A new synthetic route to candesartan cilexetil intermediates

Abstract

The application discloses a new synthesis process of candesartan cilexetil intermediate, and synthesis steps of the process comprise the following steps: taking 7-nitroisatin as raw material, carrying out nucleophilic substitution reaction with halogenated biphthalonitrile to obtain compound II, carrying out nucleophilic substitution reaction on the compound II to obtain compound III, carrying out nitro reduction on the compound III to obtain compound IV, and finally carrying out tetraethyl orthocarbonate cyclization reaction on the compound IV to obtain compound I. The method reduces the use and waste of raw materials with dangerous toxicity, has mild reaction conditions, improves production safety, is low in cost, is strong in controllability, is small in environmental pollution, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, and more specifically, relates to a method for preparing a candesartan medoxomil intermediate. Background Technology

[0002] Candesartan cilexetil is a potent, highly selective angiotensin II receptor antagonist antihypertensive drug developed by Takeda Pharmaceutical Company of Japan. It was first marketed in Sweden in November 1997. Its chemical name is (±)-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, and its chemical structural formula is: .

[0003] 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester; 2-ethoxy-1-[[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole]-7-carboxylic acid ester (compound I) is a key intermediate in the synthesis of candesartan cilexetil, with the following structural formula: .

[0004] R is selected from any one of the following functional groups: substituted or unsubstituted C1-C6 low-chain hydrocarbon groups, preferably ethyl.

[0005] There are currently many reported synthetic routes for compound I in the literature, as follows: The synthetic route for compound I reported by Matsuno et al. is as follows:

[0006] According to literature reports, the synthesis of compound I from the starting material ethyl 2-carboxy-3-nitrobenzoate requires the rearrangement of sodium azide and sodium hydride, followed by the reduction of nitroamine via stannous chloride dihydrate, and finally the cyclization reaction of tetraethyl orthocarbonate to obtain compound I. Because the sodium azide used in the reaction decomposes into nitrogen gas and metallic sodium upon heating, releasing a large amount of heat, and reacts with acids to produce azidoic acid (HN3), which is highly toxic and explosive, it poses a significant safety hazard if not properly controlled during large-scale production.

[0007] The synthetic route reported in US5196444 is as follows:

[0008] This route requires first reacting acyl chlorides with azides to generate acyl azides, then reacting them with tert-butanol in a rearrangement reaction, followed by nucleophilic substitution, nitro reduction, and cyclization reactions to obtain compound I. This route also uses the hazardous substance sodium azide, and the generated acyl azides are thermally unstable, easily decomposing and exploding, posing a significant safety hazard. Furthermore, acyl azides are prone to self-decomposition, consuming raw materials and affecting product purity. The rearrangement reaction has a high heat of reaction, which also affects the acyl azides; therefore, the feeding rate needs to be controlled to manage heat transfer. The process is cumbersome, time-consuming, and inefficient.

[0009] The synthetic route reported in CN103304543A is as follows:

[0010] This route uses methyl 2-amino-3-nitrobenzoate and 4-aldehyde-2-biphenylcarbamate as raw materials, and obtains compound I through reactions such as aldehyde-amine condensation, nitro reduction, and cyclization. The reaction conditions are relatively mild, but the reaction heat is very high and the temperature rises rapidly. If the large-scale production process is not properly controlled, it is extremely dangerous, thus posing a safety hazard.

[0011] The synthetic route reported in CN107089972A is as follows:

[0012] This route uses 2-ethoxybenzimidazole-7-carboxylic acid alkyl ester directly as raw material, avoiding the use of the hazardous substance sodium azide. However, it is prone to producing isomer impurities, and the raw material is expensive, increasing production costs and making it unsuitable for industrial production.

[0013] Therefore, the current preparation methods for candesartan cilexetil intermediates need further improvement. Summary of the Invention

[0014] The technical problem to be solved by the present invention is to provide a method for synthesizing candesartan medoxomil intermediate (compound I) that is simple to prepare, has mild reaction conditions, and is safe and harmless in the preparation process, in light of the current state of the prior art. This method can solve the safety problems caused by the use of dangerous chemical reagents such as sodium azide and the problem of excessively high reaction costs in the prior art.

[0015] This invention is carried out through the following reaction steps:

[0016] Wherein, R is selected from any one of the following functional groups: substituted or unsubstituted C1~C6 low-chain hydrocarbon groups, preferably ethyl.

[0017] This invention includes the following steps: (1) Using 7-nitroindigo as a raw material, 2-{4-[(7-nitro-2,3-dioxane-2,3-dihydro-1H-indol-1-yl)methyl]phenyl}benzene-1-carboxylonitrile (compound II) was obtained by nucleophilic substitution reaction with halobiphenyl nitrile in an organic solvent. (2) Compound II was subjected to an oxidative ring-opening reaction and an esterification reaction to yield compound III; (3) Compound III was reduced by nitro to give compound IV; (4) Compound IV and tetraethyl orthocarbonate were cyclized in glacial acetic acid to give candesartan cilexetil intermediate (compound I).

[0018] Compared with existing technologies, the advantages of this invention are as follows: This route uses 7-nitroindigo as the starting material, replacing the azides and expensive intermediates commonly used in traditional routes; the target product is synthesized through four steps: nucleophilic substitution, oxidative ring opening, nitro reduction, and cyclization, avoiding the classic acyl azide rearrangement reaction; in summary, this route has strong reaction controllability, high product yield, and reduces the use and waste of hazardous and toxic raw materials, with mild reaction conditions, improving production safety; at the same time, the preparation method of this invention has simple process steps and the product is easy to purify, showing high industrial development prospects. Attached Figure Description

[0019] Figure 1 Example 1: 1H spectrum of compound II.

[0020] Figure 2 Example 1: 13C spectrum of compound II.

[0021] Figure 3 Example 3: 1H spectrum of compound IV.

[0022] Figure 4 Example 3: 13C spectrum of compound IV. Detailed Implementation

[0023] The present invention will be further illustrated below through specific embodiments and clinical trials. It should be understood that the following description is only for explaining the present invention and does not limit its content. Example 1

[0024] Synthesis of 2-{4-[(7-nitro-2,3-dioxane-2,3-dihydro-1H-indol-1-yl)methyl]phenyl}benzene-1-carboxynitrile (Compound II)

[0025] In a three-necked flask, 38 g of 7-nitroindigo, 400 ml of DMF, and 41 g of potassium carbonate were added. The mixture was stirred at room temperature for 10 minutes, followed by the addition of 60 g (1.1 eq) of 4'-bromomethyl-2-cyanobiphenyl. The mixture was heated to 40-45 °C and reacted for 2 hours, with TLC monitoring the reaction. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under high vacuum. The residue was dissolved in 1000 ml of dichloromethane and washed five times with 500 ml of water each time. The organic layer was separated and concentrated to obtain 69.8 g of compound II (92%). 1 H-NMR(DMSO):7.97-7.93(m,3H),7.79-7.77(m,1H),7.61-7.56(m,2H),7.52-7.48(m,4H), 7.31-7.28(dd,1H),5.06(s,2H). 13 C-NMR(DMSO):179.86,159.58,144.05,141.52,136.80,135.90,135.47,133.91,133.53, 131.91,130.12,128.79,128.34,128.21,127.12,123.51,121.97,118.51,110.13,45.35. Example 2

[0026] Synthesis of ethyl 2-({[4-(2-cyanophenyl)phenyl]methyl}amino)-3-nitrobenzoate (Compound III)

[0027] (a) In a three-necked flask, 30 g of compound II obtained in the previous step, 17.7 g of 30% hydrogen peroxide, and 2 g of potassium ethoxide were added, along with 150 ml of ethanol as solvent. The mixture was reacted at 30-40 °C for 6 hours. 250 ml of water was added to the mixture, and the mixture was extracted three times with 500 ml of dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10:1) to give 28.6 g of compound III. (91.08%) (b) In a three-necked flask, add 30 g of compound II obtained in the previous step, 35.6 g of peracetic acid, and 300 ml of ethanol. Heat to 50 °C and react for 5-6 hours. Monitor the reaction by TLC. After the reactants have reacted completely, cool to room temperature, add 250 ml of water to the mixture, and extract three times with 500 ml of dichloromethane. Dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 26.1 g of compound III (83.12%). Example 3

[0028] Synthesis of ethyl 3-amino-2-({[4-(2-cyanophenyl)phenyl]methyl}amino)benzoate (Compound IV)

[0029] In a three-necked flask, 25 g of compound III prepared in Example 3(a), 0.13 g of 10% palladium on carbon, and 250 ml of tetrahydrofuran were added to a 500 ml autoclave. The air was replaced three times with hydrogen, and the pressure was increased to 0.3 MPa. The temperature was raised to 35-40 °C for reaction. The reaction was allowed to proceed for approximately 4 hours, and TLC analysis confirmed complete reaction. The product was discharged, filtered, and the filter cake was washed with 50 ml of tetrahydrofuran. The mother liquor was concentrated to obtain 20.1 g of compound IV (87%). 1 H-NMR(DMSO):7.95-7.94(dd,1H),7.80-7.77(m,1H),7.61-7.56(m,2H),7.54-7.52(m,2H),7.45-7.44(d,2H),7.10-7.0 8(dd,1H),6.94-6.92(dd,1H),6.82-6.79(t,1H),6.28-6.25(t,1H),4.94(s,2H),4.20-4.17(m,4H),1.24-1.21(t,3H). 13 C-NMR(DMSO):167.99,144.32,142.52,140.84,137.43,136.35,133.90,133.53,1 30.08,128.57,128.26,128.11,121.72,120.79,119.02,118.60,118.57,110.09. Example 4

[0030] Synthetic compound I

[0031] In a three-necked flask, add 20g of compound IV obtained in the previous step, 13.5g of tetraethyl orthocarbonate, and 0.3g of glacial acetic acid. Heat to 40-50℃ and react for 5 hours. After the reaction is complete, concentrate under reduced pressure. Add 100ml of methanol to the residue and stir at room temperature. After solidification, cool to 0-10℃ and stir to precipitate crystals. Filter and dry the solid under reduced pressure to obtain 20.4g (89%) of compound I.

Claims

1. A method for preparing a candesartan cilexetil intermediate, characterized in that... Includes the following steps: ； Wherein, R is selected from any one of the following functional groups: substituted or unsubstituted C1~C6 low-chain hydrocarbon groups, preferably ethyl; (1) Using 7-nitroindigo as a raw material, react with 4 in an organic solvent. ’ - Bromomethyl-2-cyanobiphenyl undergoes nucleophilic substitution to give 2-{4-[(7-nitro-2,3-dioxoylide-2,3-dihydro-1H-indol-1-yl)methyl]phenyl}benz-1-carboxynitrile (compound II); (2) Compound II was converted into compound III by oxidative ring-opening and esterification. (3) Compound III was reduced by nitro to give compound IV; (4) Compound IV and tetraethyl orthocarbonate were cyclized in glacial acetic acid to give candesartan cilexetil intermediate (compound I).

2. The method for preparing the candesartan cilexetil intermediate according to claim 1, characterized in that: The organic solvent in step (1) is selected from one or more of acetonitrile, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, preferably dimethylformamide.

3. The method for preparing the candesartan cilexetil intermediate according to claim 1, characterized in that: The oxidant in step (2) is hydrogen peroxide, peracetic acid, potassium permanganate, ammonium persulfate, or potassium peroxymonosulfate, preferably hydrogen peroxide.

4. The method for preparing the candesartan cilexetil intermediate according to claim 1, characterized in that: The amount of oxidant used in step (2) is 1.2~2eq, preferably 2eq.

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