CN101200455B - Method for preparing sartan drug main ring 5-(4'-formyl biphenyl-2-group)-1H-tetrazole treating hypertension - Google Patents
Method for preparing sartan drug main ring 5-(4'-formyl biphenyl-2-group)-1H-tetrazole treating hypertension Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title claims abstract description 12
- 206010020772 Hypertension Diseases 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title abstract description 10
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 26
- 230000032050 esterification Effects 0.000 claims abstract description 17
- 238000005886 esterification reaction Methods 0.000 claims abstract description 17
- 238000005893 bromination reaction Methods 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 15
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000003647 oxidation Effects 0.000 claims abstract description 10
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 230000031709 bromination Effects 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 54
- -1 benzyl ester Chemical class 0.000 claims description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 20
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 18
- NWAUPHAHIDQCHS-UHFFFAOYSA-N 1,1'-biphenyl;2h-tetrazole Chemical compound C1=NN=NN1.C1=CC=CC=C1C1=CC=CC=C1 NWAUPHAHIDQCHS-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical group O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 11
- 229910017604 nitric acid Inorganic materials 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- HQBRKMUDLIZVAS-UHFFFAOYSA-N 4-[2-(2h-tetrazol-5-yl)phenyl]benzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 HQBRKMUDLIZVAS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- 238000005286 illumination Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 8
- 229960004249 sodium acetate Drugs 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004576 sand Substances 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 231100000614 poison Toxicity 0.000 abstract description 2
- 230000007096 poisonous effect Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000010792 warming Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000004224 protection Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004900 laundering Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 3
- 229910052753 mercury Inorganic materials 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- ZRQJTHPAIULYJV-UHFFFAOYSA-N [4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methanol Chemical compound C1=CC(CO)=CC=C1C1=CC=CC=C1C1=NN=NN1 ZRQJTHPAIULYJV-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- 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 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Abstract
The invention belongs to drug synthesis, particularly relates to the main ring of Sartan drug for the treatment of the hypertension i.e. 5-(4'-formyl biphenyl-2-base)-1H-tetrazole. The preparation method comprises the following procedures, bromination, esterification, cyclization, hydrolysis and oxidation. Utilizing the triethylamine hydrochloride to serve as the catalyst, the method of the invention inhibits the side reaction, promotes the purity and the yield of the product, avoids the residue of the poisonous matter in the drug intermediate, reduces the waste discharge, realizes the clean production and protects the environment.
Description
Technical field
The present invention relates to the preparation method of the smooth class treatment of a kind of sand hypertension drug main ring 5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole, belong to chemical pharmacy field.
Background technology
The now synthetic used main ring of husky smooth class antihypertensive drug mainly is N-trityl group-5-(4 '-bromomethylbiphenyl-2-yl)-1H-tetrazole (I).Because the preparation of this intermediate is difficulty comparatively; also be difficult to purify, its price is high always, in order further to reduce the drug manufacture cost; improve drug quality, new intermediate 5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole (II) is successfully developed.
5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole (II) is a kind of novel medicine intermediate, can be used for producing the smooth class antihypertensive drug of a plurality of sand, as valsartan, losartan, irbesartan, Olmesartan and Candesartan etc.Compare with traditional husky smooth class intermediate N trityl group-5-(4 '-bromomethylbiphenyl-2-yl)-1H-tetrazole, new intermediate has purity height, advantage that production cost is low.And when being used for sartans production, the atom utilization of new intermediate is higher than 42% of traditional intermediate far away up to 95%.
The successful Application of this intermediate can reduce the pharmaceutical production cost greatly and improve drug quality, and the consumption that enters the ordinary people for this kind new medicine creates favorable conditions, and therefore, this intermediate has vast market prospect and social value.
Have two kinds of preparation methods to be used to produce this intermediate at present:
The one, be starting raw material with p-bromobenzaldehyde and o-Cyanochlorobenzene, at first, in tetrahydrofuran (THF), make Grignard reagent with reactive magnesium with the protection of p-bromobenzaldehyde spent glycol; The reaction of o-Cyanochlorobenzene and sodium azide generates tetrazole then; again with triphenylmethyl chloride or tetrahydrofuran (THF) protection; under zinc chloride and transition-metal catalyst effect, carry out the biphenyl tetrazolium aldehyde that linked reaction obtains aldehyde radical and the two protections of tetrazyl with the Grignard reagent of p-bromobenzaldehyde second two acetals, go protection to obtain biphenyl tetrazolium aldehyde then.
The 2nd, be raw material with the sartanbiphenyl, the bromination Cheng Shatan of elder generation bromobenzyl, then with the carboxylate salt esterification, be hydrolyzed into husky smooth benzylalcohol, under the catalysis of chloro trialkyltin, obtain biphenyl tetrazolium alcohol again with sodium azide reaction, get biphenyl tetrazolium aldehyde with clorox or nitric acid oxidation at last.
Though article one the route starting raw material is cheap, reactions steps is many, and particularly there are problems such as solvent costliness, catalyzer costliness, yield be low in grignard reaction, so marketable value is little.
The second route is starting raw material with the sartanbiphenyl, and this cost of material is more cheap, and the reaction that route relates to is simpler, easily control.But, influence the purity and the yield of product because the cyclization of benzylalcohol poor stability at high temperature is easy to generate impurity like this.In addition, make catalyzer with the chloro trialkyltin in the cyclization process, because such material is extremely dangerous, it is inflammable and explosive that chance water is met oxygen, and poisonous, so be unfavorable for producing and labour protection.
Summary of the invention
The preparation method who the purpose of this invention is to provide the smooth class of a kind of sand treatment hypertension drug main ring 5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole, this preparation method can:
1, reduces the generation of impurity, improve the purity and the yield of product;
2, reduce cost, adapt to ordinary people's level of consumption;
3, simple to operate, three waste discharge is few, so as safely, clean production.
Technical solution of the present invention may further comprise the steps: bromination → esterification → cyclization → hydrolysis → oxidation, and its synthetic route is:
Wherein ring-closure reaction adopts the catalyst of triethylamine hydrochloride.
Preparation method's of the present invention concrete steps are: (1) bromination reaction: sartanbiphenyl III bromination reaction De Shatan bromobenzyl IV, under illumination condition, carry out bromination with bromine, the mol ratio of sartanbiphenyl III and bromine is 1: 0.9～1.3, solvent is tetracol phenixin, chloroform, ethylene dichloride, methylene dichloride, normal hexane or hexanaphthene, 40 ℃～70 ℃ of temperature, reaction times 4～6h;
(2) esterification: husky smooth bromobenzyl IV esterification De Shatan benzyl ester V, esterification is made esterifying agent with sodium-acetate, and mol ratio is 1: 1～2,60 ℃～100 ℃ of temperature of reaction, reaction solvent is N, dinethylformamide, reaction times 2～4h;
(3) ring-closure reaction: husky smooth benzyl ester V ring-closure reaction gets biphenyl tetrazolium ester VI, catalyzer is a triethylamine hydrochloride, molar ratio is husky smooth benzyl ester V: triethylamine hydrochloride: sodium azide=1: (1～4): (1～4), solvent is N, dinethylformamide, dimethylbenzene or toluene, reaction times 15～30h, 100 ℃～150 ℃ of temperature of reaction;
(4) hydrolysis reaction: biphenyl tetrazolium ester VI hydrolysis reaction gets biphenyl tetrazolium alcohol VII, and the mol ratio of biphenyl tetrazolium ester VI and sodium hydroxide is 1: 2～6, concentration 10%～15%, 70 ℃～90 ℃ of temperature of reaction, reaction times 15～20h;
(5) oxidizing reaction: biphenyl tetrazolium alcohol VII oxidizing reaction gets biphenyl tetrazolium aldehyde II, and oxygenant is a nitric acid, and concentration of nitric acid is 60%～80%, and solvent is toluene, chloroform, methylene dichloride, methyl alcohol, ethanol or ethyl acetate, 5 ℃～50 ℃ of temperature of reaction.
The present invention has following beneficial effect:
(1) the inventive method is bromination → esterification → cyclization → hydrolysis → oxidation, and husky smooth benzyl ester elder generation's cyclization hydrolysis has again suppressed the generation of side reaction like this, has improved the purity and the yield of product.
(2) in the preparation technology of this new intermediate, the difficult point in this step of bromination is that reaction depth is restive, will produce more dibromo by product, at this difficult point, adjusting by choice of Solvent, temperature is controlled degree of depth bromination, thereby obtain the purpose product of high yield, purity is greater than 99%, and yield is greater than 90%.To oxidizing reaction, the problem that has oxidation depth equally, product very easily further are oxidized to acid, by the optimized choice to oxygenant and solvent, use cheap oxygenant and suppressed the further oxidation of product, thereby obtained purity and all very high product of yield.
(3) for this process of ring-closure reaction, with the chloro trialkylated tin as catalyzer, but its toxicity is bigger, and in post-reaction treatment, be difficult to remove, for pharmaceutical intermediate, should avoid its use and residual, the present invention replaces the chloro trialkylated tin to react with triethylamine hydrochloride, avoid toxic substance residual in pharmaceutical intermediate, also reduced the discharging of Toxic in environment.
Embodiment
Embodiment 1:
Bromination reaction: the preparation of husky smooth bromobenzyl IV
In flask, add 19.3g (0.10mol) sartanbiphenyl III and 200ml chloroform, stir down, be warmed up to 40 ℃, open high-pressure mercury lamp illumination, slowly drip about 16.0g (0.10mol) bromine (mol ratio of sartanbiphenyl III and bromine=1: 1), the control rate of addition, reaction produces a large amount of bromize hydrogen gas, absorbs with liquid caustic soda, and bromine dripped and finishes in about 1.5 hours, added follow-up continuation of insurance temperature illumination reaction 3 hours, the 4.5h reaction finishes altogether, steams chloroform then, adds 100ml dehydrated alcohol recrystallization; Obtain white solid product 24.0g after the drying, it is 98% that HPLC analyzes content, yield 88.2%;
Esterification: the preparation of husky smooth benzyl ester V
In flask, add the husky smooth bromobenzyl IV of 27.1g (0.10mol), 10.7g (0.13mol) sodium-acetate (mol ratio of husky smooth bromobenzyl IV and sodium-acetate=1: 1.3), 160ml N, dinethylformamide, stir down, be warming up to 70 ℃ of reactions, afterreaction was complete in 4 hours, N is taken off in decompression, dinethylformamide adds 100ml water and 200ml dimethylbenzene and extracts not treated next step ring-closure reaction that directly carries out of dimethylbenzene layer;
Ring-closure reaction: the preparation of biphenyl tetrazolium ester VI
The xylene solution of the husky smooth benzyl ester V that the adding back makes in flask, add 20.6g (0.15mol) triethylamine hydrochloride and 13.0g (0.2mol) sodium azide (husky smooth benzyl ester V: triethylamine hydrochloride: the mol ratio of sodium azide=1: 1.5: 2) again, be warming up to 135 ℃ of back flow reaction, afterreaction was complete in 20 hours;
Hydrolysis reaction: the preparation of biphenyl tetrazolium alcohol VII
The biphenyl tetrazolium ester VI that ring-closure reaction makes reduces to room temperature, adding 90ml water and 10g (0.25mol) sodium hydroxide are made into the solution (mol ratio of biphenyl tetrazolium ester VI and sodium hydroxide=1: 2.5) of concentration 10%, stirring is warming up to 70 ℃ of reactions, and afterreaction was complete in 20 hours; Separate and remove dimethylbenzene, water drips about 50g concentrated hydrochloric acid, has a large amount of gases to emit, and has yellow sticky solid to separate out simultaneously; Add the 100ml ethyl acetate extraction, collect organic phase, decompression is steamed ethyl acetate and is got yellow thick biphenyl tetrazolium alcohol crude product, not purifiedly can directly carry out oxidizing reaction;
Oxidizing reaction: the preparation of biphenyl tetrazolium aldehyde II
In flask, the crude product and the 100ml chloroform that add the biphenyl tetrazolium alcohol VI of back, fully stir and make the solid dissolving, 20 ℃ of aqueous nitric acid that slowly drip 21.2g70%～75% down, the heat release of dropping process, and have reddish-brown gas to produce, nitric acid dropwises after half an hour, in reaction process, have light yellow solid to separate out, about 3h reaction finishes, and reaction finishes after-filtration, filter cake is extremely neutral with massive laundering, with the washing of 20ml chloroform, drying gets faint yellow solid powder biphenyl tetrazolium aldehyde 18.5g again, it is 99.0% that HPLC analyzes content, esterification, cyclization, hydrolysis, oxidation total recovery 74%.
Embodiment 2:
Bromination reaction: the preparation of husky smooth bromobenzyl IV
In flask, add 19.3g (0.10mol) sartanbiphenyl III and 200ml chloroform, stir down, 61 ℃ of back flow reaction heat up, open high-pressure mercury lamp illumination, slowly drip about 19.2g (0.12mol) bromine (mol ratio of sartanbiphenyl III and bromine=1: 1.2), the control rate of addition, make the liquid under the reflux condensation mode not have obvious yellow, reaction produces a large amount of bromize hydrogen gas, absorbs with liquid caustic soda, and bromine dripped and finishes in about 2 hours, added follow-up continuation of insurance temperature illumination reaction 3 hours, the 5h reaction finishes altogether; Steam chloroform then, add 100ml dehydrated alcohol recrystallization; Obtain white solid product 24.4g after the drying, it is 99% that HPLC analyzes content, yield 90%;
Esterification: the preparation of husky smooth benzyl ester V
In flask, add the husky smooth bromobenzyl IV of 27.1g (0.10mol), 10.7g (0.13mol) sodium-acetate (mol ratio of husky smooth bromobenzyl IV and sodium-acetate=1: 1.3) and 160ml N, dinethylformamide stirs down, be warming up to 90 ℃ of reactions, afterreaction was complete in 3 hours, and N, dinethylformamide are taken off in decompression, add 100ml water and 200ml dimethylbenzene and extract not treated next step ring-closure reaction that directly carries out of dimethylbenzene layer;
Ring-closure reaction: the preparation of biphenyl tetrazolium ester VI
The xylene solution of the husky smooth benzyl ester V that the adding back makes in flask, add 48.1g (0.35mol) triethylamine hydrochloride and 26.0g (0.4mol) sodium azide (husky smooth benzyl ester V: triethylamine hydrochloride: the mol ratio of sodium azide=1: 3.5: 4) again, be warming up to 135 ℃ of back flow reaction, afterreaction was complete in 18 hours;
Hydrolysis reaction: the preparation of biphenyl tetrazolium alcohol VIII
The biphenyl tetrazolium ester VI that ring-closure reaction makes reduces to room temperature, adding 140ml water and 24g (0.6mol) sodium hydroxide are made into the solution (mol ratio of biphenyl tetrazolium ester VI and sodium hydroxide=1: 6) of concentration 14.6%, stirring is warming up to 70 ℃ of reactions, and afterreaction was complete in 18 hours; Divide to fall dimethylbenzene, water drips about 200g concentrated hydrochloric acid, has a large amount of gases to emit, and has yellow sticky solid to separate out simultaneously; Add the 100ml ethyl acetate extraction, collect organic phase, decompression is steamed ethyl acetate and is got yellow thick biphenyl tetrazolium alcohol crude product, not purifiedly can directly carry out oxidizing reaction;
Oxidizing reaction: the preparation of biphenyl tetrazolium aldehyde II
In flask, the crude product and the 100ml chloroform that add the biphenyl tetrazolium alcohol VI of back, fully stir and make the solid dissolving, 30 ℃ of aqueous nitric acid that slowly drip 25g65%～70% down, the heat release of dropping process, and have reddish-brown gas to produce, nitric acid dropwises after half an hour, in reaction process, have light yellow solid to separate out, about 4h reaction finishes, and reaction finishes after-filtration, filter cake is extremely neutral with massive laundering, with the washing of 20ml chloroform, drying gets faint yellow solid powder biphenyl tetrazolium aldehyde 19.0g again, it is 99.2% that HPLC analyzes content, esterification, cyclization, hydrolysis, oxidation total recovery 76%.
Embodiment 3:
Bromination reaction: the preparation of husky smooth bromobenzyl IV
In flask, add 19.3g (0.10mol) sartanbiphenyl III and 200ml ethylene dichloride, stir down, 70 ℃ of reactions heat up, open high-pressure mercury lamp illumination, slowly drip about 16.0g (0.10mol) bromine (mol ratio of sartanbiphenyl III and bromine=1: 1), the control rate of addition, reaction produces a large amount of bromize hydrogen gas, absorbs with liquid caustic soda, and bromine dripped and finishes in about 1.5 hours, added follow-up continuation of insurance temperature illumination reaction 3 hours, the 4.5h reaction finishes altogether, steams ethylene dichloride then, adds 100ml dehydrated alcohol recrystallization; Obtain white solid product 24.2g after the drying, it is 98% that HPLC analyzes content, yield about 89%;
Esterification: the preparation of husky smooth benzyl ester V
In flask, add the husky smooth bromobenzyl IV of 27.1g (0.10mol), 10.7g (0.20mol) sodium-acetate (mol ratio of husky smooth bromobenzyl IV and sodium-acetate=1: 2) and 160ml N, dinethylformamide stirs down, be warming up to 70 ℃ of reactions, 3.5 hour afterreaction is complete, decompression steams N, dinethylformamide, add 100ml water and 200ml toluene and extract not treated next step ring-closure reaction that directly carries out of toluene layer;
Ring-closure reaction: the preparation of biphenyl tetrazolium ester VI
The toluene solution of the husky smooth benzyl ester V that the adding back makes in flask, add 20.6g (0.15mol) triethylamine hydrochloride and 13.0g (0.2mol) sodium azide (husky smooth benzyl ester V: triethylamine hydrochloride: the mol ratio of sodium azide=1: 1.5: 2) again, be warming up to 110 ℃ of back flow reaction, afterreaction was complete in 30 hours;
Hydrolysis reaction: the preparation of biphenyl tetrazolium alcohol VII
The biphenyl tetrazolium ester VI that ring-closure reaction makes reduces to room temperature, adding 90ml water and 10g (0.25mol) sodium hydroxide are made into the solution (mol ratio of biphenyl tetrazolium ester VI and sodium hydroxide=1: 2.5) of concentration 10%, stirring is warming up to 80 ℃ of reactions, and afterreaction was complete in 17 hours; Divide to fall toluene, water drips about 50g concentrated hydrochloric acid, has a large amount of gases to emit, and has yellow sticky solid to separate out simultaneously; Add the 100ml ethyl acetate extraction, collect organic phase, decompression is steamed ethyl acetate and is got yellow thick biphenyl tetrazolium alcohol crude product, not purifiedly can directly carry out oxidizing reaction;
Oxidizing reaction: the preparation of biphenyl tetrazolium aldehyde II
In flask, the crude product and the 100ml ethylene dichloride that add the biphenyl tetrazolium alcohol VI of back, fully stir and make the solid dissolving, 45 ℃ of aqueous nitric acid that slowly drip 21.2g70%～75% down, the heat release of dropping process, and have reddish-brown gas to produce, nitric acid dropwises after half an hour, in reaction process, have light yellow solid to separate out, about 3h reaction finishes, and reaction finishes after-filtration, filter cake is extremely neutral with massive laundering, with the washing of 20ml ethylene dichloride, drying gets faint yellow solid powder biphenyl tetrazolium aldehyde 18.2g again, it is 98.5% that HPLC analyzes content, esterification, cyclization, hydrolysis, oxidation total recovery 72.7%.
The invention is not restricted to these disclosed embodiment; the present invention is with the described scope of soverlay technique scheme; and the various modification of claim scope and equivalence variation; under the prerequisite that does not depart from technical solution of the present invention, any modification or improvement that those skilled in the art that the present invention did are realized easily all belong to the present invention's scope required for protection.
The abbreviation of each reactive material and chemical name are as follows among the preparation method of the present invention:
(1) 2 '-cyano group-4-methyl diphenyl (is called for short: sartanbiphenyl)
(2) 2 '-cyano group-4-bromomethylbiphenyl (are called for short: husky smooth bromobenzyl)
(3) 2 '-cyano group-4-carboxylicesters methyl diphenyl (are called for short: husky smooth benzyl ester)
(4) 5-(4 '-carboxylicesters methyl diphenyl-2-yl)-1H-tetrazole (is called for short: biphenyl tetrazolium ester)
(5) 5-(4 '-hydroxymethyl biphenyl-2-yl)-1H-tetrazole (is called for short: biphenyl tetrazolium alcohol)
(6) 5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole; (be called for short: biphenyl tetrazolium aldehyde)
Claims (2)
1. the preparation method of husky smooth class treatment hypertension drug main ring 5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole is characterized in that this preparation method may further comprise the steps: bromination → esterification → cyclization → hydrolysis → oxidation, and its synthetic route is:
Wherein ring-closure reaction adopts the catalyst of triethylamine hydrochloride.
2. the preparation method of the smooth class treatment of sand according to claim 1 hypertension drug main ring 5-(4 '-formyl biphenyl-2-yl)-1H-tetrazole is characterized in that concrete steps are:
(1) bromination reaction: sartanbiphenyl (III) bromination reaction De Shatan bromobenzyl (IV), under illumination condition, carry out bromination with bromine, sartanbiphenyl (III) is 1: 0.9～1.3 with the mol ratio of bromine, solvent is tetracol phenixin, chloroform, ethylene dichloride, methylene dichloride, normal hexane or hexanaphthene, 40 ℃～70 ℃ of temperature, reaction times 4～6h;
(2) esterification: husky smooth bromobenzyl (IV) esterification De Shatan benzyl ester (V), esterification is made esterifying agent with sodium-acetate, and mol ratio is 1: 1～2,60 ℃～100 ℃ of temperature of reaction, reaction solvent is N, dinethylformamide, reaction times 2～4h;
(3) ring-closure reaction: husky smooth benzyl ester (V) ring-closure reaction gets biphenyl tetrazolium ester (VI), catalyzer is a triethylamine hydrochloride, molar ratio is a husky smooth benzyl ester (V): triethylamine hydrochloride: sodium azide=1: (1～4): (1～4), solvent is N, dinethylformamide, dimethylbenzene or toluene, reaction times 15～30h, 100 ℃～150 ℃ of temperature of reaction;
(4) hydrolysis reaction: biphenyl tetrazolium ester (VI) hydrolysis reaction gets biphenyl tetrazolium alcohol (VII), and biphenyl tetrazolium ester (VI) is 1: 2～6 with the mol ratio of sodium hydroxide, concentration 10%～15%, 70 ℃～90 ℃ of temperature of reaction, reaction times 15～20h;
(5) oxidizing reaction: biphenyl tetrazolium alcohol (VII) oxidizing reaction gets biphenyl tetrazolium aldehyde (II), and oxygenant is a nitric acid, and concentration of nitric acid is 60%～80%, and solvent is toluene, chloroform, methylene dichloride, methyl alcohol, ethanol or ethyl acetate, 5 ℃～50 ℃ of temperature of reaction.
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| CN102093301B (en) * | 2010-12-17 | 2012-07-25 | 江苏江神药物化学有限公司 | Solvothermal synthesis method of sartanbiphenyltetrazole |
| CN103772151B (en) * | 2014-02-17 | 2016-01-20 | 江苏联化科技有限公司 | A kind of preparation method of 2-methyl-3-phenyl benzil alcohol |
| CN107935956A (en) * | 2017-10-25 | 2018-04-20 | 浙江工业大学 | A kind of pipelineization prepares the method and its reaction unit of the benzyl position bromomethyl biphenyl containing substituent |
| CN111302973A (en) * | 2020-03-26 | 2020-06-19 | 嘉兴学院 | Preparation method of normal-temperature brominated sartanbiphenyl based on bromine |
| CN116332913A (en) * | 2021-12-22 | 2023-06-27 | 浙江华海药业股份有限公司 | Preparation method of high-purity losartan |
| CN114478313A (en) * | 2021-12-24 | 2022-05-13 | 浙江华洲药业有限公司 | Method for synthesizing high-purity bromosartanbiphenyl |
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