O NH

O

Ph

OMe

OMe

N

N N

O

N

O NH

O

O

OHPh

Ph

OMe

OMe

N

N N

O

N

O NH

O

O

OH

Ph

OMe

OMe

Ph

N

N N

O

N

O NH

O

O

OHPh

Ph

OMe

OH

N

N N

O

N

O NH

O

O

OH

Ph

OMe

OH

Ph

(S)

(S)

HCl

101

105

107

104, i

106

35b, i

108

ii

ii

(S) (S)

(S)

(R)(R)

(S) (S)

………Scheme 3.11

124

Reagents: i) (2R)-2-hydroxy-3-phenylpropanoic acid (104), HATU, DIPEA,

DMF, rt; or (2S)-2-hydroxy-2-phenylacetic acid (35b), HATU, DIPEA,

DMF, rt; ii) LiOH, THF/water, rt.

The present work also describes the synthesis of isomers of

compounds 101, 95, 106 & 108 as mentioned in below scheme 3.12.

The compound 99 is treated with methyl (2R)-2-amino-3-phenyl

propionate (109) under established coupling conditions give coupled

product 110 with good yields & hydrolysis of the Boc group with

methanolic HCl provided compound 111. (2S)-2-hydroxy-3-

phenylpropionic acid (35a), (2R)-2-hydroxy-3-phenylpropionic acid (104)

and (2S)-2-hydroxy-2-phenylacetic acid (35b) were coupled with

compound 111 to give the tripeptides 112, 113, and 114 respectively,

with yields 85-95%. Hydrolysis of methyl ester was achieved in LiOH in

THF, water give compounds 115, 116, and 117 with good isolated yields,

these compound further characterized by spectral analysis by IR, 1H, 13C

NMR & MS.

125

N

N N

O

N

O OH

boc

OMe

N

N N

O

N

O NH

boc

O

Ph

OMe

OMe

N

N N

O

NH

O NH

O

Ph

OMe

OMe

N

N N

O

N

O NH

O

O

OHPh

Ph

OMe

OMe

N

N N

O

N

O NH

O

O

OHPh

Ph

OMe

OMe

N

N N

O

N

O NH

O

O

OH

Ph

Ph

OMe

OMe

N

N N

O

N

O NH

O

O

OHPh

Ph

OMe

OH

N

N N

O

N

O NH

O

O

OHPh

Ph

OMe

OH

N

N N

O

N

O NH

O

O

OH

Ph

Ph

OMe

OH

HCl

109,i ii

35a

99 110 111

113112

35b 104

iii

114

116115 117

iviv iv

(R)(R)

(R)(R) (R)

(R) (R) (R)

(R)

(R)

(S)

(S)

(S)

(S)

………Scheme 3.12

Reagents: i) D-Phenylalanine methyl ester (109), HATU, DIPEA, DMF, rt;

ii) methanolic HCl (15% w/v),rt; iii) (S)-2-hydroxy-3-phenylpropionic acid

126

(35a)/ (R)-2-hydroxy-3-phenylpropionic acid (104)/ mandelic acid (35b),

HATU, DIPEA, DMF, rt; iv) LiOH, THF/water, rt

3.6. CONCLUSION:

In summary, we have developed a practical procedure for

synthesis of (2S)-2-{[((2S, 4R)-1-[(2S)-2-hydroxy-3-phenylpropanoyl)-4-

{[7-methoxy-2-(1H-1-pyrazolyl)-4-quinolyl]oxy}tetrahydro-1H-2-pyrrolyl)

carbonyl] amino} -3-phenylpropanoic acid (95) & its isomers with >98%

ee in 40% overall yield over eight steps. The above synthesis of building

block 78, process offers the potential for facile cyclization at higher

temperatures relative to the current and known processes to potentially

control the regiochemical outcome of the cyclization for 4-hydroxy-7-

methoxyquinolin-2(1H)-one.

127

3.7. EXPERIMENTAL SECTION:

Preparation of 78:

To a mixture of diethyl malonate (82, 250.0 mL, 5 vol) and m-

anisidine (76, 50.0 g, 0.4 mole) in 500 ml RB flask was heated to 140-

150°C (note: at 140°C reflux started due to liberation of ethanol, at this

point TLC showed absence of m-anisidine). Reaction temperature slowly

raised up to 200°C, at this excess diethyl malonate distillation was

started to push the cyclization. Distillation was continued till diethyl

malonate completes and add cooled to 50°C and add methanol (250mL, 5

vol) and reflux for 30 min. Cool to 25-30°C and filter the obtained solid

(78, 55g, 92%). 1H NMR: (DMSO-d6) 3.77 ppm (s, 3H, O-CH3]; 5.55 (s,

1H, Ar-H); 6.7-6.75 (m, 2H, Ar-H); 7.6-7.66 (d, 1H, Ar-H); 11.14 (s, 1H,

OH). MS m/z 192.3 (M++1), 193.3 (M++2)

Preparation of 96:

A suspension of 4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline

(78,30.0 g, 0.157 mole) in phosphorus oxychloride (150.0 mL, 1.57 mole)

was heated at reflux for 5-6 h. After 6h, the excess POCl3 was distilled

under reduced pressure. The residue was poured into cold water (250

mL), pH was then adjusted to 9 with diluted sodium hydroxide solution

and extracted with toluene (3X 250 mL). The combined toluene layers

were washed with brine and dried over sodium sulphate. The organic

layer was then filtered and concentrated to give 2, 4-Dichloro-7-methoxy

128

quinoline (96) as off white solid. 1H NMR: (DMSO-d6) 3.98 ppm (s, 3H,

O-CH3]; 7.4 (m, 2H, Ar-H); 7.75 (s, 1H, Ar-H); 8.0-8.05 (d, 1H, Ar-H). MS

m/z 228.3 (M++1), 230.3 (M++2)

Preparation of 97:

To a mixture of 96,10.0 g, 0.04 mole), Pyrazole (3.25g, 0.048 mole)

in Xylene (100 mL) wash heated to reflux for 5-6 h. then the mixture was

cooled to rt and add water (100 mL). Separate the Xylene layer and

distilled completely under vacuum to get 97 pale yellow solid (60%).1H

NMR: (DMSO-d6) 3.95 ppm (s, 3H, OCH3]; 6.6-6.66 (d, 1H, Pyrazole-H);

7.3-7.4 (d, 1H, Ar-H); 7.41 (d, 1H,Pyrazole-H); 7.9-7.91 (d, 1H, Ar-H),

8.0-8.1 (m, 2H, Ar-H); 8.75 (d, 1H, Pyrazole-H).

Preparation of 99:

To a commercially available 98, 8.9 g 0.038 mole), in DMSO (100

mL), potassium tert-butoxide (13.1g, 0.115 mole) was added in once at

25°C. The mixture was stirred at 25°C for 1.0 h and then 4-chloro-7-

methoxy-2-pyrazol-1-yl-quinoline (97, 10.0g, 0.038 moles) was added at

25°C. The reaction mixture was stirred at 25°C for 24 h. the resulting

suspension was poured into water (500 mL) and the mixture was washed

with ethyl acetate (2 X 250 mL). The aqueous layer was acidified with

dilute hydrochloric acid to pH ~4 and extracted with dichloromethane (4

X 250 mL). The combined dichloromethane layers were washed with

129

brine and dried over sodium sulfate. The organic layer was then filtered,

and concentrated to give 99 as off white solid. 1H NMR (DMSO-d6): 1.30

(s, 9H, Boc-H); 2.30-2.70 (m, 2H, Proline-H); 3.74 (d, 2H, Proline-H); 3.90

ppm (s, 3H, OCH3]; 4.30-4.35 (m, 1H, Proline-H); 5.42 (Br-S, 1H, Proline-

H); 6.60-6.62 (d, 1H, Pyrazole-H); 7.05-7.15 (dd, 1H, Ar-H); 7.24 (d, 1H,

Ar-H); 7.40 (s, 1H, Pyrazole-H); 7.85-8.00 (m, 2H, Ar-H); 8.70-8.75 (d,

1H, Pyrazole-H). MS m/z 455 (M++1), 355 (M+-Boc)

Preparation of 101:

To a solution of 99, 2.0g, 0.004 mole) in DMSO (20 mL) was added

HATU (2.1 g, 0.0048 mole), DIPEA (1.7 g, 0.131 mole). After 1 h at rt, add

100, 0.71 g, 0.004 mole) at rt and stirred for 12 h. The reaction mixture

was diluted with ethyl acetate (100 mL) and washed with dilute

hydrochloric acid, sodium bicarbonate and brine solution. The ethyl

acetate was dried (Na2SO4), filtered and evaporated to dryness to give

101 as off white solid.

101: Yield: 91%; mp: 108-114.6°C; 1H NMR (CDCl3): 1.50 (s, 9H, Boc-

H); 2.20-2.80 (m, 2H, Proline-H); 3.05-3.25 (dd, 2H, CH2); 3.50-3.90 (m,

5H, Proline-H & COOCH3); 3.95 ppm (s, 3H, OCH3); 4.45-4.60 (m, 1H,

Proline-H); 4.90 (brs, 1H, Proline-H); 5.10-5.20 (m, 1H, CH); 6.50-6.52

(d, 1H, Pyrazole-H); 7.05-7.42 (m, 9H, Ar-H); 7.47 (d, 1H, Pyrazole-H);

7.77 (s, 1H, Ar-H); 7.90-7.92 (d, 1H, Ar-H); 8.74-8.75 (s, 1H, Pyrazole-H).

130

MS m/z 616 (M++H), 638 (M++Na), 654 (M++K); IR :(KBr) 1673 & 1622

cm-1 (CO, COO).

111: Yield: 95%; mp: 93-98°C; 1H NMR (CDCl3): 1.48 (s, 9H, Boc-H),

2.22-2.82 (m, 2H, Proline-H); 3.10-3.25 (dd, 2H, CH2); 3.55-3.95 (m, 5H,

Proline-H & COOCH3); 3.97 ppm (s, 3H, OCH3]; 4.42-4.58 (m, 1H,

Proline-H); 4.85 (Br-s, 1H, Proline-H); 5.15-5.20 (m, 1H, CH); 6.50-6.55

(d, 1H, Pyrazole-H); 7.00-7.40 (m, 9H, Ar-H); 7.47 (d, 1H, Pyrazole-H);

7.77 (s, 1H, Ar-H); 7.90-7.92 (d, 1H, Ar-H); 8.74-8.75 (s, 1H, Pyrazole-H).

MS m/z 616.5 (M++H), 638.1 (M++Na), 654.1 (M++K); IR: (KBr) 1743 &

1682 cm-1 (CO, COO).

Preparation of 102:

To a mixture of 101, 1.0g, 0.0018 mole) and anhydrous methanolic

hydrogen chloride (8% w/w, 5.0 mL) was stirred at rt for 1 h. After

completion of reaction was concentrated completely and add hexane and

distilled completely. Finally add hexane (25 mL) at rt. Stirred for 1 h and

filtered to give 102 as a white solid. This material was used in the next

step as crude without any purification.

102: Yield: 99%; mp: 200-207°C

111: Yield: 99%; mp: 198-203°C

131

Preparation of 103:

The 102, 0.5 g, 0.9 mmol) was then added DMSO, HATU (0.5 g, 1.1

mmol), and N, N’-Diisopropylethylamine (0.35 g, 2.71 mmol). After 1 h,

add (2S)-2-hydroxy-3-phenyl propanoic acid (35a, 0.15 g, 0.9 mmol) at rt

and stirred for 12 h. The reaction mixture was diluted with ethyl acetate

(100 mL) and washed with dilute hydrochloric acid, sodium bicarbonate

and brine solution. The ethyl acetate was dried (Na2SO4) filtered and

evaporated to dryness to give 103 as white solid.

Representative spectral data:

103: Yield: 96%; mp: 139-143°C; 1H NMR (CDCl3): 2.00-2.20 (m, 2H,

Proline-H), 2.20-2.40 (dd, 2H, CH2), 2.95-3.25 (dd, 2H, CH2), 3.35-3.40

(m, 2H, Proline-H), 3.65-3.70 (m, 1H, Proline-H), 3.75 (s, 3H, COOCH3),

3.95 (s, 3H, OCH3), 4.31-4.33 (t, 1H, Proline-H), 4.75-4.80 (q,1H, CH),

4.90-4.93 (q, 1H, CH), 6.52 (d, 1H, Pyrazole-H), 7.05-7.35 (m, 13H, Ar-H

& Pyrazole-H), 7.78 (s, 1H, Ar-H), 7.86-7.87 (d, 1H, Ar-H), 8.75 (s, 1H,

Pyrazole-H); 13C NMR (CDCl3): 173.5 (COO), 171.59 (CO), 169.47 (CO),

161.9, 161.0, 151.56, 149.62, 141.98, 136.13, 135.66, 129.61, 129.32,

128.97, 128.58, 128.44, 127.34, 127.15, 127.0, 126.87, 122.88, 117.7,

114.67, 108.0, 106.8, 90.6, 76.4 (O-CH), 70.5 (CH-OH), 58.8, 55.4 (O-

CH3), 53.7, 52.3, 52.1, 49.3, 41.0, 37.6, 33.0, 30.59. MS m/z 664.4

(M++H), 686.0 (M+ +Na), 701.8 (M++K); IR (KBr) 1735, 1648, 1621 cm-1

132

(CO, COO); chiral purity by HPLC: 100%; other isomer: Nil%; Chemical

purity by HPLC: 97.00%



(m, 2H, Proline-H), 3.75 (s, 3H, COOCH3), 3.85-3.90 (m, 1H, Proline-H),

3.95 (s, 3H, OCH3), 4.40 (br-H, 1H, Proline-H), 4.75-4.78 (q,1H, CH),

4.80-4.84 (q, 1H, CH), 6.51 (d, 1H, Pyrazole-H), 6.93-7.37 (m, 13H, Ar-H

& Pyrazole-H), 7.76 (s, 1H, Ar-H), 7.82-7.84 (d, 1H, Ar-H), 8.73 (s, 1H,

Pyrazole-H); MS m/z 664.0 (M++H), 686.0 (M++Na), 701.7 (M++K); IR (KBr)

1743, 1666, 1622 cm-1 (CO, COO); Chiral purity by HPLC: 94.70%; other

isomer: 5.30%; Chemical purity by HPLC: 96.88%


proline-H), 2.99-3.20 (dd, 2H, CH2), 3.20-3.40 (m, 2H, Proline-H), 3.74 (s,

3H, COOCH3), 3.80-3.83 (m, 1H, Proline-H), 3.96 (s, 3H, OCH3), 4.41-

4.33 (t, 1H, Proline-H), 4.79-4.85 (m,1H, CH, 1H, CH), 6.51 (d, 1H,

Pyrazole-H), 6.75-6.76 (d, 1H, Ar-H), 7.09-7.37 (m, 13H, Ar-H & pyrazole

H), 7.74 (d, 1H, Ar-H), 7.85-7.87 (d, 1H, Ar-H) 8.73 (s, 1H, Pyrazole-H);

13C NMR (CDCl3): 172.17 (COO), 171.54 (CO), 169.64 (CO), 161.78,

161.01, 151.24, 149.20, 141.94, 137.71, 135.68, 129.17, 129.00,

128.89, 128.51, 128.47, 128.40, 127.49, 127.30, 126.98, 122.83,

117.49, 114.550, 108.03, 106.52, 90.39, 76.35 (O-CH), 72.89 (CH-OH),

59.10, 55.32 (O-CH3), 53.47, 52.22, 52.16, 49.25, 37.82, 33.38,

133

30.43.MS m/z 650.0 (M++H), 651.1 (M++2H), 672.0 (M++Na), 687.9

(M++K); IR (KBr) 1743, 1661, 1621 cm-1 (CO, COO); Chiral purity by

HPLC: 100.0%; other isomer: Nil; Chemical purity by HPLC: 96.10%.

112: Yield: 95%; mp: 172-179.6°C; 1H NMR (CDCl3): 2.00-2.20 (m, 2H,


(m, 2H, Proline-H), 3.65-3.70 (m, 1H, Proline-H), 3.75 (s, 3H, COOCH3),

3.95 (s, 3H-OCH3), 4.22-4.25 (t, 1H, Proline-H), 4.75-4.80 (q, 1H, CH),

4.80-4.83 (q, 1H, CH), 6.45 (d, 1H, Pyrazole-H), 6.90-6.92 (d, 1H, Ar-H),

7.05-7.35 (m, 12H, Ar-H & Pyrazole-H), 7.78 (s, 1H, Ar-H), 7.82-7.85 (d,

1H, Ar-H), 8.78 (s, 1H, Pyrazole-H); 13C NMR (CDCl3): 173.5 (COO),

171.59 (CO), 169.47 (CO), 161.9, 161.0, 151.56, 149.62, 141.98, 136.13,

135.66, 129.61, 129.32, 128.97, 128.58, 128.44, 127.34, 127.15, 127.0,

126.87, 122.88, 117.7, 114.67, 108.0, 106.8, 90.6, 76.4 (O-CH), 70.5

(CH-OH), 58.8, 55.4 (O-CH3), 53.7, 52.3, 52.1, 49.3, 41.0, 37.6, 33.0,

30.59. MS m/z 664.0 (M++H), 686.0 (M++Na), 701.7 (M++K); IR (KBr)

1743, 1666, 1622 cm-1 (CO, COO); chiral purity by HPLC: 94.7%; other

isomer: Nil%; Chemical purity by HPLC: 96.88%


Proline-H), 2.32-2.45 (m, 3H, Proline-H, CH2), 2.70-2.90 (dd, 2H, CH2),

2.95-3.05 (dd, 2H, CH2), 3.40-3.50 (m, 2H, Proline-H), 3.78 (s, 3H,

COOCH3), 3.85-3.90 (m, 1H, Proline-H), 3.97 (s, 3H, OCH3), 4.40 (br-H,

1H, Proline-H), 4.80-4.90 (m, 1H, CH, 1H, CH), 5.22 (brS, OH), 6.50 (d,

134

1H, Pyrazole-H), 7.05-7.38 (m, 12H, Ar-H & Pyrazole-H), 7.40 (s, 1H, Ar-

H), 7.75 (s, 1H, Ar-H), 7.82-7.84 (d, 1H, Ar-H), 8.78 (s, 1H, Pyrazole-H);

13C NMR (CDCl3): 173.41 (COO), 171.68 (CO), 169.80 (CO), 161.87,

161.22, 151.66, 149.65, 142.06, 136.22, 129.20, 129.12, 128.54,

128.31, 127.34, 127.10, 126.78, 122.86, 117.64, 114.62, 108.10,

106.85, 90.73, 76.18 (O-CH), 70.9 (CH-OH), 58.63, 55.44 (O-CH3), 53.53,

52.39, 51.30, 41.09, 37.65, 33.09, 31.80, 22.62, 14.04; MS m/z 664.1

(M++H); IR (KBr) 1744, 1682, 1630 cm-1 (CO, COO); Chiral purity by

HPLC: 98.77%; other isomer: 5.30%; Chemical purity by HPLC: 97.26%


proline-H), 2.35-2.40 (m, 1H, proline-H), 3.00-3.20 (dd, 2H, CH2), 3.35-

3.40 (m, 2H, Proline-H), 3.78 (s, 3H, COOCH3), 3.80-3.83 (m, 1H,

Proline-H), 3.96 (s, 3H, OCH3), 4.35-4.38 (t, 1H, Proline-H), 4.79-4.85 (m,

1H, CH, 1H, CH), 5.15 (brs, OH), 6.55 (d, 1H, Pyrazole-H), 6.75-6.76 (d,

1H, Ar-H), 7.09-7.37 (m, 13H, Ar-H & pyrazole H), 7.74 (d, 1H, Ar-H),

7.85-7.87 (d, 1H, Ar-H) 8.73 (s, 1H, Pyrazole-H); 13C NMR (CDCl3):

172.17 (COO), 171.54 (CO), 169.64 (CO), 161.78, 160.91, 151.44,

149.50, 141.88, 137.67, 135.68, 129.21, 128.96, 128.91, 128.73,

128.45, 127.48, 127.41, 127.24, 127.06, 122.82, 117.56, 114.61,

107.96, 106.73, 90.48, 76.32 (O-CH), 72.94 (CH-OH), 58.92, 55.34 (O-

CH3), 53.43, 52.23, 52.17, 37.72, 32.99, 30.18; MS m/z 650.0 (M++H),

651.1 (M++2H), 672.0 (M++Na), 687.9 (M+K); IR (KBr) 1743, 1661, 1621

135

cm-1 (CO, COO); Chiral purity by HPLC: 100.0%; other isomer: Nil;

Chemical purity by HPLC: 97.37%.

Preparation of 95:

Methyl ester 103 (1.0 g, 1.51 mmol) was dissolved in a mixture of

THF (5 mL), MeOH (5 mL) and water (5 mL) and added LiOH.H2O (0.19 g,

45.3 mmol). The resulting mixture was left to stir at RT for 2 h. The

solvents were then removed under reduced pressure and the crude

product was redissolved with EtOAc and diluted with brine. The pH of

the aqueous layer was adjusted to 6 with aqueous HCl (1N) and the

aqueous phase was extracted with EtOAc (3x25 mL). The combined

organic phase were washed with water, brine, dried over MgSO4 and

concentrated under reduced pressure to afford (2S)-2-{[((2S, 4R)-1-[(2S)-

2-hydroxy-3-phenyl propanoyl)-4-{[7-methoxy-2-(1H-1-pyrazolyl)-4-

quinolyl] oxy} tetrahydro-1H-2-pyrrolyl)carbonyl]amino}-3-

phenylpropanoic acid (95) as a white solid.

Representative spectral data:

95: Yield: 95%; mp: 99.8-108°C; 1HNMR spectra in CDCl3: discussed in

results and discussion. Anal. Calcd. for (C36H35N5O7) requires: C, 66.55;

H, 5.43; N, 10.78; Found: C, 66.60; H, 5.49; N, 10.82%.

106: Yield: 92%; mp: 115-120°C; 1H-NMR spectra in CDCl3 are, i) 2.1-

2.35 (m, 1H, Proline-H), 2.7-2.8 (m,1H, Proline-H), 2.85-3.00 (dd, 2H,

136

CH2), 3.18-3.20 (d, 2H, Proline-H), 3.68-3.80 (dd, 2H, CH2), 3.92 (s, 3H,

OCH3), 3.95 (d, 1H, Proline-H),4.40-4.45 (t, 1H, Proline-H), 4.7-4.9 (m,

1H, CH & 1H, CH), 6.51-6.52 (d, 1H, Pyrazole-H), 7.06-7.28 (m, 13H, Ar-

H), 7.83-7.86 (d, 2H, Ar-H & Pyrazole-H), 8.73-8.74 (d, 1H, Pyrazole-H);

MS m/z 650.4 (M++H). 672.0 (M++Na), 685 (M++K); IR (KBr) 3421.12,

1729.6, 1621.58 cm-1 (CO, COO); Anal. Calcd. for (C36H35N5O7) requires:

C, 66.55; H, 5.43; N, 10.78; Found: C, 66.50; H, 5.39; N, 10.72%.


proline-H), 2.65-2.75 (m, 1H, proline-H), 2.87-3.05 (dd, 2H, CH2), 3.15-

3.20 (d, 2H, Proline-H), 3.80-3.83 (m, 1H, Proline-H), 3.94 (s, 3H, OCH3),

4.41-4.33 (t, 1H, Proline-H), 4.79-4.85 (m,1H, C, 1H, CH), 6.52 (d, 1H,

Pyrazole-H), 6.77-6.79 (d, 1H, Ar-H), 7.11-7.40 (m, 13H, Ar-H &

pyrazole-H), 7.75 (d, 1H, Ar-H), 7.87-7.89 (d, 1H, Ar-H) 8.76 (s, 1H,

Pyrazole-H). MS m/z 636.0 (M++H), 651.1 (M+ +2H); Anal. Calcd. for

(C35H33N5O7) requires: C, 66.13; H, 5.23; N, 11.02; Found: C, 66.18; H,

5.29; N, 11.08%.

115: Yield: 95%; mp: 120-123.3°C; 1H NMR (CDCl3): 2.15-2.35 (m, 1H,

Proline-H), 2.55-2.70 (m, 1H, proline-H), 2.79-2.93 (dd, 2H, CH2), 3.00-

3.20 (dd, 2H, CH2), 3.35-3.40 (m, 2H, Proline-H), 3.90-3.93 (m, 1H,

proline-H), 3.97 (s, 3H, OCH3), 4.35-4.40 (t, 1H, Proline-H), 4.75-4.80 (q,

1H, CH), 4.83-4.84 (q, 1H, CH), 6.55 (d, 1H, Pyrazole-H), 7.10-7.40 (m,

14H, Ar-H & Pyrazole-H), 7.78 (s, 1H, Ar-H), 7.85-7.89 (d, 1H, Ar-H),

137

8.74 (s, 1H, Pyrazole-H); MS m/z 650 (M++H); Anal. Calcd. for


5.48; N, 10.73%.


Proline-H), 2.54-2.71 (m, 1H, proline-H), 2.76-2.87 (dd, 2H, CH2), 3.05-

3.20 (dd, 2H, CH2), 3.38-3.40 (m, 2H, Proline-H), 3.64-3.70 (m, 1H,

Proline-H), 3.84-3.87 (m, 1H,proline-H), 3.94 (s, 3H, OCH3), 4.43-4.45 (t,

1H, Proline-H), 4.80-4.85 (m,1H, CH & 1H, CH), 6.55 (d, 1H, Pyrazole-H),

7.09-7.40 (m, 14H, Ar-H & Pyrazole-H), 7.80 (s, 1H, Ar-H), 7.85-7.89 (d,

1H, Ar-H), 8.76 (s, 1H, Pyrazole-H); MS m/z 650 (M++H); Anal. Calcd. for


5.37; N, 10.82%.

117: Yield: 91%; mp: 75.6-81°C; 1H NMR (CDCl3): 2.15-2.40 (m, 1H,

proline-H), 2.53-2.75 (m, 1H, Proline-H), 2.80-3.17 (dd, 2H, CH2), 3.40-

3.50 (m, 2H, Proline-H), 3.95 (s, 3H, OCH3), 3.80-3.85 (m, 1H, Proline-H),

4.00-4.10 (t, 1H, Proline-H), 4.40-4.50 (m,1H, CH, 1H, CH), 6.65 (d, 1H,

Pyrazole-H), 7.05-7.35 (m, 13H, Ar-H & Pyrazole-H), 7.60 (d, 1H, Ar-H),

7.90-7.95 (d, 1H, Ar-H) 8.76 (s, 1H, Pyrazole-H); MS m/z 636.0 (M++H),

651.1 (M++2H); Anal. Calcd. for (C35H33N5O7) requires: C, 66.13; H, 5.23;

N, 11.02; Found: C, 66.09; H, 5.19; N, 10.98%.

138

3.8 REFERENCES:

1.(a) Choo, Q.-L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.;

Houghton, M. Science 1989, 244, 359. (b) The Hepatits C Viruses;

Hagedorn, C. H., Rice, C. M., Eds.; Springer: Berlin, 2000; Curr. Top.

Microbiol. Immunol. 242.

2. Cornberg, M.; Wedemeyer, H.; Manns, M. P. Curr. Gastroenterol. Rep.

2002, 4, 23.

3. Manske, R. H. F. Chem. Rev. 1942, 30, 113-144.

4. Foley, M.; Tilley, L. Pharmacol. Ther. 1998, 79, 55-87.

5. Croft, S. L.; Coombs, G. H. Trends Parasitol. 2003, 19, 502-508.

6. (a) Bringmann, G.; Reichert, Y.; Kane, V. V. Tetrahedron 2004, 60,

3539-3574. (b) Hibino, S.; Weinreb, S. M. J. Org. Chem. 1977, 42, 232-

236.

7. Wang, H.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9097-9098.

8. Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J.

Am. Chem. Soc. 1997, 119, 6072-6094.

9. (a) Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G. J. Org. Chem.

1994, 59, 5120-5121. (b) Shen, W.; Coburn, C. A.; Bornmann, W.

G.;Danishefsky, S. J. J. Org. Chem. 1993, 58, 611-617.

10. Michael, J. P. Nat. Prod. Rep. 2003, 20, 476-493.

11.(a) Newhouse, B. J.; Bordner, J.; Augeri, D. J.; Litts, C. S.; Kleinman,

E. F. J. Org. Chem. 1992, 57, 6991. (b) Torii, S.; Xu, L. H.; Sadakane, M.;

Okumoto, H. Synlett 1992, 513. (c) Nobuhide, M.; Yoshinobu, Y.; Hiroshi,

139

I.; Yoshio, O.; Tamejiro, H. Tetrahedron Lett. 1993, 24, 8263 (d) Croisey-

Delcey, M.; Croisy, A.; Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot, P.;

Bisagni, E.; Jin, L.; Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629.

12. Llinas-Brunet, M.; Bailey, M.; Fazal, G.; Ghiro, E.; Gorys, V.; Goulet,

S.; Halmos, T.; Maurice, R.; Poirier, M.; Poupart, M.-A.; Rancourt, J.;

Thibeault, D.; Wernic, D.; Lamarre, D. Bioorg. Med. Chem. Lett. 2000,

10, 2267-2270.

13. Poupart, M.-A.; Cameron, D. R.; Chabot, C.; Ghiro, E.; Goudreau, N.;

Goulet, S.; Poirier, M.; Tsantrizos, Y. S. J. Org. Chem. 2001, 66, 4743-

4751.

14. (a) Kappe, T.; Karem, A. S.; Stadbauer, W. J. Heterocycl. Chem.

1988, 25, 857-862; (b) Knierzinger, A.; Wolfbeis, O. S. J. Heterocycl.

Chem. 1980, 17, 225-229.

15. Shobana, N.; Yeshoda, P.; Shanmugam, P. Tetrahedron 1989, 45,

757-762;

16.Glasnov, T. N.; Stadbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70,

3864-3870.

17.Blackburn, C.; LaMarche, M. J.; Brown, J.; Che, J. L.; Cullis, C. A.;

Lai, S.; Maguire, M.; Marsilje, T.; Geddes, B.; Govek, E.; Kadambi, V.;

Doherty, C.; Dayton, B.; Brodjilan, S.; Marsh, K. C.; Collins, C. A.;

Kym, P. R. Bioorg. Med. Chem. Lett. 2006, 16, 2621-2627

18. Sheibani, H., Hosseln, M., Soheila,B., Reza islami,M., Saidi Kazem.

Synthesis 2006, No 3, 435-438.

140

20. Youla S. Tsantrizos et al., US 6,608,027; date of Patent–Aug 19’ 2003

22. Dodia, N.; Shah, A. Ind. J. Heterocycl. Chem. 1999, 9, 139-142.

CHAPTER 3 CONDENSATION OF SUBSTITUTED 4...

Documents

Transcript of CHAPTER 3 CONDENSATION OF SUBSTITUTED 4...