Identification synthesis of process-related impurities (substances)

ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate

[key intermediate of Olmesartan medoxomil (Anti hypertensive drug)]

 

G. Venkannaa2, G. Madhusudhan1*, K. Mukkanti2, Y. Sampath Kumar1

1Department of Research and Development, Inogent Laboratories Private Limited

(A GVK BIO Company), 28A, IDA, Nacharam, Hyderabad 500 076, India

2Centre for Chemical Sciences and Technology, Institute of Science and Technology,

Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India

*Corresponding Author E-mail: madhusudhan.gutta@yahoo.com

 

ABSTRACT:

During the preparation of ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole- 5-carboxylate (1), derivative, eleven related substances (Impurities and analog) were observed along with the final Imidazole derivative. Those impurities were identified as, Ethyl carbinol imidazole (13), Methoxy imidazole (14), Olefinic imidazole (15), 4-Acetyl imidazole (12), Diacetyl imidazole (16), 5-Acetyl imidazole (17), Diethyl ester imidazole (9), Acetate imidazole Impurity (23), Propionate imidazole Impurity (29), Isobutyrate Imidazole Impurity (41) and butyl  Imidazole Impurity (35). Present work describes the synthesis and characterization of all these elven impurities.

 

KEYWORDS: Ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole- 5-carboxylate (1) key intermidate of olmesartan medoxomil, synthesis and characterization of impurities.

 

 


INTRODUCTION  

Barry Lee [1] synthesised several imidazole derivatives from 2,3-aminopyridine. Synthetic nucleosides have been investigated as antiviral agents over the past 40 years. These studies have demonstrated [2] that the stability of these materials toward the major pathways of nucleoside inactivation, e.g., deamination by adenosine deaminase and glycosidic cleavage by nucleoside phosphorylases, is an important factor in the design of therapeutic agents. For these reasons, benzimidazole based nucleosides have been prepared and evaluated [3, 4] as antiviral drugs.

 

The useful chemotherapeutic activity which this compound has shown in human neoplastic disease was mentioned previously; in addition, 6-thioguanine exhibits immunosuppressive activity [5], antiviral activity [6], antiparasitic activity [7], and inhibition of protein synthesis [8]. The nucleoside derivative, 6-thioguanosine, exhibits a similar spectrum of activity [9].

 

Synthetic nucleosides containing the imidazole nucleus have already been employed in numerous chemotherapeutic applications [10]. Substituted benzimidazoles and structurally related compounds are of pharmacological and therapeutically interest [11] In some cases, bioisosteric replacement within the benzimidazole scaffold leading to imidazo [4,5-b]pyridines resulted in improved properties as compared to the corresponding parent compound [12].

 

Imidazo[4,5-b] pyridines are an important class of biologically active compounds showing high affinity to corticotropin-releasing factor [13]  and also anticancer, antiviral, antimitotic, and tuberculostatic action depending on the nature and position of substituents on the heterocycle. In addition, certain members of this class display high affinity for the AT1 receptor, and are thus potent nonpeptide angiotensin II antagonists [13].

 

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl and hydroxyalkyl substituent at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)- imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressure response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration.

 

Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (1) is a key intermediate for the synthesis of olmesartan medoxomil, which can be produced via the reaction of diethyl 2-propyl-imidazole-4,5-dicarboxylate Hiroaki Yanagisawa et.al, [14, 15] explained the preparation of Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (1).

 

The above reported (Scheme-1) processes have many disadvantages and are not ideally suited for commercial scale. These processes involve use of expensive, excess volume of solvents and excess equalent of reagents. Although the problem of formation of impurities is not addressed at several occasions, removal of this impurity has often proved to be difficult, time-consuming and costly. Considering the additional steps required to removing impurities.

 

Impurities in drugs are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulation of medicines. The presence of these unwanted chemicals even in small amount may influence the efficacy and safety of pharmaceutical products. Impurity profiling study (i.e., the identity as well as the quantity of impurity in the pharmaceuticals) is now receiving important attention from regulatory authorities. The different pharmacopoeias, such as the British Pharmacopoeia (BP) and the United States Pharmacopoeia (USP), are slowly incorporating limits to allowable levels of impurities presenting in the APIs of formulations.

 

As per ICH guidelines on impurities in new drug products,2 identification of impurities below the 0.1% level is not considered to be necessary unless the potential impurities are expected to be unusually potent or toxic. In all the cases, impurities should be qualified. If data are not available to qualify the proposed specification level of an impurity, studies to obtain such data may be needed (when the usual qualification threshold limits given below are exceeded). According to ICH, the < 2g/day 0.1 % or 1 mg per day intake (whichever is lower) > 2g/day 0.05% [16].

 

I. Source of impurities:

Synthesis-related impurities can begin from various sources and from various phases of the synthesis of bulk drugs and the preparation of pharmaceutical dosage forms. Degradation products can be formed during the synthesis, isolation of the end product, storage of the bulk drug, during formulation and storage.

 

II. Formation of impurities:

a.        Formation of impurities due to incomplete material of the synthesis reaction

b.       Impurities originating from impurities in the starting

c.        Impurities originating from solvent of the reaction

d.       Impurities originating from the Catalyst

e.        Formation of impurities due to side reactions

f.         Impurities formed during  formulation and impurities while storage

 

In general the preparation of ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole- 5-carboxylate (1), involves seven steps. Synthesis of  imidazole moieties in this improved process (Scheme 1) were derived from the imidazole-4,5-dicarbonitriles (5), which were easily prepared by heating ortho esters condensation with diaminomaleonitrile, Compound (5) Acid hydrolysis of  in 6 N HCl  gave the dicarboxylic acids (7) . After esterification of compound (7) in ethanol in the presence of hydrogen chloride, the diesters  compound (9) obtained were treated with MeMgBr or EtMgCl, to afford the ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole- 5-carboxylate (1).

 

Figure-1

 

During the preparation of imidazole derivative (1) in the laboratory, ten related substances (Impurities and analog) were observed along with the final Imidazole derivative. These impurities in HPLC, ranging from 0.05 –0.8%.We have demonstrated the synthesis and complete characterization of some of the all possible impurities of Imidazole derivative (1). This investigation helped us to establish the impurity profile of (1).

 

EXPERIMENTAL SECTION:

All reagents and solvents employed were of commercial grade and were used as such, unless otherwise specified. Reaction flasks were oven-dried at 200°C, flame dried and flushed with dry nitrogen prior to use. All moisture and air-sensitive reactions were carried out under an atmosphere of dry nitrogen. TLC was performed on Kieselgel 60 F254 silica-coated aluminium plates (Merck) and visualized by UV light (xxx nm) or by spraying with a solution of KMnO4. Organic extracts were dried over anhydrous Na2SO4. Flash chromatography was performed using Kieselgel 60 brand silica gel (230-400 mesh). The melting points were determined in an open capillary tube using a Büchi B-540 melting point instrument and were uncorrected. The IR spectra were obtained on a Nicolet 380 FT-IR instrument (neat for liquids and as KBr pellets for solids). HPLC (Agilent technologies, 1200series). NMR spectra were recorded with a Varian 300 MHz Mercury Plus Spectrometer at 300 MHz (1H). Chemical shifts were given in ppm relative to trimethylsilane (TMS). Mass spectra were recorded on Waters Quattro premier XE triple quadrupole spectrometer using either electron spray ionization (ESI) or atmospheric pressure chemical ionization (APCI) technique.

 

Preparation of 4-Acetyl-2-propyl imidazole-5-carbonitrile, 10 from 5:

To a solution of 5 (10.0 g, 64.2 mmol) in THF (100 mL) was dropwise added a solution of 1 M EtMgBr in THF (194 mL, 194 mmol) at 10-15 °C under N2. After stirring at 10-15 °C for 0.5 h, the reaction mixture was diluted with EtOAc (200 mL) and saturated aqueous NH4Cl (200 mL), successively, and then acidified with aqueous KHSO4. The organic phase was separated, dried over MgSO4, and concentrated in vacuum. The residue was purified by flash column chromatography (EtOAc/ hexane, 1:1) to give crystalline 10: yield 9.18 g (81%); mp 94-95 °C.

 

1H NMR spectrum (CDCl3/TMS): (ppm) d 1.00 (t, 3H), 1.81 (Sx, 2H), 2.72 (S, 3H), 2.79 (t, 2H), 10.70 (brs, 1H). MS (ES): m/z 178 [M+1]+.

 

Preparation of Ethyl 4-Acetyl-2-propylimidazole-5-carboxylate, 12 from 10:

A solution of 10 (4.00 g, 23.2 mmol) in 6 N HCl (60 mL) was refluxed for 8 h. After evaporation of the solvent in vacuum followed by removal of a trace of H2O by codistillation with Toluene, codistillation with EtOH, the residual solid 11 was dissolved in EtOH (60 mL). To the solution was bubbled HCl gas at room temperature for 20 min. After standing at room temperature for 16 h, the solution was concentrated in vacuo. The residue was dissolved in EtOAc and aqueous NaHCO3 and neutralized with powdered NaHCO3. The organic phase was separated, dried over MgSO4, and concentrated in vacuum. The residue was purified by flash column chromatography (EtOAc/ cyclohexane, 1:1) to give crystalline 12,  yield 3.07 g (59%); mp 81.5-83°C. 1H NMR spectrum (CDCl3/TMS): (ppm) d 0.98 (t, 3H ), 1.43 (t, 3H), 1.79 (Sx, 2H), 2.76 (S, 3H), 2.77 (t, 2H), 4.45 (q, 2H), 10.44 (br s, 1H). MS (ES): m/z 224.9 [M+1]+.

 

Preparation of Ethyl 4-(1-Hydroxy-1-methylpropyl)-2-propylimidazole-5-carboxylate, 13 from 12:

To a solution of 12 (460 mg, 2.05 mmol) in THF (5 mL) was added a solution of 2 M EtMgCl in THF (2.25 mL, 4.5 mmol) at -45 to -40 °C under N2. After stirring at -40°C for 2.5 h, EtOAc and saturated aqueous NH4Cl were added, and then the mixture was stirred for 0.5 h. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/ Ethylactete, 1:20) to give 13 as a syrup: yield 357 mg (69%); 1H NMR spectrum (CDCl3/TMS): (ppm) d 0.86 (t, 3H), 0.92 (t,3H), 1.28 (t, 3H), 1.59 (S,3H), 1.72 (sx, 2H), 1.77-1.90 (m, 1H), 1.90- 2.05 (m, 1H), 2.66 (t, 2H), 4.31 (q, 2H), 6.06 (br s, 1H). IR (Neat) 3196, 1711 (sh), 1676 cm- 1. MS (ES): m/z 255 [M+1]+.

 

Preparation of ethyl 4-(2-methoxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate, 14 from 6:

Compound 14 was prepared by using the method described for the preparation of (9), yield (69%); 1H NMR spectrum (CDCl3/TMS): (ppm) d 0.86 (t, 3H), 0.92 (t, 3H), 1.28 (t, 3H), 1.59 (s, 3H), 1.72 (sx, 2H ), 1.77-1.90 (m, 1H), 1.90- 2.05 (m, 1H), 2.66 (t, 2H), 3.71 (s, 3H), 4.31 (q, 2H), 6.06 (br s, 1H). MS (ES): m/z 255 [M+1]+.

 

Preparation of Ethyl 4-Isopropenyl-2-propylimidazole-5-carboxylate, 15 from 1:

To a solution of 1 (10.0 g, 41.6 mmol) in benzene  (200 mL) was dropwise added POCl3 (8.53 mL, 91.5 mmol), and the mixture was refluxed for 1 h. Pyridine (10.0 mL, 124 mmol) was added to the reaction mixture at room temperature, and the mixture was refluxed for 1 h. After removal of the solvent by evaporation in vacuo, the residue was dissolved in EtOAc and aqueous NaHCO3 and neutralized with powdered NaHCO3. The organic phase was separated, washed with aqueous NaCl, dried over Na2SO4, and concentrated in vacuum to give a crystalline residue, which was washed with disisopropyl ether: yield 8.39 g (91%); mp 132-133.5 °C.  1H NMR spectrum (CDCl3/TMS) (ppm): d 0.99 (t, 3H), 1.36 (t, 3H), 1.77 (sx, 2H), 2.19 (s, 3H), 2.70 (t, 2H), 4.35 (q, 2H), 5.31-5.32 (m, 2H), 5.55 (br s, 1H); IR (KBr) 1714 cm-1. MS (ES): m/z 223 [M+1]+.

 

Preparation of 1,1'-(2-propyl-1H-imidazole-4,5-diyl) diethanone, 16 from 10:

Compound 16 was prepared by using the method described for the preparation of (13), yield (81%); 1H NMR spectrum (CDCl3/TMS): (ppm) d 0.98 (t, 3H), 1.85 (m, 2H), 2.3 (m, 2H), 2.45 (s, 6H), 10.44 (br s, 1H); IR (KBr) 3430, 2925.4, 1644 cm-1. MS (ES): m/z 195 [M+1]+.

 

 

Preparation of 1-(4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazol-5-yl) ethanone, 17 from 16:

Compound 17 was prepared by using the method described for the preparation of (13) to give 17 as a syrup: yield (69%); 1H NMR spectrum (CDCl3/TMS): (ppm) d 0.98 (t, 3H), 1.43 (s, 6H), 1.65 (m, 2H), 1.85 (m, 2H), 2.45 (s, 3H); IR (KBr) 3435, 2969, 1714 cm-1. MS (ES): m/z 193 [M+1]+.

 

Preparation of 2-Methyl imidazole-4,5-dicarboxylic Acid, 21 from 18:

Compound 21 was prepared by using the method described for the preparation of (7). Yield 86%, m.p.262-265°C; IR (KBr) 3426, 1725, 1665 cm-1; 1H NMR spectrum (CDCl3/TMS): (ppm) d 2.72 (s, -CH3 ), 13.7 -14.0 (brs,2H -COOH). MS (ES): m/z 171 [M+1]+.

 

Preparation of Diethyl 2-Methylimidazole-4,5-dicarboxylate, 22 from 21:

Compound (22) was prepared by using the method described for the preparation of (9). Yield 86%,  d 97.8% purity by HPLC and Mp 84-86 °C. MS (ES): m/z 227 [M+1]+.

 

Preparation of Ethyl 4-(1-hydroxy-1-methylethyl)-2-Methylimidazole-5-Carboxylate, 23  from 22:

Compound (23) was prepared by using the method described for the preparation of (1). Yield 86%, 99.4% purity by HPLC and mp 101-104. MS (ES): m/z  213[M+1]+. 1H NMR  spectrum (CDCl3/TMS) ppm: d 1.32 (s, 3H), 1.36 (t, 3H), 4.33 (q, 2H), 5.6 (br s,-NH); MS (ES): m/z  227 [M+1]+; IR (KBr): 3354, 2932.63, 1667.29 cm-1.

 

Preparation of 2-Ethylimidazole-4,5-dicarboxylic Acid, 27  from 24:

Compound (27) was prepared by using the method described for the preparation of (7). Yield 86%, m.p.87-90°C; MS (ES): m/z 198.9 [M+1]+.

 

Preparation of Diethyl 2-Ethylimidazole-4,5-dicarboxylate, 28 from 27:

Compound (28) was prepared by using the method described for the preparation of (9). Yield 83%,  d 97.8% purity by HPLC and M.p. 84-86 °C.1H NMR spectrum (CDCl3/TMS) ppm: d 0.97 (t, 3H), 1.38 (t, 6H), 2.73  (m, 2H), 4.37 (q, 4H). MS (ES): m/z 241 [M+1]+.

 

Preparation of Ethyl 4-(1-hydroxy-1-methylethyl)-2-Ethylimidazole-5-Carboxylate, 29 from 28:

Compound (29) was prepared by using the method described for the preparation of (1). Yield 82%, 99.4% purity by HPLC and m.p 100-102.1H NMR spectrum (CDCl3/TMS) ppm: d 0.97 (t, 3H), 1.35-1.41 (m, 6H), 1.624 (s, 6H), 2.67 (m, 2H), 4.35 (q, 2H); MS (ES): m/z  227 [M+1]+; IR (KBr): 3357, 2978.97, 1670.28 cm-1.

 

Preparation of 2-Butylimidazole-4,5-dicarboxylic Acid, 33 from 30:

Compound (33) was prepared by using the method described for the preparation of (7) .Yield 87%, m.p.260-263°C; MS (ES): m/z 213 [M+1]+.

 

Preparation of Diethyl 2-butylimidazole-4,5-dicarboxylate, 34 from  33:

Compound (34) was prepared by using the method described for the preparation of (9). Yield 81%, d 97.8% purity by HPLC and m.p 85-88°C. MS (ES): m/z 269 [M+1]+.

 

Preparation of Ethyl 4-(1-hydroxy-1-methylethyl)-2-butylimidazole-5-Carboxylate, 35 from 34:

Compound (35) was prepared by using the method described for the preparation of (1) (35, Syrup). Yield: 86%; 99.4% purity by HPLC. 1H NMR spectrum (CDCl3/TMS): ppm d 0.93 (t, 3H), 1.36 (s, 6H), 1.63 (s, 6H ), 1.76 (sx, 2H), 2.67 (t, 2H), 4.37 (q, 2H). MS (ES): m/z 255 [M+1]+; IR (KBr) 3418, 2962, 1722 cm-1.

 

Preparation of 2-Isopropy imidazole-4,5-dicarboxylic Acid, 39 from 36:

Compound (39) was prepared by using the method described for the preparation of (7). Yield 80%, m.p.242-245°C; MS (ES): m/z 198.9 [M+1]+.

 

Preparation of Diethyl 2-Isopropylimidazole-4, 5-dicarboxylate, 40 from 39:

Compound (40) was prepared by using the method described for the preparation of (9). Yield: 82%, d 98.2% purity by HPLC and Mp 86-89°C; MS (ES): m/z 255 [M+1]+.

 

Preparation of Ethyl 4-(1-hydroxy-1-methylethyl)-2- Iso propylimidazole-5- Carboxylate, 41 from 40:

Compound (41) was prepared by using the method described for the preparation of (1). Yield 86%, 99.4% purity by HPLC and m.p 98-101°C; 1H NMR  spectrum (CDCl3/TMS) ppm: d 1.3 (s, 6H), 1.58 (s, 6H), 1.41 (t, 3H), 3.15 (m, 1H), 4.35 (q, 2H), 5.6 (br s, -NH); MS (ES): m/z  241 [M+1]+ ; IR (KBr); 3393, 2980.52,1677 cm-1.


 

RESULTS AND DISCUSSION:

 

Scheme-1

 


 

When the synthesis of the impurity is very problematic, moreover impossible. In these exceptional cases the synthesis can be omitted from the protocol of impurity profiling and the impurity standard can be prepared using preparative HPLC. Taking an important view of impurity profile and these stringent levels in imidazole derivative (1), begin to study the impurity levels in ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole- 5-carboxylate (1).

 

While conducting experiments in the laboratory for the preparation of ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole- 5-carboxylate (1) we have found eleven impurities in high performance liquid chromatographic (HPLC) method whose area percentage ranged from 0.08 to 0.5%. The same samples were analyzed by LC-MS method and identified peaks of Impurity (9) m/z 255, Impurity (13) m/z 255, Impurity (14) m/z 255, Impurity (15) m/z 223, Impurity (12) m/z 255, Impurity (16) m/z 195, Impurity (17) m/z 211, Impurity (23) m/z 213, Impurity (29) m/z 227, Impurity (35) m/z 254, Impurity (41) m/z 241.These impurities were synthesized individually and characterized based on the spectroscopic data (HPLC, IR, NMR and MS). The structures of these impurities were shown in table (Table: 1).

 

i. The synthetic path ways of impurities formation

The intermediate used in the preparation of ethyl 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (1) is imidazole-4,5-dicarbonitriles (5), the some amount of the starting material (4) remains as unreacted with hydrochloric acid and carry forward for the next stages which result in the occurrence of impurity (13), (12), (16) and (17) at the final stage. During the Grignard reaction of (9) ethyl magnesium bromide containing methanol, result in the formation of impurity (14). In the preparation of the intermediate compound (1), the dehydration of compound (1) in the presence of acidic medium to form impurity (15).

 

During the preparation of compound (1), the traces amount of ortho esters (18), (24), (30) and (36) is carry forward to further reaction and react with diaminomaleonitrile (2) resulted in the formation of imidazole-4,5-dicarbonitriles (19), (25), (31) and (37) which undergoes acid hydrolysis of (19), (25), (31) and (37) in 12 N HCl gave the dicarboxylic acids (21), (27), (33), and (39). After esterification of (21), (27), (33), (39) in ethanol in the presence of hydrogen chloride, the diesters (22), (28), (34) and 40 obtained were treated with EtMgCl, to afford the impurities (23), (29), (35) and (41).


 

Table: 1 Compound (1) impurities

S.No

Compound/Impurity

m/z

Structure

RRT

Purity by HPLC (%)

Nature

1

Compound-1

241

 

1.0

99.5

Intermediate

2

Impurity -9

255

 

1.33

98.2

Process related

3

Impurity -13

255

 

1.84

95.8

Process related

4

Impurity -14

255

 

1.72

96.2

Process related

5

Impurity -15

223

 

0.92

98.4

Process related

6

Impurity -12

225

 

0.75

95.7

Process related

7

Impurity -16

195

 

0.64

96.7

Process related

8

Impurity -17

211

 

0.62

94.8

Process related

9

Impurity -23

213

 

0.47

97.1

process related

10

Impurity -29

227

 

0.85

98.4

Process related

11

Impurity -35

254

 

2.1

97.3

Process related

12

Impurity -41

241

 

2.2

98.3

Process related

 


ii. Synthesis of impurities

The 4-acetyl impurity (12) has been synthesized according to the synthetic sequence shown in (Scheme 2). Treatment of dicyanoimidazole (5) with methyl magnesium chloride in THF followed by acidic work up afforded the corresponding acetyl derivative (10), which on acid hydrolysis under reflux provided the corresponding acid (11). The imidazole acid (11) on esterification with ethanol and thionyl chloride provided the ethyl ester of ethyl 4-Acetyl-2-propylimidazole-5-carboxylate (12). Compound (12) were treated with  EtMgCl to afford the (Scheme 2)  ethyl 4-(1-Hydroxy-1-methylpropyl)-2-propylimidazole-5-carboxylate (13).


 

Scheme-2

 

 

The impurity (14) is prepared (Scheme 3) from diester compound (6) with Grignard reagent as methyl magnesium chloride in THF at ambient temperature.

 

 

Scheme 3

 

Preparation of (Scheme 4) dehydro imidazole impurity (15), originated from the imidazole ester derivative (1). Dehydration of (1) with POCl3 in benzene under reflux conditions provided the corresponding dehydro impurity

 

(15),

Scheme 4

 

The synthesis of 5-acetyl impurity (17) commenced from the imidazole acid derivative 8, which is one of the intermediates in the synthesis of (10). The Grignard reaction of (10) with excess moles of methyl magnesium chloride (15eq.CH3MgCl) in anhydrous THF afforded 5-acetyl imidazole derivative (16), which on further reaction  with methyl magnesium chloride (4.5eq.CH3MgCl) in anhydrous THF afforded1-(4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazol-5-yl) ethanone (17),

 

Scheme 5

 

The acetate imidazole impurity (23) has been synthesized according to the (Scheme 6) imidazole-4,5-dicarbonitriles (19), which were  prepared by heating ortho esters (18) with diaminomaleonitrile , which on acid hydrolysis under reflux provided the corresponding acid (21). The imidazole acid (21) on esterification with ethanol and thionyl chloride provided the compound (22), which on further treatment  with ethyl magnesium chloride in THF followed by acidic work up afforded the corresponding impurity ethyl 4-(2-hydroxypropan-2-yl)-2-methyl-1H-imidazole-5-carboxylate (23),

 

Scheme 6

The Propionate imidazole Impurity (29) is prepared (Scheme 7) by compound (24) condensations with diaminomaleonitrile (2) by heating to gave imidazole-4,5-dicarbonitriles (25). Acid hydrolysis of (25) in hydrochloric acid gave the dicarboxylic acids (27). After esterification of (27) in ethanol in the presence of hydrogen chloride, the diester (28) obtained were treated with ethyl magnesium chloride to afford the impurity ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl) imidazole-5-carboxylate

 

(29).

Scheme -7

The butyl imidazole impurity (36) is prepared  (Scheme -8) by the condensation of compound (2) with (30) to give compound (31), which on further hydrolysis with hydrochloric acid to give impurity (33). The imidazole acid (33) on esterification with ethanol and thionyl chloride provided the compound (34), which on further treatment  with ethyl magnesium chloride in THF followed by acidic work up afforded the corresponding impurity ethyl 2-butyl-4-(2-hydroxypropan-2-yl)-1H-imidazole-5-carboxylate (35).

 

Scheme -8  

 

The is butyrate imidazole impurity (41) was prepared (Scheme-9) from  imidazole-4,5-dicarbonitriles (37), which were prepared by heating ortho esters (36) with   diaminomaleonitrile (2). Acid hydrolysis of 38 in hydrochloric acid gave the dicarboxylic acids (39). After esterification of (39) in ethanol in the presence of thionyl chloride, the diesters (40) obtained were treated with ethyl magnesium chloride, to afford the ethyl 4-(2-hydroxypropan-2-yl)-2-isopropyl-1H-imidazole-5-carboxylate (41).

 

 

Scheme -9

 

iv. Spike of impurities 4, 6, 7, 8, 9, 10 with Compound 1

A typical analytical LC chromatogram of a laboratory batch of imidazole derivative compound 1 bulk drug was recorded using the LC method. The target impurities under study are marked as impurity (9) retention time ratio (RRT): 1.33, molecular weight (MW): 255), impurity (13) (RRT: 1.84, MW: 255), impurity (14) (RRT: 1.72, MW: 255), impurity (15) (RRT: 0.92, MW: 223), impurity (12) (RRT: 0.75, MW: 225), impurity (16) (RRT: 0.64, MW: 195), impurity (17) (RRT: 0.62, MW: 211), impurity (23) (RRT: 0.47, MW: 213),  impurity (29) (RRT: 0.85, MW: 227), impurity (35) (RRT: 2.1, MW: 254), impurity (41) (RRT: 2.2, MW: 241. The HPLC compatible method is described in which all the impurities are used to detect (Fig: 2, Fig: 3). The structures of these impurities are shown in Table: 1. Impurities (15), (12), (16), (17), (23) and (29) are polar and impurities (9), 13, 14, (35) and (41) are non-polar with respect to imidazole derivative (1).

 

Fig. 2: HPLC chromatogram of imidazole derivative (1) laboratory Sample spiked with eleven impurities.

 

 

Fig. 3:  HPLC chromatogram of imidazole derivative (1) laboratory sample spiked with eight impurities.

 

 

 


CONCLUSION:

The possible process-related impurities of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate [key intermediate of Olmesartan medoxomil (anti hypertensive drug)] are identified by LC-MS data followed by confirmation by chemical synthesis and characterization using analytical tools such as HPLC and  1HNMR, C13 NMR , IR, Mass  and Melting point.

 

ACKNOWLEDGEMENT:

The authors thank Inogent Laboratories Private Limited (A GVK BIO Company) for the financial support and encouragement.

 

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Received on 07.02.2015         Modified on 25.02.2015

Accepted on 19.03.2015         © AJRC All right reserved

Asian J. Research Chem 8(5): May 2015; Page 307-317

DOI: 10.5958/0974-4150.2015.00051.6