CN111747902B - Candesartan cilexetil intermediate and application thereof - Google Patents
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Abstract
The invention provides a candesartan cilexetil intermediate which is synthesized by the following route, the intermediate is synthesized, the formation of more byproducts in the reduction step in the prior art method is effectively avoided, and the diamine is purified by salifying and crystallizing oxalic acid in the subsequent step of synthesizing candesartan cilexetil by the intermediate, so that high-quality candesartan cilexetil raw material drug can be obtained
Description
Technical Field
The invention relates to a candesartan cilexetil intermediate and application thereof in synthesis of candesartan cilexetil.
Background
Candesartan Cilexetil (Candesartan Cilexetil) is a hypotensive drug developed by the company martian in japan and first marketed in sweden 12 months in 1997. The chemical structural formula of candesartan cilexetil is as follows:
patent WO2015090635a1 discloses a method for preparing candesartan cilexetil by directly condensing biphenylcarboxylic acid with cyclohexyl chloroethyl carbonate, then reducing the nitro group of the obtained ester, removing trityl and tert-butyloxycarbonyl (Boc) protection simultaneously under acidic conditions to obtain diamine hydrochloride, and finally cyclizing the diamine hydrochloride with tetraethyl orthoformate to obtain candesartan cilexetil.
Patent CN101646659B discloses a method for preparing candesartan cilexetil, which comprises directly condensing biphenyl carboxylic acid with cyclohexyl chloroethyl carbonate, then subjecting the obtained ester to amino deprotection group and nitro group reduction to obtain diamine hydrochloride, and finally cyclizing the diamine hydrochloride with tetraethyl orthoformate to obtain candesartan cilexetil.
The synthesis technology of candesartan cilexetil in the prior art mainly has the following defects:
1) in the nitro reduction step, due to the influence of the side chain of the cyclohexyl carbonate, side reactions in the nitro reduction step are more, impurities which are not easy to remove are formed, the purity of a reduced product is not high, and the quality control of the raw material medicine is not facilitated.
2) The effect of removing impurities from diamine hydrochloride is not ideal, and the HPLC purity of the diamine hydrochloride prepared by the method disclosed in the patent WO2015090635A1 is only 94.2%, which is not beneficial to the quality control of raw material medicaments.
Therefore, in order to overcome the defects of the prior art, the synthesis method of candesartan which has mild reaction conditions, high conversion rate, high purity, low cost and is suitable for industrial production still needs to be developed.
Disclosure of Invention
One object of the present invention is to provide a candesartan cilexetil intermediate compound 1, which has a structural formula shown in formula 1 below:
wherein Ph 3 C is trityl and Boc is tert-butyloxycarbonyl.
According to the candesartan cilexetil intermediate compound 1 disclosed by the invention, the candesartan cilexetil intermediate compound 1 is a crystal, wherein the melting point of the candesartan cilexetil intermediate compound 1 crystal is 172.6-173.5 ℃, and the candesartan cilexetil intermediate compound 1 crystal has the following crystal form characteristics: using Cu-ka radiation, the X-ray powder diffraction of the candesartan cilexetil intermediate compound 1 crystal has characteristic peaks at diffraction angles 2 θ of 10.1 ° ± 0.2 °, 10.5 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.4 ° ± 0.2 °, 17.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.9 ° ± 0.2 °, 23.4 ° ± 0.2 °.
Another object of the present invention is to provide a preparation method of candesartan cilexetil intermediate compound 1, comprising the following steps:
compound 2 is reduced to compound 1 using ferric oxyhydroxide (feo (oh))/hydrazine hydrate reducing agent in the presence of activated carbon in tetrahydrofuran.
According to the preparation method of the candesartan cilexetil intermediate compound 1, the molar ratio of the compound 2, the ferric oxide hydroxide and the hydrazine hydrate is 1: 0.3-0.6: 3-5, preferably, 1: 0.5: 3.5.
according to the preparation method of the candesartan cilexetil intermediate compound 1, the weight ratio (g/g) of the compound 2 to the activated carbon is 1: 0.1 to 0.15, preferably, 1: 0.12.
according to the preparation method of the candesartan cilexetil intermediate compound 1, the reaction temperature is controlled to be 35-50 ℃, and preferably 40-45 ℃.
According to the preparation method of the candesartan cilexetil intermediate compound 1, the candesartan cilexetil intermediate compound 1 is a crystal, wherein the melting point of the candesartan cilexetil intermediate compound 1 crystal is 172.6-173.5 ℃, and the candesartan cilexetil intermediate compound 1 crystal has the following crystal form characteristics: using Cu-ka radiation, the X-ray powder diffraction of the candesartan cilexetil intermediate compound 1 crystal has characteristic peaks at diffraction angles 2 θ of 10.1 ° ± 0.2 °, 10.5 ° ± 0.2 °, 11.8 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.6 ° ± 0.2 °, 13.4 ° ± 0.2 °, 17.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.9 ° ± 0.2 °, 23.4 ° ± 0.2 °.
Still another object of the present invention is to provide a process for preparing candesartan cilexetil comprising the steps of:
step 1: in ethyl acetate, potassium carbonate is used as an acid-binding agent, and a compound 1 prepared by the preparation method of the candesartan cilexetil intermediate compound 1 and cyclohexyl chloroethyl carbonate are condensed to obtain a compound 3;
the mol ratio of the compound 1 to the cyclohexyl chloroethyl carbonate is 1: 1-1.5, preferably 1: 1.1;
the molar ratio of the compound 1 to the potassium carbonate is 1: 0.4-1.2, preferably 1: 0.6;
the reaction temperature is controlled to be 55-70 ℃, and preferably 60-65 ℃;
step 2: in ethyl acetate, under the action of hydrobromic acid, deprotecting the compound 3 and salifying with oxalic acid to obtain an oxalate compound 4;
the molar ratio of the compound 3 to the hydrobromic acid is 1: 3-5, preferably 1: 4;
the reaction temperature of deprotection is controlled to be 35-50 ℃, and preferably 40-45 ℃;
the molar ratio of the compound 3 to the oxalic acid is 1:2-3, preferably, 1: 2.4;
the reaction temperature for salifying with oxalic acid is controlled to be 25-40 ℃, and preferably 30-35 ℃;
the oxalate compound 4 is a crystal, wherein the melting point of the oxalate compound 4 crystal is 101.5-124.0 ℃, and the oxalate compound 4 crystal has the following crystal form characteristics: using Cu-K α radiation, X-ray powder diffraction of the oxalate compound 4 crystal has characteristic peaks at diffraction angle 2 θ positions of 3.0 ° ± 0.2 °, 5.7 ° ± 0.2 °, 6.4 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.7 ° ± 0.2 °, 12.3 ° ± 0.2 °, 12.8 ° ± 0.2 °, 13.5 ° ± 0.2 °, 15.6 ° ± 0.2 °, 17.7 ° ± 0.2 °, 20.0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.4 ° ± 0.2 °, 25.0 ° ± 0.2 °;
and step 3: a free oxalate compound 4, wherein the obtained free alkali is directly cyclized with tetraethyl orthocarbonate under the action of acetic acid to obtain candesartan cilexetil;
the molar ratio of oxalate compound 4, tetraethyl orthocarbonate and acetic acid is 1: 1.5-2.0, preferably, 1:1.6: 1.8;
the reaction temperature is controlled to be 15-30 ℃, and preferably 20-25 ℃.
The invention has the beneficial effects that:
(1) according to the invention, by synthesizing the intermediate compound 1 of candesartan cilexetil, the formation of more byproducts in the reduction step in the prior art method is effectively avoided.
(2) In the subsequent step of synthesizing the candesartan cilexetil by the intermediate compound 1, oxalic acid salifying and crystallizing are adopted to purify diamine, the HPLC purity is improved to 99.3%, and then the high-quality candesartan cilexetil raw material drug with the purity of 99.95% is obtained.
(3) The method has the advantages of mild reaction conditions in each step, high conversion rate, effective reduction of cost and suitability for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of intermediate compound 1 prepared in example 1 of the present invention.
FIG. 2 is an X-ray powder diffraction pattern of oxalate compound 4 prepared according to example 3 of the invention.
FIG. 3 is an HPLC chromatogram of oxalate compound 4 prepared in example 3 of this invention.
FIG. 4 is an HPLC chromatogram of candesartan cilexetil prepared in example 4 of the present invention.
Detailed Description
The present invention is further illustrated by the following specific examples, but the embodiments of the present invention are not limited thereto.
All instrument reagent information of the invention is as follows: the solvent and the reagent used in the invention are purchased from Allantin reagent company, and the reagents are analytically pure; high resolution mass spectrometry data were measured using a Waters Xevo G2-S QTof high resolution mass spectrometer; nmr spectroscopy data were measured using Bruker AVANCE III HD 400M; HPLC purity was measured using Agilent 1260 or Waters 2695 HPLC.
Example 1: preparation of intermediate Compound 1
Adding 20g of compound 2, 35.5g of tetrahydrofuran and 2.4g of activated carbon into a reaction bottle, adding 1.2g of ferric oxide hydroxide while stirring, slowly heating to 40-45 ℃, dropwise adding 5.8g of hydrazine hydrate (80% w/w) within 1 hour, preserving heat at 40-45 ℃, reacting for 20-30 hours, controlling in a TLC (ethyl acetate: n-hexane 4:5, V/V) plate, cooling the synthetic liquid to 20-25 ℃ after the reaction is finished, filtering, adding 20g of tetrahydrofuran into a filter cake, leaching, combining the filtrates, desolventizing the filtrate to dryness, recrystallizing the residue with 50g of ethyl acetate and 5g of water to obtain 17.7g of intermediate compound 1 crystal, wherein the yield is 92%, the HPLC purity is 98.5%, and the X-ray powder diffraction pattern is shown in figure 1. ESI-HRMS (m/z): C 45 H 41 N 6 O 4 [M+H + ]Theoretical calculation value: 729.3184, found: 729.3175, respectively; 1 HNMR(400MHz,CDCl 3 )δ:7.70(d,J＝7.5Hz,1H),7.40(m,1H),7.32(m,2H),7.26(m,4H),7.21(m,6H),7.04(d,J＝7.5Hz,2H),6.97(m,6H),6.93(d,J＝7.5Hz,2H),6.86(m,1H),6.47(d,J＝8.0Hz,1H),5.00(m,1H),4.05(m,1H),1.28-1.17(m,9H). 13 CNMR(CDCl 3 ,100Hz)δ:170.1,164.7,155.6,145.7,141.9,141.4,137.0,130.7,130.6,130.3,130.2,129.5,128.5。
example 2: preparation of Compound 3
Adding 15g of compound 1, 40.05g of ethyl acetate and 1.7g of potassium carbonate into a reaction bottle, heating to 40-45 ℃, dropwise adding 4.7g of cyclohexyl ethyl chloride carbonate, heating to 60-65 ℃, keeping the temperature and stirring for 3-5 hours, controlling the temperature in a TLC (ethyl acetate: n-hexane-4: 5 (glacial acetic acid) and V/V), cooling to 20-25 ℃, filtering, adding 10g of ethyl acetate into a filter cake for leaching, combining filtrate, adding 10g of water into the filtrate for washing once, adding 42g of ethyl acetate into an ethyl acetate layer to obtain an ethyl acetate feed liquid of a compound 3, and directly using the ethyl acetate feed liquid of the compound 3 in the next reaction.
Example 3: preparation of oxalate compound 4
Controlling the temperature of the ethyl acetate feed liquid of the compound 3 obtained in the previous step to be 10-15 ℃, stirring, dropwise adding 20.2g of hydrobromic acid (33% w/w), after dropwise adding, heating to 40-45 ℃, carrying out heat preservation reaction at 40-45 ℃ for 3 hours, cooling to 0-5 ℃, carrying out heat preservation stirring for 1 hour, filtering, adding 10g of ethyl acetate, and leaching to obtain a crude and wet deprotected product of the compound 3. Adding 60g of ethyl acetate into the crude wet product, adding undissolved clear solution, dropwise adding sodium bicarbonate aqueous solution to adjust the pH value to 6-7, dissolving clear solution, standing for layering, adding 10g of saturated salt water into an organic layer for washing once, then adding 10g of anhydrous sodium sulfate and 1g of activated carbon, drying at 40-45 ℃, decoloring for 1 hour, filtering, drying filtrate, adding 114g of acetonitrile for dissolving, adding 4.4g of oxalic acid, heating to 30-35 ℃, stirring at 30-35 ℃ for 4 hours, cooling to 0-5 ℃, stirring at 0-5 ℃ for 1 hour, filtering, drying the wet product at 45 ℃ under reduced pressure to obtain 8.7g of oxalate compound 4, wherein the total yield of the two steps of deprotection and salt formation is 70%, and the X-ray powder diffraction pattern is shown in figure 2. HPLC purity is 99.3% (see FIG. 3), ESI-HRMS (m/z): C 30 H 33 N 6 O 5 [M+H + ]Theoretically calculated values are as follows: 557.2507, found: 557.2515, respectively; HPLC chromatographic conditions for oxalate purity: a chromatographic column: YMC-TriartC184.6X 150mm,3 μm; mobile phase A: 0.1% phosphoric acid in water; mobile phase B: acetonitrile; flow rate: 1.0 ml/min; detection wavelength: 220 nm; column temperature: 30 ℃; sample introduction amount: 10 mul; diluting liquid: acetonitrile-water-ammonia (95:5: 0.02).
The elution gradient is shown in table 1 below:
TABLE 1
| T(min) | 0 | 15 | 42 | 42.01 | 50 |
| A(％) | 55 | 10 | 10 | 55 | 55 |
| B(％) | 45 | 90 | 90 | 45 | 45 |
Example 4: preparation of candesartan cilexetil
Putting 9g of oxalate compound 4 prepared by the method in example 3 and 40g of ethyl acetate into a reaction bottle, controlling the temperature to be 10-15 ℃, keeping the oxalate compound undissolved, dropwise adding 5% potassium carbonate aqueous solution until the pH value is 6-7, dissolving the oxalate compound clearly, standing and layering, washing an organic layer with 5g of saturated saline solution, adding 5g of anhydrous sodium sulfate and 0.5g of activated carbon into the organic layer, drying and decoloring the organic layer at 40-45 ℃, filtering, desolventizing a filtrate to be dry, adding 15g of toluene, 4.3g of tetraethyl orthocarbonate and 1.3g of acetic acid, carrying out heat preservation reaction at 20-25 ℃ for 12 hours, cooling to 0-5 ℃, carrying out heat preservation and stirring for 3 hours, filtering, and drying a wet product at 45 ℃ under reduced pressure to obtain 8.5g of crude candesartan cilexetil product with the yield of 93%.
6.5g of crude candesartan cilexetil and 31g of acetone are put into a reaction bottle, stirred, heated to 40-45 ℃, kept warm and stirred for 10 minutes at 40-45 ℃, filtered while hot, the filtrate heated to 40-45 ℃, 17.8g of sodium bicarbonate aqueous solution preheated to 40-45 ℃ (0.03g of sodium bicarbonate dissolved in 17.8g of water) is dripped, the dripping time is 10-15 minutes, after dripping, the temperature is slowly reduced to 30-35 ℃, kept warm and stirred for 3 hours at 30-35 ℃, then cooled to 0-5 ℃, kept warm and stirred for 3 hours at 0-5 ℃, filtered to obtain a wet candesartan cilexetil product, and dried at 45 ℃ to obtain 6.0g of dry candesartan cilexetil with the crystallization yield of 92.3%. ESI-HRMS (m/z): C 33 H 35 N 6 O 6 [M+H + ]Theoretical calculation value: 611.2613, found: 611.2605, respectively; HPLC purity 99.95% (see fig. 4), HPLC chromatographic conditions: a chromatographic column:
C183.9X 150mm,4 μm; mobile phase A: acetonitrile-glacial acetic acid-water (57:1: 43); mobile phase B: acetonitrile-glacial acetic acid-water (90:1: 10); flow rate: 1.0 ml/min; detection wavelength: 254 nm; column temperature: 30 ℃; sample introduction amount: 10 mu l of the mixture; diluting liquid: acetonitrile-water (3: 2).
Claims (10)
1. A preparation method of candesartan cilexetil comprises the following steps:
step 1: reducing compound 2 to compound 1 in tetrahydrofuran in the presence of activated carbon using ferric hydroxide/hydrazine hydrate reducing agent;
step 2: in ethyl acetate, potassium carbonate is used as an acid-binding agent, and the compound 1 and cyclohexyl chloroethyl carbonate are condensed to obtain a compound 3;
and step 3: in ethyl acetate, under the action of hydrobromic acid, deprotecting the compound 3 and salifying with oxalic acid to obtain an oxalate compound 4;
and 4, step 4: a free oxalate compound 4, wherein the obtained free alkali is directly cyclized with tetraethyl orthocarbonate under the action of acetic acid to obtain candesartan cilexetil;
wherein in the step 1, the reaction temperature is controlled to be 35-50 ℃; in the step 3, the reaction temperature of deprotection is controlled to be 35-50 ℃; in the step 4, the reaction temperature is controlled to be 15-30 ℃.
2. The process for the preparation of candesartan cilexetil according to claim 1 wherein,
in step 2:
the mol ratio of the compound 1 to the cyclohexyl ethyl chlorocarbonate is 1: 1-1.5;
the molar ratio of the compound 1 to the potassium carbonate is 1: 0.4-1.2;
controlling the reaction temperature to be 55-70 ℃;
in step 3:
the molar ratio of the compound 3 to the hydrobromic acid is 1: 3-5;
the mol ratio of the compound 3 to the oxalic acid is 1: 2-3;
controlling the reaction temperature of the salt formation with oxalic acid to be 25-40 ℃;
in step 4:
the molar ratio of oxalate compound 4, tetraethyl orthocarbonate, and acetic acid is 1: 1.5-2.0.
3. The process for the preparation of candesartan cilexetil according to claim 2 wherein,
in step 2:
the mol ratio of the compound 1 to the cyclohexyl ethyl chlorocarbonate is 1: 1.1;
the molar ratio of the compound 1 to the potassium carbonate is 1: 0.6;
controlling the reaction temperature to be 60-65 ℃;
in step 3:
the molar ratio of the compound 3 to the hydrobromic acid is 1: 4;
controlling the reaction temperature of deprotection to be 40-45 ℃;
the molar ratio of the compound 3 to the oxalic acid is 1: 2.4;
the reaction temperature for salifying with oxalic acid is controlled to be 30-35 ℃;
in step 4:
the molar ratio of oxalate compound 4, tetraethyl orthocarbonate, and acetic acid is 1:1.6: 1.8;
the reaction temperature is controlled to be 20-25 ℃.
4. The process for the preparation of candesartan cilexetil according to claim 1 wherein in step 1 the molar ratio of compound 2, ferric oxide hydroxide and hydrazine hydrate is 1: 0.3-0.6: 3 to 5.
5. The process for the preparation of candesartan cilexetil according to claim 4 wherein in step 1 the molar ratio of compound 2, ferric oxide hydroxide and hydrazine hydrate is 1: 0.5: 3.5.
6. the process for the preparation of candesartan cilexetil according to claim 1 wherein in step 1 the weight ratio of compound 2 to activated carbon is 1: 0.1 to 0.15.
7. The process for the preparation of candesartan cilexetil according to claim 6 wherein in step 1 the weight ratio of compound 2 to activated carbon is 1: 0.12.
8. the candesartan cilexetil preparation method according to claim 1, wherein the reaction temperature is controlled to 40-45 ℃ in step 1.
9. An oxalate compound 4 having a structural formula represented by formula 4 below:
10. the oxalate compound 4 of claim 9, wherein said oxalate compound 4 is crystalline, wherein said oxalate compound 4 crystalline has a melting point of 101.5-124.0 ℃, and has the following crystalline form characteristics: using Cu-ka radiation, the X-ray powder diffraction of the oxalate compound 4 crystal has characteristic peaks at diffraction angles 2 θ of 3.0 ° ± 0.2 °, 5.7 ° ± 0.2 °, 6.4 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.7 ° ± 0.2 °, 12.3 ° ± 0.2 °, 12.8 ° ± 0.2 °, 13.5 ° ± 0.2 °, 15.6 ° ± 0.2 °, 17.7 ° ± 0.2 °, 20.0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.4 ° ± 0.2 °, 25.0 ° ± 0.2 °.
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| WO2015090635A1 (en) * | 2013-12-20 | 2015-06-25 | Farma Grs, D.O.O. | A new process for the preparation of candesartan cilexetil |
| CN110028461A (en) * | 2019-05-29 | 2019-07-19 | 珠海润都制药股份有限公司 | A kind of Preparation Method And Their Intermediate of candesartan Cilexetil |
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| CN102617358A (en) * | 2012-03-06 | 2012-08-01 | 连云港市金囤农化有限公司 | Preparation method of arylamine |
| CN102887890A (en) * | 2012-11-06 | 2013-01-23 | 峨眉山天梁星制药有限公司 | Synthesis method of candesartan cilexetil |
| WO2015090635A1 (en) * | 2013-12-20 | 2015-06-25 | Farma Grs, D.O.O. | A new process for the preparation of candesartan cilexetil |
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