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CHAPTER-4: New Synthetic Approach to Prepare Aripiprazole,

Preparation and Characterization of its Related Compounds

4.1: Introduction

Aripiprazole68 (27) is used for the treatment of schizophrenia

which is a most common type of psychosis caused by an excessive

neurotransmission activity of the dopaminergic nervous system in the

central nervous system. It is a novel antipsychotic agent which is an

agonist of dopamine (DA) auto receptors and an antagonist of

postsynaptic DA receptors.

Aripiprazole was developed by Otsuka Pharmaceutical Co. Ltd.

Aripiprazole is known to be effective towards reducing the positive

symptoms of schizophrenia with less side-effects as compared to the

psychotic drugs known in the literature. Aripiprazole induced catalepsy

is at 10 times higher dose than that required for the antagonism of APO-

induced stereotypy (ED50 value of 7.8 mol/kg po). Aripiprazole showed

lower potential to induce catalepsy than the standard agent and did not

show α1-adrenoreceptor antagonist activity. In addition to the dual

activities, Aripiprazole reversed reserpine-induced increase in tyrosine

hydroxylase activity in mouse and rat brain 69-71.

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Table 4.1: Product details

Name of the drug Aripiprazole

Active ingredient Aripiprazole

Innovator Otsuka Pharmaceuticals

Marketed by Bristol Mayer Squib

Melting point 139-139.5°C

Dosage details 2, 5 10, 15, 20 and 30 mg tablets

Approval date November 15, 2002

Brand Name Abilify

Therapeutic

category Schizophrenia

Structure

Chemical Name 7-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy)-

3,4-dihydroquinolin-2(1H)-one

Molecular formula C23 H27 Cl2N3O2

Molecular weight 448.39

Solubility Soluble in dichloromethane

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4.2: Reported Synthetic Schemes of Aripiprazole

The first reported synthesis for Aripiprazole by Oshiro et al.,72

involves the reaction of a suspension of 7-(4-bromobutoxy)-3,4-

dihydrocarbostyril (88), sodium iodide in acetonitrile and refluxed for 30

minutes. To this suspension, 1-(2,3-dichlorophenyl)-piperazine (89),

triethylamine were added and the reaction was refluxed for 3 hours.

After work up of the reaction mass, the resulted crude residue was

recrystallized from ethanol twice to yield Aripiprazole (27) as colorless

flake crystals (scheme 4.1).

Scheme 4.1

Oshiro et al., also described other schemes for the synthesis of

compound 27 as represented by schemes 4.2, 4.3, 4.4 and 4.5 as below.

However, the reference doesn’t disclose the experimental conditions for

each synthetic process.

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Chapter 4

Scheme 4.2

Scheme 4.3

Scheme 4.4

Scheme 4.5

Ramakrishnan et al., describes a process73 (scheme 4.6) in which

intra molecular Friedel-Craft alkylation of N-(3-methoxyphenyl)-3-

chloropropionamide (98) in presence of a Lewis acid produces 7-

126

Chapter 4

hydroxy-3,4-dihydroxycarbostyril (90). 1-Bromo-4-chlorobutane (99)

was treated with 90 using potassium carbonate under phase transfer

conditions (PTC) at temperatures ranging from 25° to 45°C to afford 7-(4-

chlorobutoxy)-3,4-dihydrocarbostyril (100) in which the dimer of 100 is

formed less when compared with other known methods. Aripiprazole

(27) was obtained by treating the compound 100 with 1-(2,3-

dichlorophenyl)-piperazine (89) at temperatures ranging from 50° to

100°C in the presence of potassium carbonate and sodium iodide in

dimethylformamide as solvent.

Scheme 4.6

Briggs and co-workers describes a process74 (scheme 4.7) for

preparation of Aripiprazole by adding a solution of 1-(2,3-

dichlorophenyl)piperazine (89) and 7-(allyloxy)-3,4-dihydro-2(1H)-

quinoline (101) in THF into an autoclave containing Rh(CO)2(acac) (102),

ligand 103. The reactor was heated under 400 psi pressure with 1:1

127

Chapter 4

H2/CO at 75°C for 16 hours. The solvent was evaporated and redissolved

in chloroform followed by work up afforded the required product 27.

Scheme 4.7

4.2.1: Summary of reported synthetic schemes

As evident from the reported synthetic schemes, the chemists were

mainly used the following fragments to build the desired molecule,

Aripiprazole in various synthetic pathways.

As can be seen from the structure, Aripiprazole is constructed

with dichloro phenyl piperazine moiety 89 and a 7-hydroxy-3, 4-

dihydrocarbostyryl moiety 90, connected through a linker comprising of

four methylene groups. The presence of the linker at the centre in

between the two moieties made the synthesis easily with double

nucleophilic displacement at terminal ends of the linker bearing with the

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Chapter 4

two potential leaving groups. In one of the possible methods, the phenyl

piperazine 89 was first reacted with a linker followed by reaction with

the hydroxyl carbostyryl moiety to form Aripiprazole. Another possible

method which was explored for the double nucleophilic displacement

was in which, the hydroxyl carbostyryl moiety was first reacted with the

linker to form an intermediate, followed by the reaction of the

intermediate with dichloro phenyl piperazine moiety to form Aripiprazole.

Apart from the nucleophilic displacement reactions, a novel approach to

the construction of the carbostyryl ring was done by Chinnapillai et al.,75

using the Schmidt reaction conditions in the last step of the synthesis.

4.3: Beckmann Rearrangement of Indanones

The Beckmann Rearrangement (BR) of ketoximes or aldoximes in

the presence of acids for example Lewis acid produces amides or

lactams. Cyclic oximes as starting materials lead to the formation of

lactams. Thus, BR, a skeletal rearrangement has become a useful way

for the incorporation of nitrogen efficiently in both cyclic and acyclic

system. The reaction mechanism of BR (scheme 4.8) can be represented

as shown below

Scheme 4.8

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Chapter 4

In the transition state, a concerted [1,2]-sigmatropic

rearrangement occurs, and then, the primary product is tautomerised to

give the desired product immediately. Beckmann rearrangement of 1-

indanone was reported by Lansbury and Mancuso76 where in the

rearrangement of 1-indanone was only 20% at 110°C to 120°C in the

presence of polyphosphoric acid (PPA). Byoung Se Lee and Dae Yoon Chi

improved the yields of the Beckmann rearrangement of 1-indanone in

the presence of a Lewis acid, aluminum chloride to 91%. This method

was very efficient as well as mild because the reaction undergoes at

room temperature and even at lower temperatures like -40°C77.

1-Indanone oxime (104) was converted into its 1-indanone oxime

tosylate (105) and three equivalents of aluminium chloride were utilized

to obtain hydrocarbostyril from the tosylate. The trans isomer of tosylate

gave the hydrocarbostyril 106 in major quantity and cis isomer gave the

regioisomer, 3,4-dihydro-1(2H)-quinolinone (107) in minor quantity.

Thus an increase in ratio of trans to the cis isomer of the tosylate gave

more amount of the required product, hydrocarbostyril (scheme 4.9).

Byoung et al., also reported the rearrangement of substituted

indanones78, 79 in the same reference.

Scheme 4.9

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Chapter 4

Katsuhiko Hino et al., reported the use of Beckmann

rearrangement in the synthesis of benzazocine and benzazepine

derivatives. They mentioned the use of polyphosphoric acid in the

conversion of 2-methyl-1-tetralone oxime to give 3-methyl-2,3,4,5-

tetrahydro-1H-1-benzazepin-2-one in an excellent yield (93%). They also

reported the preparation of 3-phenyl-1,2,3,4,5,6-hexahydro-1-

benzazocin-2-one from the corresponding oxime and polyphosphoric

acid80.

Based on the precedent literature, we have attempted to utilize

this rearrangement for the synthesis of Aripiprazole in our present work.

4.4: Present work

As demonstrated above, though there were good number of

references available for the preparation of Aripiprazole, these processes

suffers with certain disadvantages in terms of use of hazardous raw

materials for example sodium azide, usage of chiral catalysts and

ligands which are not feasible for an industrial scale of manufacture.

The process disadvantages of known synthetic schemes motivated us to

design an alternate process for the preparation of Aripiprazole, which

has become basis for the present work.

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4.4.1: Results and Discussion - Retro synthetic path way for

Aripiprazole

Scheme 4.10

Based on retro synthetic analysis of Aripiprazole (scheme 4.10),

the two synthons 1-(2,3-dichlorophenyl)piperazine (89) and 6-hydroxy-

2,3-dihydro-1H-indene-1-one (111) are considered as key starting

materials for our present research work to get 6-(4-(4-(2,3-

dichlorophenyl)piperazine-1-yl)butoxy-2,3-dihydro-1H-inden-1-one

(110). 1-(2,3-dichlorophenyl)piperazine (89) was converted to the

corresponding quaternary salt (112) by reaction with 1,4-dichlorobutane

(113) and was further reacted with 6-hydroxy-2,3-dihydro-1H-indene-1-

one (111) to get indanone derivative (110). The indanone derivative was

132

Chapter 4

converted to its oxime derivative (109) and was subjected to Beckmann

rearrangement to yield Aripiprazole (27) via the formation of 6-(4-(4-(2,3-

dichlorophenyl)piperazin-1-yl)butoxy)-2,3-dihydro-1H-inden-1-one O-

tosyl oxime (108).

4.4.2: Synthesis of 8-(2,3-dichlorophenyl)-5-azoniaspiro[4.5]decane

chloride (112)

The compound 89 was condensed (scheme 4.10a) with 1,4-

dichloro butane (113) in acetone as solvent at reflux temperature for

about 15 hours in the presence of anhydrous potassium carbonate gave

the desired compound 112 in excellent yieldexcellent yidlat reflux

temperature for about 15 hours in the presence of anhydrous potassium

carbonate gave the . The resultant compound was

fully characterized by spectral data and also compared with authentic

sample81.

Scheme 4.10a

The compound 112 obtained as above was utilized as one of the

intermediate compound for the preparation of Aripiprazole in our

133

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proposed work.

134

Chapter 4

4.4.3: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazine-1-

yl)butoxy-2,3-dihydro-1H-inden-1-one (110)

The compound 112 was reacted with compound 111 in the

presence of mild base and dimethyl formamide as solvent at 60-70ºC to

get the title compound 110 (scheme 4.10b). The resultant compound

was analyzed by IR, NMR & Mass spectral data. It is further compared

with the product obtained in known methods by HPLC analysis.

Scheme 4.10b

The compound 110 obtianed in the above process was used as

one of the intermediate compound for the preparation of Aripiprazole as

a part of new approach.

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Chapter 4

4.4.4: Synthesis of (E)-6-(4-(4-(2,3-dichlorophenyl)piperazine-1-

yl)butoxy)-2,3-dihydro-1H-inden-1-oxime (109)

The indanone derivative 110 was reacted with hydroxylamine

hydrochloride (scheme 4.10c) in methanol at reflux temperature for

about 3 hours to obtain the corresponding oxime 109 in about 80.0%

yield as a crystalline solid and it was confirmed by the respective

spectral data. This compound was found to be trans isomer with a

purity of 95.0% by HPLC analysis.

Scheme 4.10c

In the IR spectrum (Fig.4.1), the broad peak corresponding to one

hydroxy function appeared at 3411 cm-1. 1H-NMR Spectrum (Fig.4.2)

displayed the signals at 7.00-.7.20 (m, 3H, Ar-H), 6.95 (m, 1H Ar-H),

6.85 (m, 1H Ar-H), 6.30 (m, 1H Ar-H), 4.20 (t, 2H, J=5.6, CH2), 3.95 (t,

2H, J=6.4, CH2), 3.20-3.80 (br, 8H, CH2), 2.75-2.85 (m, 4H, CH2), 2.20

(m, 2H, CH2), 1.95 (m, 2H, CH2) was in conformity with the assigned

structure of oxime (109). In the positive mode ES mass spectrum

(Fig.4.3), M+1 peak at m/z 448 corresponds to the molecular weight, 447

of 109 was observed along with the two chlorines isotopic abundance

136

Chapter 4

peak at m/z 450 (1: 0.7 ratio) and thus further confirms its assigned

structure.

137

Chapter 4

138

Chapter 4

4.4.5: Synthesis of (6-(4-(4-(2,3-dichlorophenyl)piperazin-1-

yl)butoxy)-2,3-dihydro-1H-inden-1-one O-tosyl oxime (108).

The oxime derivative 109 was converted (scheme 4.10d) to its tosyl

oxime 108 by reaction with p-toluene sulfonyl chloride (p-TsCl) in the

presence of sodium hydroxide and acetone at 0-5ºC to yield the expected

compound with around 65.0% yield. It was characterized with complete

spectral data.

Scheme 4.10d

In the IR spectrum (Fig.4.4), the peak corresponding to SO2

functional group appeared at 1190 cm-1. The 1H-NMR Spectrum (Fig.4.5)

displayed with signals at 7.91-7.98 (dd, 2H, Ar-H), 7.34-7.39 (m, 2H,

Ar-H), 7.08-7.19 (m, 3H, Ar-H), 7.00 (m, 2H Ar-H), 6.59 (m, 1H Ar-H),

4.01 (t, 2H, CH2), 3.72 (t, 2H, CH2), 3.39-3.58 (br, 12H, CH2), 2.43 (s,

3H, CH3), 1.79-1.92 (m, 2H, CH2), 1.64-1.69 (m, 2H, CH2) was in

conformity with the assigned structure of oxime (109). In the positive

mode mass spectrum (Fig.4.6), M+1 peak at m/z 602 corresponds to the

molecular weight of 108 could be 601. Thus, the spectral data is in

conformity with its assigned structure.

139

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140

Chapter 4

4.4.6: Synthesis of Aripiprazole (27)

The tosylated oxime 108 was conveniently transformed into the

targeted compound 27 using Beckman rearrangement conditions

(scheme 4.10e). The compound 108 was treated with aluminium

chloride in the presence of dichloromethane at ambient temperature

gave the desired compound 27. It was further purified by

recrystallization from isopropyl alcohol to yield the compound as white

crystalline solid. The final compound was fully characterized by their

spectral data and also compared with that of authentic sample.

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Chapter 4

Scheme 4.10e

The UV spectrum (Fig.4.7) of Aripiprazole (27) recorded in

methanol (conc=0.001% w/v) using Perkin-Elmer UV-VIS spectro

photometer model Lambda 35. It exhibited two peaks with maxima at λ

217 and 255 nm. The FT-IR spectrum (Fig.4.8) of Aripiprazole as KBr

pellet shows at 3193 cm-1(N-H stretching), 1678 cm-1 (-C=O stretching),

and 1138 cm-1 (aromatic C-Cl stretching). The 1H NMR spectrum

(Fig.4.9) recorded in CDCl3 showed characteristic signals at δ 8.54 (s,

NH), 7.11-7.16 (m, 2H, Ar-H), 7.03 (d, 1H, J=8.4, Ar-H), 6.96 (m, 1H, Ar-

H), 6.51 (m, 1H, J=8.4, Ar-H), 6.36 (s, 1H, Ar-H), 3.96 (t, 2H, J=6.0, Ar-

H), ), 3.07 (br, 4H, CH2), 2.88 (t, 2H, J=8.0, CH2), 2.65 (br, 4H, CH2),

2.62 (t, 2H, J=8.0, CH2), 2.48 (t, 1H, J=7.2, CH2), 1.65-1.85 (m, 4H,

CH2). The EI mass spectrum (Fig.4.10) displayed a protonated molecular

ion with characteristic two chlorine isotopic abundance at m/z = 448

which corresponds to the molecular formula C23H27Cl2N3O2. The possible

mass fragmentation pattern for Aripiprazole is shown below (scheme

4.10f), and the major fragment ion assigned as 8-(2,3-dichlorophenyl)-8-

aza-5-azoniaspiro [4.5]decane (27a)

142

Chapter 4

Scheme 4.10f

NH

OON

N

Cl

Cl

27

m/z=448 m/z=285

N

N

Cl

Cl

27a

143

Chapter 4

144

Chapter 4

145

Chapter 4

4.5: Retro synthetic path way for 6-(4-(4-(2,3-dichlorophenyl)

piperazine-1-yl)butoxy)-2,3dihydro- 1H-inden-1-oxime (109).

Scheme 4.11

146

Chapter 4

Based on retro synthetic analysis of Aripiprazole intermediate in

two possible methods (scheme 4.11), the key oxime intermediate 109

was prepared by either reaction with compound 114 with 112 or

reaction in between compounds 115 and 89.

4.5.1: Synthesis of 6-hydroxy-2,3-dihydro-1H-inden-1-one oxime

(114)

The indanone 111 and hydroxylamine hydrochloride was taken in

methanol and heated to reflux in the presence of sodium acetate

provided compound 114 as off-white crystalline solid (scheme 4.11a).

The resultant product was fully characterized by spectral data.

Scheme 4.11a

The IR Spectrum (Fig.4.11) exhibited a broad absorption centered

at about 3370 cm-1 corresponding to hydroxy function. In 1H-NMR

spectrum (Fig.4.12), the down field region was characterized by the

presence of signals due to aromatic protons at δ 7.15 (d, 1H, J=8.0, Ar-

H), 7.00 (d, 1H, J=2.4, Ar-H), 6.80 (dd, 1H, J=2.4, 8.0, Ar-H), and

indoline oxime protons at δ 2.90 (t, 2H, CH2), 2.85 (t, 2H, CH2). The

mass spectrum (Fig.4.13) displayed a molecular ion peak at m/z 164

(M+1). Thus, all the spectral data was in conformity with the assigned

structure of 114.

147

Chapter 4

148

Chapter 4

4.5.2: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazine-1-

yl)butoxy)-2,3-dihydro-1H-inden-1-oxime (109) Method 1

Compounds 112 and 114 were condensed together under mild

basic conditions in dimethyl formamide at 60-70°C, followed by

systematic workup gave the title compound 109 in appreciable yield.

The resulted compound was fully characterized by its spectral data and

compared with the previous sample (Scheme 4.11b).

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Chapter 4

Scheme 4.11b

4.5.3: Synthesis of 6-(4-bromobutoxy)-2,3-dihydro-1H-inden-1-one

oxime (115).

6-Hydroxy Indanone (111) and 1,4-dibromobutane (116) were

reacted (scheme 4.11c) under basic conditions to give an alkylated

product, which is in situ reacted with hydroxylamine HCl in methanol

media provided the desired compound 115 in good yield. The resultant

compound was fully characterized by complete spectral data.

Scheme 4.11c

IR Spectrum (Fig.4.14) exhibited a broad absorption at about 3426

cm-1 corresponding to oxime OH function. In 1H-NMR spectrum

(Fig.4.15), the down field region was characterized by the presence of

signals due to aromatic protons at δ 7.30 (s, 1H, Ar-H), 7.10-7.15 (m,

2H, Ar-H), and aliphatic protons at δ 4.05 (t, 2H, J=5.6, CH2), 3.95 (t,

150

Chapter 4

2H, J=5.6, CH2), 3.58 (m, 2H, CH2), 3.10 (m, 2H, CH2) 1.90 (br, 4H, CH2).

The ES mass spectrum (Fig.4.16) displayed a molecular ion peak at m/z

298 (M+1) along with the bromine isotopic abundance at m/z 300. Thus,

all the spectral data was in conformity with the assigned structure of 6-

(4-bromobutoxy)-2,3-dihydro-1H-inden-1-one oxime (115).

151

Chapter 4

152

Chapter 4

4.5.4: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazine-1-

yl)butoxy) -2,3-dihydro-1H-inden-1-oxime (109) Method 2

The compound 115 obtained in the previous step was condensed

with 89 using potassium carbonate, catalytic amount of TBAB in

methanol media to result crude required compound 109, which was

further recrystallized from methanol (scheme 4.11d). The resulted

compound was fully characterized by its spectral data and also

compared with the previous sample.

Scheme 4.11d

Compound 109 obtained from the above methods 1 and 2 were

converted in to Aripiprazole, characterized by their individual spectral

data and were also found to be matching with the authentic sample.

4.6: Related Compounds or impurities

The purity of Aripiprazole synthesized by above routes was

analyzed by HPLC along with the authentic sample. We found that, there

are three major82 (approximately 0.1%) unknown peaks (impurities) in

the authentic sample and one major unknown peak in our synthesized

sample were observed. Both the samples were further subjected to

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Chapter 4

preparative HPLC to isolate the targeted related compounds. These four

related compounds were identified by their respective spectral data and

assigned the structures as 7-(4-bromo-butoxy)-1H-quinolin-2-one (117),

7,7'-(butane-1,4-diylbis(oxy))bis(3,4-dihydroquinolin-2(1H)-one) (118), 7-

[4-(7-4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy-3,4-dihydro-

quinolin-2-yloxy)-butoxy]-3,4-dihydro-1H-quinolin-2-one (119) and 6-(4,

3-(hydroxyimino)-2,3-dihydro-1H-inden-5-yloxy)butoxy)-2,3-dihydro-1H-

inden-1-one oxime (120). Further to this, all the four compounds were

individually synthesized and compared with the isolated samples.

4.6.1: Preparation of Related Compound 117

This related compound 117 was prepared by reaction of

compound 88 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ /

121) in THF media to give (scheme 4.12) the corresponding bromo

dehydro derivative.

Scheme 4.12

The IR spectrum (Fig.4.17) of resultant related compound (117)

has carbonyl absorption peak at 1655 cm-1. The 1H-NMR spectrum

(Fig.4.18) characterized by three aromatic protons at 7.70-7.90 (d, 1H,

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Chapter 4

Ar-H), 7.40-7.50 (d, 1H, Ar-H), 6.70 (m, 1H, Ar-H), two olefinic protons

at 6.80 (d, 1H, C=C-H), 6.45-6.65 (d, 1H, C=C-H) and eight aliphatic

methylene protons at 4.05 (t, 2H, OCH2), 3.50 (t, 2H, BrCH2), 2.00 (m,

4H, CH2). Presence of exchangeable amide (Fig.4.18a) NH proton

appeared at 12.40-12.60 (s, NH). The mass spectrum (Fig.4.19)

displayed a molecular ion peak at m/z 296 (M+) along with the bromine

isotopic abundance and this spectral data confirming the assigned

structure.

155

Chapter 4

156

Chapter 4

157

Chapter 4

4.6.2: Preparation of Related Compound 118

Dimeric related compound 118 was obtained by the reaction of

compound 90 (scheme 4.13) with 88 in the presence of sodium

hydroxide as base and dimethyl formamide as solvent. The sample was

further purified by recrystallization from 1,4-dioxane.

Scheme 4.13

The IR spectrum (Fig.4.20) of related compound (118) displayed a

carbonyl functional group at 1679 cm-1 and NH functional group at

3204 cm-1. The 1H-NMR spectrum (Fig.4.21) characterized by presence of

amide at 9.97 (s, 1H, NH), aromatic protons with two proton

integration at 7.03 (d, 2H, J=8.2, Ar-H), 6.48 (d, 2H, J=8.4, Ar-H), 6.44

(s, 2H, Ar-H) and aliphatic protons at 3.94 (b, 4H, CH2), 2.78(t, 4H,

J=7.2, CH2), 2.41 (t, 2H, J=7.2, CH2), 1.82 (br, 4H, CH2). The positive

mode mass spectrum of (118) showed a protonated molecular (Fig.4.22)

ion peak at m/z 381(M+1). This spectral data is in conformity with the

assigned structure.

158

Chapter 4

159

Chapter 4

160

Chapter 4

4.6.3: Preparation of Related Compound 119

Similarly, related compound 119 was prepared (scheme 4.14)

comprising the reaction of Aripiprazole (27, as reactant) with compound

88 involving the use of sodium hydride as a base in tetrahydrofuran at

reflux conditions. The resulted sample was fully characterized by the

spectral data.

Scheme 4.14

The Mass spectrum displayed peaks at m/z 665 and 683

corresponding to M+1 and M+ NH4 respectively. These peaks confirm the

molecular ion to be m/z 664 and the molecular ion has characteristic

isotopic abundance for two chlorine atoms. On comparing with the

parent 1H-NMR spectral data a difference in integration of quinolin

moiety 88 was observed, which was almost twice. Hence, based on the

proton NMR (Fig.4.23) and Mass (Fig.4.24) spectral data, it was assumed

that the quinolinone 88 may be incorporated on to Aripiprazole and

161

Chapter 4

assigned the compound 119 as a dimeric structure. The assigned

structure was in confirmation with the spectral data.

162

Chapter 4

4.6.4: Preparation of Related Compound 120

Finally, the related compound 120 was prepared (scheme 4.15)

comprising the reaction between 114 and 115 in the presence of

potassium carbonate and acetone media at reflux conditions.

Scheme 4.15

The IR spectrum (Fig.4.25) of related compound 120 resulted in a

broad hydroxy functional group at 3181 cm-1. The 1H-NMR spectrum

(Fig.4.26) characterized by presence of aromatic protons at 7.20 (d, 2H,

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Chapter 4

J=8.0, Ar-H), 7.15 (d, 2H, J=3.2, Ar-H), 6.94 (dd, 2H, J=2.4, 8.4, Ar-H)

and aliphatic protons at 4.00 (t, 4H, J=6.4, CH2), 3.48(t, 4H, CH2), 2.95

(br, 4H, CH2), 2.05 (m, 2H, CH2), 1.95 (m, 2H, CH2). The positive mode of

mass spectrum (Fig.4.27) displaying protonated molecular ion at m/z

381 is in conformity with the assumed structure of 120.

164

Chapter 4

165

Chapter 4

4.7: Conclusion

Thus, we have developed a simple, new and scalable synthetic

route to Aripiprazole. We have also established two different alternate

synthetic approaches to prepare Aripiprazole key intermediate. Further,

we have identified, synthesized and characterized the related compounds

formed during the synthesis of Aripiprazole.

4.8: Experimental Section

Preparation of compound 112: To a mixture of 89 (20 g, 0.0865 mol)

and acetone (150 mL), was added anhydrous potassium carbonate (24.8

g, 0.1794 mol) and dichloro butane (113, 20.3 g, 0.16 mol). The resulted

suspension was heated to reflux for 12–15 hours to complete the

reaction. The reaction mass was cooled to room temperature and stirred

for 1 hour. The resulted solid was filtered and washed with acetone (50

mL). The crude mass containing inorganic solid was stirred in isopropyl

alcohol (500 mL) at room temperature for about 1 hour. Filtered the

mass to separate the inorganic solid and the resultant mother liquor was

subjected to distillation under vacuum. The residual mass was

triturated with hexane (100 mL) to separate the solid. The solid was

filtered and dried at 50ºC to get the title compound 112. Yield: 20.5 g

(74.0 %).

Preparation of compound 110: To a suspension of 112 (10 g, 0.0312

mol), sodium carbonate (8.0 g, 0.075 mol) in dimethyl formamide (50

166

Chapter 4

mL) was added 111 (6.0 g, 0.040 mol) and stirred at room temperature

for about 1 hour. The temperature of the reaction mass was raised to 60

-70ºC and stirred till the reaction completed. The reaction mass was

decomposed into water (250 mL) and extracted the compound into

methylene chloride (3 x 150 mL). The combined organic layers were

dried over anhydrous sodium sulfate and distilled off the solvent. The

crude compound was recrystallized from methanol (150 mL). The

resulted compound was further purified from isopropyl alcohol (100 mL)

and dried at 60ºC under vacuum to get the title compound 110. Yield:

10.1 g (74.8 %).

Preparation of compound 109: The compound 110 (8.0 g, 0.018 mol),

sodium acetate (3.0 g, 0.036 mol), hydroxyl amine hydrochloride (2.5 g,

0.036 mol) were taken in methanol (40 mL). Heated the reaction mass

to reflux for about 3 hours and cooled the reaction mass to room

temperature. Filtered the compound and washed with water (50 mL)

followed by chilled methanol (20 mL). The wet compound was dried at 50

ºC till the constant weight obtained. Yield: 6.4 g (80.0 %). IR (cm-1): 3411

(OH); 1H NMR (CDCl3, δ ppm): 1.95 (m, 2H, CH2), 2.20 (m, 2H, CH2),

2.75-2.85 (m, 4H, CH2), 3.20-3.80 (br, 8H, CH2), 3.95 (t, 2H, J=6.4, CH2),

4.20 (t, 2H, J=5.6, CH2), 6.30 (m, 1H, Ar-H), 6.85 (m, 1H, Ar-H), 6.95 (m,

1H, Ar-H), 7.00-7.20 (m, 3H, Ar-H); Mass: 448 (M+1). C H N analysis

calcd. for C23H27Cl2N3O2: C, 61.61; H, 6.07; N, 9.37. Found: C, 61.68; H,

5.99; N, 9.41.

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Preparation of tosylated oxime (108): To a stirred solution of 109 (5.0

g, 0.011 mol) and p-toluenesulfonyl chloride (2.3 g, 0.012 mol) in

acetone (100 mL) was added 4 N sodium hydroxide (3.0 mL, 0.012 mol)

at 0–5ºC slowly for about 10 minutes. The resultant reaction mass was

stirred for about 30 minutes and raised to room temperature and stirred

for 1 hour. The reaction mass was quenched into ice cold water and

extracted into methylene chloride (2 x 100 mL). The combined organic

layer was subjected to distillation and the residual mass was purified

from ethyl acetate (50 mL) to get the title compound 108. Yield: 4.3 g,

65.0 %. IR (cm-1): 1190 (SO2). 1H NMR (CDCl3, δ ppm): 1.64-1.69 (m, 2H,

CH2), 1.79-1.92 (m, 2H, CH2), 2.43 (s, 3H, CH2), 3.39-3.59 (br, 12H,

CH2), 3.72 (t, 2H, CH2), 4.01 (t, 2H, CH2), 6.59 (m, 1H, Ar-H), 7.00 (m,

2H, Ar-H), 11Hand 7.08-7.19 (m, 3H, Ar-H), 7.34-7.39 (m, 2H, Ar-H)

and 7.91-7.98 (m, 1H, Ar-H). Mass: 602 (M+1). C H N analysis calcd. for

C30H33Cl2N3O4S: C, 59.80; H, 5.52; N, 6.97; Found: C, 59.73; H, 5.41; N,

6.87.

Preparation of Aripiprazole (27). To a solution of 108 (3.0 g, 0.0049

mol) in methylene chloride ( 50 mL) was added aluminum chloride (1.95

g, 0.014 mol) at -15ºC. The mixture was stirred for 1 hour and then

raised to room temperature and stirred for another 4 to 6 hours. The

mass was quenched into ice cold water. The product was extracted into

methylene chloride (3 x 50 mL). The combined organic layer was dried

over sodium sulfate and evaporated under reduced pressure. The crude

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residual mass was subjected column chromatography followed by

recrystallization from isopropyl alcohol to obtain compound 27 as white

crystalline solid. Yield: 1.5 g (71.5%). IR (cm-1): 3193 (N-H) 1678 (C=O).

1H NMR (CDCl3, δ ppm): 1.65-1.85 (m, 4H, CH2), 2.48 (t, 1H, J=7.2,

CH2), 2.62 (t, 2H, J=8.0, CH2), 2.65 (br, 4H, CH2), 2.88 (t, 2H, J=8.0,

CH2), 3.07 (br, 4H, CH2), 3.96 (t, 2H, J=6.0, Ar-H), 6.36 (s, 1H, Ar-H),

6.51 (m, 1H, J=8.4, Ar-H), 6.96 (m, 1H, Ar-H), 7.03 (d, 1H, J=8.4, Ar-

H), 7.11-7.16 (m, 2H, Ar-H), δ 8.54 (s, NH); 13C NMR (200 MHz, δ ppm

CDCl3): 23.2, 24.4, 27.1, 30.9, 51.1, 53.1, 58.0, 67.7, 102.2, 108.6,

115.4, 118.4, 124.3, 127.2, 128.3, 133.8, 138.2, 151.1, 172.4; Mass:

448 (M+). C H N analysis calcd. for C23H27Cl2N3O2: C, 61.61; H, 6.07; N,

9.37. Found: C, 61.68; H, 6.05; N, 9.43.

Preparation of compound 114: The compound 111 (10.0 g, 0.067 mol),

sodium acetate (11.0 g, 0.133 mol), hydroxyl amine hydrochloride (9.3 g,

0.133 mol) were taken in methanol (50 mL). Heated the reaction mass

to reflux for about 3 hours and cooled the reaction mass to room

temperature. Filtered the compound and washed with water (50 mL)

followed by chilled methanol (20 mL). The wet compound was dried at

50 oC till the constant weight to get 114 (9.3 g, 85.0 %). IR (cm-1): 3370

(O-H). 1H NMR (DMSO+ CDCl3, δ ppm): 2.85 (t, 2H, CH2), 2.90 (t, 2H,

CH2), 6.80 (dd, 1H, J=2.4, 8.0, Ar-H), 7.00 (d, 1H, J=2.4, Ar-H), 7.15 (d,

1H, J=8.0, Ar-H). Mass: 164 (M+1). C H N analysis calcd. for C9H9NO2:

C, 66.25; H, 5.56; N, 8.58. Found: C, 66.28; H, 5.55; N, 8.63.

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Preparation of 109 (Method 1): To a suspension of 112 (10 g, 0.0312

mol), sodium carbonate (8.0 g, 0.075 mol) in dimethyl formamide (50

mL) was added 114 (6.1 g, 0.037 mol) and stirred at room temperature

for about 1 hour. The temperature of the reaction mass was raised to

60-70oC and stirred till the reaction completion. The reaction mass was

decomposed into water (250 mL) and extracted the compound into

methylene chloride (3 x 150 mL). The combined organic layers were

dried over anhydrous sodium sulfate and distilled off the solvent. The

crude compound was recrystallized from methanol (150 mL). The

resulted compound was further purified from isopropyl alcohol (100 mL)

and dried at 60 oC under vacuum to get the title compound 109. Yield:

9.8 g (70.0%).

Preparation of 115: The compound 111 (4.0 g, 0.027 mol), 1,4-

dibromobutane (116, 22.6 g, 0.104 mol), potassium carbonate (7.0 g,

0.050 mol), catalytic amount of TBAB (0.2 g) were heated to 60ºC and

stirred for 1 hour then raised the temperature of the mass to 90 – 100ºC

and stirred till the reaction completion. Excess 1,4 dibromobutane was

distilled under vacuum and water (50 mL) was added and stirred. The

product was extracted into methylene chloride (3 x 50 mL). The

combined organic layers were dried over sodium sulfate and distilled the

solvent completely. The residual mass (4.5 g, 59%) was taken in

methanol (50.0 mL) and stirred for clear dissolution. To the resulting

solution, hydroxylamine hydrochloride (1.56 g, 0.022 mol), sodium

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Chapter 4

acetate (3.07 g, 0.037 mol) were added and heated to reflux. The

reaction mass was stirred at reflux temperature for completion of

reaction. Filtered the mass and distilled off the solvent from the mother

liquors. Hexane (25.0 mL) was added and stirred to separate the solid.

The resulting solid was filtered and washed with hexane (10 mL). The

crude compound was recrystallized from ethyl acetate to get 115. Yield:

4.8 g, 60.0% (on compound 111). IR (cm-1): 3426 (O-H); 1H NMR (CDCl3,

δ ppm): 1.90 (br, 4H, CH2), 3.10 (m, 2H, CH2), 3.58 (m, 2H, CH2), 3.95 (t,

2H, CH2), 4.05 (t, 2H, CH2), 7.10-7.15 (m, 2H, Ar-H), 7.30 (s, 1H, Ar-H);

Mass: 298 (M+1). C H N analysis calcd. for C13H16BrNO2: C, 52.36; H,

5.41; N, 4.70. Found: C, 52.41; H, 5.36; N, 4.75.

Preparation of 109 (Method 2): Compound 115 (4.0 g, 0.013 mol),

compound 89 (4.0 g, 0.017 mol), potassium carbonate (2.27 g, 0.016

mol), catalytic amount of TBAB were taken in methanol (50 mL) and

heated to reflux till the reaction completion. Filtered the reaction mass

to separate the inorganic solids and solvent was distilled off completely

from the mother liquors. The resultant crude product was recrystallized

from methanol to give the title compound. Yield: 5.1 g (87.5%).

Preparation Related Compound 117: Compound 88 (10 g, 0.034 mol)

was taken in tetrahydrofuran (200.0 mL), and 121 (30.4 g, 0.134 mol)

was added, stirred at 25–35°C until reaction completion. The reaction

mass was filtered and the filtrate was distilled off under reduced

pressure. The residual product was dissolved in water (200.0 mL), and

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Chapter 4

pH of the mass was adjusted to 10.0 with aqueous sodium hydroxide.

The reaction mixture was extracted with dichloromethane (100 x 2 mL)

and dried over anhydrous sodium sulphate. The solvent was distilled off

under reduced pressure to yield 8.5 g of title compound (117). IR (cm-1):

1655 (C=O]; 1H NMR (CDCl3, δ ppm): 2.00 (m, 4H, CH2), 3.50 (t, 2H,

BrCH2), 4.05(t, 2H, OCH2), 6.45-6.65 (d, 1H, C=C-H), 6.80 (d, 1H, C=C-

H), 6.70 (m, 1H, Ar-H), 7.40-7.50 (d, 1H, Ar-H), 7.7-7.90 (d, 1H, Ar-H)

and 12.40-12.60 (s, 1H, NH); 13C NMR (200 MHz, CDCl3, δ ppm): 27.2,

28.9, 33.1., 66.6, 98.4, 111.3, 113.4, 117.4, 128.4, 139.8, 140.0, 160.3,

163.5 ; Mass: 296 (M+). C H N analysis calcd. for C13H14BrNO2: C,

52.72; H, 4.76; N, 4.73. Found: C, 52.68; H, 4.79; N, 4.69.

Preparation of Related Compound 118: Sodium hydroxide (7.3 g,

0.182 mol), 90 (30 g, 0.184 mol) and methanol (100 mL) were heated to

reflux for 2 h. The solvent was distilled off completely under vacuum and

dimethyl formamide (100 mL) was added and stirred for clear

dissolution. To this solution, was added suspension of 88 (50 g, 0.167

mol) in dimethyl formamide (100 mL) and stirred at room temperature

till the reaction completion. The resultant solid was filtered and washed

with water (50 mL). The wet cake was suspended in aqueous sodium

hydroxide solution (1.5 g in 350 mL), stirred for 10-15 minutes, filtered,

washed with water, and dried at 80°C. The crude compound was

recrystallized from 1,4-dioxane to yield the title compound 118 (Yield:

16.8 g). IR (cm-1): 1679 (C=O) and 3204 (NH). 1H NMR (CDCl3, δ ppm):

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Chapter 4

1.82 (br, 4H, CH2), 2.41 (t, 2H, J=7.2, CH2), 2.78(t, 4H, J=7.2, CH2), 3.94

(b, 4H, Ar-H), 6.44 (s, 2H, Ar-H), 6.48 (d, 2H, J=8.4, Ar-H), 7.03 (d, 2H,

J=8.2, Ar-H) and 9.97 (s, 1H, NH). 13C NMR (200 MHz, δ ppm CDCl3):

23.8, 25.2, 30.4., 67.1, 101.8, 107.5, 115.2, 138.9, 157.7, 169.7; Mass:

381 (M+1). C H N analysis calcd. for C22H24N2O4 C, 69.46; H, 6.36; N,

7.36. Found: C, 69.41; H, 6.43; N, 7.42.

Preparation of Related Compound 119: The compound 27 (30.0 g,

0.066 mol), 60% w/w sodium hydride (10.7 g, 0.267 mol) and

tetrahydrofuran (150 mL) were stirred at reflux temperature for 1 h. A

solution of 88 (30.0 g, 0.100 mol) in tetrahydrofuran (120 mL) was

added at reflux temperature and continued the reflux until the reaction

is completed. Cooled the reaction mass to 0-5°C, acetic acid (10 mL) was

added and extracted with dichloromethane. The dichloromethane was

distilled completely under reduced pressure. The resulting crude

residual mass was subjected to column chromatography to afford the

required compound 119 (Yield: 25 g.). 1H NMR (CDCl3, δ ppm): 1.10–

1.40 (br, 8H, CH2), 1.65-1.85 (br, 6H, CH2), 2.40–2.45 (m, 2H, CH2), 2.50

(m, 4H, CH2), 2.60 (s, 2H, CH2), 2.70 (m, 2H, CH2), 2.80(m, 2H, CH2),

3.00 (br, 4H, CH2), 3.95 (br, 4H, CH2), 6.30 (s, 1H, Ar-H), 6.45 (m, 1H,

Ar-H), 6.55(s, 1H, Ar-H), 6.90 (m, 1H, Ar-H), 6.95 (m, 1H, Ar-H), 7.15 (m,

1H, Ar-H), 7.20 (s, 1H, Ar-H) and 8.40 (s, 1H, NH). Mass: 665 (M+1). C H

N analysis calcd. for C36H42Cl2N4O4: C, 64.96; H, 6.36; N, 8.42. Found:

C, 64.82; H, 6.51; N, 8.35.

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Chapter 4

Preparation of Related Compound 120: The compound 114 (10.0 g,

0.061 mol), compound 115 (18.2 g, 0.061 mol), potassium carbonate

(12.62 g, 0.092 mol) and acetone (100.0 mL) were stirred at ambient

temperature for 2 hours. The reaction mass slowly heated to reflux and

stirred for 5 hours. The inorganic solids were filtered off and the solvent

was distilled under vacuum from the mother liquors. The residue was

triturated with cyclohexane to separate the solid material. The resulted

solid was filtered and dried to get the desired compound 120. Yield: 6.0

g. IR (cm-1): 3181 (O-H); 1.95 (m, 2H, CH2), 2.05 (m, 2H, CH2), 2.95 (br,

4H, CH2), 3.48(t, 4H, CH2), 4.00 (t, 4H, J=6.4, CH2), 6.94 (dd, 2H, J=2.4,

8.4, Ar-H), 7.15 (d, 2H, J=3.2, Ar-H), 7.20 (d, 2H, J=8.0, Ar-H); Mass:

381 (M+1). C H N analysis calcd. for C22H24N2O4: C, 69.46; H, 6.36; N,

7.36. Found: C, 69.56; H, 6.45; N, 7.46.