RO133502A2 - Alternative method for preparing 2-ethoxy-benzimidazole-7-carboxylic acid derivative - Google Patents

Abstract

The invention relates to a process for preparing a 2-ethoxy-benzimidazole-7-carboxylic acid derivative to be used in the synthesis of antihypertensive drugs. According to the invention, the process consists in the condensation reaction of 4-(2-cyanobiphenyl) benzyl bromide with methyl 2-amino-3-nitrobenzoate in dimethylformamide medium, at a temperature of 100°C, resulting in 1-[(2'-cyanobiphenyl)-4-yl-methyl] -2-ethoxy-benzimidazole-7-carboxylic acid methyl ester.

Description

Alternative method of obtaining a 2-ethoxy-benzimidazole-7-carboxylic acid derivative

The invention relates to a process for the preparation of an intermediate used in the synthesis of drugs having an action on the renin-angiotensin-aldosterone system (angiotensin II AT1 receptor antagonists) which are known as sartans.

Hypertension (HTA) is known to be a major public health problem, being the most common cardiovascular disease and one of the causes that keep heart disease in the first place in terms of morbidity and mortality.

The antihypertensive drugs are very numerous and varied, both in terms of mechanism of action and structure.

According to the mechanism of action, antihypertensive agents can be classified into agents with peripheral vascular action, with inhibitory action on the adrenergic vegetative nervous system, with action on the renin-angiotensin-aldosterone system and with diuretic action.

Drugs acting on the renin-angiotensin-aldosterone system (angiotensin II AT1 receptor antagonists) are known as Sartani.

The renin-angiotensin-aldosterone (SRAA) system is today considered a complex neurohormonal system, with a central role in controlling blood pressure (TA) values, controlling the structure and functionality of the cardiovascular system and maintaining the hydroelectrolyte balance.

In the antihypertensive medication, the selective antagonists for the AT1 receptors are of the greatest therapeutic importance. Chemically, non-peptide angiotensin II receptor antagonists are heterocyclic compounds with a large structural variety.

Depending on the chemical structure, sartans can be classified into the following classes of compounds:

- Biphenyl-tetrazolic, imidazolic ring compounds: losartan (1) [US5128355], irbesartan (2) [WO

2007/122508], olmesartan (3) [US2015 / 239854]

1.Losartan

2. Irbesartan

3. Olmesartan

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- Compounds with biphenyl-tetrazole, non-imidazole ·. valsartan (4) [W02004 / 101534], candesartan (5) [Joumal of Medicinal Chemistry, 1993, vol. 36, (15), pp. 2182 2195; US 5705517; EP1420016 A, 2004; WO2006 / 63578]

4. Valsartan

5. Candesartan

6.Eprosartan

- Non-biphenyl-tetrazolic, imidazolic nucleus compounds: eprosartan (6) [WO 2011/4384],

-Non-biphenyltetrazolic, non-imidazolic compounds: telmisartan (7) [WO2004 / 87676], azilsartan (8) [US 5243054, US 2005/0187269]

7.Telmisartan

The technical problem to be solved by the invention is to identify an alternative method for the synthesis of 1 - [(2'-cyanobiphenyl) -4-yl methyl] -2-ethoxy-benzimidazole-7-carboxylic acid methyl ester. two medicines from the sartans class: Candesartan and Azilsartan.

Candesartan cilexetil (9) is known to have been developed at Takeda Chemical Industries Ltd., in order to identify a long-acting non-peptide angiotensin II receptor antagonist. The drug is marketed by AstraZeneca and Takeda Pharmaceuticals under the following trade names: Blopress, Atacand, Amias and Ratacand. Candesartan cilexetil is the prodrug of candesartan (2-ethoxy-1 - [[2 - (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylic acid).

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9. Candesartan cilexetyl (±) -l - [[((cyclohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) [1, rbiphenyl] -4-yl ] methyl] benzimidazol-7-carboxylate,

One of the synthesis pathways of Candesartan cilexetil is described in Scheme No. [Joumal of Medicinal Chemistry, 1993, vol. 36, (15), pp. 2182 2195; US 5705517; EP 1420016; WO2006 / 63578J. This synthesis pathway consists in the condensation reaction between 2-tert-butoxycarbonyl amino-3-nitro benzoate of alkyl (1) (R = methyl or ethyl) with 4- (2-cyanobiphenyl) -benzyl (2) bromide. Compound 2- [N- (tert-butoxycarbonyl) -N - [(2'-cyanophenyl-4-yl] -methyl] amino] -3-nitro benzoate (R = methyl, ethyl) (3), obtained in following the hydrolysis reaction in acid medium, it generates compound (4): alkyl (R = methyl, ethyl) 2 - [(2'-cyanobiphenyl) amino J3-nitrobenzoate, which by reduction leads to the formation of derivative (5): 3amino2 - [[ Alkyl (2'-cyanobiphenyl4-yl) methyl] amino] benzoate (R = methyl, ethyl) Cyclo-condensation reaction with tetraethyl orthocarbonate and acetic acid, or with triethylortoformate of compound (5), yields the ester of [1]. (2'-cyanobiphenyl) -4-yl methyl] -2-ethoxy-benzimidazole-7-carboxylic acid (6) Compound (6) is further treated with trimethyl tin azide in toluene at reflux to generate compound (7) which in following the hydrolysis reaction in basic medium leads to the formation of candesartan (2-ethoxy-1 - [[2 '- (1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] -benzimidazole-7-carboxylic compound. (8) (2-ethoxy-1 - [[2 '- (Ntriphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] -benz imidazole-7-carboxylic acid) obtained as a result of the protective reaction with trityl chloride and triethyl amine in the corresponding solvent, is subjected to the esterification reaction with 1-halogenoethyl cyclohexyl carbonate, generating candesartan cilexetyl trityl (9), a compound which after the hydrolysis reaction (in acidic medium) leads to the obtaining of candesartan cilexetil.

Compound (6): 1 - [(2'-cyanobiphenyl) -4-yl methyl] -2-ethoxy-benzimidazole-7-carboxylic acid ester is also a key intermediate in the synthesis of another sartan: azilsartan, the synthesis of which is described in Scheme No. 2. [Joumal of Medicinal Chemistry 1996, 39, 5228 - 5235].

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Scheme No.4 Synthesis of Candesartan cilexetil

Scheme No.2 Synthesis of Azilsartan Medoximil

The process for obtaining 1 - [(2'-cyanobiphenyl) -4-yl methyl] -2-ethoxybenzimidazole-7-carboxylic acid methyl ester is represented by Reaction Scheme No. 3.

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Scheme No. 3 Synthesis of 1 - [(2'-cyanobiphenyl) -4-yl methyl] -2-ethoxybenzimethyl-7-carboxylic acid methyl ester

The synthesis starts from italic anhydride (10), which is nitrated with nitric acid, in sulfuric acid medium [H. Sanielevici, F. Urseanu, Synthesis of aromatic intermediates 1, 1983, 315-317]. A mixture of acids is obtained: 3-nitrophthalic and 4-nitrophthalic. By recrystallization from hot water, the harder soluble 3-nitrophthalic acid (11) is obtained, which further by esterification with trimethyl orthoformate (TOF) in the presence of methanol concentrated sulfuric acid [J. Med. Chem. 1993, 36 (15), 2182-2195., EP 1420016] results in the ester of 3-nitrophthalic acid, methyl 2-carboxy-3-nitrobenzoate (12). The methyl ester is further subjected to a chlorination reaction. The chlorination reaction can be carried out using as chlorinating agents: thionyl chloride [WO 06063578], thionyl chloride in the presence of Ν, Ν-diethylfomamide, [J. Med. Chem. 1993, 36 (15), 2182-2195] or phosphorus pentachloride [Journal of the Chemical Society 109, 1916,233.], Obtained acid chloride, methyl-2- (chlorocarbonyl) -3-nitrobenzoate (13), is in further treated with sodium azide, leading to the formation of the corresponding azide, methyl-2- (azidocarbonyl) -3-nitrobenzoate (14), which without being isolated from the reaction mass, by heating to reflux in iert-butanol leads to the formation of the intermediate key in the synthesis of candesartan, methyl 2- (N- / er- -butoxycarbonylamino) -3-nitrobenzoate (1), crystallized product in the form of light yellowish prisms. By condensation between the compound

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By applying the invention, the advantage is obtained, that, obtaining the methyl ester of 1 - [(2-cyanobiphenyl) -4-ylmethyl] -2-ethoxy-benzimidazole-7-carboxylic acid occurs in high yields, through a sequence of 2 phases starting from from methyl-2- (azidocarbonyl) -3-nitrobenzoate:

> synthesis of methyl 2-amino-3-nitro-benzoate (14);

> methyl 2 - ((2'-cyanobiphenylamino) -3-nitrobenzoate (4) synthesis, with a 100% conversion of 4- (2-cyanobiphenyl) -benzyl bromide (2) and with 70-80 recovery % of methyl 2-amino-3-nitrobenzoate

The invention is further illustrated by 9 non-limiting examples:

Example 1

Synthesis of 3-nitrophylic acid (11)

A mixture of 148 g (1 mol) phthalic anhydride (10), 247 mL nitric acid and 202 mL sulfuric acid is heated slowly, with stirring, to 75 ° C, then very slowly to 80 ° C, when energetically triggered. nitration reaction. After the nitration reaction is further softened, the reaction mass temperature is raised to 100 ° C, and maintained for 2 hours at the same temperature, under vigorous stirring. Cool the reaction mass, under stirring, to 70 ° C, then by ice-cooling to 45 ° C, pour over a mixture of ice cold water (500 g ice and 100 mL cold water). Filter the precipitate formed (a mixture of 3-nitrophenic acid and 4-nitrophthalic acid) and wash with cold water. The crude product obtained is recrystallized from water, yielding 85.87 g of pure 3-nitrophenic acid (mp = 217-218 ° C, CSS: Silicagel GF254, elution system: ethyl acetate: methanol: acetic acid = 90:13 : 1, (v: v: v), row 40.66%)

Elemental analysis: C ₈ H ₅ NO6; M = 211.14 g / mol

Calculated values: C: 45.51%; H: 2.39%; N: 6.63%

Experimental values: C: 45.46%; H: 1.67%; N: 6.65%.

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H-NMR (dmso-d6, δ ppm, J Hz): 8.29 (dd, 1H, H-4, 0.8, 8.0); 8.21 (dd, 1H, H-6, 0.8, 8.0); 7.78 (t, 1H, H-5, 8.0).

¹³ C-NMR (dmso-d6, δ ppm): 166.08 (C-8); 165.86 (C-7); 146.51 (C-3); 135.07 (C-5); 131.33 (C-6); 130.78 (Cl); 130.63 (C-4); 127.68 (C-2).

Example 2

Synthesis of methyl 2-carboxy-3-nitro-benzoate (12)

To a solution of 25 g (0.118 moles) of 3-nitrophthalic acid (11) and 57 mL of methanol, 17.21 mL of trimethyl orthoformate (106.12 g / mol, 0.9676 g / cm ^3, 0.16 moles) and 2.2 was added with stirring. mL concentrated sulfuric acid (1.98 g / cm ³ ), then heated to reflux, with stirring for 23 hours. The reaction is monitored by thin layer chromatography (CSS), elution system: ethyl acetate: methanol: acetic acid (90: 13: 1) (v: v: v). At the end of the reaction regime, the solvent is removed by vacuum distillation. The crude product obtained is purified by recrystallization from water. Yield 23 g of methyl-2-carboxy-3-nitro-benzoate (3) (mp = 162.5-165 ° C, CSS: Silicagel GF254, elution system: ethyl acetate: methanol: acetic acid = 90: 13: 1, (v: v: v); row 86.56%).

Elemental analysis: C9H7NO6; M = 225.17 g / mol

Calculated values: C: 48.0%; H: 3.14%; N: 6.22%.

Experimental values: C: 47.78%; H: 2.77%; N: 6.48%.

H-NMR (dmso-d6, δ ppm, JHz): 8.33 (dd, 1H, H-5, 1.4, 8.0); 8.21 (dd, 1H, H-3, 1.4, 8.0); 7.82 (t, 1H,

H-4, 8.0), 3.86 (s, 3H, H-9, CH ₃ ).

^{, 3} C-NMR (dmso-d6, δ ppm): 165.75 (C-7); 164.78 (C-8); 146.54 (C-6); 134.88 (C-4); 130.87 (C-3);

130.61 (C-2); 129.94 (C-5); 128.05 (C-l); 53.07 (C-9).

Example 3

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Synthesis of methyl-2- (chlorocarbonyl) -3-nitrobenzoate (13)

Over a solution of 4.5 g (0.02 mol) methyl-2-carboxy-3-nitro-benzoate (12), 25 mL chloroform and 1 ml Ν, Ν-dimethylformamide, under stirring and cooling (temp. 5 ° C) bite 2.7 mL (4.40 g, 0.037 mol) thionyl chloride. After adding the whole amount of thionyl chloride, the reaction was stirred for a further 30 minutes at room temperature, then heated at reflux for 4 hours. At the end of the reaction regime, the reaction mass is cooled to room temperature, then to 0-5 ° C and then the pH is adjusted to 10-10.5 with 20% sodium carbonate solution.

The phases are separated and the aqueous phase is further extracted with 25 mL chloroform. The combined organic phases were washed with 25 mL of distilled water (pH = 8), dried over anhydrous sodium sulfate and filtered. The resulting organic phase contains methyl-2- (chlorocarbonyl) -3-nitrobenzoate which is used in the next step of synthesis without isolating the compound from the reaction mixture.

Example 4

Synthesis of methyl 2- (azidocarbonyl) -3-nitrobenzoate (14)

Over a mixture of 1.82 g (0.028 moil) sodium azide and 10 mL of Ν, Ν-dimethylformamide, at 5 ° C, the chloroform solution containing methyl-2- (chlorocarbonyl) -3-nitrobenzoate (13) is dripped. ), obtained at the previous stage (Example 3), and stirred for another hour at the same temperature. When the reaction is ready, add 40 ml of water to the reaction mixture at 5 ° C. The phases are separated and the aqueous phase is extracted with 50 ml of chloroform. The combined organic phases were washed with 40 mL of water and dried over anhydrous sodium sulfate. The resulting chloroform solution contains methyl-2- (azidocarbonyl) -3-nitrobenzoate (14) and is sent to the next step of synthesis without azide isolation.

Example 5

Synthesis of methyl 2- (tert-butoxycarbonylamino) -3-nitrobenzoate (1)

Above the chloroform solution obtained in the previous step (Example 4), containing methyl-2 (azidocarbonyl) -3-nitrobenzoate (14) drop 9 mL (0.095 moles) of tert -butanol at 30 ° C and stir for a further 15 minutes. at the same temperature. The reaction mixture is gradually heated to a temperature of 95 ° C. The reaction mixture was stirred at the same temperature for a further 30 minutes, then cooled to 30 ° C. Over the cooled mixture, drop 40 mL of distilled water and stir for 60 minutes to precipitate the product. The precipitate obtained was washed with water, dried, and dissolved in ethyl acetate. The residue obtained by vacuum concentration of ethyl acetate, anhydrized with anhydrous sodium sulfate. (3.55 g), purified by flash chromatography on silica gel column, hexane elution system: ethyl acetate (5: 1) (v.v), then by recrystallization from methanol. Thus, 3.44 g of 2-tert-

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12/15/2017 Methoxycarbonylamino) -3-nitrobenzoate in the form of weak yellow crystals (mp = 104-105.5 ° C; CSS: Silicagel GF254, elution system: ethyl hexamacetate system (5: 1) (v: v) ; row. 58%).

Elemental analysis: C13H16N2O6; M = 296.28 g / mol

Calculated values: C: 52.7%; H: 5.45%; N: 9.45%.

Experimental values: C: 52.65%; H: 5.22%; N: 9.52%.

CH ₃ h (-CH ₃ ch ₃ 'H-NMRidmso-dâ, δ ppm, JHz): 9.53 (bs, 1H, NH, deuterable); 8.11 (dd, 1H, H-4, 1.6, 8.3); 8.05 (dd, 1H, H-6, 1.6, 8.3); 7.46 (t, 1H, H-5, 8.3); 3.84 (s, 3H, H-8); 1.42 (s, 9H, H-ll) ¹³ C-NMR (dmso-d6, δ ppm): 165.71 (07); 152.70 (09); 144.65 (C-3); 134.47 (04); 131.00 (02); 128.52 (CH-6); 126.67 (Cq-I); 125.00 (CH-5), 80.62 (010); 52.70 (08); 27.85 (011) .FT-IR (A1R solid, vcm-j: 3284m; 3089w; 3014w; 2987w; 1728m; 1697vs; 1606w; 1580w; 1534s; 1491m; 1443w; 1394s; 1359m; 1310sh; 1271s; 1210m; 1153s ; 1132m; 1044w; 1012m; 981w; 91 lw; 839w; 770m; 747m; 713m.

Example 6

Synthesis of 2- (tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl) methyl) amino) -3-nitrobenzoate (3) (BBN)

A mixture of 4.47g (0.015 moles) of 2- (tert-butoxycarbonylamino) -3-methyl nitrobenzoate (1), 50 mL of acetonitrile and 4 g (0.0289 moles) of anhydrous potassium carbonate is heated to 30 ° C, The mixture was stirred for 45 minutes, followed by the addition of 8 g (0.0294 moles) of 4- (bromomethyl) -2'-cyanobiphenyl (2) dissolved in 25 mL acetonitrile. The reaction mixture was further stirred for 14 hours at reflux. The reaction is monitored by thin layer chromatography (CSS), elution system: heptane: ethyl acetate (2: 1) (v: v), UV visualization. At the end of the reaction regime, the reaction mixture is filtered, after which the filtrate is concentrated to the rotary evaporator. The crude product obtained was purified by recrystallization from methyl alcohol to give 4.38 g of pure methyl 2- (tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl) methyl) amino) 3-nitrobenzoate (3). pale yellow crystals with mp = 150.7-151.7 ° C; CSS: Silicagel GF254, elution system: heptane system: ethyl acetate (2: 1) (60% row.)

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BBN 'H-NMR (dmso-d6, δ ppm, JHz): 8.16 (dd, 1H, H-4, 1.2, 8.2); 8.05 (dd, 1H, H-6, 1.2, 8.2); 7.54 (d; 1H; H-21, 7.7); 7.79 (t, 1H, H-23, 7.7); 7.67 (t, 1H, H-5, 8.2); 7.60-7.54 (m, 2H, H-22, H-24); 7.46 (d, 2H, H15, H-17, 8.0); 7.26 (d, 2H, H-14, H-18, 8.0); 4.70 (d, 1H, H-12A, syst. AB, 14.8); 4.55 (d, 1H, H-12B, syst. AB, 14.8); 3.61 (s, 3H, H-8); 1.26 (s, 9H, H-ll).

¹³ C-NMR (dmso-d6, δ ppm): 164.53 (C-7); 159.66 (0 ??); 153.29 (C-9); 148.16 (Cq); 144.14 (03); 134.80 (04); 131.69 (02); 137.08 (); 136.78 (); 133.95 (CH); 133.77 (CH); 133.57 (CH); 130.13 (CH); 129.74 (CH); 129.18 (CH); 128.49 (2 CH); 128.23 (CH); 118.47 (020); 110.86 (025); 80.22 (010); 53.09 (012); 52.71 (08); 27.56 (011).

FT-IR (AIR in solid, v cm ' ¹ ): 3091w; 2983w; 2953w; 2223w; 1701vs; 1530s; 1476w; 1457w; 1434w; 1386s; 1366m; 1317sh; 1294vs; 1224m; 1163m; 1130m; 1013w; 970w; 936w; 853w; 766S; 703w.

Example 7

Synthesis of methyl 2-amino-3-nitro-benzoate (15)

The chloroform solution obtained in the previous step (Example 4), containing methyl-2- (azidocarbonyl) -3 nitrobenzoate (14) is concentrated in the rotary evaporator. To the obtained residue add 50 ml of water, then heat under stirring for 1 hour at 50 ° C; then add 50 ml of methyl alcohol and continue heating at 60 ° C for 2 hours with stirring. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. After washing with water and anhydrization, the ethyl acetate solution was concentrated in vacuo, and the obtained residue was purified on the chromatographic column (ethyl hexamacetate = 5: 1). The product obtained is recrystallized from acetone-water. Thus 2.43 g of methyl 2-amino-3-nitrobenzoate were obtained as weak yellow crystals (mp 93.9-95.7 ° C; CSS: Silicagel GF254, elution system: ethyl hexamacetate system ( 4: 1) (v: v); row 62%).

Elementary analysis ·. CgHgNzCh; M = 196.16 g / mol Calculated values'. C: 48.98%; H: 4.11%; N: 14.28%.

Experimental values. C: 49.21%; H: 4.11%; N: 14.28%.

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H-NMR (dmso-d6, δ ppm, JHz): 8.35 (bs, 2H, NH, deuterable); 8.33 (dd, 1H, H-4, 1.6, 8.5); 8.20 (dd, 1H, H-6, 1.6, 7.7); 6.74 (dd, 1H, H-5, 7.7, 8.5); 3.86 (s, 3H, H-8).

¹³ C-NMR (dmso-d6, δ ppm): 166.85 (C-7); 146.31 (C-3); 139.32 (C-4); 132.70 (C-2); 132.10 (C-6);

114.16 (C-5); 113.87 (C-1); 52.39 (C-8).

FT-IR (ATR in solid, v cm ¹ ): 3450s; 3313s; 3100w; 2962m; 2925m; 2853w; 1697vs; 1617s; 1551 s;

151 lvs; 1456sh; 1436m; 135lw; 1249vs; 1187m; 1099s; 1020s; 949m; 846m; 797m; 775m; 744s; 700w.

Example 8

Synthesis of methyl 2 - ((2'-cyanobiphenylamino) -3-nitrobenzoate (4) (MBN)

Over a solution of 7g (0.014 moles) methyl 2- (tert-butoxycarbonyl ((2'-cyanobiphenyl-4yl) methyl) amino) -3-nitrobenzoate (3) (product prepared according to Example 6) and 20 mL methylene chloride drop at 30 ° C, under stirring, 21.40 mL of trifluoroacetic acid (0.279 moles). The evolution of the reaction is controlled by thin layer chromatography (CSS), elution system: heptane: ethyl acetate (2: 1) (v: v), UV visualization. At the end of the reaction regime, the reaction mixture is concentrated in vacuo, and the crude product is recrystallized from ethyl acetate, yielding 2.70 g methyl 2 - ((2'-cyanobiphenylamino) -3nitrobenzoate, yellow amorphous powder; CSS: Silicagel GF254, elution system: hexane system: ethyl acetate (6: 4) (v: v); 50% row and single spot at CSS in hexane system: ethyl acetate (6: 4) (v: v).

Example 9

Synthesis of methyl 2 - ((2'-cyanobiphenylamino) -3-nitrobenzoate (4) (MBN)

Over a mixture of 3.92g (0.02 moles) methyl 2-amino-3-nitro-benzoate (15) (product prepared according to Example 7), 30 mL dimethylfomamide and 4.14 g (0.03 moles) Anh. potassium carbonate, dripped at 30 ° C under stirring, 2.72 g (0.01 mol) 4- (bromomethyl) -2'-cyanobiphenyl (2) dissolved in 20 mL dimethylfomamide, for 2 hours. The reaction mass is further stirred for 3 hours at 100 ° C. The evolution of the reaction is controlled by thin layer chromatography (CSS), elution system: hexane: ethyl acetate (4: 1) (v: v), UV visualization. . At the end of the reaction regime, the reaction mixture is filtered hot and concentrated in vacuo, and the crude product is recrystallized from chloroform-methanol. The obtained product contains a mixture of unreacted methyl 2 - ((2'-cyanobiphenylamino) -3-nitrobenzoate (4) and 2-amino-3-nitro-benzoate (15). The product is purified by flash chromatography.

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12/15/2017 Silica gel column, hexane elution system: ethyl acetate (4: 1) (v: v), then by recrystallization from chloroform-methanol to give 2.9 methyl 2 - ((2'-) cyanobiphenylamino) -3-nitrobenzoate, yellow precipitate, CSS: Silicagel GF254, elution system: hexane: ethyl acetate (4: 1) (v: v); row. 75%. Also separated were 1 , 5 g of metal 2-amino-3-nitro-benzoate, compound of high purity, and which can be used as an intermediate to be used as such for the synthesis of methyl 2 - ((2'-cyanobiphenylamino) -3nitrobenzoate (4) (MBN).

Elemental analysis: C22H17N3O4; M = 387,388 g / mol

Calculated values: C: 68.21%; H: 4.42%; N: 10.85%.

Experimental values: C: 68.12%; H: 5.02%; N: 10.90%.

'H-NMRiCDCh, δ ppm, JHz): 8.09 (dd, 1H, H-5, 1.6, 8.0); 8.01 (dd, 1H, H-3, 1.6, 8.0); 6.73 (t, 1H, H-4, 8.0); 7.55 (d, 2H, H-12, H-14, 8.4); 7.43 (d, 2H, H-ll, H-15, 8.4); 7.76 (dd, 1H, H-18, 1.3, 7.7); 7.65 (td, 1H, H-20, 7.7, 1.3); 7.51 (dd, 1H, H-21, 1.3, 7.7); 7.45 (td, 1H, H-19, Ί.Ί, 1.3); 4.24 (s, 2H, H-9); 3.89 (s, 3H, H-8).

¹³ C-NMR (CDC1 ₃ , δ ppm): 167.69 (C-7); 145.24 (C-1); 144.82 (016); 138.21 (010); 137.69 (013); 118.59 (022); 116.92 (02); 111.17 (017); 136.98 (05); 133.76 (018); 132.83 (C-20); 131.59 (03); 130.01 (021); 129.24 (012, 014); 128.13 (011, 015); 127.64 (019); 114.95 (C-4); 52.47 (C-8);

50.61 (C-9) .C-17 = 128.5-15.7-1.1 = 111.7 ppm

FT-IR (solid ATR, v cm ' ¹ ): 3651w, 3299 w, 3091m, 2958m, 2218s, 2159s, 2096s, 2030s, 1977s, 1695s, 1600m, 1577m, 1520m, 1478m, 1442m, 1410m, 1346m, 1318w , 1284m, 1258s, 1202s, 1123s, 1107s, 1047m, 981m, 830, 822m, 760s, 737s, 714s, 640m, 594m, 55m, 514m, 451m, 412m

Claims (2)

Process for obtaining 1 - [(2'-cyanobiphenyl) -4-yl methyl] -2-ethoxybenzimidazole-7-carboxylic acid methyl ester, characterized in that the process proceeds through a 2-phase sequence starting from methyl. 2- (azidocarbonyl) -3-nitrobenzoate: > synthesis of methyl 2-amino-3-nitro-benzoate by the transposition of Curtius of hot methyl 2- (azidocarbonyl) -3nitrobenzoate and in the presence of water: Methyl 2- (azidocarbonyl) -3-nitrobenzoate Methyl 2-amino-3-nitro-benzoate> methyl synthesis 2 - ((2'-cyanobiphenylamino) -3-nitrobenzoate (4), in the presence of potassium carbonate, at a molar ratio, 2-amino-3-nitro -methyl benzoate: 4- (2-cyanobiphenyl) -benzyl bromide: potassium carbonate, dimethylformamide medium, at a molar ratio = 2: 1: 3, at 100 ° C with a 100% conversion of bromide of 4 - (2-cyanobiphenyl) -benzyl (2) and with 70-80% recovery of methyl 2-amino-3-nitro-benzoate of 42-amino-3-nitro-benzoate of methyl (2-cyanobiphenyl) ) 1 - [(2'-cyanobiphenyl) -4-yl methyl] 2-ethoxy-benzimidazole-7-carboxylic acid