chapter – 5 synthesis of new carbazole derivatives as...

168

CHAPTER – 5

Synthesis of new carbazole derivativesas -adrenoreceptor blockers

169

5.1 Introduction

β-Adrenergic receptors play a role in many diseases of the heart

and the brain. They have been shown to be altered in the thalamus of

patients suffering from Schizophrenia, Alzheimer’s disease, panic

disorder, aging, fear, anxiety, depression, and stress.1-7

The common structural features of -adrenoreceptor blockers

include either an arylethanolamine or an aryloxyisopropanolamine

moiety. The compounds differ in the nature of the aryl group, as well as

the group linked to the amine moiety. Carvedilol (-adrenoreceptor

blocker) contains an oxyisopropanolamine moiety with aromatic

substituents linked to both the oxy and amine ends of the molecule,

which provide its combined activity.8 It has been shown for a number of

carbazoles that contain phenoxypropanolamines that the β-blocking

activities of the two optical antipodes differ by a factor of at least 50.9

The (S)-enantiomer generally appears to be the most potent one.

Stereoselectivity of the carvedilol enantiomers has estabilished and found

that (S)-(-)enantiomer of carvedilol is effecting for -adrenoreceptor

blocker and vasodilation.10

The above studies prompted us to prepare compounds having (S)-

amino moiety in between the carbazole and methoxyphenoxyethylamine

that might exhibit higher activity.

170

NH

OHO

NH

O

H3CO

INSERTION OF AMINO ACID

NH

OOH

NH

R

O

HN O

H3CO

AMINO ACID

(S)

CARVEDILOL NEW CARBAZOLE ANALOGS

5.2. Literature Background

Berridge et al., reported11 the synthesis of carazolol (5) (Scheme

5.1), starting from the commercially available 4-hydroxy carbazole (1).

NH

O O

H2N

CH3

CH3

Dioxanereflux, N

H

OOH

NH

CH3

CH3

NH

OH

ClO

(1)(2)

(3)

(5)

KOH, Toluene

(4)

…..Scheme 5.1

Dubois et al., synthesized12 iodine containing analogue of carazolol

(CYBL8E) (11) (Scheme 5.2) by reaction of 4-hydroxy carbazole (1) with

the chiral auxiliary (6) results S-epoxide (7) and then treated with 1,1-

dimethylpropargylamine (8) followed by addition of tributyltinhydride in

171

the presence of azobisisobutyronitrile (AIBN) in toluene and halogenated

with iodine in chloroform.

NH

HO O2N

SO

OO O

K2CO3,Butanone

NH

OO

NH2H3CH3C CH

EthanolNH

OOH

NH

H3C CH3

CH nBu3SnH,AIBN, Toluene

NH

OOH

NH

H3CCH3

SnBu3 I2, CHCl3

NH

OOH

NH

H3CCH3

I

(1) (6)(7)

(9)

(10) (11)

(8)

…..Scheme 5.2

Zheng et al., reported13 the synthesis of fluorocarazolol (20)

(Scheme-5.3 & 5.4), starting from 4-hydroxy carbazole (1).

172

H3C

OOH H3C S

O

OCl

Pyridine,0-5°C

H3C SO

OO

CH3

O

18F-, Kryptofx 222,K2CO3

H3C

O18F

(12) (13) (14)

(15)

…..Scheme 5.3

NH

HOKOH,Toluene

NH

OKO

OTs

Acetonitrile

NH

OO

NH3,Methanol

NH

OOH

NH2

(1) (16)

(18) (19)

(15), NaCNBH3,Acetic acid

NH

OOH

NH CH3

18F

(20)

(17)

…..Scheme 5.4

173

Wiedemann et al., reported14 the synthesis of carvedilol (22)

(Scheme-5.5) by ring opening of 4-[(oxirane-2-yl)methoxy)-9H-carbazole

(3) with 2-(2-methoxyphenoxy)ethylamine (21) in ethyl acetate at reflux

temperature.

NH

O OEthy acetate, reflux

NH

O NH

(3)

(22)

H2NO

H3CO

OH

(21)

O

H3CO

…..Scheme 5.5

Crowell et al., reported15 the synthesis of (S)-4-[2-hydroxy-3-([4-(4-

carbamoylphenoxy)phenyl]-2-methylpropylamino)propoxy]carbazole (24)

(Scheme 5.6) by ring opening of chiral oxirane (18) with 4-(4-(2-amino-2-

methylpropyl)phenoxy)benzamide (23) in the presence of acetic acid in

methanol at 60°C.

174

NH

OO

(24)

(18)

H2N

O

NH2

O Acetic acid, water,methanol, 60°C

(23)

OHN

HO

O

NH2

O

(S)HN

…..Scheme 5.6

Thomas et al., described16 the synthesis of carvedilol (22) (Scheme

5.7), starting from 4-hydroxy carbazole (1) by the following reaction

sequence.

NH

O NO

O

H3CO

Ethanol, NaOH, reflux

NH

O NHOH

O

H3CO

(26) (22)

(1)

OCH3O

N O

O

Cl

(25)

K2CO3, KI,Sodium dithionite,Ethanol, reflux

O

NH

HO

…..Scheme 5.7

175

Zoltan et al., reported17 the synthesis of carvedilol (22) (Scheme

5.8) by ring opening of epichlorohydrin (2) with compound 27 and

condensation with 4-hydroxycarbazole (1) followed by deprotection with

Pd/C.

NH

OH

NH

O NHOH

O

H3CO

(29) (22)

(1)Ph N

HO

H3CO

(27)

ClO

Ph NO

H3CO

(28)

Cl

OH

Dioxane, K2CO3

Pd/C, H2

(2)

NH

O NOH

O

H3COPh

…..Scheme 5.8

5.3. Present work

Literature survey revealed a wide range of -adrenoreceptor

blockers of carbazole and their derivatives. On this basis, it was thought

appropriate to synthesize carvedilol analogue containing different amino

acid. This chapter also deals with the preparation of various carbazole

containing acyclic and cyclic amino acid by ring opening of oxirane (3)

with acyclic and cyclic amino acids or their derivatives.

176

5.4. Results and Discussion

5.4.1. Preparation of carvedilol derivatives containing (S)-amino acid

5.4.1.1. Preparation of compound 31a from compound 30a:

Boc-L-tert-leucine (30a) was prepared according to the method

described in the literature.15 Boc-L-tert-leucine (30a) was treated with 4-

nitrophenylchloro formate in the presence of 4-dimethylaminopyridine

(DMAP) at 0-5°C to gave mixed anhydride and treated with 2-(2-

methoxyphenoxy)ethylamine (21) at room temperature (Scheme 5.9) gave

tert-butyl-(S)-1-(2-(2-methoxyphenoxy)ethylcarbamoyl)-2,2-dimethyl-

propylcarbamate (31a).

NH

CH3H3C

O

OH

(30a)

O

OH3C

H3CH3C

H2NO

H3CO

( 21)NH

CH3H3C

O

HN

(31a)

O

OH3C

H3CH3C O

H3CO

4-Nitrophenylchloroformate,DMAP, ACN, 25-30°C

CH3 CH3

…..Scheme 5.9

The product 31a was characterized by its spectral data. Thus, its

IR (KBr) spectrum showed characteristic peaks at 3364 cm-1 (s, -NH str.),

and 1702 cm-1 (s, -C=O str.). Its 1H NMR (300 MHz, CDCl3) spectrum

showed signals at 0.97 (s, 9H, -C(CH3)3), 1.42 (s, 9H, -C(CH3)3), 3.59-

3.64 (m, 2H, -NHCH2-), 3.74 (s, 4H, -OCH3 & -NHCHCO-), 4.06-4.13 (m,

2H, -OCH2-), 5.28-5.31 (m, 1H, -CONHCH2-), 6.45-6.46 (m, 1H, -

177

CONHCH-), 6.89-6.99 (m, 4H, Ar-H) ppm. Its MS (ESI, m/z) showed the

[M + H]+ ion peak at 381 corresponding to a molecular mass of 380.

The above reaction has been found to be a general one and

extended to other amino acids (31b, 31c, 31d) whose structures were

assigned based on their spectral data (Table-5.1).


Deprotection of compound 31a in the presence of concentrated

hydrochloric acid in methylene chloride at room temperature (Scheme

5.10) gave corresponding (S)-N-(2-(2-methoxyphenoxy)ethyl)-2-amino-

3,3-dimethyl- butanamide (32a).

NH

CH3H3C

O

HN

(31a)

O

OH3C

H3CH3C

(32a)

Con. HCl,DCM, 25-30°C

O

H3CO

H2N

CH3H3C

O

HN

O

H3COCH3CH3

…..Scheme 5.10

The product 32a was characterized by its spectral data. Thus, Its

1H NMR (300 MHz, CDCl3) spectrum showed signals at 0.98 (s, 9H, -

C(CH3)3), 2.28 (br. 3H, -NH2 & -CONH), 3.07 (s, 1H, -CCHCO-), 3.62-3.69

(m, 2H, -NHCH2-), 3.88 (s, 3H, -OCH3), 4.03-4.13 (m, 2H, -OCH2-), 6.87-

178

6.99 (m, 4H, Ar-H) ppm. Its MS (ESI, m/z) showed the [M + H]+ ion peak

at 281 corresponding to a molecular mass of 280.

The above reaction was extended to other compounds (32b, 32c,

32d) whose structures were assigned by their spectral data (Table-5.2).


Compound 32a on condensation with 4-[(oxirane-2-yl)methoxy)-

9H-carbazole (3) in isopropyl alcohol at 75-80°C (Scheme 5.11) gave N-

(2-(2-methoxyphenoxy)ethyl)-1-(3-(9H-carbazol-4-yloxy)-2-hydroxypropyl)

-L-tert-leucine carboxamide (33a). The product 33a was characterized

by its spectral data. Thus, its IR (KBr) spectrum showed peak at 1654

cm-1 (s, -C=O str.). Its 1H NMR (300 MHz, CDCl3) spectrum showed

signals at 0.93 (s, 9H, -C(CH3)3), 2.62-2.73 (m, 4H, -NHCH2-), 3.49-

3.65 (m, 2H, -NHCHCO- & -CHOH-), 3.68-3.76 (s, 3H, -OCH3), 3.91-4.06

(m, 4H, -OCH2-), 6.76-8.27 (m, 12H, -CONH & Ar-H), 8.36 (s, 1H, -NH)

ppm. Its MS (ESI, m/z) showed the [M + H]+ ion peak at 520

corresponding to a molecular mass of 519.

179

H2N

CH3H3C

O

HN

(32a)

NH

OO

NH

OOH

NH

CH3H3C

O

HN

O

H3CO

(33a)

IPA, 75-80°C

(3)

O

H3COCH3

H3C

…..Scheme 5.11


extended to other compounds (33b, 33c, 33d) whose structures were

assigned by their spectral data (Table-5.3).

5.4.1.4. Preparation of compound 31e from compound 30e:

Boc-trans-cyclohexyl-L-proline (30e) was prepared according to the

method described in the literature.15 Boc-trans-cyclohexyl-L-proline

(30e) was treated with 4-nitrophenylchloroformate in the presence of

DMAP at 0-5°C to gave mixed anhydride and followed by reacted with 2-

(2-methoxyphenoxy)ethylamine (21) at room temperature (Scheme 5.12)

gave (2S,4S)-tert-butyl 2-(2-(2-methoxyphenoxy)-4-cyclohexylpyrrolidine-

1-carboxylate (31e).

180

N OH

OOH3C

H3CH3C O

H2NO

H3CO

(21)

(30e)

NHN

O

OH3C

CH3H3C O

O

H3CO

(31e)


…..Scheme 5.12

The product 31e was characterized by its spectral data. Thus, its

IR (KBr) spectrum showed characteristic peaks at 3325 (m, -NH str.), and

1682 (s, -C=O str.). Its 1H NMR (300 MHz, CDCl3) spectrum showed

signals at 0.88-0.92 (m, 2H, -CH2), 1.09-1.16 (m, 4H, -CH2CH2-), 1.35

(s, 9H, -C(CH3)3), 1.59-1.76 (m, 8H, -3 x CH2 & -2 x CH), 2.23-2.35 (m,

1H, -NCH2), 2.95-3.02 (m, 1H, -NCH2), 3.65-3.68 (m, 3H, -NHCH2 & -

CHCO), 3.85 (s, 3H, -OCH3), 4.05-4.08 (m, 2H, -OCH2), 4.24-4.28 (m,

1H, - CONH), 6.90-6.98 (m, 4H, Ar-H) ppm. Its MS (ESI, m/z) showed

the [M + H]+ ion peak at 446 corresponding to a molecular mass of 445.


Deprotection of compound 31e in the presence of acid at room

temperature (Scheme 5.13) gave corresponding amino (2S,4S)-N-(2-(2-

methoxyphenoxy)ethyl)-4-cyclohexylpyrrolidine-2-carboxamide (32e).

181

NHN

O

OH3C

CH3H3C O

O

H3CO

(31e)

HNHN

OO

H3CO

(32e)

Con. HCl,DCM, 25-30°C

…..Scheme 5.13

The product 32e was characterized by its spectral data. Thus, Its

1H NMR (300 MHz, CDCl3) spectrum showed signals at 0.82-0.86 (m,

2H, -CH2), 1.07-1.09 (m, 4H, -CH2CH2-), 1.52-1.65 (m, 7H, 3 x CH2 & -

CH), 2.01-2.06 (m, 1H, -CH), 2.52-2.58 (m, 1H, -NHCH2), 3.04-3.07 (m,

1H, -NHCH2), 3.56-3.69 (m, 3H, -NCH2 & -COCH), 3.80 (s, 3H, -OCH3),

4.01-4.05 (m, 2H, -OCH2), 6.83-6.89 (m, 4H, Ar-H) 8.06 (br, 1H, -

CONHCH2) ppm. Its MS (ESI, m/z) showed the [M + H]+ ion peak at 347



Compound 32e on condensed with oxirane (3) in isopropyl alcohol

at 75-80°C (Scheme 5.14) gave (2S,4S)-N-(2-(2-methoxyphenoxy)ethyl)-1-

(3-(9H-carbazol-4-yloxy)-2-hydroxypropyl)-4-cyclohexylpyrrolidine-2-

carboxamide (33e). The product 33e was characterized by its spectral

data.

182

NNH

OO

H3CO

(33e)

HNHN

OO

H3CO

(32e)

NH

OO

(3)

IPA, 75-80°C

OOH

NH

…..Scheme 5.14

Thus, it’s IR (KBr) spectrum showed typical peak at 1654 cm-1 (s, -

C=O str.). Its 1H NMR (300 MHz, CDCl3) spectrum showed signals at

0.9 (s, 2H, -CH2), 1.15-1.98 (m, 4H, -CH2), 1.57-1.65 (m, 5H, -CH2 & -

CH), 1.99-2.25 (m, 3H, -CH & -CH2), 3.05-3.10 (m, 1H, -CHCO), 3.46-

3.61 (m, 4H, N(CH2)2), 3.71 (s, 3H, -OCH3), 3.88-4.04 (m, 3H, -NHCH2 &

-OCH), 4.14-4.54 (m, 4H, -OCH2), 6.67-8.26 (m, 11H, Ar-H), 11.37 (s,

1H, -NH) ppm. Its MS (ESI, m/z) showed the [M + H]+ ion peak at 586


183

5.4.2. Preparation of carbazole derivative containing acyclic (S)-

amino acid


Oxirane (3) was prepared according to the method described in the

literature.14 Oxirane (3) on condensation with L-valine (34a) in the

presence of potassium carbonate in water at 75-80°C (Scheme 5.15) gave

(S)-2-(3-(9H-carbazol-4-yloxy)-2-hydroxypropylamino)-3-methylbutanoic

acid (35a).

The product 35a was characterized by its spectral data. Thus, its

IR (KBr) spectrum showed characteristic peaks at 3406 cm-1 (s, -NH str.),

and 1606 cm-1 (s, -C=O str.). Its 1H NMR (300 MHz, DMSO-d6) spectrum

showed signals at 0.91-0.96 (m, 6H, -CH(CH3)2), 1.98-2.02 (m, 1H, -

CH(CH3)2), 2.93-3.17 (m, 3H, -NHCHCO- & -CHCH2NH-), 4.15-4.22 (m,

3H, -OCH2CHCH2-), 6.66-8.21 (m, 7H, Ar-H) 11.28 (s, 1H, NH) ppm.

Its 13C NMR (75 MHz, DMSO-d6) spectrum showed signals at

18.6, 18.7, 18.8, 29.7, 50.9, 51.2, 66.9, 67.4, 67.6, 69.9, 70.1, 100.4,

104.0, 110.4, 111.5, 118.6, 121.7, 122.6, 124.5, 126.4, 138.9, 141.1,

154.7, 172.0, 172.3. Its MS (ESI, m/z) showed the [M + H]+ ion peak at

357 corresponding to a molecular mass of 356.

184

NH

OO

(3)

H2N

CH3H3C

O

OH

K2CO3,H2O,75-80°C

NH

O

(35a)

OH

NH

H3C CH3

O

OH

(34a)

…..Scheme 5.15


extended to other compounds (35b, 35c, 35d, 35e, 35f, 35g, 35h, 35i,

35j, 35k) whose structures were assigned based on their spectral data

(Table-5.4).

5.4.3. Preparation of carbazole derivatives containing cyclic (S)-

amino acid


Ring opening of oxirane (3) with 4-hydroxy-L-proline (36a) in the

presence of potassium carbonate in water at 75-80°C (Scheme 5.16) gave

(2S,4R)-1-(3-(9H-carbazol-4-yloxy)-2-hydroxypropyl)-4-hydroxy-

pyrrolidine-2-carboxylic acid (37a). The product 37a was characterized

by its spectral data. Thus, its IR (KBr) spectrum showed a characteristic

peak at 1625 cm-1 (s, -C=O str.). Its 1H NMR (300 MHz, DMSO-d6)

spectrum showed signals at 2.04-2.09 (m, 2H, -CHCH2CH-), 2.74-2.81

(m, 1H, -CHCH2N-), 3.04-3.15 (m, 2H, -NCH2CH-), 3.58-3.59 (m, 1H, -

CHCH2N-), 3.80-3.84 (m, 1H, -CH2CHCO -), 4.16-4.30 (m, 4H, -

185

OCH2CHO- & -CH2CHOH), 6.66-8.24 (m, 7H, Ar-H), 11.29 (s, 1H, -NH)

ppm. Its MS (ESI, m/z) showed the [M + H]+ ion peak at 371


NH

OO

(3)

K2CO3,H2O,75-80°C

NH

O

(37a)

OHN

(36a)

HN

O

OH

OH

OHO

OH

…..Scheme 5.16

The above reaction was found to be applicable to other

compounds (37b, 37c) whose structures were assigned through their

spectral data (Table-5.5).

186

All the above reactions (Scheme 5.9 to Scheme 5.14) are briefly

summarized and given below:

NH

R

O

OH

(30a-d)

O

OH3C

H3CH3C

H2NO

H3CO

( 21)


NH

R

O

HN

(31a-d)

O

O

CH3

H3C

H3C

O

H3CO

H2N

R

O

HN

(32a-d)

O

H3COCon. HCl,DCM, 25-30°C

NH

OO

NH

OOH

NH

R

O

HN

H3CO

(33a-d)

IPA, 75-80°C

(3)

31a) R=C(CH3)331b) R=CH(CH3)231c) R=CH2Ph31d) R= (CH2)2CH3

32a) R=C(CH3)332b) R=CH(CH3)232c) R=CH2Ph32d) R=(CH2)2CH3

33a) R=C(CH3)333b) R=CH(CH3)233c) R=CH2Ph33d) R=(CH2)2CH3

…..Scheme 5.17

187

The above reaction in scheme 5.15 is briefly summarized and

depicted below:

NH

OO

(3)

H2N

R1

O

OR2

K2CO3,H2O,75-80°C

HN

O

(35a-k)

OHNH

R1

O

OR2

(34a-k)

35a) R1=CH(CH3)2, R2=H,35b) R1=H, R2=H,35c) R1=CH3, R2=H,35d) R1=C(CH3)3, R2=H,35e) R1=CH2Ph, R2=H,35f) R1=(CH2)3CH3, R2=H,

35g) R1=CH(CH3)CH2CH3, R2=H,35h) R1=CH2CH(CH3)2, R2=H,35i) R1=(CH2)2CH3, R2=H,35j) R1=CH2CH(CH3)2, R2=CH3,35k) R1=CH(CH3)2, R2=CH3,

…..Scheme 5.18

The above reaction in scheme 5.16 is briefly summarized and

depicted below:

NH

O O

(3)

K2CO3,H2O, 75-80°C

NH

O

(37a-c)

OHN

(36a-c)

HN

O

OH

R

37a) R=OH,37b) R=C6H5,37c) R=C6H11

OHO

R

…..Scheme 5.19

188

5.5. 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) General procedure for preparation of compound 31a from

compound 30a: Compound 30a (3.0 g, 0.01299 mol) was dissolved in

ACN (30 mL) at room temperature and cooled to 5-10°C. DMAP (1.46 g,

0.01364 mol) was added at 5-10°C and stirred for 10 min. Solution of 4-

nitrophenychloroformate, prepared by dissolving 4-

nitrophenychloroformate (2.75 g, 0.01364 mol) in ACN (20 mL) was

added at 5-10°C and stirred for 30 min. Compound 21 (2.28 g, 0.01364

mol) was added and then the reaction mixture temperature was slowly

raised to 20-25°C and stirred at the same temperature till completion of

reaction. Thereafter, the reaction mixture was filtered to remove

insoluble. The clear filtrate was concentrated at 40°C under reduced

pressure. The resulting oily mass was dissolved in methylene chloride

(50 mL) and washed with 10% w/w aqueous sodium carbonate solution

(3 x 20 mL). The organic layer was separated and washed with 2.5%

w/w aqueous ammonia (5 x 30 mL) followed by DM water (30 mL).

189

Finally, the clear solution was washed with 3% w/w aqueous

hydrochloric acid solution (30 mL) followed by DM water (30 mL). The

organic layer was separated and concentrated completely at 40°C under

reduced pressure to yield 31a [4.04 g, 82%].



methylene chloride (10 mL) at room temperature. Con. HCl (3.0 g,

0.02625 mol) was added and stirred at 25-30°C until completion of

reaction. After completion of reaction, DM water (20 mL) was added and

stirred for 10 min. The aqueous layer was separated and washed with

methylene chloride (10 mL). The aqueous layer pH was adjusted to 8.5-

9.0 with 10% w/w aqueous sodium carbonate and concentrated

completely at 60°C under reduced pressure. The resulting solid was

dissolved in methylene chloride (15 mL) and filtered insoluble. The clear

filtrate was concentrated completely at 35°C under reduced pressure to

afford 32a [2.26 g,.77%].



isopropyl alcohol (10 mL) at 25-30°C and heated to 75°C. Compound 3

(1.0 g, 0.00418 mol) was added in one lot at 75°C and stirred at the same

temperature till completion of reaction. Thereafter, the reaction mass

was concentrated completely and cooled to room temperature. The

resulting oily mass was dissolved in methylene chloride (20 mL) and

190

washed with DM water (2 x 30 mL). The organic layer was separated and

concentrated completely at 35°C under reduced pressure to afford 33a

[1.6 g,.74%]

4) Preparation of compound 31e from compound 30e: Compound 30e

(3.0 g, .0101 mol) was dissolved in ACN (30 mL) at room temperature and

cooled to 5-10°C. DMAP (1.13 g, 0.010605 mol) was added at 5-10°C and

stirred for 10 min. Solution of 4-nitrophenychloroformate, prepared by

dissolving 4-nitrophenychloroformate (2.14 g, 0.010605 mol) in ACN (20

mL) was added at 5-10°C and stirred for 30 min. Compound 21 (1.77 g,

0.010605 mol) was added and then the reaction mixture temperature

was slowly raised to 20-25°C and stirred at the same temperature till

completion of reaction. Thereafter, the reaction mixture was filtered to

remove insoluble. The clear filtrate was concentrated at 40°C under

reduced pressure. The resulting oily mass was dissolved in methylene

chloride (50 mL) and washed with 10% w/w aqueous sodium carbonate

solution (3 x 20 mL). The organic layer was separated and washed

successively with 2.5% w/w aqueous ammonia (5 x 30 mL) followed by

DM water (30 mL). Finally, the clear solution was washed with 3% w/w

aqueous hydrochloric acid solution (30 mL) followed by DM water (30

mL). The organic layer was separated and concentrated completely at

40°C under reduced pressure to yield 31e [3.82 g,.85%].


(3.5 g, 0.00785 mol) was dissolved in methylene chloride (10 mL) at room

191

temperature. Con. HCl (2.23 g, 0.019625 mol) was added and stirred at

25-30°C until completion of reaction. After completion of reaction, DM

water (20 mL) was added and stirred for 10 min. The aqueous layer was

separated and washed with methylene chloride (10 mL). The aqueous

layer pH was adjusted to 8.5-9.0 with 10% w/w aqueous sodium

carbonate and concentrated completely at 40°C under reduced pressure.

The resulting solid was dissolved in methylene chloride (15 mL) and

filtered insoluble. The clear filtrate was concentrated completely at 35°C

under reduced pressure to afford 32e [2.12 g,.78%].


(1.88 g, 0.005434 mol) was dissolved in isopropyl alcohol (10 mL) at 25-

30°C and heated to 75°C. Compound 3 (1.0 g, 0.00418 mol) was added

in one lot at 75°C and stirred at the same temperature till completion of

reaction. Thereafter, the reaction mass was concentrated completely and

cooled to room temperature. The resulting oily mass was dissolved in

methylene chloride (20 mL) and washed with DM water (2 x 30 mL). The

organic layer was separated and concentrated completely at 35°C under

reduced pressure to afford 33e [1.83 g,.75%].


compound 34a: Compound 34a (7.31 g, 0.0624 mol), was dissolved in

11% w/w aq. potassium carbonate (60 mL) at room temperature and

heated to 75°C. Compound 3 (3.0 g, 0.0125 mol) was added in one lot at

75-80°C and stirred at same temperature until completion of reaction.

192

Thereafter, the reaction mixture was cooled to RT and filtered through

hyflo bed. The clear filtrate pH was adjusted to 6.2-6.5 with 10% w/w

hydrochloric acid (25 mL). The separated solid was filtered, washed with

water and dried under reduced pressure to yield 35a [3.7 g,.84%].


compound 36a: Compound 36a (8.2 g, 0.0627 mol), was dissolved in

11% w/w aq. potassium carbonate (60 mL) at room temperature and

heated to 80°C. Compound 3 (3.0 g, 0.0125 mol) was added in one lot at

80-85°C and stirred at same temperature until completion of reaction.

Thereafter, the reaction mixture was cooled to RT and filtered through

hyflo bed. The clear filtrate pH was adjusted to 6.2-6.5 with 10% w/w

hydrochloric acid (27 mL). The separated solid was filtered, washed with

water and dried under reduced pressure to yield 37a [3.84 g,.83%].

193

Table-5.1: Reaction condition and yield of compounds 31b-d.

S. No. Startingmaterial Reagent /solvent Reaction

conditionsProductobtained Yield (%)

1 30b 4-Nitrophenychloro formate/DMAP/ACN

20-25°C 31b(R=CH(CH3)2,)

80

2 30c 4-Nitrophenychloro formate/DMAP/ ACN

20-25°C 31c(R=CH2Ph)

86

3 30d 4-Nitrophenychloro formate/DMAP/ ACN

20-25°C 31d(R=(CH2)2CH3)

84


S. No. Startingmaterial Reagent / solvent Reaction

conditionsProductobtained Yield (%)

1 31b Con.HCl / DCM 20-25°C 32b(R=CH(CH3)2,)

80

2 31c Con.HCl / DCM 20-25°C 32c(R=CH2Ph) 77

3 31d Con.HCl / DCM 20-25°C32d

(R=(CH2)2CH3) 79

194


S. No. Startingmaterial Solvent Reaction

conditions Product obtained Yield (%)

1 32b IPA 75-80°C 33b(R=CH(CH3)2,)

74

2 32c IPA 75-80°C 33c(R=CH2Ph)

76

3 32d IPA 75-80°C 33d(R=(CH2)2CH3)

74

Table-5.4: Reaction condition and yield of compounds 35b-k.

S. No. Startingmaterial Reagent used Reaction


1 34b K2CO3/ H2O 75-80°C 35b(R1= H, R2=H)

85

2 34c K2CO3/ H2O 75-80°C 35c(R1= CH3, R2=H)

86

3 34d K2CO3/ H2O 75-80°C 35d(R1=C(CH3)3, R2=H)

86

195

4 34e K2CO3/ H2O 75-80°C 35e(R1=CH2Ph, R2=H)

85

5 34f K2CO3/ H2O 75-80°C 35f(R1=(CH2)3CH3, R2=H)

84

6 34g K2CO3/ H2O 75-80°C 35g(R1=CH(CH3)CH2CH3,

R2=H)

85

7 34h K2CO3/ H2O 75-80°C 35h(R1=CH2CH(CH3)2,

R2=H)

82

8 34i K2CO3/ H2O 75-80°C 35i(R1=(CH2)2CH3, R2=H)

88

9 34j K2CO3/ H2O 75-80°C 35j(R1=CH2CH(CH3)2,

R2=CH3)

85

10 34k K2CO3/ H2O 75-80°C 35k(R1=CH(CH3)2,

R2=CH3)

83

196

Table-5.5: Reaction condition and yield of compounds 37b-c.

S. No. Startingmaterial Reagent used Reaction


1 36b K2CO3/ H2O 80-85°C 37b(R=C6H5)

85

2 36c K2CO3/ H2O 80-85°C 37c(R=C6H11)

86

197

Table-5.1: Spectral data for compounds 31b-d.

S. No. Productobtained

IR (KBr)cm-1

1H-NMRδ, ppm

Massm/z

(M+1)

1 31b(R=CH(CH3)2,)

3302 (s, -NHstr.), 1664 (s, -C=O str.)

DMSO-d6; 0.79-0.84 (m, 6H, -CH(CH3)2), 1.37 (s,9H, -C(CH3)3), 1.87-1.94 (m, 1H, -CH(CH3)2),3.35-3.50 (m, 2H, -NHCH2-), 3.74 (s, 4H, -OCH3& -NHCHCO-), 3.90-3.97 (m, 2H, -OCH2-), 6.60-6.63 (m, 1H, -CONHCH-), 6.83-6.97 (m, 4H, Ar-H), 8.03-8.05 (m, 1H, -CONHCH2-).

367

2 31c(R=CH2Ph)

3360 (s, -NHstr.), 1665 (s, -C=O str.)

CDCl3; 1.35 (s, 9H, -C(CH3)3), 2.96-2.98 (m, 2H,-CH2Ph), 3.51-3.54 (m, 2H, -NHCH2-), 3.75 (s,3H, -OCH3), 3.82-3.84 (m, 1H, -NHCHCO-), 3.89-3.94 (m, 1H, -OCH2), 4.27-4.29 (m, 1H, -OCH2),5.00 (br, 1H, -CONHCH), 6.36 (br, 1H, -CONHCH2), 6.75-6.90 (m, 4H, Ar-H), 7.04-7.19(m, 5H, Ar-H).

415

3 31d(R=(CH2)2CH3)

3314 (s, -NHstr.), 1659 (s, -C=O str.)

CDCl3; 0.87-0.92 (t, 3H, -CH3), 1.31-1.36 (m, 2H,-CH2CH3), 1.38 (s, 9H, -C(CH3)3), 1.52-1.79 (m,2H, -CHCH2), 3.63-3.69 (m, 2H, -NHCH2), 3.87(s, 3H, -OCH3), 4.06-4.09 (m, 2H, -OCH2), 5.05(br, 1H, -CONHCH-), 6.75 (br, 1H, -CONHCH2),6.89-7.27 (m, 4H, Ar-H).

367

198



IR (KBr)cm-1

1H-NMRδ, ppm

Massm/z

(M+1)

1 32b(R=CH(CH3)2,)

3348 (s, -NHstr.), 1618 (s, -C=O str.)

CDCl3; 0.83-0.99 (m, 6H, -CH(CH3)2), 2.26-2.28(m, 1H, -CH(CH3)2), 3.36-3.38 (m, 1H, NH2CHCO-),3.65-3.70 (m, 2H, -NHCH2-), 3.85 (s, 3H, -OCH3),4.04-4.12 (m, 2H, -OCH2-), 6.86-6.96 (m, 4H, Ar-H), 7.81-7.83 (m, 1H, -CONHCH2-).

267

232c

(R=CH2Ph)3486 (s, -NHstr.), 1667 (s, -C=O str.)

DMSO-d6; 3.04-3.06 (m, 2H, -CH2Ph), 3.37-3.53(m, 2H, -NHCH2-), 3.74 (s, 3H, -OCH3), 3.85-3.92(m, 1H, - OCH2), 3.99-4.03 (m, 1H, - NHCHCO-),6.88-6.99 (m, 4H, Ar-H), 7.20-7.23 (m, 5H, Ar-H),8.77 (m, 1H, -CONHCH2).

315

3 32d(R=(CH2)2CH3)

3395 (s, -NHstr.), 1666 (s, -C=O str.)

CDCl3; 0.82-0.87 (t, 3H, -CH3), 1.29-1.42 & 1.71-1.76 (m, 2H, -CH2CH2CH3), 3.29-3.33 (m, 1H, -NH2CH-), 3.56-3.61 (m, 2H, -NHCH2), 3.79 (s, 3H,-OCH3), 4.01-4.04 (m, 2H, -OCH2), 6.89-7.27 (m,4H, Ar-H), 7.69 (br, 1H, -CONHCH2).

267

199



IR (KBr)cm-1

1H-NMRδ, ppm

Massm/z

(M+1)

1 33b(R=CH(CH3)2,)

1651 (s, -C=Ostr.)

CDCl3; 0.83-.91 (m, 6H, -CH(CH3)2), 1.97-2.03 (m,1H, -CH(CH3)2), 2.88-2.98 (m, 4H, -NHCH2), 3.47-3.52 (m, 1H, -NHCH), 3.70 (s, 3H, -OCH3), 3.92-3.99 (m, 4H, -OCH2), 4.01-4.05 (m, 1H, -CH2CH),6.71-8.11 (m, 11H, Ar-H), 7.54-7.59 (m, 1H, -CONH), 8.34 (s, 1H, -NH)

506

2 33c(R=CH2Ph)

1651 (s, -C=Ostr.)

CDCl3; 2.80-2.91 (m, 4H, -CH2Ph & -NHCH2), 3.05-3.45 (m, 2H, -NHCH2), 3.57-3.59 (m, 1H, -NHCH),3.68 (s, 3H, -OCH3), 3.90-3.98 (m, 4H, -OCH2),4.17-4.19 (m, 1H, -CH2CH), 6.39-8.24 (m, 16H, Ar-H), 7.84-7.89 (m, 1H, -CONH), 8.16 (s, 1H, -NH).

554

3 33d(R=(CH2)2CH3)

1651 (s, -C=Ostr.)

DMSO-d6; 0.83-0.88 (m, 3H, -CH3), 1.31-1.34 (m,2H, -CH2CH3), 1.85-1.90 (m, 2H, -CH2CH2), 3.02-3.32 (m, 2H, -NHCH2), 3.45-3.49 (m, 2H, -NHCH2),3.71 (m, 3H, -OCH3), 3.92-4.35 (m, 5H, -OCH2 & -NHCH), 4.47-4.49 (m, 1H, -CH2CH), 6.65-8.21 (m,11H, Ar-H), 9.40 (br, 1H, -CONH), 11.33 (s, 1H, -NH).

506

200

Table-5.4: Spectral data for compounds 35b-k.

S. No. Product obtained IR (KBr)cm-1

1H-NMR (DMSO-d6)δ, ppm

Massm/z

(M+1)

1 35b(R1= H, R2=H)

1603(s, -C=Ostr.)

2.90-3.25 (m, 4H, -NHCH2CO & -NHCH2CH), 4.13-4.15 (m, 3H, -OCH2CHOH), 6.65-8.25 (m, 7H, Ar-H), 11.30 (s, 1H, -NH).

315

2 35c(R1= CH3, R2=H)

1605(s, -C=Ostr.)

1.18-1.28 (m, 3H, -CHCH3), 2.85-3.12 (m, 3H, -NHCH2- & -NHCHCO), 4.09-4.15 (m, 3H, -OCH2CHOH), 6.64-8.23 (m, 7H, Ar-H), 11.37 (s,1H, -NH).

329

3 35d(R1=C(CH3)3, R2=H)

1606(s, -C=Ostr.)

0.93-0.97 (m, 9H, -C(CH3)3), 2.50-2.81 (m, 2H, -NHCH2), 2.91-2.94 (m,1H, -NHCHCO), 4.12-4.23(m, 3H, -OCH2CHOH), 6.65-8.21 (m, 7H, Ar-H),11.29 (s, 1H, -NH).

371

4 35e(R1=CH2Ph, R2=H)

1606(s, -C=Ostr.)

2.89-3.13 (m, 3H, -NHCH2- & -NHCHCO), 3.56-3.60 (m, 2H, -CH2Ph), 4.4.04-4.16 (m, 3H, -OCH2CHOH), 6.69-8.23 (m, 12H, Ar-H), 11.28 (s,1H, -NH).

405

535f

(R1=(CH2)3CH3,R2=H)

1604(s, -C=Ostr.)

0.81-0.85 (m, 3H, -CH2CH3), 1.22-1.35 (m, 4H, -CH2CH2CH3), 1.65-1.69 (m, 2H, -CHCH2CH2), 2.94-3.22 (m, 3H, -NHCH2- & -NHCHCO), 4.16-4.27 (m,3H, -OCH2CHOH), 6.65-8.26 (m, 7H, Ar-H), 11.36(s, 1H, -NH).

371

635g

(R1=CH(CH3)CH2CH3, R2=H)

1606(s, -C=Ostr.)

0.82-0.92 (m, 6H, -CH2CH3 &, -CHCH3), 1.23-1.28(m, 1H, -CH2CH3), 1.53-1.57 (, 1H, -CH2CH3), 1.73-1.76 (m, 1H, -CHCH3), 2.87-3.18 (m, 3H, -NHCH2-& -NHCHCO), 4.16-4.22 (m, 3H, -OCH2CHOH),6.65-8.21 (m, 7H, Ar-H), 11.30 (s, 1H, -NH).

371

201

735h

(R1=CH2CH(CH3)2,R2=H)

1607 (s, -C=O str.)

0.83-0.90 (m, 6H, -CH(CH3)2), 1.47-1.65 (m, 3H, -CHCH2 & -CH(CH3)2), 2.67-3.15 (m, 3H, -NHCH2- &-NHCHCO), 4.07-4.23 (m, 3H, -OCH2CHOH), 6.65-8.22 (m, 7H, Ar-H), 11.29 (s, 1H, -NH).

371

835i

(R1=(CH2)2CH3,R2=H)

1607 (s, -C=O str.)

0.82-0.88 (m, 3H, -CH2CH3), 1.39-1.44 (m. 2H, -CH2CH3), 1.67-1.69 (m, 2H, -CHCH2CH2), 2.99-3.28 (m, 3H, -NHCH2- & -NHCHCO), 4.17-4.31 (m,3H, -OCH2CHOH), 6.65-8.26 (m, 7H, Ar-H), 11.39(s, 1H, -NH).

357

935j

(R1=CH2CH(CH3)2,R2=CH3)

1738 (s, -C=O str.)

0.91-0.93 (m, 6H, -CH(CH3)2), 1.66-1.79 (m, 3H, -CHCH2 & -CH(CH3)2), 3.21-3.24 (m, 1H, -NHCH2-),3.41-3.44 (m, 1H, -NHCH2-), 3.77 (s, 3H, -OCH3),4.14-4.27(m, 3H, -NHCHCO & -OCH2), 4.43-4.45(m, 1H, -CHOH), 6.68-8.22 (m, 7H, Ar-H), 11.34 (s,1H, -NH).

385

1035k

(R1=CH(CH3)2,R2=CH3)

1728 (s, -C=O str.)

CDCl3; 0.97-1.02 (m, 6H, -CH(CH3)2), 2.04-2.09 (m,1H, -CH(CH3)2), 2.91-3.19 (m, 3H, -NHCH2- & -NHCHCO), 3.73 (s, 3H, -OCH3), 4.22-4.31 (m, 3H, -OCH2CHOH), 6.65-8.26 (m, 7H, Ar-H), 8.23 (s, 1H,-NH).

371

202

Table-5.5: Spectral data for compounds 37b-c.


IR (KBr)cm-1

1H-NMR (DMSO-d6)δ, ppm

Massm/z

(M+1)

1 37b(R=C6H5)

1620 (s, -C=Ostr.)

2.13-2.34 (m, 2H, -CHCH2), 2.60-2.63 (m, 1H, -CHCH2), 2.95-3.02 (m, 2H, -NCH2), 3.35-3.39 (m,2H, -NCH2), 3.58-3.63 (m, 1H, -NCHCO), 4.06-4.17(m, 3H, -OCH2CHOH), 6.66-8.21 (m, 12H, Ar-H),11.29 (s, 1H, -NH).

431

2 37c(R=C6H11)

1584 (s, -C=Ostr.)

0.84-0.99 (m, 6H, -(CH2)3), 1.47-1.63 (m, 6H, -(CH(CH2)2 & -CHCH2), 1.96-2.05 (m, 2H, -(CH(CH2)2 & -CHCH2), 2.05-2.08 (m, 1H, -NCH2CHC), 2.65-2.69 (m, 1H, -NCH2CHC), 2.83-2.95 (m, 2H, NCH2CHOH), 3.06-308 (m, 1H, -NCHCO), 3.95-4.11 (m, 3H, -OCH2CHOH), 6.62-8.20 (m, 7H, Ar-H), 11.33 (s, 1H, -NH).

437

203

5.6. Spectral data

IR spectrum of compound 31a:

1H NMR spectrum (300MHz, CDCl3) of compound 31a:

NH

CH3H3C

O

HN

(31a)

O

OH3C

H3CH3C O

H3COCH3

NH

CH3H3C

O

HN

(31a)

O

OH3C

H3CH3C O

H3COCH3

204

Mass spectrum of compound 31a:


NH

CH3H3C

O

HN

(31a)

O

OH3C

H3CH3C O

H3COCH3

(32a)

H2N

CH3H3C

O

HN

O

H3COCH3

205



(32a)

H2N

CH3H3C

O

HN

O

H3COCH3

NH

OOH

NH

CH3H3C

O

HN

O

H3CO

(33a)

H3C

206



NH

OOH

NH

CH3H3C

O

HN

O

H3CO

(33a)

H3C

NH

OOH

NH

CH3H3C

O

HN

O

H3CO

(33a)

H3C

207

1H NMR spectrum (300MHz, DMSO-d6) of compound 35a:

13C NMR spectrum (75MHz, DMSO-d6) of compound 35a:

NH

O

(35a)

OH

NH

H3C CH3

O

OH

NH

O

(35a)

OH

NH

H3C CH3

O

OH

208



NH

O

(35a)

OH

NH

H3C CH3

O

OH

NH

O

(37a)

OHN

OHO

OH

209

1H NMR spectrum (300MHz, DMSO-d6) of compound 37a:


NH

O

(37a)

OHN

OHO

OH

NH

O

(37a)

OHN

OHO

OH

210

5.7. References

1. Joyce, J. N., Lexow, N., Kim, S. J., Artymyshyn, R., Senzon, S.,

Lawrence, D., Cassanova, M. F., Kleinman, J. R., Bird, E. D.,

Winokur, A. Synapse, 10, 1992, 228.

2. Kalaria, R. N., Andorn, A. C., Tabaton, M., Whitehouse, P. J.,

Karik, S. I., Unnerstall, J. R. J. Neurochem. 53, 1989, 1772.

3. Lemmer, B., Langer, L., Ohm, T., Bohl, J. Naunyn-Schmiedeberg’s

Arch. Pharmacal. 347, 1993, 214.

4. Corwin, J., Peselow, E., Feenan, K., Rotrosen, J., Fieve, R. Biol.

Psychiatry, 27, 1990, 813.

5. Cole, B. J., Koob, G. F. J. Pharmacal. Exp. Ther. 247, 1988, 902.

6. Laverdure, B., Boulenger, J. P. Encephale, 17, 1991, 481.

7. Berridge, C. W., Dunn, A. J. J. Neurosci. 9, 1989, 3513.

8. Otto-Erich, B. Pharm. Rev. 43, 1988, 204.

9. Lefkowitz, R. J., Caron, M. G., Stiles, G. L. New Eng. J. Med.

307, 1984, 1570.

10. Morris, T. H., Kanumann, A. J. Naunyn-Schmiedebergs Arch.

Pharmacol. 327, 1984, 176.

11. Berridge, M. S., Cassidy, E. H., Terris, A. H., Vesselle, J. M. Nucl.

Med. Biol. 19, 1992, 563.

12. Dubois, E. A., Van den Bos, J. C., Doornbos, T., Van Doremalen,

P. A. P. M., Somsen, G. A., Vekemans, J. A. J. M., Janssen, A. G.

211

M., Batink, H. D., Boer, G. J., Pfaffendorf, M., Royen, E. A. V.,

Van Zwieten, P. A. J. Med. Chem. 39, 1996, 3256.

13. Zheng, L., Berridge, M. S., Ernsberger, P. J. Med. Chem. 37,

1994, 3219.

14. Wiedemann, F., Kampe, W., Thiel, M., Spaner, G., Roesch, E.,

Dietmann, K. US 4503067, 1985.

15. Crowell, T. A., Evrard, D. A., Jones, C. D., Muehj, B. S., Rito, C.

J., Shuker, A. J., Thorpe, A. J., Thrasher, K. J. US 6686372,

2004.

16. Thomas, P., Erik, F., Peter, T. S. EP 1282601, 2004.

17. Zoltan, R., Jozsef, B., Gyula, S., Tamas, G., Donath, G. V.,

Norbert, N., Kalman, N., Judit, C., Tibor, S., Laszlo, B., Imre, D.,

Zoltan, G., Kotay, P. N., Peter, S. EP 0918055, 2003.

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