An Improved Process for Trimethobenzamide Hydrochloride - Organic

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals ... Organic Process Research & Development 2016 20 (2), 140-1...
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AN IMPROVED PROCESS FOR TRIMETHOBENZAMIDE HYDROCHLORIDE Neelakandan Kaliaperumal, Manikandan Haridoss, Santosha N, and Prabhakaran B Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op400113a • Publication Date (Web): 28 Jun 2013 Downloaded from http://pubs.acs.org on July 2, 2013

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AN IMPROVED PROCESS FOR TRIMETHOBENZAMIDE HYDROCHLORIDE

Neelakandan K a,b*,Manikandan Hb, Santosha Na, and B Prabhakarana *Corresponding author .Fax: +91 20 39821445.E- mail address: [email protected] a b

API Research Centre, Emcure Pharmaceutical Limited, Hinjawadi, Pune,411057, India. Department of chemistry, Annamalai University, Chidhambaram, India.

ABSTRACT: An improved process for preparation of trimethobenzamide hydrochloride conforming to regulatory specification is reported. Specifically, a process for preparation of trimethobenzamide hydrochloride, which is free from the associated impurities that are normally encountered during coupling of 4-(2-dimethylaminoethoxy)benzyl amine with 3,4,5-trimethoxy benzoic acid is described. Introduction: Trimethobenzamide of formula (I), chemically known as N-[p-[(2-dimethylamino)ethoxy] benzyl]-3,4,5trimethoxybenzamide is administered as its hydrochloride salt (Ia) and is used as an antiemetic agent for nausea associated with gastrointestinal disturbances, motion sickness or induced by the administration of other therapeutics agents.1

O

OMe N

N H

O

OMe OMe

Trimethobenzamide (I) Trimethobenzamide hydrochloride (Ia)

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Trimethobenzamide hydrochloride (Ia) for administration as an injection (100 mg/ml) was approved by USFDA on January 1, 1982 under the brand name ‘TIGAN’. Later, on December 13, 2001, it was approved for administration as an oral capsule (300 mg). Various researchers have attempted to synthesize trimethobenzamide hydrochloride of formula (Ia). US 2,879,2932 discloses a method for preparing trimethobenzamide hydrochloride comprising reaction of 4(dimethylaminoethoxy)benzylamine with 3,4,5-trimethoxybenzoyl chloride in presence of organic solvent such as benzene or acetonitrile. 4-Dimethylaminoethoxy benzylamine in turn, was prepared by refluxing 4-hydroxybenzaldehyde with 2-dimethylaminoethylchloride in chlorobenzene as solvent to obtain 4dimethylaminoethoxy benzaldehyde, which on reductive amination gave 4-dimethylaminoethoxy benzylamine. Further, the use of thionyl chloride as an acid activating agent for 3,4,5-trimethoxybenzoic acid, during coupling reaction with 4-dimethylaminoethoxy benzylamine at high temperature, is likely to give an associated impurity II. OMe OMe O

OMe NH

O O

OMe

N

OMe OMe

II US 4,983,6333 discloses a method for preparing trimethobenzamide hydrochloride comprising reaction of acid halides, acid anhydrides or mixed anhydrides of 3,4,5-trimethoxybenzoic acid with 4(dimethylaminoethoxy)benzylamine in presence of organic solvent using base. However, the specification does not disclose any purity of the final product and further duplication of these experiments at our laboratory resulted in formation of desmethyltrimethobenzamide of formula (III) which is further

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converted to formula (II) due to the elimination of one of the N-methyl group during coupling reaction, which is very difficult to eliminate from the final product without affecting the yield. O OMe N H

H N

O

OMe OMe

Desmethyl impurity (III) Thus, there is a need to develop a process for the preparation of trimethobenzamide hydrochloride (Ia), which controls the formation of impurities below regulatory limit and does not require column chromatography or repeated crystallization for getting the desired purity.

Result and discussion: An improved process for preparation of trimethobenzamide hydrochloride, which is free from associated impurities and does not utilize column chromatography or other tedious purification methods, is reported. We started our campaign by following the reported process2 and got the required compound 1 contaminated with known impurities II and III. These impurities were identified by LCMS and isolated. To control these impurities we screened several reagents for coupling reaction of benzyl amine IV with trimethoxy benzoic acid V (Scheme-1). The efforts are summarized in table-1. Scheme-I

N

O N

O

HO

O Reagent

+

O MeO

NH2 IV

OMe

OMe

N H

OMe

OMe OMe

V

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I

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Table-1 Sr. No.

Reagent

Results

Reference

1

SOCl2/Cat.DMF

Formation of Desmethyl impurity (4.0%), acid Ref. 3,4 dimer (0.5%) and acid V (5.0%) was observed.

2

Tert.butyl chloroformate/TEA

53% (Low yield), formation of Desmethyl (0.78 %) Ref. 5 and acid V (20%) was observed.

3

DCC/Cat. DMAP

By-product DCU was present in API

Ref. 6,7

4

CDI

80% yield with one unknown impurity up to 2%

Ref. 8,9

5

EDAc.HCl/HOBT

63% (Low yield) and tedious work up.

Ref. 10

6

Boric acid

Incomplete reaction after 72 h.

Ref. 11

During this preliminary screening we found that reaction in which CDI was used as coupling reagent was monitored by TLC and found that reaction was relatively clean and free from above discussed impurities. Hence we decided to focus our attention on optimization of the process by using CDI as coupling reagent. In further study we had evaluated purity of resulting product by UPLC (fig-I) in which we encountered with one impurity which closely eluted with the drug substance and unfortunately we were unable to separate it on TLC. The resulting impurity was identified by LCMS as amine dimer-VI. Figure-I

The targeted impurity was prepared synthetically as per Scheme-II and structure was confirmed by 1H NMR and Mass spectrometry.

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Scheme-II

N

O

N

O

O

N

CDI ACN

O

NH2

N H

IV

N H

Amine dimer-VI

In order to control the impurity (VI) and to improve quality as well as yield of the API we carried out several experiments by altering mole eq. of coupling reagent CDI. The results are summarized in Table-2

Table-2 S.NO

Mol eq. of CDI

% Amine dimer Impurity-VI

% purity of Ia

1

2.50

2.08

97.39

2

2.22

1.25

98.44

3

2.00

0.29

99.59

4

1.75

0.14

99.74

5

1.40

0.06

99.77

6

1.25

0.01

99.81

7

1.00

Incomplete reaction

The optimum quantity of CDI was found to be 1.25 mol. eq. in which presence of impurity-II, impurityIII and impurity-VI was found below regulatory limits and purifications such as column chromatography or repeated crystallization were not required to attain desired purity.

Synthesis of Ia using optimized reaction conditions is depicted in Scheme-III

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Scheme-III

OH

O N

N Methanolic Ammonia/ Raney Ni

i) Na2CO3

+ ii) MEK iii) Ethyl Acetate

Cl

CHO

CHO

VII

IX

VIII

N

O N

O

OH

O

i) CDI

+ MeO

OMe

ii) K2CO3 iii) Ethyl acetate

OMe

O OMe

N H

NH2

IV

OMe

V

I N

O

OMe

.HCl

i) aq. HCl O

ii) Acetone

OMe

N H

OMe OMe

Ia

Based on the optimized conditions batch was carried out on 50 Kg scale and results were reproduced on plant level.

Conclusion In conclusion we have successfully developed an improved, commercially viable manufacturing process for trimethobenzoamide with high purity and satisfactory yield.

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Experimental details: Samples and Chemicals All the raw materials were purchased from commercial suppliers and used as such without further purification. Example 1: Preparation of 4-dimethylaminoethoxy benzyl amine (IV): 4-Hydroxybenzaldehyde (50 kg; 0.41 mol), sodium carbonate (151.90 kg; 1.43 mol) and 2dimethylamino ethyl chloride hydrochloride (100.30 kg; 0.70 mol) were added to 500 lit methyl ethyl ketone (MEK) at 25 oC to 30 oC with stirring. The reaction mixture was heated to 75-80 oC for 18hrs till completion of reaction as monitored by TLC. The mixture was cooled to 25 oC to 30 oC and filtered. The filtrate mixture was concentrated under reduced pressure to give oily mass. Desired product was confirmed by Mass spectroscopy (M/Z: 194). 1H-NMR (CDCl3): δ 2.35 (s, 6H, CH3, CH3), 2.76 (t, 2H, CH2), 4.15 (t, 2H, CH2), 7.03 (d, 2H, CH,CH), 7.83 (d, 2H, CH,CH), 9.88 (s, 1H, CHO). The Oily mass of 4-dimethylaminoethoxy benzaldehyde, Raney-nickel (7.50 kg; 15 %) and methanolic ammonia (300 lit; 20% solution) were taken in a pressure reactor and heated to 50-55oC for 8 hours at hydrogen pressure 8-10 kg / cm2. After completion of reaction as monitored by TLC, the mixture was cooled to 25 oC to 30 oC and filtered. The filtrate was concentrated under reduced pressure to provide a pure viscous oily material. This was stored as toluene solution.(yield: 63.63 kg, ),HPLC Purity ≥ 98 %, 1

H-NMR (CDCl3): δ 1.35 (brs, 2H, NH2), 2.33 (s, 6H, CH3,CH3), 2.72 (t, 2H, CH2), 3.80 (brs, 2H, CH2),

4.06 (t, 2H, CH2), 6.89 (d, 2H, CH,CH ), 7.21 (d, 2H,CH,CH), Mass:195,(M+H)+.

Example 2: Preparation of Trimethobenzamide Hydrochloride (I a): 3,4,5-Trimethoxy benzoic acid (63.00 kg; 0.29 mol), N, N-carbonyldiimidazole (CDI 60.65 kg; 0.37 mol) and ethyl acetate (378 lit) were added to a flask and heated to a temperature of 50-55oC for 2 hours. After reaction completion as monitored by TLC, the mixture was cooled to 30 oC to 35 oC. 4-Dimethylamino ethoxy benzyl amine (63.42 kg; 0.33 mol) obtained after removal of toluene by distillation just before use), potassium carbonate (41.00 kg; 0.30 mol) were taken in ethyl acetate (378 lit) at 25 oC to 30 oC under nitrogen atmosphere. A reaction mixture consisting of N-(3, 4, 5-trimethoxybenzoyl) imidazole was added to the above reaction mixture in drop wise manner so that the temperature is maintained below 10

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o

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C. After completion of addition reaction mixture was stirred for 2.5 hours till completion of reaction as

monitored by TLC. Water (63 lit) was added to the reaction mixture and organic layer separated and washed with 2% KHSO4 solution (126 lit). Layers were separated and the organic layer obtained was concentrated under reduced pressure. The residue was dissolved in acetone (756 lit) followed by addition of aqueous hydrochloric acid (30 %) solution (9.45 lit) to give title compound Ia as white solid. (Yield: 103 kg, 82%) Purity by HPLC ≥ 99.5 %.1 H-NMR (DMSO-d6): δ 2.82 (s, 6H, CH3, CH3), 3.48 (t, 2H, CH2), 3.70 (s, 3H, CH3), 3.82 (s, 6H, CH3,CH3),

4.33 (t, 2H, CH2), 4.42 (d, 2H, CH2), 6.97 (d,

2H,CH,CH), 7.25-7.29 (m, 4H, CH,CH,CH,CH ), 9.01 (brs, 1H, NH), 10.41 (brs, 1H, HCl). 13 C-NMR (DMSO-d6): δ 42.08 (CH2), 42.60 (CH3,CH3), 55.05 (CH2), 56.04 (CH3,CH3), 60.03 (CH3), 62.46 (CH2), 104.94 (CH, CH), 114.50 (CH,CH), 128.74 (CH,CH), 129.48 (C), 132.76 (C), 139.88 (C), 152.53 (C, C), 156.40 (C), 165.40 (C). Mass: 424.92, (M+H)+ IR: 3308 cm-1 (-NH stretch), 2957cm-1 (-C-H aliphatic stretch), 1628cm-1 (-C=O stretch) 1582cm-1 (-C=C- ring stretch), 1236cm-1 (-C-N- stretch),1128cm-1 (-CO- stretch).Elemental analysis: Calculated: C (59.36 %), H (6.88 %), N (6.59 %), Obtained : C (59.53 %), H (6.79 %), N (6.53 %).DSC: peak obtained at 187.65 ºC. Example 3: Preparation of Amine-dimer impurity (VI): 4-Dimethylaminoethoxy benzyl amine (10 g; 1mol), N, N-carbonyldiimidazole (CDI 6.26 g; 0.75 mol) was added to Acetonitrile (80 ml) at 25 oC to 30 oC under nitrogen atmosphere. The reaction mass heated to 80-85oC and stirrer for 2.5 hours. After reaction completion as monitored by TLC, distilled out the reaction mass completely under vacuum below 40oC and then mixture was cooled to 25oC to 30oC. Crude Compound was loaded and it’s isolated in column chromatography. Yield: 5.2 g

1

H-NMR (CDCl3): δ

2.32 (s, 12H, CH3, CH3, CH3, CH3), 2.71 (t, 4H, CH2,CH2), 4.03 (t, 4H, CH2,CH2), 4.27 (d, 4H, CH2,CH2), 4.70 (brs, 2H, NH,NH), 6.84 (d, 4H, CH,CH,CH,CH), 7.16 (d,4H, CH,CH,CH,CH).Mass:415,(M+H)+

Acknowledgment We thank Mr. Samit Mehta, our management, analytical and IPM team of Emcure Pharmaceuticals Ltd., for encouragement and support.

Supporting Information Available

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Additional characterization data of compounds Ia, II, III, IV, V and VI are provided. This material is available free of charge via the Internet at http://pubs.acs.org.

Reference: 1) Sheiner,B.; Canad, M. A.J.; 1960, 83, 1377-1378. 2) Goldberg, M. W.; Montclair, U.; Teitel, S.; Nutley, N. J.; US2879293,1959. 3) Itoh, Y.; Kato, H.; Koshinaka, E.; Ogauua, N.; Nishino, H.; Sakaguchi, J.; US 4,983,633, 1991. 4)

Rossetti, V.; Dondoni, A.; Fantin, G.; US 4,507,499, 1985.

5) Tani, J.; Yamada, Y.; Oine, T.; Ochiai, T.; Ishida, R.; Inoue, I.; J. Med. Chem. 1979, 22, 95. 6) Palle, R.V.; Nariyam, S. M.; Balaram, S.; Kaliaperumal, N.; WO109654 A2,2007. 7) Montalbetti, C. A. G. N.; Falque, V.; Tetrahedron, 2005, 61, 10827–10852. 8) Stephane, C.; Thomas, D.; Nicolas,M. Fedou.; Julian, D. Smith.; Steven, J. R. Twiddle.; Org. Process Res. Dev., 2013, 17 (2), pp 193–201 9) Wright, W. B.; Tomcufcik, A. S.; Chan, P. S.; Marsico, J. W.; Press, J. B. J. Med. Chem. 1987, 30, 2277. 10) Kim, D.; Wang. L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino, J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.; Carver, G.; Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A.; Emini, E. A.; Bioorg. Med. Chem. Lett. 2005, 15, 2129. 11) Tang, P.; Organic Synthesis, 2005, Vol. 81, p.262.

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AN IMPROVED PROCESS FOR TRIMETHOBENZAMIDE HYDROCHLORIDE

Neelakandan K a,b*,Manikandan Hb, Santosha Na, and B Prabhakarana *Corresponding author .Fax: +91 20 39821445.E- mail address: [email protected] a b

API Research Centre, Emcure Pharmaceutical Limited, Hinjawadi, Pune,411057, India. Department of chemistry, Annamalai University, Chidhambaram, India.

ABSTRACT ABSTRACT:

An improved process for preparation of trimethobenzamide hydrochloride

conforming to regulatory specification is reported. Specifically, a process for preparation of trimethobenzamide hydrochloride, which is free from the associated impurities that are normally encountered during coupling of 4-(2-dimethylaminoethoxy)benzyl amine with 3,4,5-trimethoxy benzoic acid is described.

N

O N

O

OH

O

i) CDI

+ MeO

OMe

ii) K2CO3 iii) Ethyl acetate

OMe

O OMe

N H

NH2

V

OMe

VI

I N

O

.HCl

i) aq. HCl O

ii) Acetone

OMe

N H

OMe OMe

Ia

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OMe