Preparation method of an intermediate of an irbesartan isomer

Abstract

The present application relates to a preparation method of an intermediate of an irbesartan isomer, which comprises Step 1: reacting 4-formylphenylboronic acid with o-halobenzonitrile to obtain a compound 2 in the following formula; Step 2: reacting the compound 2 with 1-amino-1-cyclopentanecarboxamide to obtain 1-[2'-cyano-(1,1'-biphenyl)-4-ylmethylamino]cyclopentane-1-carboxamide, the structure of which is shown as a compound 3 in the following formula; reacting 1-[2'-cyano-(1,1'-biphenyl)-4-ylmethylamino]cyclopentane-1-carboxamide with trimethyl orthobutyrate to obtain a compound 4. The present application has the effects of reducing the operation difficulty of preparing the irbesartan isomer and its intermediate and improving the yield. #imgabs0#

Description

Technical Field

[0001] This application relates to the field of irbesartan isomers, and particularly to a preparation method of an intermediate of irbesartan isomers. Background Art

[0002] Irbesartan is an angiotensin II receptor antagonist antihypertensive drug used to treat essential hypertension and type 2 diabetic nephropathy with combined hypertension. Currently, the synthetic route for preparing irbesartan is as Figure 1 shown.

[0003] When synthesizing irbesartan intermediate 3 in the synthetic route of irbesartan, a by-product isomer 4 will be produced. The chemical structural formula of isomer 4 is as Figure 2 shown.

[0004] This isomer 4 will generate an irbesartan isomer (i.e., isomer 4 is an intermediate of the irbesartan isomer), and the irbesartan isomer is an important potential process impurity in the preparation process of irbesartan. To better produce and prepare irbesartan, it is necessary to conduct in-depth research on the irbesartan isomer.

[0005] Currently, the way to obtain the irbesartan isomer is to separate the irbesartan isomer from the reaction solution in the irbesartan synthesis process by using chromatography separation technology. Since the content of the irbesartan isomer in the reaction solution of the irbesartan synthesis process is very low, the separation by using chromatography separation technology is difficult, the separation speed is slow, and the yield is very low. Summary of the Invention

[0006] In order to reduce the operation difficulty of preparing the irbesartan isomer and its intermediate and improve the yield, this application provides a preparation method of an intermediate of the irbesartan isomer.

[0007] The preparation method of an intermediate of the irbesartan isomer provided by this application adopts the following technical solution:

[0008] First aspect, a preparation method of 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide, comprising the following steps:

[0009] Step 1: React p-formylphenylboronic acid with o-halobenzonitrile to obtain compound 2 in the following formula (1);

[0010] Step 2: Then react compound 2 with 1-amino-1-cyclopentanecarboxamide to obtain 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide, and its structure is shown as compound 3 in the following formula (1).

[0011] (1)

[0012] By adopting the above technical solution, a substitution reaction is carried out between formylphenylboronic acid and o-halobenzonitrile, and the benzonitrile group is grafted onto benzaldehyde to obtain compound 2. Then, compound 2 is subjected to reductive amination reaction with 1-amino-1-cyclopentanecarboxamide to graft 1-amino-1-cyclopentanecarboxamide onto the compound to obtain compound 3. As an intermediate for synthesizing the irbesartan isomer, compound 3 can obtain the irbesartan isomer after certain reaction conditions. Compared with obtaining the irbesartan isomer by chromatography separation technology, obtaining the irbesartan isomer by organic synthesis through the above reaction formula involves simpler reactions, lower process operation difficulty, and higher yield, achieving the purpose of reducing the operation difficulty of preparing the irbesartan isomer and its intermediate and increasing the yield.

[0013] Optionally, the specific operation of step 1 is as follows: Dissolve 14 - 16 g of formylphenylboronic acid in 160 - 180 ml of aprotic polar organic solvent, add 1 - 3 g of noble metal catalyst, 21.5 - 3 g of o-halobenzonitrile and 23 - 27 g of Na2CO3 to obtain a mixture. Heat the above mixture at 80 - 100 °C for more than 3 hours. After the reaction is completed, carry out extraction and concentration, and obtain compound 2 after purification by silica gel chromatography.

[0014] By adopting the above technical solution, the operation of the above process is simple and the added reagents are easily available, so as to reduce the operation difficulty of preparing the irbesartan isomer and its intermediate. The noble metal catalyst can accelerate the substitution reaction between formylphenylboronic acid and o-halobenzonitrile, and because the molecules of the aprotic polar solvent have polarity and produce a solvation effect, the solvent can participate in catalyzing the substitution reaction between formylphenylboronic acid and o-halobenzonitrile, so as to further improve the synthesis reaction rate and save the time cost of preparation synthesis.

[0015] Optionally, dissolve 9 - 11 g of compound 2 in 100 mL of alcohol solvent, add 6.4 - 6.7 g of 1-amino-1-cyclopentanecarboxamide, stir the above mixture at room temperature for 3 - 4 hours, then add 1 - 2 g of reducing agent in batches, and stir for another 6 - 7 hours until the reaction is completed. After extraction, washing and drying, obtain compound 3 after purification by silica gel chromatography.

[0016] By adopting the above technical solution, the operation of the above process is simple and the added reagents are easily available, so as to reduce the operation difficulty of preparing the irbesartan isomer and its intermediate. After compound 2 and 1-amino-1-cyclopentanecarboxamide carry out reductive amination reaction for a period of time, then add the reducing agent in batches and continue the reductive amination reaction, which can avoid excessive reaction.

[0017] Optionally, the o-halobenzonitrile is selected from one of o-fluorobenzonitrile, o-chlorobenzonitrile and o-bromobenzonitrile.

[0018] By adopting the above technical solutions, the halogen atoms in o-halobenzonitrile are easily replaced by other groups and it is one of the important intermediates in organic synthesis. Therefore, the above reagents can all successfully replace the boric acid group in p-formylphenylboronic acid with a benzonitrile group to obtain Compound 2.

[0019] Optionally, the noble metal catalyst is selected from at least one of tetrakis(triphenylphosphine)palladium, palladium chloride dimer, tricarbonyl(triphenylphosphine)rhodium, platinum(II) acetylacetonate, iridium(III) chloride dimer, and chloro(triphenylphosphine)gold(I).

[0020] By adopting the above technical solutions, the above reagents are all noble metal catalysts. Noble metal catalysis has high catalytic activity and also has characteristics such as high temperature resistance and oxidation resistance, so as to be able to more effectively accelerate the substitution reaction of p-formylphenylboronic acid and o-halobenzonitrile, and the catalytic activity temperature of noble metal catalysis can adapt to the relatively high reaction temperature in Step 1.

[0021] Optionally, the aprotic organic solvent is selected from one of N,N-dimethylformamide solution and dimethyl sulfoxide solution.

[0022] By adopting the above technical solutions, while the above reagents are used as solvents, their molecules all have polarity, enabling the above reagents to participate in the catalytic substitution reaction of p-formylphenylboronic acid and o-halobenzonitrile to further increase the reaction rate.

[0023] Optionally, the reducing agent is selected from one of sodium cyanoborohydride, sodium triacetoxyborohydride, and 2-methylpyridine borane.

[0024] By adopting the above technical solutions, Compound 2 reacts with 1-amino-1-cyclopentanecarboxamide. The carbonyl group reacts with the amine to form an imine, and then the above reducing agent is used to reduce the imine to an amine, so as to obtain Compound 3.

[0025] In a second aspect, a preparation method of an intermediate of an irbesartan isomer provided by the present application adopts the following technical solutions.

[0026] A preparation method of an intermediate of an irbesartan isomer, comprising the following step: reacting 1-[2'-cyano-(1,1'-biphenyl)-4-ylmethylamino]cyclopentane-1-carboxamide with trimethyl orthobutyrate to obtain Compound 4, and the structure is as shown in Compound 4 in Formula (2) below.

[0027] (2)

[0028] By adopting the above technical solution, 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide (i.e., Compound 3) and trimethyl orthobutyrate are subjected to a series of reactions such as hydrolysis, dehydration condensation, and ammonolysis cyclization to obtain Compound 4. The intermediate of the irbesartan isomer is obtained through organic synthesis. The reactions involved are relatively simple, the process operation difficulty is small, and the yield is relatively higher.

[0029] Optionally, 4 - 6 g of Compound 3, 7 - 8 g of trimethyl orthobutyrate, and 15 - 25 ml of a weak acid are added to 15 - 25 ml of a dry benzene solvent, refluxed and heated for 18 - 22 h, and then the solvent is removed to obtain a residue. The residue is dissolved in 90 - 110 ml of an aqueous sodium hydroxide solution, and then extraction and drying are carried out. Compound 4 is obtained after purification by silica gel chromatography.

[0030] By adopting the above technical solution, the operation of the above process is simple and the added reagents are easily available, so as to reduce the operation difficulty of preparing the irbesartan isomer and its intermediate. The weak acid can be used as a solvent and has a catalytic effect, so that the reaction between Compound 3 and trimethyl orthobutyrate is more complete and the reaction rate is faster.

[0031] Optionally, the weak acid is selected from one of acetic acid, oxalic acid, formic acid, and propionic acid.

[0032] By adopting the above technical solution, the above weak acids can all be used as solvents and are soluble in benzene solvents, so that the solubility of Compound 3 and trimethyl orthobutyrate in benzene solvents is higher, so that the reaction between Compound 3 and trimethyl orthobutyrate is more complete; and the weak acid has a catalytic effect and can accelerate the reaction between Compound 3 and trimethyl orthobutyrate.

[0033] In summary, the present application includes at least one of the following beneficial technical effects:

[0034] 1. Compared with obtaining the irbesartan isomer by chromatography separation technology, obtaining the irbesartan isomer by organic synthesis through the above reaction formula involves relatively simple reactions, small process operation difficulty, and higher yield, achieving the purpose of reducing the operation difficulty of preparing the irbesartan isomer and its intermediate and improving the yield;

[0035] 2. 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide (i.e., Compound 3) and trimethyl orthobutyrate are subjected to a series of reactions such as hydrolysis, dehydration condensation, and ammonolysis cyclization to obtain Compound 4. The intermediate of the irbesartan isomer is obtained through organic synthesis. The reactions involved are relatively simple, the process operation difficulty is small, and the yield is relatively higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is the synthetic route diagram for preparing irbesartan in the background technology of the present application.

[0037] Figure 2 It is the chemical structural formula diagram of by-product isomer 4 in the background technology of this application. Detailed implementation manners

[0038] I. Examples:

[0039] Example 1:

[0040] Dissolve 15 g of 4-formylphenylboronic acid in 170 ml of N,N-dimethylformamide solution, add 2 g of tetrakis(triphenylphosphine)palladium, 21.8 g of 2-fluorobenzonitrile and 25 g of Na2CO3 to obtain a mixture. Heat the above mixture at 90 °C for more than 3 hours until the reaction is complete. Cool the reaction solution and pour it into water. Extract it twice with 200 ml of dichloromethane respectively, then combine the organic phases, dry with anhydrous sodium sulfate and concentrate under reduced pressure. After purification by silica gel chromatography, compound 2 is obtained.

[0041] Dissolve 10 g of compound 2 in 100 mL of methanol, add 6.6 g of 1-amino-1-cyclopentanecarboxamide, stir at room temperature for 4 hours, then add 1.5 g of sodium cyanoborohydride in batches, and stir for another 6 hours until the reaction is complete. Extract with 150 ml of dichloromethane respectively, then combine the organic phases, wash with 100 ML of saturated sodium chloride solution, dry with anhydrous sodium sulfate and filter. Evaporate the solvent to dryness under reduced pressure, and purify the residue on silica gel chromatography to obtain compound 3.

[0042] Add 5 g of compound 3, 7.5 g of trimethyl orthobutyrate and 20 ml of acetic acid to 20 ml of dry toluene, reflux and heat for 20 h, then remove the solvent to obtain a residue. Dissolve the residue in 100 ml of sodium hydroxide aqueous solution, extract three times with 100 ml of dichloromethane respectively, combine the organic matters, dry, and purify by silica gel chromatography to obtain compound 4.

[0043] Example 2:

[0044] A preparation method of an intermediate of irbesartan isomer, which is different from Example 1 in that: 2-fluorobenzonitrile is replaced by 2-chlorobenzonitrile.

[0045] Example 3:

[0046] A preparation method of an intermediate of irbesartan isomer, which is different from Example 1 in that: 2-fluorobenzonitrile is replaced by 2-bromobenzonitrile.

[0047] Examples 4 - 7:

[0048] A preparation method of an intermediate of irbesartan isomer, which is different from Example 3 in that, as shown in Table 1:

[0049] Table 1:

[0050]

[0051] Example 8:

[0052] A method for preparing an intermediate of an irbesartan isomer, which is different from Example 3 in that the addition amount of acetic acid is 15 mL.

[0053] Example 9:

[0054] A method for preparing an intermediate of an irbesartan isomer, which is different from Example 3 in that the addition amount of acetic acid is 25 mL.

[0055] II. Comparative Examples

[0056] Comparative Example 1:

[0057] A method for preparing an intermediate of an irbesartan isomer, which is different from Examples 1-9 in that 15 g of 1-amino-1-cyclopentanecarboxamide is subjected to a series of reactions to form an intermediate of irbesartan, and the reaction route is shown in the following formula (3); then the reaction solution of the above synthesis process is put into a chromatography column to perform chromatography separation on the intermediate of the irbesartan isomer in the reaction solution for production.

[0058] (3)

[0059] III. Performance Test Method

[0060] 1) The final products obtained in Examples 1-9 and Comparative Example 1 are respectively detected and characterized for their molecular structures by a nuclear magnetic resonance spectrometer.

[0061] The test results of the above performance test on the final products of Examples 1-9 and Comparative Example 1 are as follows:

[0062] HNMR(400 MHz, CDCl3), δ: 0.82 (t, J = 7.2 Hz, 3H, CH3), 1.22 - 1.29 (m, 2H, CH2), 1.49 - 1.58 (m, 2H, CH2), 1.88 - 1.91 (m, 6H, 3CH2), 2.00 - 2.06 (m, 2H, CH2), 2.21 (t, J = 7.6 Hz, 2H, CH2), 4.73 (s, 2H, NCH2), 6.92 - 6.96 (m, 8H, ArH); Ms(ESI + ) : M = 386, Found(387, M + 1).

[0063] 2) The yields of Examples 1-9 and Comparative Example 1 were calculated according to the yield calculation formula: yield = amount of raw materials to generate the desired product / amount of raw materials fed × 100%, and the results are shown in Table 2;

[0064] 3) The products of each step of Examples 1-9 and the final product of Comparative Example 1 were respectively subjected to high performance liquid chromatography to detect the purity of the intermediate of the irbesartan isomer in the products. The results are shown in Table 2.

[0065] Table 2:

[0066]

[0067]

[0068] 4. Results Analysis and Summary

[0069] First, the above-mentioned H NMR spectrum detection data can prove that the molecular structure of the final products of Examples 1-9 and Comparative Example 1 is the same as the molecular structure of the intermediate of irbesartan isomers, which can prove that the final products obtained in Examples 1-9 and Comparative Example 1 are intermediates of irbesartan isomers.

[0070] In the first aspect, it can be seen from Examples 1-9, Comparative Example 1 and Table 2 that o-fluorobenzonitrile, o-chlorobenzonitrile and o-bromobenzonitrile are used in Examples 1-3, respectively, and the yield and purity of compound 2 in Example 3 are 95% and 98.6%, respectively, which are higher than the yield and purity of Examples 1-2. From the above, it can be seen that the synthetic route of synthesizing compound 2 by substitution reaction of o-bromobenzonitrile and p-formylphenylboronic acid has a higher yield and a higher purity of compound 2.

[0071] In the second aspect, the molar ratio of p-formylphenylboronic acid to o-bromobenzonitrile in Example 3 is 1:1.2, the molar ratio of p-formylphenylboronic acid to o-bromobenzonitrile in Example 4 is 1:1.4, and the molar ratio of p-formylphenylboronic acid to o-bromobenzonitrile in Example 5 is 1:1. As shown in Table 2, the yield and purity of compound 2 in Example 3 are greater than those in Example 4, and the yield of compound 2 in Example 5 is the same as that in Example 3 but the purity is lower than that in Example 3.

[0072] In Example 4, the amount of o-bromobenzonitrile is too small, resulting in a decrease in the yield and purity of compound 2; in Example 5, the amount of o-bromobenzonitrile is too large, but the yield of compound 2 does not increase compared to Example 3, but instead reduces the purity of compound 2. As can be seen from the above, when 15g of p-formylphenylboronic acid and 21.8g of o-bromobenzonitrile (i.e., the molar ratio of the two is 1:1.2) is used, the maximum yield and purity of compound 2 can be achieved, and the input amount of o-bromobenzonitrile can be reduced to reduce costs.

[0073] In the third aspect, the molar ratio of sodium cyanoborohydride, compound 2 and 1-amino-1-cyclopentylcarboxamide in Example 3 is 1:2:2, the molar ratio of sodium cyanoborohydride, compound 2 and 1-amino-1-cyclopentylcarboxamide in Example 6 is 1:3:3, and the molar ratio of sodium cyanoborohydride, compound 2 and 1-amino-1-cyclopentylcarboxamide in Example 7 is 1:1.3:1.3. As shown in Table 2, the yield and purity of compound 3 in Example 3 are greater than those in Example 6, and the yield of compound 3 in Example 7 is the same as that in Example 3 but the purity is lower than that in Example 3.

[0074] In Example 6, the amount of reducing agent (sodium cyanoborohydride) is too little, resulting in an incomplete reductive amination reaction, thereby reducing the yield and purity of compound 3; in Example 7, the amount of reducing agent is too much, but the yield of compound 3 does not increase compared with Example 3, but the purity of compound 3 is reduced. From the above, it can be obtained that when 1.5g of sodium cyanoborohydride, 10g of compound 2 and 6.6g of 1-amino-1-cyclopentylformamide (i.e., the molar ratio of the three is 1:2:2) is used, the yield and purity of compound 3 can be maximized, and the input amount of sodium cyanoborohydride can be reduced to reduce costs.

[0075] In the fourth aspect, the amount of acetic acid added in Example 3 is 20ML, the amount of acetic acid added in Example 8 is 15ML, and the amount of acetic acid added in Example 8 is 20ML. As shown in Table 2, the yield and purity of the intermediate of irbesartan isomers in Example 3 are greater than those in Example 8, and the yield and purity of the intermediate of irbesartan isomers in Example 9 are the same as those in Example 3.

[0076] In Example 8, the amount of acetic acid added was too little, so that the reaction between compound 3 and trimethyl orthobutyrate was not thorough enough, resulting in a decrease in the yield and purity of the intermediate of the irbesartan isomer in Example 8; in Example 9, the amount of acetic acid added was too much, but the yield and purity were not improved compared with Example 3. It can be seen from the above that when the amount of acetic acid added was 20ML, the yield and purity of the intermediate of the irbesartan isomer were maximized while reducing the input amount of sodium cyanoborohydride to reduce costs.

[0077] Finally, it can be seen from Table 2 that the yield and purity of the intermediates of the irbesartan isomers in Comparative Example 1 are significantly lower than those in Examples 1-9, which further illustrates that compared with obtaining the irbesartan isomers by chromatographic separation from the reaction solution of the traditional synthesis process of irbesartan, the intermediates of the irbesartan isomers obtained by organic synthesis can greatly improve the yield and purity of the intermediates of the irbesartan isomers.

[0078] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereby. Therefore, all equivalent changes made according to the structure, shape, and principle of the present application shall be covered within the protection scope of the present application.

Claims

1. A preparation method of 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide, characterized in that, It includes the following steps: Step 1: React 4-formylphenylboronic acid with o-halobenzonitrile to obtain compound 2 in the following formula (1); Step 2: Then dissolve compound 2 in a methanol solvent, add 1-amino-1-cyclopentanecarboxamide and react, and then add sodium cyanoborohydride in batches to obtain 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide, the structure of which is shown as compound 3 in the following formula (1). In formula (1), R is a halogen group.

2. The preparation method of an intermediate of an irbesartan isomer according to claim 1, characterized in that: The specific operation of the above step 1 is: dissolve 14-16 g of 4-formylphenylboronic acid in 160-180 ml of an aprotic polar organic solvent, add 1-3 g of a noble metal catalyst, 20-23 g of o-halobenzonitrile and 23-27 g of Na2CO3 to obtain a mixture, heat the above mixture at 80-100 °C for more than 3 hours, perform extraction and concentration after the reaction is completed, and obtain compound 2 after purification by silica gel chromatography.

3. The preparation method of 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide according to claim 1, characterized in that: The specific operation of the above step 2 is: dissolve 9-11 g of compound 2 in 100 mL of an alcohol solvent, add 6.4-6.7 g of 1-amino-1-cyclopentanecarboxamide, stir the mixture at room temperature for 3-4 hours, then add 1-2 g of sodium cyanoborohydride in batches, and then stir for 6-7 hours until the reaction is completed. After extraction, washing and drying, obtain compound 3 after purification by silica gel chromatography.

4. The preparation method of an intermediate of 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide according to claim 2, characterized in that: The o-halobenzonitrile is selected from one of o-fluorobenzonitrile, o-chlorobenzonitrile and o-bromobenzonitrile.

5. The preparation method of 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide according to claim 2, characterized in that: The noble metal catalyst is selected from at least one of tetrakis(triphenylphosphine)palladium, palladium chloride dimer, tricyclohexylphosphine carbonyl rhodium, platinum acetylacetonate, iridium chloride dimer, triphenylphosphine gold chloride.

6. The preparation method of 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide according to claim 2, characterized in that: The aprotic organic solvent is selected from one of N,N-dimethylformamide solution and dimethyl sulfoxide solution.

7. A preparation method of an intermediate of an irbesartan isomer, characterized in that, It includes the following steps: React 1-[2'-cyano-(1,1'-biphenyl)-4-methylamino]cyclopentane-1-carboxamide with trimethyl orthobutyrate to obtain compound 4, the structure of which is shown as compound 4 in the following formula (2).

8. The preparation method of an intermediate of an irbesartan isomer according to claim 7, characterized in that: The specific operation of the above reaction is: add 4-6 g of compound 3, 7-8 g of trimethyl orthobutyrate and 15-25 ml of a weak acid to 15-25 ml of a dry benzene solvent to obtain a mixed solution. Compound 3 is prepared by the method described in claims 1-6 above. Heat the above mixed solution under reflux for 18-22 h, then remove the solvent to obtain a residue. Dissolve the residue in 90-110 ml of an aqueous sodium hydroxide solution, then perform extraction and drying, and obtain compound 4 after purification by silica gel chromatography.

9. The preparation method of an intermediate of an irbesartan isomer according to claim 8, characterized in that: The weak acid is selected from one of acetic acid, oxalic acid, formic acid and propionic acid.

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