An improved process for trimethobenzamide hydrochloride

Article abstract of DOI:10.1021/op400113a

An improved process for the preparation of trimethobenzamide hydrochloride conforming to regulatory specification is reported. Specifically, a process for the 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.

Full text of DOI:10.1021/op400113a

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Full Paper
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
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Neelakandan K a,b*,Manikandan Hb, Santosha Na, and B Prabhakarana
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*Corresponding author .Fax: +91 20 39821445.E- mail address: Neelakandan.K@emcure.co.in
a API Research Centre, Emcure Pharmaceutical Limited, Hinjawadi, Pune,411057, India.
bDepartment 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 4ꢀ(2ꢀdimethylaminoethoxy)benzyl amine with 3,4,5ꢀtrimethoxy benzoic acid is described.
Introduction:
Trimethobenzamide of formula (I), chemically known as Nꢀ[pꢀ[(2ꢀdimethylamino)ethoxy] benzyl]ꢀ3,4,5ꢀ
trimethoxybenzamide 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
H
N
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).
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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 4ꢀ
(dimethylaminoethoxy)benzylamine with 3,4,5ꢀtrimethoxybenzoyl chloride in presence of organic solvent
such as benzene or acetonitrile. 4ꢀDimethylaminoethoxy benzylamine in turn, was prepared by refluxing
4ꢀhydroxybenzaldehyde with 2ꢀdimethylaminoethylchloride in chlorobenzene as solvent to obtain 4ꢀ
dimethylaminoethoxy benzaldehyde, which on reductive amination gave 4ꢀdimethylaminoethoxy
benzylamine.
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Further, the use of thionyl chloride as an acid activating agent for 3,4,5ꢀtrimethoxybenzoic acid, during
coupling reaction with 4ꢀdimethylaminoethoxy benzylamine at high temperature, is likely to give an
associated impurity II.
OMe
OMe
O
OMe
NH
O
OMe
OMe
O
N
OMe
II
US 4,983,6333 discloses a method for preparing trimethobenzamide hydrochloride comprising reaction of
acid halides, acid anhydrides or mixed anhydrides of 3,4,5ꢀtrimethoxybenzoic acid with 4ꢀ
(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 Nꢀmethyl group during coupling reaction,
which is very difficult to eliminate from the final product without affecting the yield.
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O
OMe
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N
H
H
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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 (Schemeꢀ1). The efforts are summarized in tableꢀ1.
Scheme-I
N
O
N
HO
O
O
Reagent
+
O
OMe
OMe
N
MeO
OMe
H
NH2
OMe
OMe
IV
V
I
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Table-1
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Sr. No. Reagent
Results
Reference
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1
SOCl2/Cat.DMF
Formation of Desmethyl impurity (4.0%), acid Ref. 3,4
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dimer (0.5%) and acid V (5.0%) was observed.
Tert.butyl chloroformate/TEA 53% (Low yield), formation of Desmethyl (0.78 %) Ref. 5
and acid V (20%) was observed.
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DCC/Cat. DMAP
CDI
Byꢀproduct DCU was present in API
80% yield with one unknown impurity up to 2%
63% (Low yield) and tedious work up.
Incomplete reaction after 72 h.
Ref. 6,7
Ref. 8,9
Ref. 10
Ref. 11
EDAc.HCl/HOBT
Boric acid
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 (figꢀI) 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 dimerꢀVI.
Figure-I
1
The targeted impurity was prepared synthetically as per SchemeꢀII and structure was confirmed by H
NMR and Mass spectrometry.
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Scheme-II
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N
N
N
O
O
O
CDI
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ACN
O
NH2
N
N
H
H
IV
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 Tableꢀ2
Table-2
S.NO Mol eq. of CDI % Amine dimer ImpurityꢀVI
% purity of Ia
97.39
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7
2.50
2.22
2.00
1.75
1.40
1.25
1.00
2.08
1.25
0.29
0.14
0.06
0.01
98.44
99.59
99.74
99.77
99.81
Incomplete reaction
The optimum quantity of CDI was found to be 1.25 mol. eq. in which presence of impurityꢀII, impurityꢀ
III and impurityꢀVI 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 SchemeꢀIII
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Scheme-III
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N
OH
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O
Methanolic
Ammonia/
Raney Ni
N
i) Na2CO3
+
ii) MEK
iii) Ethyl Acetate
Cl
CHO
CHO
IX
VII
VIII
N
O
O
OH
N
O
i) CDI
+
O
ii) K2CO3
iii) Ethyl acetate
OMe
OMe
MeO
OMe
N
H
OMe
NH2
OMe
V
IV
I
.HCl
N
O
i) aq. HCl
ii) Acetone
O
OMe
OMe
N
H
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
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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):
4ꢀHydroxybenzaldehyde (50 kg; 0.41 mol), sodium carbonate (151.90 kg; 1.43 mol) and 2ꢀ
dimethylamino 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 75ꢀ80 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
1
confirmed by Mass spectroscopy (M/Z: 194). HꢀNMR (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 4ꢀdimethylaminoethoxy benzaldehyde, Raneyꢀnickel (7.50 kg; 15 %) and methanolic
ammonia (300 lit; 20% solution) were taken in a pressure reactor and heated to 50ꢀ55oC for 8 hours at
hydrogen pressure 8ꢀ10 kg / cm2. After completion of reaction as monitored by TLC, the mixture was
o
o
cooled to 25 C to 30 C 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 %,
1HꢀNMR (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):
3,4,5ꢀTrimethoxy benzoic acid (63.00 kg; 0.29 mol), N, Nꢀcarbonyldiimidazole (CDI 60.65 kg; 0.37 mol)
and ethyl acetate (378 lit) were added to a flask and heated to a temperature of 50ꢀ55oC for 2 hours. After
o
o
reaction completion as monitored by TLC, the mixture was cooled to 30 C to 35 C. 4ꢀDimethylamino
ethoxy benzyl amine (63.42 kg; 0.33 mol) obtained after removal of toluene by distillation just before
o
o
use), potassium carbonate (41.00 kg; 0.30 mol) were taken in ethyl acetate (378 lit) at 25 C to 30 C
under nitrogen atmosphere. A reaction mixture consisting of Nꢀ(3, 4, 5ꢀtrimethoxybenzoyl) imidazole was
added to the above reaction mixture in drop wise manner so that the temperature is maintained below 10
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oC. 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 HꢀNMR (DMSOꢀd6): 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), 7.25ꢀ7.29 (m, 4H, CH,CH,CH,CH ), 9.01 (brs, 1H, NH), 10.41 (brs, 1H, HCl). 13 CꢀNMR
(DMSOꢀd6): 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 cmꢀ1 (ꢀNH stretch), 2957cmꢀ1 (ꢀCꢀH aliphatic
stretch), 1628cmꢀ1 (ꢀC=O stretch) 1582cmꢀ1 (ꢀC=Cꢀ ring stretch), 1236cmꢀ1 (ꢀCꢀNꢀ stretch),1128cmꢀ1 (ꢀCꢀ
Oꢀ 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.
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Example 3: Preparation of Amine-dimer impurity (VI):
4ꢀDimethylaminoethoxy benzyl amine (10 g; 1mol), N, Nꢀcarbonyldiimidazole (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 80ꢀ85oC 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
1
Compound was loaded and it’s isolated in column chromatography. Yield: 5.2 g HꢀNMR (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.
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Reference:
1) Sheiner,B.; Canad, M. A.J.; 1960, 83, 1377ꢀ1378.
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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Neelakandan K a,b*,Manikandan Hb, Santosha Na, and B Prabhakarana
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*Corresponding author .Fax: +91 20 39821445.E- mail address: Neelakandan.K@emcure.co.in
a API Research Centre, Emcure Pharmaceutical Limited, Hinjawadi, Pune,411057, India.
bDepartment of chemistry, Annamalai University, Chidhambaram, India.
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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
O
OH
N
O
i) CDI
+
O
ii) K2CO3
iii) Ethyl acetate
OMe
OMe
MeO
OMe
N
H
OMe
NH2
OMe
VI
V
I
.HCl
N
O
i) aq. HCl
ii) Acetone
O
OMe
OMe
N
H
OMe
Ia
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