CN100413853C - Synthetic intermediate of Irbesartan, preparation method and use thereof - Google Patents
Synthetic intermediate of Irbesartan, preparation method and use thereof Download PDFInfo
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- CN100413853C CN100413853C CNB2006101529361A CN200610152936A CN100413853C CN 100413853 C CN100413853 C CN 100413853C CN B2006101529361 A CNB2006101529361 A CN B2006101529361A CN 200610152936 A CN200610152936 A CN 200610152936A CN 100413853 C CN100413853 C CN 100413853C
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- 239000002947 C09CA04 - Irbesartan Substances 0.000 title claims description 13
- 229960002198 irbesartan Drugs 0.000 title claims description 13
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 title description 12
- 238000002360 preparation method Methods 0.000 title description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 13
- -1 1-amino cyclopentyl nitrile Chemical class 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims 3
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 abstract description 11
- 229950001902 dimevamide Drugs 0.000 abstract description 9
- GVUPCWCOWHNOHV-UHFFFAOYSA-N 1-aminocyclobutane-1-carbonitrile Chemical compound N#CC1(N)CCC1 GVUPCWCOWHNOHV-UHFFFAOYSA-N 0.000 abstract 1
- POEDHWVTLBLWDA-UHFFFAOYSA-N 1-butylindole-2,3-dione Chemical compound C1=CC=C2N(CCCC)C(=O)C(=O)C2=C1 POEDHWVTLBLWDA-UHFFFAOYSA-N 0.000 abstract 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002994 raw material Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001409 amidines Chemical class 0.000 description 6
- BIMWFHVLFZYVIE-UHFFFAOYSA-N 5-[5-(bromomethyl)-2-phenylphenyl]-1-trityltetrazole Chemical compound N=1N=NN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C1=CC(CBr)=CC=C1C1=CC=CC=C1 BIMWFHVLFZYVIE-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229910000062 azane Inorganic materials 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LQOBMKYCRQDMTN-UHFFFAOYSA-N 3-(2-ethylphenyl)pentan-3-amine;hydrochloride Chemical compound Cl.CCC1=CC=CC=C1C(N)(CC)CC LQOBMKYCRQDMTN-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- ZSHBJAZLLXXHGK-UHFFFAOYSA-N CCCCC1C(=CC=C(C1(C2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)C(=O)O)C)C(=O)O Chemical compound CCCCC1C(=CC=C(C1(C2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)C(=O)O)C)C(=O)O ZSHBJAZLLXXHGK-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- HQZBTAJPDVTKMM-UHFFFAOYSA-N NCC1=CC=CC=C1.C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NN=NN1 Chemical compound NCC1=CC=CC=C1.C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NN=NN1 HQZBTAJPDVTKMM-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QFZOXIMOTKRVIS-UHFFFAOYSA-N [N].C(CCC)[Sn](CCCC)(CCCC)CCCC Chemical compound [N].C(CCC)[Sn](CCCC)(CCCC)CCCC QFZOXIMOTKRVIS-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The invention discloses a new method to synthesize erbasatan, which comprises the following steps: adopting valeramide and 5-(4-xylyl bromide-2-raidcal)-1-trityl-1H-tetrazole as original material; transmitting into N-((2'-(1-trityl-1H-tetrazole-5 radical) biphenyl-4-radical)-methyl) valeramide; reacting with 1-amino cyclobutyl cyanide to obtain key intermediate N-(1-cyano cyclopentyl)-N'-((2'-(1-trityl-1H-tetrazole-5 radical) biphenyl-4-radical)-methyl) pentyl ether disposed by terpolyphosgene; conversing the intermediate into the product.
Description
Technical field:
The present invention relates to pharmaceutical chemistry and organic chemistry filed, more specifically, the present invention relates to synthetic intermediate of irbesartan and its production and use.
Background technology:
Hypertension is modal cardiovascular disorder.Hypertension markization morbidity was 11.29% to 940,000 crowd's sample census more than 15 years old in 1991 in China, compared with 1979-1980, and morbidity has increased by 25% in the period of 10.The not only direct harm humans health of hypertension is also quickened atherosclerotic process greatly, and elevation of blood pressure is the primary hazard factor of Chinese population cerebral apoplexy, coronary heart disease, heart failure and kidney disease.Therefore, particularly important to hypertensive control.
Irbesartan (INN:IRBESARTAN) is the receptor antagonist of known Angiotensin II.Angiotensin is the important participant of renin-angiotensin-aldosterone system, blood pressure there is very strong regulating effect, it is a kind of good antihypertensive drug, having very big exploitation is worth, exploitation this product not only can be benefited for numerous hyperpietics, for the doctor provides capable weapon, and can create huge economic benefit.
Its structure of irbesartan is shown below:
Its chemistry is by name: 2-butyl-3-(2 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl) methyl isophthalic acid, 3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone.Disclosed in the past synthesis technique has a lot, but roughly can be classified as two preparation routes from the reactions steps examination of starting raw material and key.The one, with 2-butyl-1; 3-diazaspiracyclic [4; 4] nonane-1-alkene-4-ketone is starting raw material; carry out the azane glycosylation reaction with 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium; last deprotection obtains this product or carries out the azane glycosylation reaction with 2 '-cyano group-4-bromomethylbiphenyl, forms tetrazole with the tetrabutyl tin nitrogen thing reaction that changes again at last.As WO2004007482, WO2005051943, CN1668612, EP1060165.Reaction formula is as follows:
The 2nd, be starting raw material with 1-amino cyclopentyl acid methyl esters or 1-amino cyclopentyl acid amides, with 2 '-(1H-tetrazolium-5-yl)-biphenyl benzylamine or 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium reaction, utilize original acid methyl ester or valeryl chloride closed loop to obtain this product at last.As WO2004072064, the EP475898. reaction formula is as follows:
Or
Certainly also useful link coupled method obtains this product, as WO2004065383.Reaction formula is as follows:
The present invention compares with the technology of bibliographical information, and raw material is easy to get, and reactions steps is short, and is easy to operate.Pass of the present invention ring method is very ingenious, and the yield height, and cost is relatively low.
Summary of the invention
The problem to be solved in the present invention provides the method for the synthetic irbesartan of a kind of high-efficient simple.
The object of the present invention is to provide a kind of midbody compound (6) of novelty.
The present invention also provides the preparation method of compound (6).
And then the present invention also provides midbody compound (3).
The present invention also provides compound (6) in the purposes that is used for preparing the irbesartan compound.
The present invention is that raw material passes through through three-step reaction with valeramide and 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium, the synthetic irbesartan of highly selective.
Principal reaction step of the present invention is as follows:
1) synthetic N-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) valeramide (3)
In the time of 0～100 ℃, in organic solvent, with valeramide and 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium is a raw material, its mol ratio is 1～10: 1, is preferably 5: 1, and the reaction times is 1～40 hour, be preferably 6 hours, under alkali and phase-transfer catalyst effect, react.Above-mentioned alkali can be NaOH, KOH, LiOH, Na
2CO
3, K
2CO
3Deng mineral alkali, also can be organic basess such as triethylamine, Tributylamine, pyridine.Phase-transfer catalyst can be a hexadecyl trimethyl ammonium bromide, tetrabutyl iodate amine, triethyl benzyl ammonia chloride etc.
2) synthetic N-(1-cyano group cyclopentyl)-N '-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) penta amidine (6)
In the time of-10～40 ℃, in the organic solvent, be raw material with N-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) valeramide, add organic bases, can be triethylamine, Tributylamine, pyridine etc., its mol ratio is, 1: 1～10, be recommended as 1: 5.The organic solution of three surpalites slowly is added drop-wise in the system, with the mol ratio of raw material be 1: 1～5, be recommended as 1: 2.5, reacted 1～20 hour.Drain organic solvent and remove excess phosgene.Again add organic solvent and organic bases, the mol ratio of organic bases and raw material is 1～2: 1, then slowly drips 1-amino cyclopentyl nitrile, with the mol ratio of raw material be 1～4: 1, be recommended as 2: 1, reacted 1～20 hour.
3) synthetic irbesartan (7):
In the time of-10～20 ℃, in alcoholic solvent, be raw material with N-(1-cyano group cyclopentyl)-N-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) penta amidine, logical HCl gas is to saturated.0～20 ℃ of insulation 4 ~ 8 hours, add the alkali neutralization afterwards, transfer pH value to alkalescence, be recommended as PH=8～9, continue reaction 2～10 hours.Add concentrated hydrochloric acid and transfer pH value, be recommended as PH=1～2, reacted 0.5-3 hour to strongly-acid.Above-mentioned alcohol is: methyl alcohol, ethanol, propyl carbinol, Virahol etc.
Embodiment
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.
Embodiment one: preparation N-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) valeramide (3)
In the 10L reaction flask, with valeramide (243g), 5-(4-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazolium (268g), NaOH (57.6g), hexadecyl trimethyl ammonium bromide (5g) and toluene 8L mix, mechanical stirring, and this moment, internal temperature was 25 ℃, the reacting by heating system to interior temperature between 65-70 ℃, and keep this thermotonus 28h.Reaction solution is poured in the 2L water, and constantly stirred.Leave standstill, tell toluene layer, water layer is used ethyl acetate extraction again, merges organic phase.The anhydrous MgSO of organic phase
4Drying concentrates after crystallization purifying gets product (235g, productive rate are 85%), and purity is＞98% (HPLC).
1H NMR (400MHz, CDCl
3) δ: 0.96 (t, J=7.2Hz, 3H, CH
3), 1.35-1.41 (m, 2H, CH
2), 1.62-1.69 (m, 2H, CH
2), 2.16 (t, J=7.6Hz, 2H, CH
2), 4.37 (d, J=5.6Hz, 2H, NCH
2), 5.54 (s, br, H, NH), 6.94-6.96 (m, 6H, ArH), 7.07 (d, J=8.4Hz, 2H, and ArH) 7.14 (d, J=8.4Hz, 2H, ArH), 7.30-7.34 (m, 6H, ArH), 7.37-7.44 (m, 4H, ArH), and 7.51-7.57 (m, 2H, ArH), 8.01 (dd, J=7.2Hz, J=1.6Hz, 1H, ArH);
13C?NMR(400MHz，CDCl
3)δ：13.8，22.5，27.8，36.5，43.4，82.9，126.3，127.5，127.7，128.3，129.6，130.0，130.2，130.3，130.6，136.8，140.6，141.3，141.8，164.0，172.8；
Ms(+C，ESI)：M＝577，Found(595，M+H
2O)；
UV (methyl alcohol): 342nm, 206nm;
IR(film，cm
-1)：3308，3061，2957，2929，2866，1648，1544，1447，1266，1191，1030，754，700。
Embodiment two: preparation N-(1-cyano group cyclopentyl)-N '-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) penta amidine (6)
N-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) valeramide (120g) is dissolved in toluene 1.2L, is chilled to 0 ℃ with ice-water bath, and the adding pyridine (80mL, 4eq). the toluene solution of slow dropping phosgene under 0 ℃ (52g, 300mL).After adding, be warming up to room temperature naturally, and continue to stir 8 hours.Take out toluene and excess phosgene at low temperatures, and with toluene band phosgene once.Again use toluene (600mL) dissolving, (34mL, 2eq), (45g 2eq), adds the back stirring and spends the night then to add 1-amino cyclopentyl nitrile to add pyridine.With above-mentioned reaction solution suction filtration, the gained solid adds water and at room temperature stirred suction filtration 10 minutes.The gained solid with the ethyl acetate washing once 45-50 ℃ of vacuum-drying, gets product (125g, productive rate are 90%).
1H NMR (400MHz, CDCl
3) δ: 0.83 (t, J=7.2Hz, 3H, CH
3), 1.22-1.28 (m, 2H, CH
2), 1.49-1.57 (m, 2H, CH
2), 1.88-1.91 (m, 6H, 3CH
2), 2.01-2.05 (m, 2H, CH
2), 2.21 (t, J=7.6Hz, 2H, CH
2), 4.71 (s, 2H, NCH
2), 6.92-6.96 (m, 8H, ArH), 7.10 (d, J=8.0Hz, 2H, ArH) 7.24-7.28 (m, 6H, ArH), 7.32-7.37 (m, 4H, ArH), 7.44-7.50 (m, 2H, ArH), 7.88-7.91 (m, 1H, ArH);
13C?NMR(400MHz，CDCl
3)δ：13.8，22.4，25.9，28.3，28.4，40.4，43.8，77.6，82.9，125.8，126.3，127.5，127.7，127.9，128.2，129.6，129.7，129.9，130.2，130.3，130.5，130.8，135.7，140.3，141.3，141.7，161.6，164.0；
Ms(+C，ESI)：M＝669，Found(670，M+1)，(688，M+1+H
2O)；
UV (methyl alcohol): 385nm, 206nm;
IR(film，cm
-1)：3422，2957，2868，2368，1651，1442，1406，1180，932，754，700。
Embodiment three: preparation irbesartan (7)
N-(1-cyano group cyclopentyl)-N-((2 '-(1-trityl-1H-tetrazolium-5 base) biphenyl-4-yl)-methyl) penta amidine (90g) is dissolved in methyl alcohol (630mL), bathes at cryosel and lead to HCl gas under the cooling to saturated, temperature is less than 10 ℃ in keeping.After having led to, between 10-15 ℃, be incubated 3h, be chilled to 0 ℃ again,, regulate PH=8-9, at room temperature stir after adding and spend the night at 0 ℃ of methanol solution that drips NaOH down.Concentrate, steam and remove most of solvent, under the water-bath cooling, slowly drip concentrated hydrochloric acid, and fully stir.Transfer PH=1-2.Add the back and continue to stir the 2h. ethyl acetate extraction, after the organic phase drying concentrates, crystallization, purifying gets product (46g, productive rate are 80%).
1H NMR (400MHz, d-DMSO) δ: 0.82 (t, J=7.2Hz, 3H, CH
3), 1.26-1.31 (m, 2H, CH
2), 1.46-1.52 (m, 2H, CH
2), 1.69-1.71 (m, 2H, CH
2), 1.85-1.87 (m, 6H, 3CH
2), 2.32 (t, J=7.2Hz, 2H, CH
2), 4.71 (s, 2H, NCH
2), 7.12 (s, 4H, ArH), 7..54-7.61 (m, 2H, ArH), 7.68-7.70 (m, 2H, ArH);
13C NMR (400MHz, d-DMSO) δ: 14.1,22.0,25.9,27.1,28.0,37.3,42.7,76.3,124.3,126.7,128.2,129.7,131.0,131.1,131.4,136.7,139.0,141.5,155.7,161.6,186.1; Ms (+C, ESI): M=428, Found (429, M+1), (451, M+Na)
UV (methyl alcohol): 357nm, 206nm;
IR(film，cm
-1)：3417，2959，1698，1661，1448，1180，759，703。
Claims (5)
1. the compound of a formula (6) representative:
R represents a kind of protecting group in the formula, is CPh
3
2. method for preparing the described compound of claim 1 (6), this method comprise that handling compounds (3) with three surpalites obtains compound (4), and compound (4) reacts with 1-amino cyclopentyl nitrile and obtains compound 6 then, and reaction formula is as follows:
R represents a kind of protecting group in the formula, is CPh
3
3. method according to claim 2 is characterized in that compound (3) is by compound (1) and compound
(2) prepared in reaction obtains, and reaction formula is as follows:
4. the compound of a formula (3) representative:
R represents a kind of protecting group in the formula, is CPh
3
5. the described compound of claim 1 (6) is used to prepare the purposes of irbesartan compound, comprises formula (6)
The logical saturated HCl gas of compound prepares the irbesartan compound of formula (7), and reaction formula is as follows:
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| EP2194050A1 (en) * | 2008-12-08 | 2010-06-09 | KRKA, tovarna zdravil, d.d., Novo mesto | A new process for the preparation of irbesartan |
| CN102050761A (en) * | 2010-12-10 | 2011-05-11 | 江苏江神药物化学有限公司 | Key intermediate of Erbesartan, synthesis method thereof and method for synthesizing Erbesartan therefrom |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004007482A2 (en) * | 2002-07-16 | 2004-01-22 | Teva Pharmaceutical Industries Ltd. | Novel synthesis of irbesartan |
| WO2004072064A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspirol[4,4]-non-ene-4-one |
| EP1060165B1 (en) * | 1998-01-30 | 2004-09-01 | Bristol-Myers Squibb Company | Method for preparing an n-substituted heterocyclic derivative using a phase-transfer catalyst |
| WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
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2006
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1060165B1 (en) * | 1998-01-30 | 2004-09-01 | Bristol-Myers Squibb Company | Method for preparing an n-substituted heterocyclic derivative using a phase-transfer catalyst |
| WO2004007482A2 (en) * | 2002-07-16 | 2004-01-22 | Teva Pharmaceutical Industries Ltd. | Novel synthesis of irbesartan |
| WO2004072064A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Synthesis of 2-butyl-3-(2'-(1-trityl-1h-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspirol[4,4]-non-ene-4-one |
| WO2005051943A1 (en) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Processes for the preparation of highly pure irbesartan |
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Denomination of invention: Synthetic intermediate of irbesartan and its preparation method and application in drug preparation Effective date of registration: 20201226 Granted publication date: 20080827 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
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