CN116135839A - Preparation method of azilsartan key intermediate - Google Patents
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- CN116135839A CN116135839A CN202111365703.0A CN202111365703A CN116135839A CN 116135839 A CN116135839 A CN 116135839A CN 202111365703 A CN202111365703 A CN 202111365703A CN 116135839 A CN116135839 A CN 116135839A
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- 239000005485 Azilsartan Substances 0.000 title claims abstract description 18
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229960002731 azilsartan Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- CHPMKOFPDCKNBG-UHFFFAOYSA-N ethyl 2-[[4-(2-cyanophenyl)phenyl]methylamino]-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC([N+]([O-])=O)=C1NCC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 CHPMKOFPDCKNBG-UHFFFAOYSA-N 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 6
- -1 ethyl 3-amino-2- [ (2' -cyanobiphenyl-4-yl) -methylamino ] -benzoate Chemical compound 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 claims 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 abstract description 2
- 229940125782 compound 2 Drugs 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 abstract 1
- 238000011946 reduction process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 230000009467 reduction Effects 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000001119 stannous chloride Substances 0.000 description 3
- 235000011150 stannous chloride Nutrition 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VVQNAFBGAWCMLU-UHFFFAOYSA-N 1h-benzimidazole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1N=CN2 VVQNAFBGAWCMLU-UHFFFAOYSA-N 0.000 description 1
- DJMQLZPEBHSABD-UHFFFAOYSA-N 2-(methoxycarbonyl)-6-nitrobenzoic acid Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O DJMQLZPEBHSABD-UHFFFAOYSA-N 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- MKBIJCPQTPFQKQ-UHFFFAOYSA-N ethyl 3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC([N+]([O-])=O)=C1 MKBIJCPQTPFQKQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to preparation of an azilsartan key intermediate, and the chemical reaction formula of the method is shown as follows. Reducing compound 2 into 3-amino-2- [ (2' -nitrile biphenyl-4-yl) -methylamino by using ammonium formate as hydrogen source and palladium hydroxide carbon as catalyst]-ethyl benzoate (1). The structure of the target product is processed by HPLC, 1 H‑NMR、 13 C-NMR and MS, etc. The improved reduction process avoids the dangerous process of chemicals and highly toxic reagents, reduces the safety risk and the production cost, and has higher commercial value.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of an azilsartan key intermediate 3-amino-2- [ (2' -nitrile biphenyl-4-yl) -methylamino ] -ethyl benzoate.
Background
Azilsartan (Azilsartan) with chemical name of 2-ethoxy-1- [ [2' - (4, 5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl) biphenyl-4-yl]Methyl group]Benzimidazole-7-carboxylic acid, an angiotensin II receptor antagonist developed by the Japanese wuta-tsu pharmaceutical company (Takeda), is capable of reacting with AT 1 The receptor is tightly combined, the vasoconstriction caused by Ang II is inhibited, and the peripheral vascular resistance is reduced, so that the antihypertensive effect is shown, and the binding force is better than that of the antihypertensive effect by the same mechanismThe drug olmesartan is twice as strong. Azilsartan has two specifications of 20mg and 40mg, the commodity name is Azilva, the azilsartan is marketed in Japanese in 1 month in 2012, no import exists in China at present, and NMPA official network in 2021 month 6 shows that Hengrui 3-class imitation pharmaceutical azilsartan tablets are marketed in batches, so that the azilsartan tablet becomes the first imitation in China.
The original research company, the Wuta-tsu pharmacy, in China applied for patent CN 1067890 protects the synthetic route, and is specifically as follows:
3-nitrophthalic acid-1-methyl ester is taken as a raw material, is subjected to Curtius rearrangement, nucleophilic substitution, boc protecting group removal and hydrogenation reduction to obtain a compound 5, and is subjected to cyclization, oximation, esterification ring closure and hydrolysis to obtain azilsartan in total 8 steps. The nitro reduction in the route adopts Pd-C/H2 catalytic hydrogenation, the process is a special process, a hydrogenation reaction kettle is needed in the production process, and the investment of production cost and the safety risk are increased to a certain extent.
Referring to the reported synthetic routes, there are 3 other methods for nitro reduction of compound 4:
(1) reduction of stannous chloride: WO2011/145100 reports that adding stannous chloride to ethyl acetate, stirring at reflux, can reduce compound 4 to compound 5; however, the generated by-product stannic chloride and excessive stannous chloride are difficult to post-treat and difficult to control;
(2) hydrogenation reduction: introducing hydrogen into a reaction system by taking Raney nickel as a catalyst, and carrying out hydrogenation reduction to obtain a compound 5, wherein flammable and explosive hydrogen is used as a reducing agent in the method;
(3) reduction of hydrazine hydrate: CN 108658961 uses ferric trichloride as a catalyst, and uses hydrazine hydrate to realize nitro reduction, and the yield is only 64%; in the method, hydrazine hydrate is an easy-to-explode reagent, has high safety risk and genotoxicity, and is not suitable for medicine production.
Disclosure of Invention
The invention aims to optimize the hydrogenation reduction reaction in the CN 1067890 route, avoid dangerous chemical processes and extremely toxic reagents, and find a method which is more suitable for industrial production and safe and convenient to operate.
The invention adopts the following technical scheme:
the steps are as follows: adding ethyl 2- [ [ (2 '-cyanobiphenyl-4-yl) methyl ] amino ] -3-nitrobenzoate (2) into a solvent, and carrying out reduction reaction with ammonium formate (3) under the catalysis of palladium hydroxide carbon to obtain a compound (1), namely ethyl 3-amino-2- [ (2' -cyanobiphenyl-4-yl) -methylamino ] -benzoate.
The chemical reaction formula is as follows:
the molar ratio of formula (2) to ammonium formate (3) described in the above step is 1:1.5 to 3.0, more preferably 1:3.0.
The reaction solvent in the above step is at least one of acetonitrile, tetrahydrofuran and isopropanol, and more preferably acetonitrile.
The weight ratio of the formula (2) to palladium hydroxide carbon in the above step is 1:5 to 10%, more preferably 1:10%.
The reaction temperature in the above steps is 65 ℃ to 85 ℃, more preferably 85 ℃; the reaction time is 1h to 3h, more preferably 1h.
Compared with the prior art, the invention has the following technical advantages:
(1) The invention does not involve special reactions such as hydrogenation, reduces the safety risk, reduces the investment of production cost, and is suitable for commercial production;
(2) The invention does not use a highly toxic reagent, is green and environment-friendly, and accords with the quality source design principle (QbD);
(3) The invention has high reaction yield, low production cost and higher economic value.
Drawings
In order to more clearly illustrate the embodiments of the present invention, the drawings that are used in the description of the embodiments will be briefly described below.
The azilsartan key intermediate prepared in the embodiment 1 of the invention: FIG. 1 is a hplc diagramSpectrum, FIG. 2 is 1 An H-NMR spectrum, FIG. 3 is 13 C-NMR spectrum, FIG. 4 shows MS spectrum.
Detailed Description
The novel preparation method of 3-amino-2- [ (2' -cyanobiphenyl-4-yl) -methylamino ] -benzoic acid ethyl ester (compound 1) is as follows:
example 1
20.0 g of 2- [ [ (2' -cyanobiphenyl-4-yl) methyl]Amino group]Ethyl 3-nitrobenzoate (2) (1.0 eq) is added into a 500 mL three-mouth bottle, 200 mL acetonitrile is added for stirring and clearing, 4.75 g ammonium formate (1.5 eq) and 2.0 g palladium hydroxide carbon (10%) are sequentially added, heating and stirring are carried out, after the reaction is stable, 4.75 g ammonium formate is added, reflux is continued for 1h, and TLC monitors the end point of the raw material reaction. The filtrate was obtained after filtration, hydrochloric acid was added to adjust ph=2 to 3, filtration and rinsing with ethyl acetate to obtain an off-white solid, which was added to water, and ph=10 to 11 was adjusted with an aqueous sodium hydroxide solution, extracted with ethyl acetate (100 mL ×2), and the organic phases were combined and concentrated to dryness under reduced pressure to obtain compound (1) (16.75 g, 90.6%) with a purity of 93.4%. 1 H-NMR（400 MHz, DMSO-d6）δ （ppm）：1.21～1.25(3H,t), 4.17～4.22(4H,q), 4.92(2H,s), 6.23～6.26(1H,t), 6.79～6.83(1H,t), 6.92～6.94(1H,d), 7.09～7.11(1H,d), 7.44～7.46(2H,d), 7.52～7.62(4H,m) , 7.77～7.81(1H,t), 7.93～7.95(1H,d)； 13 C-NMR（100 MHz, DMSO-d6）δ （ppm）：14.49, 49.28, 60.85, 110.60, 119.02, 119.07, 119.50, 121.33, 122.18, 128.56, 128.69, 129.02, 130.53, 133.96, 134.34, 136.84, 137.91, 141.32, 142.96, 144.80, 168.44。ESI-MS m/z：372.3 [M+H] + 。
Example 2
20.0 g of ethyl 2- [ [ (2' -cyanobiphenyl-4-yl) methyl ] amino ] -3-nitrobenzoate (2) (1.0 eq) was added to a 500 mL three-necked flask, 200 mL acetonitrile was added to the flask and dissolved, 4.75 g ammonium formate (1.5 eq) and 2.0 g palladium hydroxide carbon (10%) were sequentially added, heated and stirred, and the reaction was refluxed for 2 hours, and TLC monitored for starting material reaction end point. The filtrate was obtained after filtration, and hydrochloric acid was added to adjust ph=2 to 3, filtration and rinsing with ethyl acetate to obtain an off-white solid, which was added to water, and ph=10 to 11 was adjusted with an aqueous sodium hydroxide solution, extracted with ethyl acetate (100 mL ×2), and the organic phases were combined and concentrated to dryness under reduced pressure to obtain compound (1) (15.38 g, 83.2%).
Examples 1-2, the experimental results are shown in Table 1.
Table 1: molar ratio of Compound (2) to ammonium formate (3)
Example 3
20.0 g of ethyl 2- [ [ (2' -cyanobiphenyl-4-yl) methyl ] amino ] -3-nitrobenzoate (2) (1.0 eq) is added into a 500 mL three-necked flask, 200 mL tetrahydrofuran is added to stir and dissolve, 4.75 g ammonium formate (1.5 eq) and 2.0 g palladium hydroxide carbon (10%) are sequentially added, heating and stirring are carried out, after the reaction is stable, 4.75 g ammonium formate is added, reflux is continued for 1h, and TLC monitors the end point of the raw material reaction. The filtrate was obtained after filtration, and hydrochloric acid was added to adjust ph=2 to 3, filtration and rinsing with ethyl acetate to obtain an off-white solid, which was added to water, and ph=10 to 11 was adjusted with an aqueous sodium hydroxide solution, extracted with ethyl acetate (100 mL ×2), and the organic phases were combined and concentrated to dryness under reduced pressure to obtain compound (1) (16.20 g, 87.6%).
Example 4
20.0 g of ethyl 2- [ [ (2' -cyanobiphenyl-4-yl) methyl ] amino ] -3-nitrobenzoate (2) (1.0 eq) is added into a 500 mL three-necked flask, 325 mL isopropanol is added to stir and dissolve, 4.75 g ammonium formate (1.5 eq) and 2.0 g palladium hydroxide carbon (10%) are sequentially added, heating and stirring are carried out, after the reaction is stable, 4.75 g ammonium formate is added, reflux is continued for 1h, and TLC monitors the end point of the raw material reaction. The filtrate was obtained after filtration, and hydrochloric acid was added to adjust ph=2 to 3, filtration and rinsing with ethyl acetate to obtain an off-white solid, which was added to water, and ph=10 to 11 was adjusted with an aqueous sodium hydroxide solution, extracted with ethyl acetate (100 mL ×2), and the organic phases were combined and concentrated to dryness under reduced pressure to obtain compound (1) (15.29 g, 82.7%).
Examples 3-4, experimental results are shown in Table 2.
Table 2: screening of solvents
Example 5
20.0 g of ethyl 2- [ [ (2' -cyanobiphenyl-4-yl) methyl ] amino ] -3-nitrobenzoate (2) (1.0 eq) is added into a 500 mL three-necked flask, 200 mL acetonitrile is added to stir and dissolve, 4.75 g ammonium formate (1.5 eq) and 1.0 g palladium hydroxide carbon (5%) are sequentially added, heating and stirring are carried out, after the reaction is stable, 4.75 g ammonium formate is added, reflux is continued for 3h, and TLC monitors the end point of the raw material reaction. The filtrate was obtained after filtration, and hydrochloric acid was added to adjust ph=2 to 3, filtration and rinsing with ethyl acetate to obtain an off-white solid, which was added to water, and ph=10 to 11 was adjusted with an aqueous sodium hydroxide solution, extracted with ethyl acetate (100 mL ×2), and the organic phases were combined and concentrated to dryness under reduced pressure to obtain compound (1) (15.70 g, 84.9%).
The results of the experiment are shown in Table 3.
Table 3: catalyst dosage screening
The method for synthesizing the azilsartan key intermediate provided by the invention is described in detail. Specific examples are set forth herein to illustrate embodiments and preferred conditions of the invention, and the description of the examples above is intended to aid in understanding the methods and core concepts of the invention.
Claims (5)
1. A method for synthesizing an azilsartan key intermediate (compound 1), which is characterized by comprising the following chemical reaction formula:
the method comprises the following specific steps:
the steps are as follows: adding ethyl 2- [ [ (2 '-cyanobiphenyl-4-yl) methyl ] amino ] -3-nitrobenzoate (2) into a solvent, and carrying out reduction reaction with ammonium formate (3) under the catalysis of palladium hydroxide carbon to obtain a compound (1), namely ethyl 3-amino-2- [ (2' -cyanobiphenyl-4-yl) -methylamino ] -benzoate.
2. The process for the synthesis of azilsartan key intermediate (compound 1) according to claim 1, characterized in that the molar ratio of formula (2) to ammonium formate (3) in step (a) is comprised between 1:1.5 and 3.0, more preferably between 1:3.0.
3. The process for the synthesis of azilsartan key intermediate (compound 1) according to claim 1, characterized in that the reaction solvent in the step is at least one of acetonitrile, tetrahydrofuran, isopropanol, more preferably acetonitrile.
4. The process for the synthesis of azilsartan key intermediate (compound 1) according to claim 1, characterized in that the weight ratio of formula (2) to palladium carbon hydroxide in step (a) is 1:5% -10%, more preferably 1:10%.
5. The process for the synthesis of azilsartan key intermediate (compound 1) according to claim 1, characterized in that the reaction temperature in step (a) is 65 ℃ to 85 ℃, more preferably 85 ℃; the reaction time is 1h to 3h, more preferably 1h.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1051355A (en) * | 1989-10-24 | 1991-05-15 | 武田药品工业株式会社 | Benzimidizole derivatives, its production method and application thereof |
| US20040116710A1 (en) * | 2002-03-13 | 2004-06-17 | Wallace Eli M. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
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