chapter-3 an efficient, commercially viable and greener...

76 Chapter-3

CHAPTER-3

AN EFFICIENT, COMMERCIALLY VIABLE AND

GREENER PROCESS FOR THE PREPARATION

OF RANOLAZINE: AN ANTIANGINAL AGENT

77 Chapter-3

3.1 INTRODUCTION

Angina also known as Angina pectoris is indication for heart

disease caused by lack of blood circulation to the heart. The most

widespread reason for the angina is Atherosclerosis. In coronary heart

disease patients, arteries become narrow and stiff when compared with

the healthy heart arteries. These narrow and stiff arteries cause

difficulties to reach oxygen rich blood for heart. About 17 million

Americans are suffering with coronary heart diseases and about 9

millions are suffering with chronic angina.

Ranolazine1-4 is the one of the medicament used to manage

chronic angina, developed by Roche Bioscience (formerly Syntex) and

marketed by CV Therapeutics. USFDA was approved Ranolazine 2 under

brand name of Ranexa® in January 27, 2006. Subsequently European

medical agency (EMEA) approved in July 09, 2008. Latter on it was

approved in few other developing countries. Ranexa ® is available in

market in the form of 500 mg and 1000 mg film coated tablet and the

maximum daily dosage should be less than 2.0g. Over dosage of Ranexa

® lead to dizziness, nausea, and vomiting. Worldwide sales of Ranexa®

by December 2011 is about 400 millions USD (~2000 crores) with the

consumption of 1, 00, 678 kg. Major contribution is from USA i.e. about

300 millions USD. The above mentioned particulars of the angina drugs

motivated us to develop efficient, cost effective and moderately greener

process for the synthesis of ranolazine.

78 Chapter-3

3.1.1 PRODUCT PROFILE

1. Generic name : Ranolazine

2. Chemical structure :

N

NO

HN O

O

OH

3. Chemical names :

(±)-N- (2, 6-dimethylphenyl)-4-[2-

hydroxy-3-(2-methoxyphenoxy)

propyl]-1-piperazine acetamide

4. Molecular formula : C24H33N3O4

5. Molecular weight : 427.54

6. CAS No : 142387-99-3

7. Therapeutic category : Anti Angina

8. Indication : Chronic angina

3.1.2 PHYSICAL CHARACTERISTICS

1. Description of API : White to off white solid

2. Melting point : 119-120 °C

3. Solubility of API : Dichloromethane and methanol

(FDA Label)

3.1.3 MARKET INFORMATION

1. Applicant : Roche Bioscience (formerly Syntex)

2. Patentee : Roche Bioscience (formerly Syntex)

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3. Marketed by : CV Therapeutics

4. Brand name : Ranexa

5. USFDA Approval date : January 27, 2006

3.2 LITERATURE REVIEW

Amongst the various synthetic routes described for the

preparation of Ranolazine, some of the key approaches are discussed

here under. Kluge.F.A et al 5 have reported two synthetic approaches for

preparation of Ranolazine 2 using commercially available 2-Methoxy

phenol 25 and 2, 6-dimethyl aniline 20 as key starting materials. The

first synthetic route commenced with the synthesis of methyl oxirane

derivative 27. Key intermediate methyl oxirane derivative 27 was

synthesized from 25 and epichlorohydrin 26 in presence of NaOH

employing Williamson reaction conditions. Thus obtained 27 treated

with piperazine 23 in ethanol to obtain hydroxyl piperazine derivative

33. Thereafter, reaction of hydroxyl piperazine derivative 33 with phenyl

acetamide derivative 22 in dimethylformamide afforded dihydrochloride

salt of ranolazine 2, which was treated with ammonia to furnish

ranolazine 2(Scheme 3.1).

Second synthetic path way for the preparation of ranolazine

involves the condensation of piperazinyl acetamide intermediate 24 and

methyl oxirane 27 in mixture of methanol and toluene (Scheme 3.2).

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O

OHOCl+

O

O

NaOH

1,4-dioxane

O

Ethanol

NH

HN

25 26 27

23

O

O

33

N

OH NH

NH2

ClCl

O

+Triethyl amine

dichloromethane

HN

Cl

O

N

NO

HN O

O

OH

20 21 22

. 2HCl

DMF

Ammonia

N

NO

HN O

O

OH

2. 2HCl

2

Scheme 3.1: Synthesis of ranolazine 2 (product patent route)

O

OHOCl+

O

O

NaOH

1,4-dioxane

O

Ethanol

NH

HN

25 26 27

23NH2

ClCl

O

+TEA

DCM

HN

Cl

O

20 21 22

MethanolToluene

N

NO

HN O

O

OH

2

HN

N

O NH

24

Scheme 3.2: Synthesis of ranolazine 2 (product patent route)

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Mingfieng.S et al reported7 similar approach for the synthesis of

Ranolazine 2 utilizing hydroxy propyl halide intermediate 94 instead of

methyl oxirane compound 27. The requisite hydroxy propyl halide

intermediate 94 prepared by reacting 2-methoxy phenol 25 with 1, 3-

dichloropropan-2-ol 93 in presence of NaOH and mixture of ethanol &

water as shown in Scheme 3.3.

O

OH

+

NaOH

Ethanol, Water

Ethanol

NH

HN

25 9394

23NH2

ClCl

O

+TEA

DCM

HN

Cl

O

20 21 22

N

NO

HN O

O

OH

2

HN

N

O NH

24

Cl Cl

OH

O

O X

OHX=Cl, Br

K2CO3

MethanolToluene

Scheme 3.3: Synthesis of ranolazine 2

Eva.C.A et al.6 discovered an alternative synthetic path way for

preparation of Ranolazine. As depicted in Scheme 3.3 reaction of phenyl

acetamide derivative 22 with diethanolamine in presence of

triethylamine and subsequent chlorination using thionyl chloride

furnishes dichloro compound 91. Condensation of dichloro compound

91 with amino isopropanol derivative 92 provided Ranolazine 2. Amino

isopropanol derivative 92 is achieved by reaction of methyl oxirane

compound 27 with ammonia.

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HN

Cl

O

22

HN

N

O

90

DiethanolamineTEA, MIBK, NaI OH

OH

Thionyl chlorideChloroform

HN

N

O

91

Cl

Cl

O

O

NaOH

1,4-dioxane

92

O

O

O27NH2

OH

Aq. acetoneTriethyl amine

N

NO

HN O

O

OH

2

Scheme 3.4: Synthesis of ranolazine 2

The above discussed reported synthetic pathways for the

preparation of ranolazine 2 suffer from the intrinsic disadvantages such

as

(i) moderate yield and purities

(ii) longer reaction times

(iii) lengthy operations and tedious workup procedures

(iv) formation of large number of impurities.

(v) usage of carcinogenic and expensive solvents like 1, 4 dioxane and

ethers

(vi) highly energy consumed operations like fractional distillation at

elevated temperature (above 200 ˚C).

Drawbacks associated with the reported procedures motivated us

to develop an efficient, commercially viable, robust, moderately greener

and large scale synthesis for ranolazine 2.

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3.3 PRESENT WORK

3.3.1 OBJECTIVE

To develop an efficient, commercially viable, robust, moderately

greener and large scale synthesis for ranolazine 2. In addition,

comprehensive study of Ranolazine 2 and its key intermediates impurity

profile including identification, synthesis and characterization of all

potential impurities.

3.3.2 RESULT AND DISCUSSION

As per the retero synthetic pathway synthesis of ranolazine 2

involves majorly four reactions (Figure 3.1).

N

NO

HN O

O

OH

N

NHO

HN

+

O

O

O

O

OHOCl+

O

HN

+HN

NH

NH2

+ Cl

O

ClCl

1

Figure 3.1: Retro-synthetic pathway for ranolazine.

1. Formation of N-alkyl linkage.

2. Williamson ether synthesis.

3. Piperazine condensation reaction.

4. Chloro acetyl chloride condensation reaction.

All the raw materials (2, 6-dimethyl aniline, chloroacetyl chloride,

piperazine, 2-methoxy phenol and epichlorohydrin) obtained from the

retro synthetic pathway were commercially available in tonnage scale.

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Based on the retro synthetic pathway way (Figure 3.1) 2-((2-

methoxyphenoxy) methyl)oxirane 27 and N-(2, 6-dimethylphenyl)-2-

(piperazin-1-yl) acetamide 24 are identified as key synthetic fragments

for the preparation of ranolazine 2. In view of this detailed study was

carried out to overcome the disadvantages associated with the key

synthetic fragments 27 & 24.

3.3.2.1 SYNTHESIS OF 2-((2-METHOXYPHENOXY)METHYL)OXIRANE

27

Methyl oxirane compound 27 is also used as a key synthetic

fragment for synthesis of methocarbamol, moprolol and mephenoxalone

8 along with the ranolazine 2 (Figure 3.2).

O

O

O

O

O

O O NH2

O

OH

Methocarbamol

Mephenoxalone

Moprolol

NH

O

OHHN

O

Figure 3.2: API prepared from methyl- oxirane 27 as key intermediate.

Reported processes for the synthesis of 27 involved the reaction of

2-methoxyphenol 25 with epichlorohydrin 26 in presence of NaOH and

1, 4- dioxane by employing Williamson ether reaction conditions. These

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processes sfuffer from the intrinsic disadvantages such as (i) moderate

yield (~60%) and less purity (~60%), (ii) use of carcinogenic and highly

expensive organic solvents like 1, 4-dioxane and ethers and (iii)

purification of crude compound using highly energy consumed fractional

distillation.9-10

Formation impurities during the synthesis of methyl oxirane

compound 27 plays a significant role on the yield and purity of the 27.

To minimize the formation of impurities in 27, identification of all

potential impurities observed during the synthesis of 27 is desired.

3.3.2.1.1 Reaction mechanism

Reaction of 2-methoxy phenol 25 with epichlorohydrin 26 usually

proceed via two mechanisms i.e. either (i) direct nucleophilic

substitution (SN2) of chlorine with phenoxide (path-1)or (ii) opening of

epoxide ring with phenoxide (path-2) followed by intramolecular

nucleophilic substitution (SNi) of chlorine with alkoxide ion (Scheme 3.6).

O

OHNaOH

O

O Na O

O

OSN2

Ring opening

O

O Cl

O Na

Intramolecularcyclisation

SNi

path 1

path 225

3

27

ClO

26

ClO

Scheme 3.6: Possible mechanism for synthesis of 27

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3.3.2.1.2 Identification of impurities

Crude compound 27 was prepared by reproducing the process

reported in literature and thus obtained crude compound 27 was

analysed in LC-MS. Based on the reaction mechanism (Scheme 3.6),

reaction conditions and molecular weight obtained in LC-MS analysis,

impurities were anticipated as chloro hydroxy compound 28, diphenyl

compound 29 and dihydroxy compound 30 (Figure 3.3). These

impurities were synthesized and confirmed by their spectral data (Mass,

IR and NMR).

O

O Cl

OH O

O OH

OHO

O O

OH O

28 29 30

Figure 3.3: Structures of related compounds 28, 29 and 30.

Based on the chemistry knowledge, reaction mechanism and

process R&D experience the following process parameters are identified

as key parameters for the synthesis of methyl oxirane compound 27 and

these conditions are plays key role for the formation of above mentioned

potential impurities.

(a) solvent,

(b) epichloro hydrin 26 mole ratio

(c) NaOH mole ratio

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3.3.2.1.3 Solvent screening for synthesis of 27

Several solvents including non polar solvents (toluene), polar

solvents (water), chlorinated solvents (dichloromethane), polar aprotic

solvents (N, N-dimethylformamide), mixture of toluene & water and

water & 1, 4-dioxane are examined. Better yield and purity was obtained

in water medium (Table 3.1, entry 3) as compared with the other organic

solvents. By considering the experimental results, cost, economic

significance and greener components water was identified as suitable

solvent for the synthesis of 27.

Table 3.1: Synthesis of 27 using different solvents

Entry Solvent*

Yield of

27

(%)

Purity by HPLC (%)

27

(%)

28

(%)

29

(%)

30

(%)

1. Water & 1,4-Dioxane 96 72.6 24.0 --- ---

2. Toluene &water 94 58.4 1.3 23.2 0.1

3. Water 96 84.0 7.8 3.7 1.5

4. Toluene 76 62.0 3.8 26.5 1.2

5. Dimethylformamide 96 81.5 0.3 13.7 0.04

6. Dichloromethane 93 70.4 4.1 12.4 3.7

7. Neat 63 54.8 0.0 19.6 0.3

3.3.2.1.3 Impact of epichlorohydrin 26 mole ratio in synthesis of 27

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Various mole ratios of epichlorohydrin 26 were screened to check

the impact of the 26 in preparation of 27. Experimental results revealed

that higher amount of diphenyl impurity 29 observed when lesser

amount of epichlorohydrin 26 was used (Table 3.2, entry 1). This

indicates that usage of less equivalence of 26 facilitate the availability of

unreacted 2-methoxyphenoxide in reaction mixture. Unreacted 2-

methoxyphenoxide remained in reaction mixture would have reacted

with 27 and leading to increase in diphenyl impurity 29. Optimal results

were obtained when 3.0 mole ratio of epichloro hydrin 26 was used

(Table 3.2, entry 3).

Table 3.2: Synthesis of 27 using different mole ratios of epichlorohydrin 3

Entry Compound 26 mole ratio

Yield of 27

(%)

Purity by HPLC (%)

27 (%) 28 (%) 29 (%) 30 (%)

1. 1.0+ 84 45.3 0.1 34.7 0.4

2. 2.0 94 82.5 1.3 10.0 1.8

3. 3.0 99 85.5 2.5 5.3 1.9

4. 5.0 99 85.4 9.6 2.2 1.1

3.3.2.1.4 Impact of NaOH mole ratio in synthesis of 27

Experimental results obtained by using different mole ratios of

NaOH as shown in Table 3.3, indicates that; 1) by decreasing the NaOH

mole ratio, higher level of chloro hydroxy compound 28 is observed, 2)

by increasing the sodium hydroxide mole ratio higher level of diphenyl

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impurity 29 were found. These results manifested that reaction was

preceded through two steps, first step is opening of epoxide ring with

phenoxide and second step is the intramolecular cyclization of chlorine

with alkoxide as shown in Path 2, Scheme 3.6. Optimum results were

obtained with 1.5 mole ratio of NaOH (Table 3.3, entry 4) when

compared with the other mole ratios of NaOH.

Table 3.3: Synthesis of 27 using different mole ratios of NaOH

Entry NaOH mole ratio

Yield of

27 (%)

Purity by HPLC (%)

27 (%) 28 (%) 29 (%) 30 (%)

1. 0.5 99 39.5 55.8 1.2 1.8

2. 1.0 93 76.2 18.8 2.3 0.9

3. 1.25 99 84.4 6.0 4.3 1.6

4. 1.50 99 85.5 2.5 5.3 1.9

5. 2.0 94 81.3 0.8 9.1 2.6

6. 3.0 94 67.9 0.3 20.0 2.9

In view of the above experimental results to further improve the

yield and purity of compound 27, NaOH was added in two lots rather

than in single lot since reaction was preceded through in-situ chloro

hydroxyl compound 28. In first lot, 0.5 mole ratio NaOH was used for

the synthesis of chloro hydroxyl compound 28 and second lot 1.0 mole

ratio NaOH was used for intramolecular cyclization of chloro hydroxyl

compound 28 obtained in first step. This modification facilitates us to

90 Chapter-3

improve the yield and purity of 27 (Table 3.4, entry 1) by controlling all

potential impurities. Formation of diphenyl impurity 29 in methyl

oxirane compound 27 is significantly controlled to below 1.0% by

removing the aqueous layer (containing unreacted 2-methoxyphenoxide),

which is obtained after completion of first step. Dihydroxy compound 30

was reduced by employing the aqueous NaOH solution washings to the

organic phase containing mixture of methyl oxirane compound 27 and

epichlorohydrin 26. Excess epichlorohydrin 26 (2.0 mole ratio of 26

remain in organic phase) was collected from the organic phase by

distillation at below 80 °C under reduced pressure and reused for the

preparation of 27.

Table 3.4: Synthesis of 27 by addition of NaOH in single lot and two

lots.

Entry Sodium hydroxide mode of addition

Yield of

27

(%)

Purity by HPLC (%)

27

(%)

28

(%)

29

(%)

30

(%)

1. Two lots (0.5 mole ratio first and 1.0 mole ratio in second lot)

95 95.9 0.5 0.6 0.2

2. Single lot (1.5 mole ratio)

99 85.5 2.5 5.3 1.9

By included all optimum conditions methyl oxirane compound 27

was prepared consistently in laboratoary and same process was

implemented in commercial scale (Table 3.5).

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Table 3.5: Synthesis of 27 by included all optimal conditions.

Entry Yield of

27

(%)

Purity by HPLC (%)

27

(%)

25

(%)

26

(%)

28

(%)

29

(%)

30

(%)

1. 95 97.2 0.2 0.2 0.1 0.4 0.3

2. 94 98.3 0.2 0.3 0.1 0.3 0.4

3. 94 98.2 0.2 0.1 0.1 0.3 0.3

The improved process having some advantages over the existing

processes including

(a) Yield was improved from ~60% to ~95%,

(b) Purity was improved from ~60% to ~98%

(c) Usage of carcinogenic and partially recoverable solvents like 1,4-

dioxane and ethers were avoided.

(d) All the potential impurities were identified, synthesized and

controlled in 27 at below 0.5% level.

(e) Highly energy consumed operations like fractional distillation at

more than 200 ˚C is avoided.

(f) Excess epichlorohydrin 26 (2.0 mole ratios) used for the reaction

was recovered and reused for synthesis of 27.

3.3.2.2 SYNTHESIS OF N-(2, 6-DIMETHYLPHENYL)-2-(PIPERAZIN-1-

YL) ACETAMIDE 24

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Preparation of N-alkyl piperazine derivative 24 involves the

chloroacylation of 2, 6-dimethyl aniline 20 using chloroacetyl chloride

21 to obtain N-chloroacetyl dialkyl aniline compound 22. Thus obtained

compound 22 was treated with piperazine 23 to afford N-alkyl

piperazine derivative 24.

After screening the various key reaction conditions (solvent, base,

temperature), we have synthesized dialkyl aniline compound 22 with

96% of the yield and 99.8% of purity using 0.5 mole ratio of Na2CO3 as

base in DCM solvent system. This step was earlier reported with the 80%

yield and ~95% purity using triethylamine as base. In addition to the

enhancement of yield and purity, tedious workup process in the reported

process was avoided by adopted simple crystallization technique.

Reaction of N-chloroacetyl dialkyl aniline compound 22 with

piperazine 23 suffers with few disadvantages such as (i) moderate yield ~

70%, (ii) No information available about the purity of N-alkyl piperazine

derivative 24, (iii) formation of large amount of bis acetamide compound

31 and (iv) usage of excess mole ratio of 23 leads to formation of

dihydroxy piperazine analogue 34 in subsequent reaction.

In order to improve the yield and purity of 24, the key parameters

like solvent and piperazine mole ratios are examined. Experimental

results revealed that acetone as solvent (Table 3.6, entry 3) using 3.0

mole ratio of 23 (Table 3.7, entry 3) offered compound 24 with optimum

yield (76%) and purity (99.6%) as shown in Table 3.6 and Table 3.7.

93 Chapter-3


Entry Solvent

Temp. ( °C)

Time (hrs)

Yield of 24 (%)

Purity of 24 (%)

Purity of 31 (%)

1. Methanol 60-65 2 76 99.5 0.1

2. Toluene 60-65 2 71 98.8 0.2

3. Acetone 50-55 2.5 71 98.7 0.4

4. Aq. HCl 60-65 2.5 61 98.7 0.4

5. Water 60-65 2 66 98.9 0.9

6. IPA 60-65 4 56 96.6 2.9

7. DMF 60-65 1.5 --- --- ---

Table 3.7: Synthesis of 24 using different mole ratios of piperazine

Entry Piperazine 23 Mole ratio

Yield of 24 (%)

Purity of 24 (%)

Purity of 31 (%)

1. 1.0 21 63.8 34.6

2. 2.0 53 98.0 1.8

3. 3.0 76 99.6 0.1

4. 4.0 77 99.5 0.1

By incorporated the all optimal conditions, we could able to

synthesize compound 24 with 76% of yield, 99.6% of purity and 0.3% of

piperazine 23. Excess piperazine 23 present in N-alkyl piperazine

compound 24 reacted with the methyl oxirane compound 27 in

subsequent step and leds to formation of related compounds 33 and 34.

94 Chapter-3

HN

O

N

NNH

O

31

O

O

HON

NH

33

O

O

HON

NOH

O

O34

Figure 3.4: Structures of related compounds 31, 33 and 34.

Attempts were made to remove the related compounds 33 and 34

in ranolazine 2 but we could not succeed since solubility profile of

ranolazine 2 and related compound 34 are similar. In view of this,

piperazine content in compound 24 was restricted to below 0.008% to

avoid the formation of the related compounds 33 and 34 in subsequent

stages by employing acidic (HCl or H3PO4) water washings to the crude

compound 24.

NaOHWater

Methanol

AcetoneMethanol80%

96%

97% 77%

O

OHOCl+

O

O

O

NH

HN

25 26 27

23NH2

ClCl

O

+TEA

DCM

HN

Cl

O

20 21 22

N

NO

HN O

O

OH

1

HN

N

O NH

24

2

Scheme 3.5: Improved synthesis of Ranolazine 2.

95 Chapter-3

After developing the efficient process for the synthesis of key

intermediates of 2 (methyl oxirane compound 27 and N-alkyl piperazine

derivative 24), our focus was moved towards final condensation step.

3.3.2.3 SYNTHESIS OF RANOLAZINE 2

Synthesis of ranolazine 2 involves condensation of methyl oxirane

compound 27 and N-alkyl piperazine derivative 24. Previously reported

processes involves (i) usage of mixture of solvents for reaction, (ii)

laborious workup procedures like distillation, extractions, washings and

recrystallization, (iii) purification of crude compound 2 by isolate

dihydrochloride salt of 2 as intermediate or usage of commercially not

viable techniques such as column chromatography.

In order to improve the process efficiency, various solvents were

screened for the synthesis of compound 2. Experimental results revealed

that acetone and acetonitrile offered compound 2 with better yield and

purity when compared with the other solvents depicted in Table 3.8. By

considering cost and solubility, acetone was selected as suitable solvent

for the synthesis of 2. This modification avoided laborious workup

procedure like distillation, extraction and washings and allowed us to

isolate crude compound 2 by simple crystallization at lower temperature

(0-5 º C). Thus obtained crude compound 2 was subjected to purification

in mixture of methanol and acetone (1:4 volumes) to afford pure

ranolazine 2(99.9%).

96 Chapter-3


Entry Solvent

Temp. ( °C)

Time (hrs)

Yield of 2 (%)

Purity of 2 (%)

1. Methanol 60-65 4.5 78 92.0

2. Ethyl acetate 75-80 13.5 80 97.0

3. Acetone 50-55 12 88 98.0

4. Acetonitrile 80-85 8 88 98.0

5. Water 95-100 7.5 61 73.0

6. IPA 80-85 8.5 71 94.0

7. DMF 75-80 4.5 89 94.0

3.4 Related substances of Ranolazine

As per the ICH guidelines, proposed limits for any known or

unknown impurity in ranolazine is less than or equal to 0.05% since

Ranolazine 2 was high dosage pharmaceutical compound (maximum

daily dosage is less than or equal to 2000 mg). The stringent regulatory

requirements indicate the importance of the potential impurities during

the synthesis of Ranolazine 2. Till now no literature precedence

available for the identification, synthesis, characterization and

controlling of the possible potential impurities formed during the

synthesis of ranolazine 2 and its key intermediates. In view of this,

comprehensive study on related compounds formed in the synthesis of

crude compound 2, and its key starting materials 27 & 24 is desired.

97 Chapter-3

In this perspective to find out the possible process related

impurities in compound 2 and its key intermediates 27 & 24, crude

compound 2 and its key intermediates 27 & 24 are analysed by Liquid

Chromatographic-Mass Spectrometry (LC-MS). Based on molecular

weight obtained in LC-MS, reaction mechanism and reaction conditions

probable impurities were anticipated and their structures were described

in figure 3.5.

O

O Cl

OH O

O OH

OHO

O O

OH O

28 29 30

HN

N

O NNH

OHN

Cl

O

Cl

31 32

O

HO

O

N

NH

O

HO

O

N

N

O

OH

O

33

34

HN

N

O N N

OH N

HN

O

HN

N

O NOH

OHN

N

O NOH

OO

O

35

36 37

Figure 3.5: Structures of ranolazine related substances

98 Chapter-3

These impurities were synthesized, characterized by spectral data

such as Mass, IR and NMR. Root cause for formation of these impurities

were identified and controlled in below 0.05% in final active

pharmaceutical ingredient and as well as in finished pharmaceuticals.

3.4.1 Synthesis and root cause for formation of related substance 28.

Related compound 28 is process related impurity formed during

synthesis of methyl oxirane compound 27. As explained above O-

alkylation of compound 25 with 26 proceeds via an in situ chloro

hydroxyl compound 28. This compound was restricted to below 1.0% in

methyl oxirane compound 27 and further controlled in ranolazine 2 at

below 0.05% level. Compound 28 was synthesized in two ways. First

synthetic route involves the reaction of 2-methoxy phenol 25 with

epichlorohydrin 26 using 0.5 mole ratios of sodium hydroxide.

Alternatively compound 28 was prepared by treating 27 with HCl.

OCl

26

O

OHNaOH

O

O Na

O

O Cl

OH

H2O25 28

O

O

O27

HCl, water

O

O Cl

OH

28

Path-1

Path-2

Scheme 3.7: synthesis of compound 28

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The ESI-Mass spectrum of chloro hydroxyl compound 28 (Fig.3.6)

displayed a protonated molecular ion at 217 m/z with positive segment

polarity and ammonium adduct molecular ion at 234.2 m/z. The IR

spectrum (Fig.3.7), absorption at 3458 cm-1 for alcoholic hydroxyl group,

2937 cm-1 for aliphatic alkyl group, 1594 & 1508 cm-1 for alkene group

and 1250 & 1225 for alkyl ether group were observed. The 1H NMR

spectrum (figure 3.8) shows the methyloxy protons at δ 3.8 (s, 3H, CH3),

methylene protons attached to chlorine at 3.68-3.72 (dd, 2H, CH2),

methylene protons attached to phenoxy group at δ 4.05-4.09 (dd, 2H,

CH2), CH proton attached to alcohol group at δ 4.2 (m, 1H, CH), hydroxyl

proton at δ 5.5 (s, 1H, OH) and aromatic protons at δ 6.8-7.0 (m, 4H, Ar-

H).

Figure 3.6: ESI mass spectrum of compound 28

O

O Cl

OH

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Figure 3.7: IR spectrum of compound 28

Figure 3.8: 1H NMR spectrum of compound 28

O

O Cl

OH

O

O Cl

OH

101 Chapter-3


Related compound 29 is formed as impurity during synthesis of

27, a key intermediate for the preparation of 2. Compound 29 was

derived from reaction of residual amount of 2-methoxy phenoxide

sodium ion with the 27 (scheme 3.8).

O

OHNaOH

O

O Naring

opening

O

O Cl

O Na

25

26

O

O O

OH O

29

SNi

ring opening

O

O

O27

Scheme 3.8: Root cause for formation of 29

Formation of related compound 29 was high when excess amount

of (more than 1.5 mole ratio) NaOH was used for synthesis of 27. This

impurity was controlled in below 0.05% in ranolazine 2 and it was

prepared by reaction of 2-methoxy phenol 25 with epichlorohydrin 26 in

presence of NaOH and 1, 4-dioxane at 100 °C.

O

O O

OH O

29

NaOH, 1,4-Dioxane

100 0 C

O

OH

25

26


102 Chapter-3

The ESI-Mass spectrum of diphenyl compound 29 (Fig.3.9)

displayed a protonated molecular ion at 305 m/z. The IR spectrum

(Fig.3.10), absorption at 2922 cm-1 for alkyl group, 1593 & 1508 cm-1 for

alkene group and 1252 & 1223 for arylalkyl ether group were observed.

The 1H NMR spectrum (figure 3.11) showed the methyloxy protons peak

at δ 3.7 (s, 6H, CH3), methylene protons attached to phenoxy group at δ

4.05-4.2 (dd, 4H, CH2), CH proton attached to alcohol group at δ 4.2 (m,

1H, CH), hydroxyl proton at δ 5.3 (s, 1H, OH) and aromatic protons at δ

6.8-7.0 (m, 8H, Ar-H).


O

O O

OH O

103 Chapter-3



O

O O

OH O

O

O O

OH O

104 Chapter-3


Dihydroxy compound 30 is process related impurity observed in

synthesis of methyl oxirane compound 27. Reaction of chloro hydroxy

compound 28 (in situ intermediate) with NaOH in presence of water

leads to the formation of compound 30. This impurity was restricted to

below 0.5% in methyl oxirane compound 27 by employing basic water

washings and further controlled to below 0.05% in final ranolazine 2.

Compound 30 was prepared by reaction of 2-methoxy phenol 25 with

glycidol 95 in presence of NaOH (Scheme 3.10).

NaOHO

OH25

O

O OH

OH

30

OHO+

95


In ESI-Mass spectrum, sodium adduct of dihydroxy compound 30

(Fig.3.12) displayed at 220.9 m/z. In the IR spectrum (Fig.3.13),

absorption at 3274 cm-1 for alcoholic group, 2928 cm-1 for aliphatic alkyl

group, 1595 & 1508 cm-1 for aromatic alkene group and 1257 & 1227

for alkyl ether group were observed. The 1H NMR spectrum (figure 3.14)

in DMSO showed methyloxy protons at δ 3.7 (s, 3H, CH3), hydroxyl

protons at δ 4.6 (s, 1H, OH) & 4.9 (s, 1H, OH) and aromatic protons at δ

6.8-7.0 (m, 4H, Ar-H). Hydroxy protons δ 4.6 (s, 1H, OH) & 4.9 (s, 1H,

OH) were absent when the compound was analysed 1H NMR spectrum

(figure 3.15) by using duterated water (D2O).

105 Chapter-3



O

O OH

OH

O

O OH

OH

106 Chapter-3

Figure 3.14: 1H NMR spectrum of compound 30 in DMSO

Figure 3.15: 1H NMR spectrum of compound 30 in D2O

O

O OH

OH

O

O OH

OH

107 Chapter-3


Bis acetamide compound 31 is process related compound formed

during the reaction of N-acetyl alkyl aniline 22 with piperazine 23. High

amount of compound 31 was observed when 1.0 and 2.0 mole ratios of

piperazine 23 were used for the synthesis of N-alkyl piperazine derivative

24. Formation of compound 31 was controlled to below 7% during the

reaction of 22 and 23 by using 3.0 mole ratios of 23. Thus observed

compound 31 (below 7%) eliminated from the reaction mixture by simple

filtration and this impurity was restricted to below 0.05% in ranolazine

2. Compound 31 was prepared by treating N-acetyl alkyl amine 22 with

piperazine 23 in methanol.

Methanol

NH

HN

23

HN

Cl

O

22

HN

N

O N

31

NH

O


The ESI-Mass spectrum, displayed bis acetamide compound 31

(Fig.3.16) protonated molecular ion peak of at 409.2 m/z. The IR

spectrum (Fig.3.17), absorption at 3303 cm-1 for amine group, 2943 cm-1

for aliphatic alkyl group and 1682 for amide group were observed. The

1H NMR spectrum (figure 3.18) in CDCl3 showed the methyl protons at δ

2.2 (s, 12H, CH3), methylene protons in piperazine δ 2.8 (t, 8H, CH2),

108 Chapter-3

methylene protons attached to piperazine at δ 3.2 (s, 4H, CH2) and

aromatic protons at δ 7.1-7.2 (m, 6H, Ar-H).



HN

N

O NNH

O

HN

N

O NNH

O

109 Chapter-3



Related compound 32 is process related impurity, formed during

the synthesis of dialkyl aniline compound 32 due to the contamination

of chloroacetyl chloride with dichloroacetyl chloride. This impurity was

controlled in ranolazine 2 at below 0.05% and it was prepared by

reaction of compound 20 with dichloroacetyl chloride 96 in presence of

sodium carbonate (Scheme 3.12).

NH2

+ ClCl

O

Cl

Dichloromethane

Na2CO3

20 96

HN

Cl

Cl

O

32


HN

N

O NNH

O

110 Chapter-3

The ESI-Mass spectrum, exhibited deprotonated (negative

segment) molecular ion peak of compound 32 (Fig.3.19) at 232 m/z. In

the IR spectrum (Fig.3.20), peaks at 3247 cm-1 for amine group and

1675 cm-1 for amide keto group were observed. The 1H NMR spectrum

(figure 3.21) in CDCl3 shows the methyl protons at δ 2.3 (s, 6H, CH3),

CH proton attached to dichloro compound δ 6.1 (s, 1H, CH), aromatic

protons at δ 7.1-7.2 (m, 4H, Ar-H) and amine proton at δ 7.7 (s, 1H, NH).



HN

Cl

Cl

O

HN

Cl

Cl

O

111 Chapter-3



Hydroxy piperazine compound 33 is observed as impurity during

the reaction of N-alkyl piperazine derivative 24 with the methyl oxirane

compound 27. This impurity was formed by reaction of residual quantity

of piperazine 23 present in N-alkyl piperazine derivative 24 with the

methyl oxirane compound 27 during the synthesis of ranolazine 2.

Formation of compound 33 in ranolazine 2 was restricted to below

0.05% by controlling piperazine 23 in compound 24 to below 0.02% and

it was prepared by treating methyl oxirane compound 27 with piperazine

23 in methanol (Scheme 3.13).

HN

Cl

Cl

O

112 Chapter-3

Methanol

NH

HN

23

O

O

O27

O

O

HON

NH

33


The ESI-Mass spectrum, displayed protonated molecular ion peak

of compound 33 (Fig.3.22) at 267 m/z. The IR spectrum (Fig.3.23)

absorption at 3436 cm-1 for amine group, 2976 cm-1 for aliphatic alkyl

group and 1221 for C-N group were observed. The 1H NMR spectrum

(figure 3.24) in CDCl3 shows the methyloxy protons at δ 3.1 (s, 3H, CH3),

methylene protons in piperazine δ 2.6-2.8 (t, 8H, CH2) and aromatic

protons at δ 6.8-7.0 (m, 4H, Ar-H).


O

O

HON

NH

113 Chapter-3



O

O

HON

NH

O

O

HON

NH

114 Chapter-3


Compound 34 is process related compound, derived by reaction of

compound 33 with methyl oxirane compound 27. As discussed above,

compound 33 is process related impurity formed by reaction of residual

quantity of piperazine 23 present in N-alkyl piperazine derivative 24

with the methyl oxirane compound 27. Related compound 33 and

compound 34 in ranolazine 2 was controlled to below 0.05% by using

compound 24 having less than 0.02% of piperazine 23. Residual

quantity of 23 present in compound 24 was eliminated by employing

acidic water (phosphoric acid) washings. Compound 34 was prepared by

reaction of methyl oxirane compound 27 with piperazine 23 in methanol

(Scheme 3.14).

Methanol

NH

HN

23

O

O

O27

O

O

HON

NOH

O

O34


The ESI-Mass spectrum, exhibited protonated molecular ion peak

of compound 34 (Fig.3.25) at 447.2 m/z. In the IR spectrum (Fig.3.26),

peaks at 3179 cm-1 for alcoholic group, 2933 cm-1 for aliphatic alkyl

group, 1250 for ether group and 1222 for C-N group were observed. The

1H NMR spectrum (figure 3.27) in CDCl3 shows the piperazine methylene

protons at δ 2.5-2.6 (m, 8H, CH2), methylene protons attached to

piperazine at δ 2.5 (d, 4H, CH2), methyloxy protons at δ 3.8 (s, 3H, CH3),

115 Chapter-3

methylene protons attached to phenoxy oxygen at δ 4.0 (d, 4H, CH2) and

aromatic protons at δ 6.8-7.0 (m, 8H, Ar-H).



O

O

HON

NOH

O

O

O

O

HON

NOH

O

O

116 Chapter-3



Synthesis of ranolazine involves the reaction of N-alkyl piperazine

derivative 24 and Methyl oxirane compound 27 in acetone. Compound 25

was formed as impurity in the synthesis of ranolazine 2. This compound

was derived from the reaction of two equivalents of N-alkyl piperazine

derivative 24 with the epichlorohydrin 26 present in methyl oxirane

compound 27. Compound 25 was prepared by reaction of N-alkyl

piperazine derivative 24 with epichlorohydrin 26 and it was controlled to

below 0.05% in final ranolazine 2.

HN

N

O N N

OH N

HN

O

35

HN

N

O NH

Cl

O

24

26

Acetone


O

O

HON

NOH

O

O

117 Chapter-3

The Mass spectrum, displayed protonated molecular ion peak of

compound 35 (Fig.3.28) at 551.4 m/z. In the IR spectrum (Fig.3.29),

peaks at 3394 cm-1 for alcoholic group, 3262 cm-1 for amine group, 1662

cm-1 for amide keto group and 1162 cm-1 for alcohol group were

observed. The 1H NMR spectrum (figure 3.30) in CDCl3 showed the

methyl protons at δ 2.1 (s, 12H, CH3), methylene group protons between

two piperazines at δ 2.2-2.4 (d, 4H, CH2), piperazine methylene protons

at δ 2.5 (m, 16H, CH2), acetanilide methylene protons at δ 3.1 (s, 4H,

CH2), aromatic protons at δ 7.0-7.1 (m, 6H, Ar-H) and amine proton at δ

9.2 (s, 2H, NH).


HN

N

O N N

OH N

HN

O

118 Chapter-3



3-Methoxy isomer of ranolazine 36 and 4-methoxy isomer of

ranolazine 37 were prepared by following the procedure used for the

synthesis of ranolazine 2 using 3-methoxy phenol and 4-methoxy phenol

HN

N

O N N

OH N

HN

O

HN

N

O N N

OH N

HN

O

119 Chapter-3

as in put material instead of 2-methoxy phenol 25. These isomers were

characterized by spectral techniques such as IR, Mass and NMR.

3.5 CONCLUSION

In conclusion, efficient, commercially viable, robust, moderately

greener and large scale process was developed for the preparation of

ranolazine 2. The possible potential impurities formed during the

synthesis of ranolazine 2 and its key intermediate N-alkyl piperazine

derivative 24 & methyl oxirane compound 27 were identified and root

cause for thier formation also presented. All impurities were synthesized

and characterized by using spectroscopic techniques (Mass, IR and

NMR).

3.6 EXPERIMENTAL SECTION

3.6.1 Process description

3.6.1.1 2-((2-methoxyphenoxy)methyl)oxirane (27)

O

O

O

NaOH solution (prepared by dissolving 16.1 g (0,402 mol) in 100

mL) was added to the reaction mixture containing 2-methoxy phenol

(25) (100 g, 0.805 mol) and water (400 mL) at ambient temperature.

Epichlorohydrin (26) (223.5 g, 2.416 mol) was added to reaction mass at

25-35 °C and stirred at same temperature for 11 hours. Organic phase

was separated, water (400 mL) and NaOH solution containing 32.2 g

120 Chapter-3

(0.805 mol) of NaOH in 100 mL of water was added to the organic phase.

After stirring the reaction mixture at 28 °C for 6 hours, layers were

separated. Organic phase was washed with 5% NaOH solution (200 mL).

Organic phase was distilled at below 85 °C under reduced pressure to

afford 95% of title compound with 98.4% purity. Excess quantity of

compound 26 was collected from distillate and reused.

IR (KBr, cm–1): 2935 (Ali, CH), 1594 and 1509 (C═C, aromatic), 1258

and 1231 (C-O-C, Aryl ethers) & 1125 (C-O epoxide).

1H NMR (400 MHz, DMSO–d6): δH 6.8-7.0 (m, 4H, Ar-H), 3.8-4.3 (dd,

2H, J ═ 5.6 Hz, 5.4 Hz, CH2), 3.7 (s, 3H, CH3), 3.2-3.4 (m, 1H, CH), 2.7-

2.8 (dd, 2H, J ═ 5.6 Hz, 5.3 Hz, CH2).

M/S (m/z): 181 (M+ + H).

3.6.1.2 2-chloro-N-(2,6-dimethylphenyl)acetamide (22)

HN

Cl

O

To the stirring suspension of Na2CO3 (43.8, 0.413 mol), 2,6-

dimethyl aniline 20 (100 g, 0.826 mol) and DCM (500 mL), chloroacetyl

chloride 21 (100 g, 0.99 mol) was added slowly at 12 °C and strirred at

same temperature for 1-2 hours. Water (1.0 L) was added to the reaction

mixture, DCM was distlled completely at below 40 °C under vacuum.

The resultan reaction mixture was cooled to ambient temperature and

stirred for 1 hour. The resulted solid was collected by filtration, washed

121 Chapter-3

with water (200 mL) and dried at 70 °C afforded 97% of title compound

with 99% of purity.

IR (KBr, cm–1): 3214 (Amine, NH), 3037 (Aromatic, =CH), 2973 (Ali, CH),

1645 (Amide, C=O), 1594 and 1537 (Aromatic, C═C).

1H NMR (400 MHz, CDCl3–d6): δH 7.8 (s, 1H, N-H), 7.0-7.3 (m, 3H, Ar-

H), 4.3 (s, 2H, CH2), 2.2 (s, 6H, CH3).

M/S (m/z): 197.9 (M+ + H).

3.6.1.3 N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (24)

HN

N

O NH

N-chloroacetyl dialkyl aniline compound (22) (100 g, 0.505 mol),

methanol (300 mL) and piperazine (23) (130.6 g, 1.518 mol) were heated

to 60 °C and stirred at same temperature for 4 hours. Methanol was

completely distilled at below 65 under vacuum. To the resultant reaction

mixture, water (800 mL) was added at 29 °C and stirred for 1 hour.

Separated undesired solid was filtered and washed with water (300 mL).

Filtrate pH was adjusted to 5.0–5.5 by using H3PO4 solution (44%, 140

mL) at 28 °C and stirred for 0.5 hours. Separated piperazine salt was

filtered. Filtrate was washed with water (100 mL) and pH was adjusted

to 10.5–10.8 by using aqueous NaOH solution (20%, 160 mL). DCM (200

mL) was added to the reaction mixture at 28 °C and stirred for 5

minutes. Organic and aqueous phases were separated, aqueous phase

122 Chapter-3

was extracted with DCM (2 x 500 mL) and the combined organic was

washed with water (300 mL). Upto 80% of organic phase was distilled at

below 40 °C, cyclohexane (500 mL) was added to the reaction mass at 40

°C and heated to 70 °C. The obtained reaction mixture was cooled to 28

°C and stirred for 1 hour. The resulted solid was collected by filtration,

washed with cyclohexane (100 mL) and dried at 55 °C to afford 89 g of

title compound with 99.8 % purity.

IR (KBr, cm–1): 3337 (Amine, NH), 3299 (Amine, NH), 2949 (Ali, CH),


1H NMR (400 MHz, CDCl3–d6): δH 8.7 (s, 1H, N-H), 7.0-7.1 (m, 3H, Ar-

H), 3.2 (s, 2H, CH2), 3.0 (t, 4H, CH2), 2.7 (t, 4H, CH2), 2.2 (s, 6H, CH3).

M/S (m/z): 248.1(M+ + H).

3.6.1.4 2-(4-(3-(2-methoxyphenoxy)-2-hydroxypropyl)piperazin-

1-yl)-N-(2,6-dimethylphenyl)acetamide (Ranolazine 2).

N

NO

HN O

O

OH

The suspension of methyl oxirane compound (27) (47.5 g, 0.264

mol), N-alkyl piperazine derivative (24) (50 g, 0.202 mol) and acetone

(250 mL) were stirred at 56 °C for 17 hours. The resultant reaction

mixture was cooled to 3 °C and stirred for 3.5 hours. The resulted solid

was filtered and washed with pre cooled acetone (50 mL). Methanol (7

mL) and wet compound was heated to 60 °C to get the clear solution.

123 Chapter-3

Acetone (28 mL) was added to the reaction mixture, cooled to 3 °C and

stirred for 4 hours. The resulted solid was collected by filtration, washed

with pre cooled acetone (5 mL) and dried at 73 °C under vacuum to

afford 59 g of title compound 2 with 99.9% purity.

IR (KBr, cm–1): 3331 (Amine, NH), 3002 (Aromatic, =CH), 2955, 2936

and 2834 (Ali, CH), 1686 (Amide, C=O), 1592 and 1495 (Aromatic, C═C),

1254 and 1022 (Ether, C-O-C) & 1125 (C-N).

1H NMR (500 MHz, DMSO–d6): δH 9.1 (s, 1H, N-H), 6.8-7.1 (m, 6H, Ar-

H), 4.8 (s, 1H, OH), 3.9 (s, 1H, CH), 3.8-3.9 (dd, 2H, J=6.5 Hz, 10.7 Hz,

CH2), 3.8 (s, 3H, CH3), 3.1 (s, 2H, CH2), 2.4-2.6 (m, 10H, CH2) 2.1 (s, 6H,

CH3).

13C NMR (500 MHz, DMSO–d6): 18.23, 39.16, 39.83, 39.50, 39.76,

39.87, 53.18, 53.31, 55.50, 61.13, 61.44, 66.63, 71.96, 112.37, 113.64,

120.74, 120.03, 126.32, 127.62, 134.97, 135.06, 148.36, 149.17,

167.97.

M/S (m/z): 428.4(M+ + H).

CHN analysis: Anal. Calcd for C24H33N3O4 (427.54): C 67.42, H 7.78, N

9.83.; Found: C 67.62 H 7.47, N 9.68.

3.6.1.5 1-(2-methoxyphenoxy)-3-chloropropan-2-ol (28).

O

O Cl

OH

124 Chapter-3

Methyl oxirane compound (27) (10 g, 0.055 mol) and concentrated

HCl (40 mL, 0.383 mol) mixture was stirred at 28 °C for 9 hours.

Toluene (200 mL) followed by water (200 mL) were added to the reaction

mass at 28 °C and stirred for 15 minutes. Organic phase and aqueous

phase were separated, aqueous phase was extracted with toluene (10

mL) and combined organic phase was distilled completely at below 70 °C

under vacuum. The resultant crude was subjected to fractional

distillation under reduced pressure, at vapor temperature 145–150 °C

(bath temperature 215–235 °C) afforded 9.8 g of title compound.

IR (KBr, cm–1): 3458 (Alcohol, OH), 2937 (Ali, CH), 1594 and 1508

(Aromatic, C═C), 1250 and 1225 (C-O-C, Aryl ethers) & 1125 and 1027

(C-O Alcohol).

1H NMR (400 MHz, DMSO–d6): δH 6.8-7.0 (m, 4H, Ar-H), 5.5 (s, 1H,

OH), 4.2 (m, 1H, CH), 4.05-4.09 (dd, 2H, dd, J ═ 4.8, 4.8 Hz, CH2), 3.68-

3.72 (dd, 2H, dd, J ═ 4.8 , 4.8 Hz, CH2), 3.8 (s, 3H, CH3).

M/S (m/z): 217 (M+ + H).

3.6.1.6 1,3-bis(2-methoxyphenoxy)propan-2-ol (29).

O

O O

OH O

NaOH (24.1 g, 0.604 mol) and water (40 mL) followed by

epichlorohydrin (26) (18.6 g, 0.50 mol) were added to the reaction

mixture containing 2-methoxy phenol (25) (50 g, 0.402 mol) and 1, 4-

125 Chapter-3

dioxane (130 mL) at 28 °C. Resultant mixture was heated to 100 °C and

stirred at same temperature for 6 hours. Toluene (100 mL) and water

(100 mL) was added to reaction mass at 28 °C. Organic and aqueous

phases were separated, aqueous phase was extracted with toluene (100

mL) and combined organic phase solvent was evaporated at below 75 °C

under reduced pressure. The obtained crude compound was subjected

to fractional distillation, at vapor temperature 210 °C under reduced

pressure to afford titled compound (60 g).


(Aromatic, C═C), 1252 and 1223 (C-O-C, Aryl ethers).


OH), 4.2 (m, 1H, CH), 4.05-4.2 (dd, 4H, J ═ 5.6 Hz, 4.8 Hz, CH2), 3.7 (s,

6H, CH3).

M/S (m/z): 305 (M+ + H).

3.6.1.7 3-(2-methoxyphenoxy)propane-1,2-diol (30).

O

O OH

OH

Mixture of 2-methoxy phenol (25) (20 g, 0.161 mol), NaOH (0.03 g,

0.001mol) and glycidol (95) (12.1 g, 0.163 mol) was heated to 95 °C and

stirred at same temperature for 11 hours. Acetic acid (1.0 mL), DCM (20

mL) followed by water (10 mL) was added to the reaction mixture at 3 °C

and stirred for 30 min. Organic phase and aqueous phase were

126 Chapter-3

separated, aqueous phase was extracted with DCM (20 mL) and

combined organic phase was distilled at below 40 °C under reduced

pressure. Hexane (50 mL) was added to the resultant crude compound

at 27 °C and stirred for 1 hour. Separated solid was filtered, washed

with hexane (20 mL). The obtained wet compound was purified in IPA to

afford titled compound (13.4 g).


(Aromatic, C═C), 1257 and 1227 (C-O-C, Aryl ethers) & 1125 and 1039

(C-O Alcohol).


OH), 4.6 (s, 1H, OH), 3.9 (m, 1H, CH), 3.7 (s, 3H, CH3), 3.4-3.5 (dd, 2H, J

═ 5.2 Hz, CH2).

M/S (m/z): 220.9 (M+ + H).

3.6.1.8 1,4-Bis-[(2,6-dimethylphenyl)-aminocarbonylmethyl]-

piperazine (31).

HN

N

O NNH

O

Mixture of N-chloroacetyl dialkyl aniline compound (22) (50 g,

0.253 mol), methanol (150 mL) and piperazine (23) (22 g, 0.255) was

heated to 65 °C and stirred at same temprature for 3 hours. Resulted

reaction mass was cooled to ambient temperature and stirred for 1 hour.

127 Chapter-3

Separated solid was filtered, washed with methanol (50 mL) and dried at

50 °C under vacuum to afford titled compound (50 g).

IR (KBr, cm–1): 3303 (Amine, NH), 2943 (Ali, CH), 1682 (Amide, C=O),

1500 and 1465 (Aromatic, C═C).

1H NMR (400 MHz, CDCl3–d6): δH 7.1-7.2 (m, 6H, Ar-H), 3.2 (s, 4H,

CH2), 2.8 (t, 8H, CH2), 2.2 (s, 12H, CH3).

M/S (m/z): 409.2 (M+ + H).

3.6.1.9 1-(2-methoxyphenoxy)-3-(piperazin-1-yl)propan-2-ol (33).

O

HO

O

N

NH

Methyl oxirane compound (27) (50 g, 0.277) was slowly added to

the reaction mixture containing methanol (250 mL) and piperazine (23)

(96 g, 1.114 mol) at 3 °C. After stirring reaction mixture at 3 °C for 3

hours quenched with water (200 mL). Product was extracted from

aqueous phase with dichloromethane (5 x 50 mL). Acetic acid (32.5 mL)

and water (200 mL) was added to the organic phase and stirred for 15

minutes. Organic and aqueous phases were separated, aqueous

ammonia (55 mL) was added to the aqueous phase and product was

extracted from aqueous phase with DCM (5 x 50 mL). Organic phase

solvent was evaporated completely under vacuum at below 45 °C to

afford titled compound (44.2 g).

128 Chapter-3

IR (KBr, cm–1): 3436 (Amine, NH), 2976 (Ali, CH), 1505 and 1456

(Aromatic, C═C), 1221 (C-N).

1H NMR (400 MHz, CDCl3–d6): δH 6.8-7.0 (m, 3H, Ar-H), 4.1 (m, 1H,

CH), 3.1 (s, 3H, CH3), 4.1 (d, 2H, J ═ 4.0 Hz, CH2), 2.4-2.8 (m, 8H, CH2).

M/S (m/z): 267.0 (M+ + H).

3.6.1.10 1-{4-[2-Hydroxy-3-(2-methoxyphenoxy)-propyl]-piperazin-1-

yl}-3-(2-methoxyphenoxy)-propan-2-ol (34).

O

HO

O

N

N

O

OH

O

Mixture of methyl oxirane compound (27) (50 g, 0.277 mol),

piperazine (23) (24 g, 0.278 mol) and methanol (150 mL) were heated to

65 °C and stirred at same temperature for 3 hours. The resultant

reaction mass was cooled to ambient temperature and stirred for 1 hour.

Separated solid was filtered and washed with methanol (25 mL). The

obtained wet compound was purified in methanol (125 mL) and dried at

65 °C under reduced pressure to afford titled compound (14 g).


(Aromatic, C═C), 1250 (Ether, C-O-C), 1222 (C-N).

1H NMR (400 MHz, CDCl3–d6): δH 6.8-7.0 (m, 8H, Ar-H), 4.0 (d, 4H, J ═

4.8 Hz, CH2), 3.8 (s, 6H, CH3), 2.5 (d, 4H, J ═ 5.2 Hz, CH2), 2.5-2.6 (m,

8H, CH2).

129 Chapter-3

M/S (m/z): 447.2 (M+ + H).

3.6.1.11 2,2-dichloro-N-(2,6-dimethylphenyl)acetamide (22).

HN

Cl

O

Cl

To the stirring suspension of 2, 6-dimethylaniline (20) (25 g, 0.206

mol), Na2CO3 (21.9 g, 0.206 mol) and DCM (500 mL) were added

dichloroacetyl chloride (96) (36.5 g, 0.248 mol) at 13 °C and stirred at

same temperature for 2 hours. Water (250 mL) was added to the reaction

mixture at 28 °C and DCM was distilled completely at below 45 °C. The

resultant reaction mixture was cooled to 28 °C and stirred for 1 hour.

Separated solid was filtered, washed with water (50 mL) and dried at 70

°C under reduced pressure to get the 38 g of titled compound with the

99 % purity by HPLC.

IR (KBr, cm–1): 3247 (Amine, NH), 3037 (Aromatic, =CH), 2925 (Ali, CH),


1H NMR (400 MHz, CDCl3–d6): δH 7.7 (s, 1H, NH), 7.1-7.2 (m, 3H, Ar-

H), 6.1 (s, 1H, CH), 2.3 (s, 6H, CH3).

M/S (m/z): 232 (M- - H).

3.6.1.12 1,3-Bis-{4-[(2,6-dimethylphenyl)-aminocarbonylmethyl]

piperazin-1-yl}-propan-2-ol (35).

130 Chapter-3

HN

N

O N N

OH N

HN

O

Mixture of N-alkyl piperazine compound (24) (50 g, 0.202 mol),

acetone (500 mL) and epichlorohydrin (26) (29.2 g, 0.316) were heated to

55 °C and stirred at 55 °C for 13 hours. Reaction mass cooled to

ambient temperature and stirred at same temperature for 1 hour.

Separated solid was filtered, the resulted wet compound was

recrystalized from isopropyl alcohol (90 mL) and dried at 55 °C under

vacuum to afford 50 g of the title compound with about 99% of purity.

IR (KBr, cm–1): 3394 (Alcohol, NH), 3262 (Amine, NH), 2937 (Ali, CH),

1662 (Amide, C=O), 1524 and 1475 (Aromatic, C═C) 1162 (Alcohol, C-O).

1H NMR (400 MHz, CDCl3–d6): δH 9.2 (s, 2H, NH), 7.0-7.1 (m, 6H, Ar-H),

3.8-3.7 (m, 1H, CH), 3.1 (s, 4H, CH2), 2.6-2.5 (m, 16H, CH2), 2.2-2.4 (d,

4H, J ═ 12.8 Hz, CH2), 2.1 (s, 12H, CH3).

M/S (m/z): 551.4 (M+ + H).

3.7 REFERENCES

(1) Allely, M. C.; Alps, B. J. Br. J. Pharmacol., 1988, 93, 375-382.

(2) Hale, S. L.; Kloner, R. A. J. Cardiovasc. Pharmacol. Ther., 2006,

11, 249-255.

(3) Fraser, H.; Belardinelli, L.; Wang, L.; Light, P. E.; McVeigh, J. J.;

Clanachan, A. S. J. Mol. Cell. Cardiol., 2006, 41, 1031-1038.

(4) Jerling, M. Clin. Pharmacokinet., 2006, 45, 469-491.

131 Chapter-3

(5) (a) Kluge, A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. G.;

Whiting, R. United states patent, US 4,567,264, 1986. (b) Kluge,

A. F.; Clark, R. D.; Strosberg, A. M.; Pascal, J. C.; Whiting, R. L.

European patent, EP 0,126,449, 1987. (c) Kluge, A. F.; Clark, R.

D.; Strosberg, A. M.; Pascal, J. C.; Whiting, R. Canadian patent,

CA 1256874, 1987.

(6) Agai-Csongor, E.; Gizur, T.; Haranyl, K.; Trischler, F.; Demeter-

Szabo, A.; Csehi, A.; Vajda, E.; Szab-Koml si, G. European patent,

EP 483932 A1, 1992.

(7) Lisheng, W.; Xiaoyu, F.; Hong-yuan, Z. Journal of Guangxi

University (Natural Science Edition), 2003, 28, 301-303.

(8) Shu-chun, L.; He-qing, H.; Zhong-jun, L. Chinese Journal of

medicinal chemistry, 2003, 13, 283-285.

(9) ICH harmonized tripartite guideline, Impurities in New Drug

Substances Q3A (R2), current step 4 version dated 25 October

2006.

(10) (a) Reddy, M. S.; Eswaraiah, S.; Satyanarayana, R. Indian patent

application 2942/CHE/2007. (b) Rahul, S.; Venkateswaran, S. C.;

Lalit, W. WO patent 2008/047,388, A2, 2008.

(11) Michel G.; Jef C.; Ivan V.; Dirk D. S.; Stef L. Org. Proc. Reas. &

Dev. 2003, 7, 939-941.

(12) Pchelka B. K.; Loupy A.; Petit A. Tetrahedron, 2006, 62, 10968-

10979.

132 Chapter-3

(13) HPLC method: Symmetry shield RP-18, 250 x 4.6 mm, 5µm; flow:

1 mL/min; eluent A: Water, pH adjusted to 5.0 with dil H3PO4; B:

Acetonitrile and water in the ratio of 800:200 (v/v); Gradient: 0

min: 70% A, 30% B; 5 min: 70% A, 30% B; 35 min: 30% A, 70% B;

55 min: 30% A, 70% B; 57 min: 70% A, 30% B; 65 min: 70% A,

30% B, UV detection at 223 nm.

(14) Wenchao, L.; Yingqi, L.; Xianglin, Z.; Chun, G.; Kai, Z. Chinese

Journal of Pharmaceuticals, 2004, 35, 641-642.

(15) HPLC method: Intertsil ODS-3V, 250 cm x 4.6 mm, 5 µm; flow: 0.8

mL/min; eluent A: buffer (weigh 1.36 g of potassium dihydrogen

ortho phosphate and 1.5 g of n-Hexane sulphonic acid sodium salt

into a 1000 mL of MQ Water, adjust the pH to 3.0 with dil.H3PO4)

and acetonitrile in the ratio of 90:10 (v/v); B: acetonitrile,

methanol and water in the ratio of 600:200:200 (v/v/v); Gradient:

0 min: 75% A, 25% B; 8 min: 75% A, 25% B; 20 min: 60% A, 40%

B; 40 min: 25% A, 75% B; 55 min: 25% A, 75% B; 57 min: 75% A,

25% B; 65 min: 75% A, 25% B, UV detection at 210 nm.

GC method: AT–1701, 30 m x 0.53 mm, 1.2 µm; split ratio: 1:5;

Carrier gas: Helium, 2.5psi (Make up gas: 30.0mL/min); Column

oven temperature: Initially held at 150 °C for 0 min, then

increased to 270 °C at a rate of 25 °C per minute and held at 270

°C for 20 min.

133 Chapter-3

(16) (a) Foye, W. O.; Levine, H. B.; Mc Kenzie, W. L. J. Med. Chem.

1966, 9, 61.

(17) (a) Xiao-lin, C.; Yong-zhou, H. West China Journal of

Pharmaceutical Sciences, 2004, 19, 191-193. (b) Lau, H. P. WO

patent 96/40664, 1996.

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