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 Diltiazem hydrochloride

Brand Name Cardizem

Active Ingredient Diltiazem

Innovator Tanabe Seiyaku Co., Ltd., Osaka, Japan, a

corporation of Japan

Marketed by Biovail Labs international

Chemical Name (+)-cis-3(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-

dihydro-2-(4-methoxyphenyl)-1,5-Benzothiazepin-

4(5H)-one, monohydrochloride

Chemical

Formula

C22H27ClN2O4S

Molecular Weight 450.98

Chemical

Structure

CAS Registry No 33286-22-5

Physical White to off-white crystalline powder

182

description

Solubility It is soluble in water, MeOH, and chloroform

Melting range 213 2140C

Approved

indication (US)

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 71 reported a process for preparation of Diltiazem

hydrochloride (88) by reacting (+)-cis-3-hydroxy-2,3-dihydro2-(4-

methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one (89) with N,N-

dimethylaminoethyl chloride, reaction of the resulting intermediate

(2S,3S)-5-(2-(dimethylamino)ethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-

dihydrobenzo[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 eco-

friendly. 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) (Scheme-

5.10).

196

Scheme-5.10:

5.4.2 - Studies in the synthesis of Diltiazem hydrochloride from cis-

lactam (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 N-

alkylated 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:

ClCH2CH2N(CH3)2.HCl

K2CO3, TolueneWater, 700C N

S

O

OCH3

H

OH

H

NH3C CH3

N

S

O

OCH3

H

OCOCH3

H

NH3C CH3

.HCl

CH3COCl,Acetic acid,Toluene,450C

NH

S

O

OCH3

H

OH

H

(89) (90) (88)

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, Ar-

H).

Preparation of L-Lysine salt of (2S,3S)-3-((2-aminophenyl)thio)-2-

hydroxy-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-C-

OMe); 172 (C=O thiazepinone).

NH

S

O

OCH3

H

OHH

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.