179

CHAPTER - 5 STUDIES IN THE SYNTHESIS OF DILTIAZEM HYDROCHLORIDE

180

5.1 - INTRODUCTION

Diltiazem hydrochloride (Cardizem) has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reduction in heart rate and systemic blood pressure at submaximal and maximal exercise workloads.

In

animal

models,

diltiazem

interferes

with

the

slow

inward

(depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.
70

181

Table-5.1 - PRODUCT PROFILE OF DILTIAZEM HYDROCHLORIDE

69

Generic Name Brand Name Active Ingredient Innovator

Diltiazem hydrochloride Cardizem Diltiazem Tanabe Seiyaku Co., Ltd., Osaka, Japan, a corporation of Japan

Marketed by Chemical Name

Biovail Labs international (+)-cis-3(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3dihydro-2-(4-methoxyphenyl)-1,5-Benzothiazepin4(5H)-one, monohydrochloride

Chemical Formula

C22H27ClN2O4S

Molecular Weight 450.98 Chemical Structure

CAS Registry No Physical

33286-22-5 White to off-white crystalline powder

182

description Solubility Melting range Approved indication (US) It is soluble in water, MeOH, and chloroform 213 2140C Cardizem is indicated for the management of chronic stable angina and angina caused by coronary artery spasm. Dosage strengths 120 mg, 180 mg, 200 mg & 240 mg capsules

5.2 LITERATURE RIVEW Many synthetic approaches are reported in literature for the preparation of Diltiazem or its intermediates including asymmetric synthetic approaches. Some of those reported synthetic approaches are discussed here under as the starting point towards the objective of the present work. Hiroshi et al hydrochloride
71

reported a process for preparation of Diltiazem by reacting (+)-cis-3-hydroxy-2,3-dihydro2-(4(89) with N,N-

(88)

methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one

dimethylaminoethyl chloride, reaction of the resulting intermediate (2S,3S)-5-(2-(dimethylamino)ethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3dihydrobenzo[b][1,4]thiazepin-4(5H)-one (90) with acetic anhydride

followed by conversion of the resulting Diltiazem (91) into hydrochloride salt to afford (88) (Scheme-5.1).

183

Scheme-5.1:

In the above process, reaction in step-1 was carried out under critical conditions using very strong bases, such as sodium hydride, metal sodium or sodium amide in a solvent such as dimethylsulfoxide, dioxane, toluene or xylene. Usage of sodium hydride as a base is in fact dangerous, in view of its potential pyrophoric nature because of which not preferable as it may create environment issues. Susumu et al
72

reported a process for the preparation of (88) by

reaction of (92) with (93) in toluene at reflux temperature to get (94), which up on hydrolysis with aqueous NaOH gave rise to an isolated racemic intermediate (95). The said racemic acid intermediate was subjected to chemical resolution using d-alpha-methyl benzyl amine by separating diastereomeric salt (96) in water as solvent. The said distereomeric salt was reacted with HCl in water as solvent by heating whereby required (2S,3S) isomer (97) was isolated. The said acid was reacted with Ac2O in presence of pyridine in DMF as reaction medium to give rise to (98). The said intermediate was then reacted with N,N-

184

dimethyl aminoethyl chloride in ether in presence of NaH in DMSO as reaction medium to get (91) as an oil, which was then converted to hydrochloride salt by treating with hydrochloric acid absorbed in ether to provide (88) (Scheme-5.2).

Scheme-5.2:

Mitsunori et al

73

reported a process for preparation of (88) by

reaction of (89) with N,N-dimethylaminoethyl chloride in the presence of KOH or K2CO3 in acetone or lower alkyl acetate, preferably containing a

185

small amount of water. This method, even though overcoming some drawbacks of the previous process, still it was not cost effective and ecofriendly. In fact, the reaction takes place in heterogeneous system and the recovery of solvent is very difficult, which is very important on commercial scale to meet the cost. The product having the 3-hydroxy group in free form or acetylated form was recovered and subsequently transformed into the final hydrochloride salt. In a communication to EPO (European patent office) during the prosecution of the patent application Mitsunori et al, it was mentioned that N-alkylation of (89) does not take place when the reaction solvent was toluene, though strong base such as KOH and NaNH2 was used. In the same communication, it was further stated that sodium carbonate in acetone also did not yield process effective (Scheme-5.3). Scheme-5.3:

Nakamoto et al

74

reported the chemical resolution of racemic

propionic acid intermediate (95) with L-lysine (99) to get diastereomeric

186

salt (100), treating with a mineral acid to get (97), cyclization of the resulting compound to get (89), N-alkylation in acetone as reaction medium under phase-transfer conditions by using crown ether or pyridine as catalyst. Other different aromatic solvents are generically mentioned but no specific examples were provided. The acetylation step was carried out in another solvent after the isolation of Diltiazem (91). The salification in the next step was performed in yet another solvent to afford (88) (Scheme-5.4).

Scheme-5.4:

187

Several other processes for preparation of intermediates of (88) were reported in literature, which described synthesis of various achiral and chiral intermediates and their conversion to (91) or its hydrochloride salt (88).

5.2.1 - SUMMARY OF THE REPORTED SYNTHETIC APPROACHES

As discussed above and as per the synthetic processes described in some more references75-91, although those reported synthetic procedures seem to be practicable, they still need improvement in terms of cost and commercial viability. For example, some of those procedures involve costly and commercially less preferable reagents such as crown ethers, pyridine, lipase (which requires a specialized technology to handle on industrial scale), sodium hydride etc. Also some of those procedures involve isolation of various intermediates that leads to lower yield efficiency and lengthy time cycle for overall production on industrial scale. Few more procedures involve synthesis of chiral intermediates such as (2R,3S)-3-(4-methoxyphenyl)glycidic acid methyl ester for example by enantioselective Mukaiyama aldol reaction involving the use of very costly chiral reagents, which result in increase in cost of (88).

188

5.3 - PRESENT WORK

In view of the draw backs of the reported synthetic procedures, the present work has an objective to develop an improved process for the preparation of (88) by modifying the conditions of the reported synthetic procedures, replacing costly reagents and solvents with simple, cost effective reagents and recoverable solvents, which are available

commercially and are inexpensive on commercial scale in industry to produce low cost (88) when compared to reported synthetic procedures discussed above.

As can be seen from Newport Premium database by Thomson Reuters, the worldwide consumption of (88) by June 2011 is 408,931.9 kgs. Therefore (88) is a tonnage molecule wherein the cost of the active pharmaceutical ingredient is the key driver of the business for formulators. Therefore, one need not look into a very novel and unique synthetic pathway. The objective of the present work is achieved just by tweaking the reported processes thereby giving cost effective and commercially viable process for the manufacture of (88).

This chapter aimed at synthetic studies towards the efficient and alternative synthesis of (88) to overcome the limitations of the reported

189

approaches. The detailed study aimed towards synthesis of (88) is as follows.

5.3.1

RETRO

SYNTHETIC

PATHWAY

FOR

DILTIAZEM

HYDROCHLORIDE: Scheme-5.5:

Above scheme depicts different retro synthetic pathways possible for (88).

190

5.4 - RESULTS AND DISCUSSION After reviewing the various possible retro synthetic pathways given above in scheme-5.5, normally it is believed that enantioselective process leads to the cost-effective product, since we do not lose the 50% of the other isomer as an unwanted product as in the case of chemical resolution. However, based on the discussion of reported synthetic schemes herein before, it is observed that asymmetric synthesis of required isomer of (92) so as to afford (88) will be expensive as its preparation involves expensive chiral auxiliaries, which ultimately leads to an expensive (88), though there is no loss of 50% of the other isomer, which defeats the objective of the present work. Therefore, chemical resolution methodology is still believed to be inexpensive if we operate it by carefully studying the reported procedures and by employing the appropriate conditions to simplify and improve the process to reduce the manufacturing cost of (88). Towards this objective, the present work provides the following detailed study on the synthesis of (88). Initially, (88) was prepared by (i) reacting (101) with methyl chloroformate under Darzens reaction conditions using sodium

methoxide as the base in MeOH as the solvent to get (92), (ii) reaction of the resulting glycidate with (93) by refluxing in toluene solvent to get (94), (iii) hydrolysis of resulting propionate ester with NaOH in water as solvent to get an isolated racemic intermediate (95), (iv) chemical

191

resolution of the resulting racemic acid with d-alpha-methyl benzyl amine in a mixture of MeOH and water to get precipitated diastereomeric salt (96), (v) treating the diastereomeric salt with hydrochloric acid in water to get (97), (vi) simultaneous intramolecular cyclization and

acetylation of the acid to get (102) in pyridine without using any additional solvent, (vii) treating (102) with CH3NH2 solution to get (98), (viii) reacting the resulting compound with N,N-dimethylaminoethyl chloride hydrochloride in presence of K2CO3 in DMF to get (91), (ix) (91) is converted to (88) by treating with HCl absorbed in IPA (Scheme-5.6). Scheme-5.6:

192

The draw backs in this process were the number stages, which results in poor yield. In order to provide an improved process, the synthetic scheme-5.7 was chosen for study, which was believed to be cost effective with appropriate improvements by addressing the draw backs of the reported procedures.

Scheme-5.7:

It was observed that the cost of the key intermediate cis-lactam (89) looks to be the key cost driver in the synthetic scheme-5.7 selected for

193

study for the cost reduction of (88). Therefore, the objective of the study was divided into two parts. First part dealt with cost reduction by improvements in the synthesis of cis-lactam (89). The second part dealt with cost reduction by improvements in the synthesis of (88) from (89). 5.4.1 - Studies in the synthesis of cis-lactam (89) - Results and discussion: In this study the starting point was the racemic (95), which was prepared according to synthetic scheme-5.7 and subjected to chemical resolution using d-alpha-methyl benzylamine to provide diastereomeric salt (96). The resulting salt was directly converted to (89) without isolating the intermediary D(+)-acid (97) by refluxing in toluene in presence of slightly in excess of molar equivalents of conc. HCl and by simultaneous azeotropic removal of water quantitatively. Scheme-5.8:

In an effort towards further process improvements and cost reduction of (89), the expensive d-alpha-methyl benzylamine was replaced by (99), a very inexpensive reagent, for the chemical resolution of (95). (99), being a naturally occurring product, is used in as food in poultry forms.

194

Therefore, it is a food product and is very safe and advantageous to use in the process of the present work. Further, there is a huge cost difference between d-alpha-phenylethylamine and L-lysine hydrochloride (99). (99) as hydrochloride is inexpensive than its base. Therefore, (95) was reacted with (99) in presence of NaOH in order to neutralize the hydrochloride salt to free the amine group in (99) to participate in resolution by salt formation with the acid group of (95). The resolution step was carried out in a mixture of MeOH and water as solvent system. The resulting (100) was directly converted to (89) without isolating the intermediary (97) by refluxing in toluene in presence of slightly in excess of molar equivalents of conc. HCl and by simultaneous quantitative azeotropic removal of water (Scheme-5.9). Scheme-5.9:

195

Though the process according to scheme-5.9 seems to be cost efficient, still there is scope for improvement. In an endeavor to further simplify the process, (94) was directly used in the step of resolution with (99) without the need of isolating (97) and then subjecting it to chemical resolution. (94) was first treated with molar equivalents of aqueous NaOH. The product of the reaction would be sodium salt of acid and MeOH. The reaction mixture containing these two products was directly treated in-situ with (99) in a mixture of MeOH and water as solvent system for resolution. The advantage of this process modification was; (i) there was no need of isolating (97), which results in saving of certain yield as there was no isolation, and (ii) the sodium ions present in the resulting sodium salt of acid within the reaction mixture after hydrolysis of (94) would be utilized in neutralizing the hydrogen chloride associated with (99) so that there was no need of using a base separately for neutralizing it. Though this approach was just a combining of two stages by tweaking the known processes, it has resulted in tremendous cost advantage and made the process very simple and robust. This was a very novel approach and not reported in literature before carrying out the present work. Therefore, the starting point for this approach was (94) (Scheme5.10).

196

Scheme-5.10:

5.4.2 - Studies in the synthesis of Diltiazem hydrochloride from cislactam (89) - Results and discussion: (89) was N-alkylated with N,N-dimethylaminoethyl chloride in

presence of K2CO3 in acetone as solvent under reflux conditions to get (89). The key observation in this reaction was that, the reaction did not proceed at all in dry acetone, which was observed when laboratory grade acetone was used. Whereas when commercial grade acetone was used, the reaction was observed to some extent but still not to completion. While investigating the reasons for this, the water content in both laboratory and commercial grades of acetone were measured. Laboratory grade acetone contained a water content of less than 0.1 percent weight by volume whereas commercial grade acetone contained a water content of about 0.5 percent weight by volume as measured by Karl Fischer titration method. Then the quantity of water within the reaction medium was optimized by deliberately adding varying quantities of water to the system in the beginning of the reaction itself. As the quantity of water was increased, the reaction was progressed towards completion. When

197

about 4% weight by volume of water was present in the quantity of acetone used for the reaction, the reaction was proceeded to completion comfortably. The said quantity of water in acetone came to around 3 to 4 molar equivalents with respect to the number of moles of (89) used. Further improvement of the N-alkylation step lied in usage of toluene instead of acetone. Surprisingly the reaction progressed comfortably even in toluene as the reaction medium, which was contrary to the reported procedure (Mitsunori et al). It was further advantageous that a solution of (90) in toluene that was obtained after N-alkylation step could be directly used in the next step of acetylation in situ without the isolation of Nalkylated product. This would give a tremendous advantage for simplification of the process on commercial scale. The next step was the O-acetylation reaction to get (91). Ac2O was used in many reported procedures. In this approach, first (91) was obtained, which was often isolated as a solid by crystallization to avoid excess Ac2O and the base viz. pyridine used for the O-acetylation reaction. The isolated (91) needed to be converted to (88) in an additional step. The first improvement of the present work involved the use of acetyl chloride in presence of acetic acid for O-acetylation of (90) to directly get (88) without the need of isolating the intermediary (91) base and its further conversion to its hydrochloride salt thereby providing a simple process without the need for isolation of (91). Though procedures were

198

reported for the O-acetylation using acetyl chloride, those procedures involve the use of acetic acid or Ac2O as the solvent, which is not preferable on commercial scale. The present work dealt this problem by using stoichiometric quantity of acetyl chloride and acetic acid in toluene as solvent for the reaction. (88) was directly obtained comfortably in quantitative yield with good quality. The said process is schematically represented. Scheme-5.11:
OCH3 OCH3 OCH3

H S H OH ClCH2CH2N(CH3)2.HCl K2CO3, Toluene Water, 700C S

H H OH N

CH3COCl,Acetic acid, Toluene,450C

H S H OCOCH3 N

(89)

N H

(90)
N

(88)
N .HCl CH3

H3C

CH3

H3C

5.4.3 Results and discussion on related impurities of Diltiazem hydrochloride (88):

The following compounds were identified as impurities in (88) obtained in the present work.

199

Out of these impurities; (89), (94) & (90) are intermediates of (88) and their characterization data is in agreement with the data give for those compounds herein above. (98) was prepared as per the procedure given in experimental section.

5.5 - EXPERIMENTAL SECTION Preparation of 3-(4-Methoxyphenyl)-2,3-epoxymethylpropionate (92): A stirred solution of 39.7 grams of (0.735 mol) of sodium methoxide powder in 1000 ml of MeOH was cooled to -10 to -50C. 100 grams (0.735 mol) of (101) was added slowly over a period of 60 minutes. The mixture was aged at the same temperature for 25 minutes. Then 87.1 grams (0.803 mol) of methyl chloro acetate was added drop wise slowly in about 2 hours. After reaction completion (monitored by TLC; mobile phase ethyl acetate : hexanes 1:5), pH of the reaction mixture was adjusted to 7 with very dilute hydrochloric acid very slowly at -10 to -50C. The separated solid was filtered, washed with chilled water and dried under

200

reduced pressure at 250C for 30 minutes to afford 132 grams (86.2%) of (92). Preparation of methyl 3-((2-aminophenyl)thio)-2-hydroxy-3-(4-

methoxyphenyl)propanoate (94): To a stirred solution of 100 grams (0.48 mol) of (92) in 1000 ml of toluene was added 72.0 grams (0.576 mol) of (93) and heated reflux. Reaction mixture was aged at refluxing for 5 hours. The reaction mixture was slowly cooled to room temperature and aged for 3 hours. Separated solid was filtered and dried at 600C to afford 134 grams (84%) of (94). Characterization of (94): IR spectrum of (94): (cm-1) 1680 (C=O str, amide); 3369 (OH str); 3189 (N-H str). Mass spectrum of (94): m/z 334 (M++1).
1H-NMR

spectrum of (94):

( ppm) 2.6 (s, 1H, OH), 3.7 (m, 3H, CH3 of ester), 3.9 (m, 3H, CH3 of p-OMe Ph), 4.4 & 4.8 (m, 2H, CH), 6.2 (s, 2H, NH2), 6.4-7.3 (m, 8H, ArH). Preparation of L-Lysine salt of (2S,3S)-3-((2-aminophenyl)thio)-2hydroxy-3-(4-methoxyphenyl) propanoic acid (100): To a stirred solution of 100 grams (0.299 mol) of (94) in 500 ml of MeOH was added 11.9 grams (0.299 mol) of NaOH and stirred for 30

201

minutes. 65.3 grams (0.359 mol) of L-Lysine hydrochloride (99) dissolved in 100 ml of water was added in about 30 minutes. Stirring was continued at room temperature for about one hour. Separated solid was filtered and washed with a 5:1 mixture of MeOH and water. The resulting wet compound was dried at a temperature of 500C to yield 56 grams of (100). Preparation of cis-lactam (89): Dean-Stark apparatus was arranged to a round bottom flask containing 1000 ml of toluene. 100 grams (0.215 mol) of (100) was charged and stirring was started. 50 ml of concentrated HCl was added slowly. The mixture was heated to reflux. The reaction mixture was aged under reflux condition by simultaneously collecting water azeotropically in Dean-Stark apparatus. Reflux was continued until water collection ceased. The reaction mixture was slowly cooled to room temperature. The separated solid was filtered and washed with toluene. The resulting wet compound was taken into 1000 ml of water and stirred at room temperature for about 30 minutes. The solid was filtered and dried at 700C to yield 62 grams (Yield: 95%) of (89) (Purity by HPLC: 98.6 %). Characterization of cis-lactam (89): IR spectrum of (89): (cm-1) 3189 (N-H str); 3369 (OH str); 1680 (C=O str).

202

Fig. 5.1

Mass spectrum of (89) (DIP): m/z 302 (M++1).

Fig. 5.2
1H-NMR

spectrum of (89) (DMSO-D6, 400 MHz):

( ppm) 3.1 (s, 1H, OH); 3.7 (s, 3H, OCH3); 4.9 & 4.5 (m, 2H, thiazepine CH); 6.9-7.7 (m, 8H, Ar-H); 11 (s, 1H, NH).

203

Fig. 5.3

13C-NMR

spectrum of (89) (DMSO-D6, 400 MHz):

( ppm) 55 (S-C); 57 (OCH3); 69 (C-OH); 113-134 (10 remaining carbons of phenyl rings); 141 (Ph-C-N of benzothiazepine); 159 (Ph-COMe); 172 (C=O thiazepinone).

OCH3 S H H OH O

N H

Fig. 5.4

204

DEPT spectrum of (89) (DMSO-D6 200 MHz): Methyl and methyne groups as positive peaks and methylene groups as negative peaks.

Fig. 5.5 Preparation of (2S,3S)-5-(2-(dimethylamino)ethyl)-3-hydroxy-2-(4-

methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (90): To a stirred mixture of 50 grams (0.166 mol) of cis-lactam (89) in 500 ml of toluene was added 22 grams (0.166 mol) of K2CO3. 12 ml of water was added and the reaction mixture was heated to 700C. The reaction mixture was aged at that temperature for 6 hours. Reaction completion was monitored by TLC (Mobile phase: Chloroform : MeOH 4:1). The reaction mixture was cooled to room temperature and filtered. Filtrate was washed with water. The resulting solution of (90) in toluene was

205

heated to reflux and water was removed by azeotropic distillation. Solution was cooled to room temperature. Characterization of (90): IR spectrum of (90): (cm-1) 1660 (C=O str); 3469 (OH str); 3189 (N-H str) of (2) is absent.

Fig. 5.6 Mass spectrum of (90) (DIP): m/z 373 (M++1).

Fig. 5.7

206
1H-NMR

spectrum of (90) (DMSO-D6, 400 MHz):

( ppm) 2.9 {s, 6H, -N(CH3)2}; 3.1 (s, 1H, OH); 3.5 (m, 2H, thiazepine N-CH2-CH2); 3.7 (s, 3H, OCH3); 4.1-4.3 (m, 2H, thiazepine -N-CH2); 4.9 & 4.5 (m, 2H, thiazepine CH); 6.9-7.7 (m, 8H, Ar-H).

Fig. 5.8

Preparation of Diltiazem hydrochloride (88):

The solution obtained in previous step was made up to 500 ml by adding toluene and stirring was started. 28.5 ml (0.498 mol) of acetic acid was added slowly. The reaction mixture was heated to 300C. 14ml (0.2 mol) of acetyl chloride was added slowly drop wise. After completion of addition, the temperature of the reaction mixture was raised to 450C and aged at that temperature for 4 hours with stirring. Reaction completion was monitored by TLC (Mobile phase: Chloroform : MeOH

207

4:1). Reaction mixture was cooled to 200C and stirred at that temperature for one hour. Separated solid was filtered and dried at 600C to yield 59 grams (Yield: 80%) of Diltiazem hydrochloride (1) {Purity by HPLC: 99 %; SR: + 1140 (c=10mg/ml water)}.

Characterization of Diltiazem hydrochloride (88): IR spectrum of (88): (cm-1) 3056 (Ar C-H str); 2966 (aliphatic C-H); 2389 (+N-H str); 1743 & 1680 (C=O str); 1475 (C-N str); 1255 & 1026 {C-O-C (aryl alkyl ether)}.

Fig. 5.9

208

Mass spectrum of (88) (DIP): m/z 415 (91).

Fig. 5.10

1H-NMR

spectrum of (88) (CDCl3, 200 MHz):

( ppm) 1.9 (s, 3H, -COCH3); 2.9 {s, 6H, -N(CH3)2}; 3.2 (m, 2H, thiazepine -N-CH2-CH2); 3.6 (m, 2H, N-CH2); 3.8 (s, 3H, OCH3); 5.1 & 4.5 (m, 2H, thiazepine CH); 6.9-7.8 (m, 8H, Ar-H); 12.8 (s, 1H, +NH).

209

Fig. 5.11

13C-NMR

spectrum of (88) (CDCl3, 50 MHz):

( ppm) 19.8 (COCH3); 42.5 (-N(CH3)2); 44.3 (thiazepine-N-CH2-CH2); 53.6 (thiazepine-N-CH2-CH2); 53.3 (thiazepine-S-C); 54.7 (OCH3); 70.5 (benzothiazepine-C-COCH3); 113-135 (10 remaining carbons of phenyl rings); 143 (phenylic-C-N of benzothiazepine ring); 159 (Ph-C-OMe); 167 (OCOCH3); 169 (C=O thiazepinone).

210

Fig. 5.12 DEPT spectrum of (88) (CDCl3): Methyl and methyne groups as positive peaks and methylene groups as negative peaks.

Fig. 5.13

211

Preparation

of

(2S,3S)-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-

tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate (98): (98) is prepared according to the procedure reported in Susumu et al. Step-1: To a stirred mixture of 5 g (0.01 mol) of (100) in 50 ml water was added dil. HCl {prepared by mixing 3 ml (0.02 mol) of conc. HCl in 10 ml of water} slowly. The mixture was stirred for 1 hour at room temperature. Filtered and solid was washed with water to afford 4.3 g of (97). Step-2: To a stirred mixture of 4.0 g (0.0125 mol) of (97) in 100 ml of toluene was added 6.4 g (0.0625 mol) of acetic anhydride and heated to reflux. The mixture was aged at the same temperature for 3 hours by azetropic removal of acetic acid along with toluene. After reaction completion, the reaction mixture was cooled to room temperature and the separated solid was filtered, washed with toluene and dried at 700C to afford 4.5 g of (102). Melting point: 156-1580C. Step-3: To a stirred solution of 4.0 g (0.0103 mol) of (102) in 50 ml of

DCM was added (0.015 mol) of diethylamine and aged at room temperature for 2 hours. After reaction completion, the solvent was distilled off under reduced pressure at 450C. The resulting compound

212

was triturated with 10 ml of IPA to afford 2.0 g of (98). Melting point:196-1980C. Characterization of (98): IR spectrum of (98): (cm-1) 1680 (C=O str, amide); 3369 (OH str); 3189 (N-H str). Mass spectrum of (98) (ESI): m/z 345 (M+2).
1H-NMR

spectrum of (98):

( ppm) 2.1 (s, 3H, CH3); 3.7 (s, 3H, OCH3); 4.8 & 4.4 (m, 2H, thiazepine ring hydrogens); 6.8-7.6 (m, 8H, Ar-H); 11 (s, 1H, NH). 5.6 - CONCLUSION The objective of the present work is achieved by providing cost effective, eco-friendly process, which is well suited for commercial scale up. The Diltiazem hydrochloride (88) obtained in the present novel process has >99.0% purity as determined by HPLC (as required by ICH lmits) and resulted in a crystalline form as characterized by X-ray powder diffraction. The Diltiazem hydrochloride obtained in the present process is free flowing and non-solvated solid; hence it is well suited for pharmaceutical applications. The process of the present work is cost effective, eco-friendly and amenable for scale up. The resultant improved easily scaleable and cost effective process for preparation of Diltiazem hydrochloride (88) of the present work is under evaluation for patent filing at Dr.Reddys Laboratories Ltd, Hyderabad.