CHAPTER 4 STUDIES IN THE SYNTHESIS

Transcription

1 131 CHAPTER 4 STUDIES IN THE SYNTHESIS OF OLANZAPINE

2 INTRODUCTION Development History of Olanzapine and its Properties: Eli Lilly has developed and launched olanzapine (Zyprexa), a benzodiazepine structural analog of clozapine which acts as an atypical antipsychotic with an unclear mechanism of action, and requires oncedaily oral dosing. The drug is indicated for the treatment of schizophrenia and acute mixed or manic episodes associated with bipolar I disorder (either as monotherapy or in combination with lithium or valproate) in adults and adolescents, for the maintenance monotherapy of bipolar adults, and for bipolar- and treatment-resistant depression in adults, in combination with fluoxetine Table PRODUCT PROFILE OF OLANZAPINE 62 Name of the drug Active ingredient Innovator Marketed by Brand Name Olanzapine Olanzapine Eli Lilly Eli Lilly Zyprexa Structure

3 133 Chemical name 2-Methyl-4-(4-methyl-1-piperazinyl)-10Hthieno[2,3-b][1,5]benzodiazepine Molecular formula C 17 H 20 N 4 S Molecular Weight Melting point º C CAS No Approved Indication Zyprexa is indicated for (i) the treatment of schizophrenia. (ii) the treatment of acute mixed or manic episodes associated with Bipolar I disorder. Solubility Soluble in acetonitrile and practically insoluble in water 4.2 LITERATURE REVIEW Chakrabarti et al 63 reported synthesis of (69) using the (73) as a key building block. The key intermediate (73) was prepared by: (i) reaction of sulphur powder with propionaldehyde and malononitrile to provide (70); (ii) reaction of (70) with (71) in the presence of NaH and in dry THF as a solvent to afford (72); (iii) simultaneous reduction and ring closure of (72) in the presence of stannous chloride and hydrogen chloride in ethanol to afford (73) in 13.9% overall yield; (iv) reaction of (73) with (74)

4 134 in a mixture of DMSO and toluene at reflux for under nitrogen atmosphere for 20 hours to afford (69) in 32% yield (Scheme-4.1). Scheme-4.1: Chakrabarti et al 63 reported another synthetic approach for the preparation of (69) by: (i) reaction of sulphur powder with propionaldehyde and methyl-2-cyano acetate to afford (75); (ii) reaction of (75) with (71) in the presence of NaH and in dry THF as a solvent to afford nitro ester (76); (iii) reduction of the nitro group of (76) by hydrogenation on palladium on carbon followed by reaction with (74) to afford amino ester (77); (iv) ring closure of (77) to afford (69) (Scheme- 4.2).

5 135 Scheme-4.2: Majka et al 64 reported synthesis of (69) through the use of (78). (78) was subjected to reductive N-methylation by using formaldehyde in the presence of NaH to afford (69) or N-methylation using formaldehyde in formic acid (Eschweiler-Clarke reaction) to yield (69). Majka et al reported a process for N-methylation of (78) with MeI in the presence of K 2 CO 3 in MeOH to yield (69) (Scheme-4.3). Scheme-4.3:

6 136 Rolf et al 65 reported a process for preparation of (69) by: (i) reacting (73) with (79) to afford (80); and (ii) reducing (80) to afford (69) (Scheme- 4.4). Scheme-4.4: Several other synthetic processes for preparation of (69) or its intermediates are reported in literature 66-67, which are mostly variations of the reported processes that are discussed above SUMMARY OF REPORETED SYNTHETIC APPROACHES In brief, some of the reported synthetic approaches in literature employ expensive, hazardous reagents like stannous chloride, methyl iodide etc or require more focus on the control of reaction parameters. From an industrial stand point, these processes require a strict safety measures. The reaction yields and quality of the reported processes were low, which had an adverse effect on the process and cost efficiency of Olanzapine (69) on commercial scale.

7 PRESENT WORK The objective of present work is to develop an alternative synthetic process for the preparation of (69) from largely available and inexpensive raw materials that is easier to produce on higher scale at lower cost when compared to existing routes. This chapter is dedicated to the synthetic studies towards the efficient, cost-effective and alternative synthetic approaches for the prepatation of (69) to overcome the limitations of the reported synthetic approaches as follows. POSSIBLE RETRO SYNTHETIC APPROACHES OF OLANZAPINE Fig. 4.3: Retro synthetic analysis of Olanzapine (69)

8 RESULTS AND DISCUSSION Approach-1: Initial strategy for the synthesis of (69) began with modification of Chakrabarti et al approach (Scheme-4.1) to improve the yield and quality through the cyclic amide (81) and the novel imidoyl chloride (82). Initial studies were focused on the synthesis of cyclic amide (81). The cyclic amide (81) was synthesized by: (i) reducing the nitro thiophene carbonitrile (72) in the presence of raney Nickel at a pressure of 0-5 psi to afford amino thiophene carbonitrile (84); and (ii) converting the resulting amino thiophene carbonitrile (84) to the cyclic amide (81). The said synthetic approach followed for the preparation of cyclic amide (81) is schematically represented here under. Scheme-4.7: Further studies were focused on the alternative approach for the synthesis of novel imidoyl chloride (82). In this approach, (69) was prepared by: (i) treating the key building block (73) with aq. NaOH at reflux for 12 hours gave the cyclic amide (81); (ii) treating the cyclic amide (81) with POCl 3 in the presence of dimethyl aniline gave the novel

9 139 imidoyl chloride (82); (ii) the novel imidoyl chloride (82) was then reacted with (74) in the presence of sodium hydride in DMF as a solvent (Scheme-4.8). Scheme-4.8: Approach-2: It was an endeavor to develop a second alternative approach for preparing (69) to minimize the process steps and to make process effective. As depicted in scheme 4.8, treating key building block (73) with aq. NaOH at reflux for hours gave cyclic amide (81) with 90% yield. The cyclic amide (81) was converted to (69) directly by reacting with (74) in anisole and in the presence of titanium tetrachloride (TiCl 4 ) at reflux temperature to afford (69). This approach involved direct conversion of (81) into (69) by avoiding the need of isolating the novel imidoyl chloride intermediate (82), which will be formed in situ (Scheme- 4.9).

10 140 Scheme-4.9: Synthesis of (73) was reported in Chakrabarti et al. 62 A similar process was reported for an analogous compound in Jiban et al Approach-3: Third strategy for the synthesis of (69) began with modification of the synthetic approach reported in Majka et al. From industrial point of view, it still requires feasible process for the preparation of (69) using inexpensive reagents. For instance, the synthetic process according to Majka et al requires methyl iodide for N-methylation of (78). Methyl iodide is expensive reagent and difficult to handle on large scale production. In the process according to approach-3, the key building block (73) was refluxed in a mixture of DMSO and toluene with piperazine (83) to

11 141 give (78). Then (78) was N-methylated in a solvent by employing a methylating agent other than methyl iodide to afford (69) (scheme-4.10). Scheme-4.10: Improvements in the synthesis of (78): Our initial attempts were focused on the developments of (78) from (73). (73) was reacted with 3.5 equimoles of piperazine in a mixture of DMSO and toluene at reflux temperature for hours. After completion of the reaction the reaction mixture was poured into ice-cold water, the separated solid was filtered, washed with a mixture of water & toluene and dried to afford (78) having purity of 98.03% by HPLC. During the development of (78), it was observed that dimer impurity (87) was formed under the reaction conditions and said impurity was being carried over to the next stage. (87) was initially identified by LCMS and later confirmed by its synthesis and subsequent characterization with IR, Mass and 1 H-NMR spectra. Different purification methods adapted to remove the said impurity and the details are as follows:

12 142 Table-4.2 Entry Solvent system Yield Purity by HPLC (%) No. (%) (69) (87) 1 Ethyl acetate Acetonitrile Methylene chloride MeOH Mixture of DMF and water (10%) Improvements towards the synthesis of (69) with the modifications of Majka et al synthesis: Initial attempts focused on replacement of N-methylating agent for the N-methylation reaction. For instance, replacement of methyl iodide that was reported in Majka et al synthesis was achieved by replacing it with commercially available methylating agents for instance, formaldehyde/formic acid and MeI/TEA. For example, methyl iodide was employed as a methylating agent for methylation of desmethyl olanzapine (78) in the presence of TEA as base in DMF as solvent under reflux conditions to afford (69). The formation of (69) is very less.

13 143 Alternatively methylation was carried out using 2.0 molar equivalents of formaldehyde and formic acid in MeOH as solvent medium. The formation of (69) was not observed by TLC. Even when methylene chloride or a mixture of toluene and MeOH were used for methylation, similar results were observed. Even by using formaldehyde and formic acid in water as a solvent medium under varying reaction parameters employed for methylation reaction; only 50-60% of product (69) formation was observed with 66% purity by HPLC. The major problem faced with these methylating agents was incomplete reaction. Most of the starting material was left unreacted. Table-4.3 illustrates the selection of methylating agents for methylation reaction. For comparison and subsequent selection and optimization of methyating agent, N-methylation was also carried out using methyl iodide initially and the results were compared. Table-4.3 Methylating agent Solvent Base Temperature Results medium KI/CH 3 I DMF TEA Reflux No HCHO/HCOOH MeOH C/ reflux DCM C/ product is formed

14 144 reflux Toluene + MeOH C/ reflux Water C/ 50-60% reflux Developments towards the synthesis of (69) using DMS as a methylating agent: Based on the above results, our synthetic strategy from commercial point of view focused to select a methylating agent which was easy to handle and was an inexpensive reagent when compared to reagents discussed above. Our attempts were towards the use of DMS as a methylating agent for methylation reaction. It is an easy to handle and commercially preferable reagent. Initial experiment was conducted to prepare (69) by adding DMS to the reaction mixture containing (78) and aqueous NaOH at C for completion of the reaction. (69) was formed but reaction did not go to completion as observed by TLC & the same results were observed even after altering the reaction parameters such as increasing the molar equivalents of DMS and base (NaOH), increasing the temperature (for

15 145 example: reflux conditions) and replacing the base such as K 2 CO 3, NaHCO 3. In few instances, while temperature was increased, the yields were dropped drastically. Based on these observations, it was understood that the pattern of addition of base and DMS were playing a role in the completion of the reaction, yield and quality of the product. Impact of mode of addition of DMS and base on purity and yield: Towards this objective, major strategy was focused on pattern of addition of base and DMS. Experiments were carried out by adding a mixture of DMS and aq. NaOH slowly to a solution of desmethyl Olanzapine (78) in MeOH at C to afford (69) having purity 93% in 33% yield. Even though the results seem to be better, DMS was settling at the bottom in the mixture of DMS and aq. NaOH as DMS is not water miscible. Other alternative approaches for example, adding DMS to the mixture of (78), MeOH, water and NaOH; resulted in drop in yield (38%). Then our strategy was focused on the following mode of addition of reagents for scalability in multi kilograms scale with better yield. For instance, adding DMS to a solution of (78) in a solvent (for ex: MeOH), followed by adding a solution of aq. NaOH to the above mixture, resulted in better yield (53%) and improved purity (92.5%).

16 146 Impact of molar equivalents of DMS and base (Table-4.4) on yield and purity: Table-4.4 Entry DMS (eq.) NaOH (eq.) Yield Purity by HPLC (%) No. (%) (69) (78) As depicted in table (4.4), by employing excess reagent (for example entry No. 1 & 5) the yields dropped drastically. In few instances, by using reduced moles of DMS and NaOH, it was observed that the the starting material (78) was found to be present in the resulting (69) as a known potential related substance in more than 0.15% by HPLC (ICH limit would be not more than 0.15%). The purification methods employed to get rid of the related substance (78) were not successful. Studies were focused to eliminate the related substance (78) in the reaction itself by increasing the molar equivalents of DMS and NaOH.

17 147 As evident from entry No.3 {table (4.4)} that by employing 3 molar equivalents of DMS and 6 molar equivalents of NaOH for said reaction, only about 5% of intermediate (78) was remaining and the results were improved in terms of purity and yield. The formation of dimethyl impurity (85) was observed because of the usage of excess moles of DMS for methylation of (78) in highly basic medium. The said dimethyl impurity (85) was freely soluble in aqueous medium. Hence, was easily removed during the conventional work up procedures. For example, the said dimethyl impurity (85) was getting removed by giving water washings to the organic layer obtained after reaction. N CH 3 N N N S CH 3 (85) CH 3 Impact of temperature on yield and purity: Temperature was the key reaction parameter which was playing a critical role for progression of the reaction and had impact on the yield. Table-4.5 illustrates impact of temperature on yield and purity.

18 148 Table-4.5 Entry No. Temp ( 0 C) Yield (%) Purity by HPLC to to to to to to to As evident from the table-4.5, 5-6% of starting material (78) was remaining in reaction at C. While increasing the temperature, the reaction did not go for completion and it resulted in drastically low yields. Based on the above results the optimum reaction temperature was identified as -8 to -5 0 C. Impact of solvent system: Solvent system played an important role in the progression of reaction. Table-4.6 illustrates the impact of solvent system for

19 149 completion of the reaction that lead to the decrease in yield. Further it gave the path of our major strategy towards the best cost effective and scalable process for preparing (69). Table-4.6 Entry No. Solvent Yield (%) Purity by HPLC 1 MeOH/water (40:25) MeOH/water (1:1) MeOH Water Reaction not - progressed 5 DMF/water(1:1) DCM/water Acetonitrile/water DMF Reaction not - progressed 9 DCM/MeOH (2:1) As evident from the above runs, in any given reaction, (78) was not getting converted to (69) completely and around 5-8% of (78) was remained in the reaction. Then the major strategy was focused on purification of (69) from different solvent system(s) employing different

20 150 methods for example: washing, slurrying, leaching, crystallization etc. to reduce the percentage of (78) and the details are as follows. Table-4.7 Entry Solvent Temp. Yield (%) Purity by HPLC No system ( 0 C) (%) (69) (78) 1 Acetonitrile Reflux % water ~ in DMF 3 1,4-dioxan/ water (5%) Though we succeeded in achieving the purity of (69) in 15% aq. DMF, the yields dropped drastically. In aqueous solution, the basicity of amines will be in the following order, secondary>primary>tertiary, which is due to the solvation effect and formation of ammonium salt, which increases the electron density on nitrogen that is responsible for basicity. Based on the above general theory, (78) being secondary amine is more basic than (69) in aqueous medium and tends to form acid addition salt easily when compared to (69) when contacted with an acid. Hence, studies were focused on treatment of crude (69) containing residual (78) with an acid, so that the

21 151 remaining 5-8% of (78) would be washed out. Initially purifications were tried with hydrochloric acid and formic acid but the results were not favorable interms of purity. Acetic acid was proven to be effective for the purification to get the desired results in terms of purity of (69) greater than 98% with (78) content below 0.5% by weight with improved yield. When acetic acid was employed for the purification of crude (69), there was formation of acetyl impurity (86). Therefore, the treatment of crude (69) with acetic acid was optimized at different conditions (for example temperature) to minimize the formation of (86) RESULTS AND DISCUSSION ON IMPURITIES OF OLANZAPINE OBTAINED IN THE PRESENT WORK Table-4.8 depicts the list of compounds that were identified as impurities in Olanzapine (69) and were prepared in the present work according to reported processes; and were characterized. Table-4.8 S.No. Compo Structure of impurity Chemical name und methyl-10H-benzo[b]thieno[2,3- e][1,4]diazepin-4-amine

22 methyl-4-(4-formyl-1-piperazinyl)- 10H-thieno[2,3-b][1,5]benzodiazepine methyl-4-(1-piperazinyl)-10H-thieno- [2,3-b][1,5]-benzodiazepine methyl-4-oxo-10H-thieno-[2,3- b][1,5]-benzodiazepine chloro-2-methyl-10Hbenzo[b]thieno[2,3-e][1,4]diazepine ((2-aminophenyl)amino)-5- methylthiophene-3-carbonitrile methyl-4-(4-acetyl-1-piperazinyl)- 10H-thieno-[2,3-b][1,5]-benzodiazepine Piperazine 1,4 bis-4-yl-(2-methyl)-10hthieno-[2,3-b][1,5]-benzodiazepine

23 EXPERIMENTAL SECTION Preparation of (81): 50 g (0.188 mol) of (73) was taken in 200 ml of 30% NaOH and refluxed 10 hours. The reaction mixture was cooled to room temperature; solid was filtered and washed with plenty of water. The wet compound was taken in 1000 ml of MeOH and refluxed for 15 minutes to dissolve the solid. The solution was treated with carbon and filtered hot. The filtrate was cooled to room temperature and added 500 ml of water slowly to precipitate the solid. Stirring was continued for 60 minutes. The separated solid was filtered and washed with water. Repeated the recrystallization process for one more time and recrystallized compound was dried at 60 0 C to yield 20 grams of (81) (yield: 46.5%; Purity by HPLC: 99%). Characterization of (81): IR spectrum of (81): str). (cm -1 ) 1632 (amide C=O str); 3626 & 3282 (amide -NH str and N-H

24 154 Fig. 4.1 Mass spectrum of (81) (DIP): m/z 230 (M + ). Fig. 4.2

25 155 1 H-NMR (DMSO-d 6 ) spectrum of (81): (δ ppm) 2.2 (s, 3H, CH 3 thiophene), 3.9 (s, 1H, NH), (m, 5H, CH), 8.8 (s, 1H, NH amide). Fig. 4.3 Preparation of novel intermediate (82): A mixture of 5.0 g (0.022 mol) of (81), 150 ml of toluene and 13.9 ml (0.11 mol) of N, N-dimethylaniline was stirred at C. 10 ml (0.108 mol) of POCl 3 was added slowly to the above reaction mixture at C. The resultant reaction mixture was refluxed at C for 4-5 hours. After completion of the reaction, the resultant reaction mixture is evaporated to give the desired (82).

26 156 Characterization of novel intermediate (82): IR Spectrum of (82): (cm -1 ) 3289 (N-H str). Mass Spectrum of (82) (DIP): m/z 249. Fig. 4.4 Fig. 4.5

27 157 1 H-NMR Spectrum of (82): CH). (δ ppm) 2.2 (s, 3H, CH 3 thiophene), 4.0 (s, 1H, NH), (m, 5H, Fig. 4.6 Preparation of (78): A mixture of 500 g (1.88 mol) of (73), 568 g (6.59 mol) of piperazine, 500 ml of DMSO and 2000 ml of toluene was heated to reflux. The reaction mass was maintained at reflux for 5 hours and then cooled to ambient temperature ml of water was added slowly and the solid that separated was filtered and washed with toluene, followed by water. The wet compound was then dissolved in a mixture of 216 ml of acetic acid and 2500 ml of water and washed with 6X250 ml of DCM. The

28 158 resulting solution after washing was made basic with 212 ml (40%) of NaOH solution. The solid that formed was filtered, washed with water and dried to yield 400 g of (78) (Yield: 71%) Characterization of (78) IR spectrum of (78): (cm -1 ) 3321 and 3175 (N-H str). Mass spectrum of (78) (DIP): m/z 299 (M + +1). Fig. 4.7 Fig. 4.8

29 159 1 H-NMR spectrum of (78): (δ ppm) 2.0 (s, 1H, NH-piperazine), 2.2 (s, 3H, CH 3 thiophene), (m, 8H, CH 2 ), 4.0 (m, 1H, other NH), (m, 5H, Ar-H). Preparation of (69): Fig. 4.9 Variant A for the preparation of (69): 0.55 g (60%) of sodium hydride was dissolved in 10 ml of DMF at C and the mixture was cooled to 0 0 C. 5.0 ml (0.045 mol) of N-methyl piperazine (74) was slowly added to the reaction mixture at C. Then a solution of (5.0 g; 0.02 mol) of (82) in 20 ml of DMF was added to the above reaction mixture at C. The reaction mixture was maintained at the same temperature till the completion of reaction. After conventional work up procedure gave the desired (69).

30 160 Variant B for the preparation of (69): (5.0 g; 0.02 mol) of (82) was dissolved in 50 ml of dioxane ml (0.264 ml) of (74) was slowly added to the reaction mixture at C. The reaction mixture was maintained at the same temperature till the completion of reaction. After completion of the reaction, by following the conventional work up procedure gave the crude (69). The resultant crude compound was purified by using toluene to afford (69). Variant C for the preparation of (69): 300 g (1.006 mol) of (78) was charged into 3000 ml of DCM with stirring and the mixture was cooled to below 0 0 C. 286 ml (3.06 mol) of DMS was added at the same temperature slowly and the temperature was maintained. A solution of 242 g (6.04 mol) of NaOH in 1500 ml of MeOH was cooled to C and added slowly to above reaction mass, which was maintained below 0 0 C. Maintenance was continued until the reaction was substantially complete ml of water was added and separated the aqueous layer. The organic layer was washed with water followed by aqueous acetic acid. Finally after water washing of the organic phase, DCM was evaporated and the resulting residue was dissolved in 400 ml of DMF. To the obtained solution, 100 ml of water was added to get 84 g of pure (69). (Purity by HPLC: 99.8%).

31 161 Variant D for the preparation of (69): 200 g (0.67 mol) of (78) was charged into MeOH (2400 ml) with stirring and the mixture was cooled to below 0 0 C ml (2.04 mol) of dimethyl sulfate was added at the same temperature slowly and the temperature condition was maintained. A solution of g (4.02 mol) of NaOH in 600 ml of MeOH was cooled to C. and added slowly to the above reaction mass, which was below 0 0 C. The temperature was maintained until the reaction was substantially complete. The reaction mass was quenched with water. Separated solid was washed with water followed by MeOH. The resulting crude product was purified by dissolving in dimethyl sulfoxide, followed by acetic acid addition, and then water was added to precipitate out the compound. The separated compound was filtered and washed with a mixture of dimethyl sulfoxide and water. This solid was further purified by dissolving in dimethyl sulfoxide, adding acetic acid followed by adding water to precipitate out the compound. The separated solid was filtered. This pure product was finally dissolved in dimethyl sulfoxide and sodium bicarbonate solution was added to it. The separated solid was filtered to afford 80 gm of pure (69). Purity 99.8 % by HPLC.

32 162 Characterization of (69): IR spectrum of (69): (cm -1 ) 3236 (N-H str) & 3051 (Ar C-H str), 1285 & 1220 (C-N str). Fig Mass spectrum of (69) (ESI): m/z 313 (M + +1).

33 163 1 H-NMR spectrum of (69): Fig (δ ppm) 2.21 (s, 3H, thiophene CH 3 ), 2.27 (s, 3H, N-CH 3 ), 6.34 (s, 1H, CH), (m, 4H, Ar-H), 7.60 (s, 1H, NH). Fig. 4.12

34 C-NMR spectrum of (69): (δ ppm) (Aliphatic C); (Ar-C); 143 & 140 (C-benzene bridged); 153 (C=N); 157 (C-thiophene adjacent to NH). Fig Preparation of (73) followed by (83): (73) and its base (83) were prepared by following procedure. Stage-I - Preparation of (70): 6.6 gm (0.206 mol) of sulphur and 9.75 ml (0.136 mol) of propionaldehyde were charged into round bottom flask containing 22.5 ml of DMF at C. The reaction mass was cooled to C. 9.6 ml

35 165 ( mol) of TEA was added slowly at C in minutes. The reaction mixture temperature was increased to C. Added a solution of 7.5 ml (0.11 mol) of malononitrile in 15.0 ml of DMF to the reaction mixture at C in 3-4 hours. The mixture was maintained at C for 2-4 hours. After completion of the reaction, 72.5 ml of water was charged and the reaction mixture was cooled to C. The resultant reaction mass was slowly transferred into another round bottom flask containing chilled water with stirring. The reaction mass was stirred for min, the obtained solid was collected by filtration, washed with 73.0 ml of water and suck dried for 30 minutes. The obtained wet compound was taken in 61.5 ml of MeOH and stirred for 45 minutes. The undissolved solid from the reaction mass was filtered. The filtrate obtained was subjected to distillation completely under vacuum at below 50 0 C. The reaction mass was cooled to C and 54.5 ml of water was charged to reaction mass at C. The reaction mass was stirred for min at C. The obtained product was filtered, washed with 7.5 ml of water and dried at 60 0 C to give 11.1 gm of (70). Stage-II - Preparation of (72): 72 ml of DMSO, 12.0 gm (0.085 mol) of (71), gm (0.273 mol) of potassium carbonate and 12.0 gm (0.086 mol) of (70) were charged into a round bottom flask. The mixture was heated to 65 0 C and maintained for

36 166 9 hours. The reaction mixture was cooled to 40 0 C, 14.9 ml of water was slowly added at temperature below 45 0 C. The reaction mass was stirred for 45 minutes, filtered the material and spin dried for minutes. The resultant wet compound was purified by using 53.0 ml of MeOH and dried at 65 0 C to afford 15.0 gm of the (72). Stage-III - prepration of (73) followed by (83): 70.0 ml of 1,4-Dioxane, 15.0 gm (0.058 mol) of (72) and 2.15 gm of Raney Nickel were mixed with 5.0 ml of 1,4-Dioxane by applying vacuum into a vessel. The reaction mixture was maintained under hydrogen pressure below 4 Kg/cm2 at 70 0 C for 3 hours. The reaction mixture was cooled to 35 0 C. After completion of the reaction, the reaction mixture was filtered, washed with 4.0 ml of 1,4-Dioxane and distill off the solvent 1,4-dioxane under vacuum at below 70 0 C. The residue was cooled to C then 19.0 ml of IPA and 6.2 ml of HCl were added to the residue. The mixture was heated to reflux and maintained at reflux temperature for 12 hours. Then cooled to C and maintained for 1 hour at C. The obtained product was filtered, washed with 4.0 ml of IPA and dried at 60 0 C for 3 hours to get crude (73). The crude (73) was purified from a mixture of MeOH and chloroform to give 5.8 gm of pure (73). The resultant hydrochloride was converted to its base (83) by neutralization and characterized.

37 167 Characterization of (83): (83) was confirmed by its IR, 1 H-NMR and mass spectra. IR spectrum of (83): (cm -1 ) 3299 & 3184 (N-H str). Fig H-NMR spectrum of (83): (δ ppm) 2.25 (s, 3H, thiophene CH 3 ); 6.82 (s, 1H, CH); (m, 4H, Ar-H); 11.3 (s, 1H, NH); 9.0 (s, 2H, NH 2 ).

38 168 Fig Mass spectrum of (83) (DIP): m/z 230 (M + +1). Fig. 4.16

39 169 Preparation of (80): 17.5 g of Methyl formate was slowly added to a solution of 4.5 g of sodium methoxide at C. Then a solution of 50 g (0.167 mol) of (78) in 335 ml of MeOH was added to the reaction mixture. The reaction mixture was stirred at C for 1-2 hours. Then 4.5 g of formic acid was added slowly and the reaction mixture was stirred for 30 minutes. The obtained solid was collected by filtration, washed with 50 ml of MeOH and dried the compound at C to give the 35.0 g of (80) having purity of >99% by HPLC. Characterization of (80): IR spectrum of (80): (cm -1 ) 1637 (C=O str), 3251 (N-H str). Fig. 4.17

40 170 1 H-NMR spectrum of (80) (DMSO): (δ ppm) 2.28 (s, 3H, thiophene CH 3 ); (m, 8H, CH 2 ); (m, 5H, Ar-H), 7.63 (s, 1H, NH); 8.1 (s, 1H, CHO). Mass spectrum of (80) (DIP): Fig m/z 326. Fig. 4.19

41 171 Preparation of (84): 70.0 ml of 1,4-Dioxane, 15.0 gm (0.058 mol) of (72) and 2.15 gm of Raney Nickel were mixed with 5.0 ml of 1,4-Dioxane by applying vacuum into a vessel. The reaction mixture was maintained under hydrogen pressure below 4 Kg/cm2 at 70 0 C for 3 hours. The reaction mixture was cooled to 35 0 C. After completion of the reaction, the reaction mixture was filtered, washed with 4.0 ml of 1,4-Dioxane and distill off the solvent 1,4-dioxane under vacuum at below 70 0 C. 30 ml of IPA was added and stirred for 30 minutes. The isolated solid was filtered and dried to get crude (84). The crude compound was purified through recrystallization using MeOH to afford 7.5 gm of pure (84). Characterization of (84): IR spectrum of (84): (cm -1 ) 3384 & 3304 (NH 2 str), 2205 (CN str). Fig. 4.20

42 172 1 H-NMR spectrum of (84): (δ ppm) 2.26 (s, 3H, thiophene CH 3 ), 6.20 (s, 1H, CH), (m, 4H, Ar-H), 3.70 (s, 2H, NH 2 ), 7.2 (s, 1H, NH). Fig Mass spectrum of (84) (ESI): m/z 230 (M + +1).

43 173 Fig Preparation of acetyl impurity (86): 25 g (0.084 mol) of (78) was dissolved in DCM under stirring ml ( mol) of TEA was added under stirring. The reaction mixture was cooled to C and added 6.6 g (0.084 mol) of acetyl chloride; and stirred for minutes. After completion of the reaction, 100 ml of water was added. The organic layer was separated and washed with 4 X 25 ml of water. The minimum volume of solvent from the organic layer was evaporated atmospherically and the resultant reaction mass was stirred at C for minutes. The obtained solid was filtered, washed with 5 ml of chilled DCM and dried at 60 0 C to give 12.0g of the title (86).

44 174 Characterization of acetyl impurity (86): Acetyl impurity (21) was identified by LCMS and later confirmed by its synthesis and subsequent characterization with 1 H-NMR, IR and mass spectra. IR spectrum of acetyl impurity (86): (cm -1 ) 3251 (N-H str), 1637 (C=O str). Fig Mass spectrum of acetyl impurity (86) (DIP): m/z 341 (M + +1). Fig. 4.24

45 175 1 H-NMR spectrum of acetyl impurity (86): (δ ppm) 2.0 (s, 3H, thiophene CH 3 ), 2.27 (s, 3H, CH 3 of acetyl), 3.2 (m, 4H, CH 2 attached to N of N-COCH3 side); 3.5 (m, 4H, CH 2 on other side of piperazine), 6.39 (s, 1H, Ar CH), (m, 4H, Ar-H), 7.62 (s,1h, NH). Fig Preparation of dimer impurity (87): A mixture of 10 g ( mol) of (73), 4.8 g ( mol) of piperazine, 10 ml of DMSO and 40 ml of toluene were heated to reflux and maintained at reflux for 40 minutes. The reaction mixture was cooled to C, filtered the undissolved solid from the reaction mixture under reduced pressure. The resultant solid was purified three times from MeOH to get 1.2 g of pure (87).

46 176 Characterization of dimer impurity (87): IR spectrum of dimer impurity (87): (cm -1 ) 3292 (N-H str). Fig H-NMR spectrum of dimer impurity (87): (δ ppm) [s, 6H, thiophene CH 3 ), (m, 8H, CH 2 ), 6.42 (s, 2H, thiphene-ch), (m, 8H, Ar-H), 7.65 (s, 2H, NH).

47 177 Fig Mass spectrum of dimer impurity (87) (DIP): m/z 511. Fig. 4.28

48 178 Impurities (78), (81) & (82) are intermediates in the process for preaparation of (69) in the present work CONCLUSION The present chapter-4 describes a convenient and efficient process for the preparation of an antipsychotic drug olanzapine (69). Present work affords a simple, cost-effective, devoid of expensive reagents, favors in good yields that lead to the product efficiency. The process for preparation of Olanzapine of the present work was published as sundaram et al 68 and Chandra et al. (iv)