122 Chapter 4 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 APOinduced stereotypy (ED50 value of 7.8 mol/kg po). Aripiprazole showed lower potential to induce catalepsy than the standard agent and did not show 1-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.

123 Chapter 4 Table 4.1: Product details Name of the drug Active ingredient Innovator Marketed by Melting point Dosage details Approval date Brand Name Therapeutic category Aripiprazole Aripiprazole Otsuka Pharmaceuticals Bristol Mayer Squib 139-139.5C 2, 5 10, 15, 20 and 30 mg tablets November 15, 2002 Abilify Schizophrenia

Structure

Chemical Name

7-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy)3,4-dihydroquinolin-2(1H)-one 448.39 Soluble in dichloromethane

Molecular formula C23 H27 Cl2N3O2 Molecular weight Solubility

124 Chapter 4 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)-3,4dihydrocarbostyril (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 doesnt disclose the experimental conditions for each synthetic process.

125 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)-3chloropropionamide (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 45C to afford 7-(4chlorobutoxy)-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-(2,3dichlorophenyl)-piperazine (89) at temperatures ranging from 50 to 100C 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 (89) by adding and a solution of 1-(2,3-

dichlorophenyl)piperazine

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 75C 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, 4dihydrocarbostyryl 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

128 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

129 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 1indanone was reported by Lansbury and Mancuso76 where in the rearrangement of 1-indanone was only 20% at 110C to 120C 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 -40C77. 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

130 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-2,3,4,5tetrahydro-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.

131 Chapter 4 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-hydroxy2,3-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-1one (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-(2,3dichlorophenyl)piperazin-1-yl)butoxy)-2,3-dihydro-1H-inden-1-one tosyl oxime (108). O-

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 1,4dichloro 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 Chapter 4 proposed work.

134 Chapter 4 4.4.3: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazine-1yl)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 60-70C 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.

135 Chapter 4 4.4.4: Synthesis of (E)-6-(4-(4-(2,3-dichlorophenyl)piperazine-1yl)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-1yl)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 0-5C 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 Chapter 4

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.

141 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 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 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, ArH), 6.51 (m, 1H, J=8.4, Ar-H), 6.36 (s, 1H, Ar-H), 3.96 (t, 2H, J=6.0, ArH), ), 3.07 (br, 4H, CH 2), 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)-8aza-5-azoniaspiro [4.5]decane (27a)

142 Chapter 4 Scheme 4.10f

Cl Cl N N O 27 m/z=448 N H O

Cl Cl N N

27a m/z=285

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 7.15 (d, 1H, J=8.0, ArH), 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 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 60-70C, 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).

149 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 7.30 (s, 1H, Ar-H), 7.10-7.15 (m, 2H, Ar-H), and aliphatic protons at 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

153 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-dihydroquinolin-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-1Hinden-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,

154 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. structure was in confirmation with the spectral data. The assigned

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,

163 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 1215 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 The solid was

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

filtered and dried at 50C 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 -70C 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 60C 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 C till the constant weight obtained. Yield: 6.4 g (80.0 %). IR (cm-1): 3411 (OH); 1H NMR (CDCl3, 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.

167 Chapter 4 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 05C 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, 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 -15C. 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

168 Chapter 4 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, 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, CH 2), 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, ArH), 7.11-7.16 (m, 2H, Ar-H), 8.54 (s, NH);
13C

NMR (200 MHz, 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, 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.

169 Chapter 4 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), 1,4dibromobutane (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 60C and stirred for 1 hour then raised the temperature of the mass to 90 100C 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

170 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, 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 2535C 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

171 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, 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=CH), 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, 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 80C. 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, ppm):

172 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, 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 C 22H24N2O4 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 0-5C, 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, ppm): 1.10 1.40 (br, 8H, CH2), 1.65-1.85 (br, 6H, CH2), 2.402.45 (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.

173 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.