CN115466222B - Preparation method of telmisartan intermediate - Google Patents
Preparation method of telmisartan intermediate Download PDFInfo
- Publication number
- CN115466222B CN115466222B CN202210897609.8A CN202210897609A CN115466222B CN 115466222 B CN115466222 B CN 115466222B CN 202210897609 A CN202210897609 A CN 202210897609A CN 115466222 B CN115466222 B CN 115466222B
- Authority
- CN
- China
- Prior art keywords
- methyl
- acid
- reaction
- propyl
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 25
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- NHFKECPTBZZFBC-UHFFFAOYSA-N 4-amino-3-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1N NHFKECPTBZZFBC-UHFFFAOYSA-N 0.000 claims abstract description 28
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- ILXRSCZVHSZGCS-UHFFFAOYSA-N 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propyl-1h-benzimidazole Chemical compound C1=CC=C2N(C)C(C3=CC(C)=C4N=C(NC4=C3)CCC)=NC2=C1 ILXRSCZVHSZGCS-UHFFFAOYSA-N 0.000 claims abstract description 19
- XWAJTVCEILFDGU-UHFFFAOYSA-N 7-methyl-2-propyl-3h-benzimidazole-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2NC(CCC)=NC2=C1C XWAJTVCEILFDGU-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- 238000005580 one pot reaction Methods 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 238000003482 Pinner synthesis reaction Methods 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- 239000012065 filter cake Substances 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 21
- 239000000706 filtrate Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 13
- 238000000967 suction filtration Methods 0.000 claims description 13
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- YGDWEPGDZRXIEK-UHFFFAOYSA-N [2-(dimethylamino)phenyl]azanium;chloride Chemical compound Cl.CN(C)C1=CC=CC=C1N YGDWEPGDZRXIEK-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- -1 N-methylphthalamide hydrochloride Chemical compound 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 9
- IWRJMQUPCKSBFP-UHFFFAOYSA-N 2-n-methylbenzene-1,2-diamine;hydrochloride Chemical compound Cl.CNC1=CC=CC=C1N IWRJMQUPCKSBFP-UHFFFAOYSA-N 0.000 abstract description 3
- 230000020477 pH reduction Effects 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 52
- 239000000243 solution Substances 0.000 description 24
- AZUHIVLOSAPWDM-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)-1h-imidazole Chemical compound C1=CNC(C=2NC=CN=2)=N1 AZUHIVLOSAPWDM-UHFFFAOYSA-N 0.000 description 21
- 239000002994 raw material Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000004321 preservation Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 2
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 description 1
- XDTTUTIFWDAMIX-UHFFFAOYSA-N 3-methyl-4-nitrobenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1[N+]([O-])=O XDTTUTIFWDAMIX-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940101564 micardis Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001546 nitrifying effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000010887 waste solvent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole, which comprises the following steps: taking 3-methyl-4-aminobenzoic acid and n-butyronitrile as starting materials, and preparing 4-butyrylimine-3-methylbenzoic acid by a Pinner reaction one-pot method in the presence of Lewis acid; under the action of hypochlorite and alkali, 4-butyrylimine-3-methylbenzoic acid is subjected to cyclization reaction by a one-pot method, 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid is prepared through acidification, and then the cyclization reaction is carried out with N-methyl o-phenylenediamine hydrochloride under an acidic condition to prepare 2-N-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole. The invention shortens the double imidazole process to 3 steps by adopting twice one-pot reaction, has simple operation, mild reaction and total molar yield of more than 85 percent, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, relates to a preparation method of a telmisartan intermediate, and in particular relates to a preparation method of a telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole (abbreviated as bisimidazole).
Background
Telmisartan is a novel antihypertensive drug, is a specific angiotensin II receptor (AT I type) antagonist, is used for treating primary hypertension, and can be used alone or in combination with other antihypertensive drugs. Telmisartan was developed by the company Boehringer Ingelheim (Boringer John) in Germany, first marketed in the United states in 1999, in Australia, belgium, england in 2000, and in our country in 2002.
Telmisartan (TELMISARTAN), trade name Micardis, chemical name: 4'- [ (1, 4' -dimethyl-2 '-propyl [2,6' -di-1H-benzoimidazole ] -1 '-yl) methyl ] - [1,1' -biphenyl ] -2-carboxylic acid, CAS number: 144701-48-4. Telmisartan has the structural formula:
Currently, the main process for preparing telmisartan is prepared by condensing and hydrolyzing 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazol-2-yl) benzimidazole (i.e. bisimidazole) and 4' -bromomethyl biphenyl-2-carboxylate (r=ch 3、C2H5), or by condensing and hydrolyzing 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazol-2-yl) benzimidazole (abbreviated as bisimidazole) and 2-cyano-4' -bromomethyl biphenyl. The 4 '-bromomethyl biphenyl-2-carboxylate and the 2-cyano-4' -bromomethyl biphenyl are easy to obtain, and the cost is relatively low and the process is simple; and the synthesis process of the bisimidazole is relatively difficult. At present, the synthetic route of 2-n-propyl-4-methyl-6-carboxyl benzimidazole (short: monoimidazole) surrounding bisimidazole or an intermediate for preparing bisimidazole is more, and mainly comprises the following methods:
The key intermediate bisimidazole of telmisartan is prepared by butyrylating, chloromethylating, sommelet reacting, cyclizing, nitrifying and reducing cyclizing by taking o-methylaniline as a raw material according to the paper published by Xu Jiang and the like, wherein the total yield of 7 steps of the reaction is 27.5% (calculated by o-methylaniline). The method has long route and low total molar yield, the process involves nitration and reduction reactions, has large environmental pollution, is not suitable for industrial production, and has no market competitiveness when used for preparing the bisimidazole.
Patent CN109320461A discloses a preparation method of 2-n-propyl-4-methyl-6-carboxyl benzimidazole, namely, in a hydrochloric acid and ethanol system at the temperature of 0-35 ℃, butyronitrile is prepared to obtain a mixture of an intermediate V and an intermediate IV under the action of anhydrous hydrogen chloride gas; in the presence of a base, converting the intermediate V into an intermediate IV, and reacting the intermediate IV with 3-methyl-4-aminobenzoic acid (a compound III) to prepare an intermediate II; and reacting the intermediate II with sodium hypochlorite solution to obtain 2-n-propyl-4-methyl-6-carboxyl benzimidazole (monoimidazole). In the route, hydrogen chloride gas is adopted in the preparation process of the intermediate V, so that the corrosiveness to equipment is extremely strong, and the hydrogen chloride gas is difficult to purchase and transport and is not suitable for industrial production. In addition, the experiments prove that the intermediate IV imidate is extremely unstable and easy to deteriorate, and is difficult to control in production.
The patent application CN104610161A takes 3-methyl-4-nitro-benzoic acid as a raw material, and is subjected to esterification, reduction, acylation, nitration, reduction and cyclization in sequence to obtain 2-N-propyl-4-methyl-6-carboxyl benzimidazole, and then is condensed with N-methyl o-phenylenediamine hydrochloride under the action of polyphosphoric acid to obtain 2-N-propyl-4-methyl-6- [ 1-methyl benzimidazole-2-yl ] benzimidazole. The route has eight steps, the reaction route is too long, the total molar yield is 34.6%, and the yield is low. The reaction involves ionic liquid 1-n-butyl-3-methylimidazole tetrafluoroborate [ bmim ] BF4, has strong irritation, has potential safety hazard in use, and is not suitable for industrial production.
In summary, the main characteristics of the existing bisimidazole preparation process are as follows:
(1) The preparation method is long in route, complex in operation and long in preparation period;
(2) The process has the advantages of long route, low total molar yield and high cost;
(3) Materials which are difficult to purchase or transport are involved in the reaction, and production is difficult to realize;
(4) The reaction involves compounds with high three wastes and great pollution, so that the three wastes in the production are treated with high cost, the total cost is high, and the market competitiveness is not realized;
(5) The process route relates to an intermediate which has poor stability and is difficult to store, the process is difficult to control, and industrial production cannot be realized.
Therefore, a preparation method of telmisartan intermediate bisimidazole, which is simple to operate, high in yield, low in cost and more suitable for industrial production, is needed in the field.
Disclosure of Invention
The invention aims to overcome the defects that the existing preparation method of telmisartan intermediate bisimidazole is overlong in route, low in yield, complex in operation, high in three wastes and the like, and is not suitable for industrial production, and the like, and provides the bisimidazole preparation method which is low in raw material cost, easy to obtain, low in toxicity, less in process three wastes, short in route and suitable for industrial production, wherein the total molar yield of the method is up to more than 85%.
The aim of the invention is achieved by the following technical scheme:
A preparation method of a telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole comprises the following synthetic route:
Comprising the following steps:
Step (1), 3-methyl-4-aminobenzoic acid and n-butyronitrile are used as starting materials, and 4-butyrylimine-3-methylbenzoic acid (short for intermediate 1) is prepared by a Pinner reaction one-pot method in the presence of Lewis acid;
Step (2), under the action of hypochlorite and alkali, 4-butyryl imine-3-methylbenzoic acid is subjected to a one-pot cyclization reaction and then is subjected to acidification treatment to prepare 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid (namely an intermediate 2);
And (3) carrying out cyclization reaction on 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid and N-methyl o-phenylenediamine hydrochloride under an acidic condition to obtain 2-N-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole.
In the step (1), the butyronitrile is used as a reaction raw material and a reaction solvent, and the weight ratio of the butyronitrile to the 4-amino-3-methylbenzoic acid is more than or equal to 5:1, preferably 5:1-15:1.
The molar ratio of the 4-amino-3-methylbenzoic acid to the Lewis acid is 1:1-1:5.
The Lewis acid is one of aluminum trichloride, zinc chloride and tin tetrachloride.
The temperature of the Pinner reaction is 80-130 ℃.
Specifically, mixing 3-methyl-4-aminobenzoic acid and butyronitrile at the temperature of 0-20 ℃, adding Lewis acid in batches, heating to 80-130 ℃ for Pinner reaction, cooling the reaction liquid to 0-20 ℃ after the reaction is finished, adding dilute hydrochloric acid according to the molar ratio of 3-methyl-4-aminobenzoic acid to hydrochloric acid (calculated as HCl) of 0.25:1-0.8:1, stirring to remove complexation of metal ions in the Lewis acid and intermediates, and filtering to obtain filtrate and filter cakes; adding dilute hydrochloric acid into a filter cake according to the molar ratio of 3-methyl-4-aminobenzoic acid to hydrochloric acid (calculated by HCl) of 0.25:1-0.8:1, pulping to remove salt, filtering, and drying the filter cake to obtain 4-butyrylimine-3-methylbenzoic acid; and recovering the filtrate to obtain the butyronitrile.
The concentration of the dilute hydrochloric acid is 1-2 mol/L.
Preferably, the amount (molar amount) of the diluted hydrochloric acid added is the same for both times.
Preferably, the beating is carried out at room temperature.
The method for recovering the butyronitrile comprises the following steps: the filtrate is layered, the organic layer is dried by anhydrous sodium sulfate and filtered, and the dried butyronitrile is distilled under reduced pressure to obtain butyronitrile. The standard for recycling the butyronitrile is that the water content of the butyronitrile is controlled to be less than or equal to 0.5 percent.
The temperature of the reduced pressure distillation is 50-60 ℃ and the pressure is less than or equal to-0.08 MPa.
In the step (2), the hypochlorite is one of sodium hypochlorite and calcium hypochlorite. The alkali is one of sodium hydroxide and potassium hydroxide.
The molar ratio of the 4-butyrylimine-3-methylbenzoic acid, the hypochlorite and the alkali is 1:2:2-1:5:5, preferably 1:2:2-1:3:3.
The reaction solvent is water.
The pH value after the acidification treatment is 4-6. Preferably, the pH of the reaction solution is adjusted to 4 to 6 by using concentrated hydrochloric acid.
Specifically, dispersing 4-butyrylimine-3-methylbenzoic acid in water according to the weight ratio of 1:3-1:5, cooling to 5-10 ℃, dropwise adding hypochlorite solution at the temperature, carrying out heat preservation reaction for 0.5-3H at 5-10 ℃ after the dropwise addition, dropwise adding alkali solution at the temperature of 5-10 ℃, carrying out reaction for 0.5-2H at 10-30 ℃ after the dropwise addition, dropwise adding concentrated hydrochloric acid to adjust the pH value of the reaction solution to 4-6 after the dropwise addition is finished, cooling to 0-5 ℃, stirring, crystallizing, carrying out suction filtration, and drying a filter cake to obtain 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid.
The mass fraction of the hypochlorite solution can be 20%; the mass fraction of the alkali solution can be 20%.
In the step (3), the acid is one of thionyl chloride and phosphorus oxychloride.
The molar ratio of the 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid to the acid is 1:1.5-1:5.
The molar ratio of the 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid to the N-methylphthalamide hydrochloride is 1:1.5-1:5.
The temperature of the cyclization reaction is 80-140 ℃.
The reaction solvent is at least one of paraxylene and DMF.
Specifically, 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid is mixed with a reaction solvent, the temperature is raised to 50-70 ℃, acid is dripped, the reaction is carried out for 1-3 hours at 70-80 ℃ after the dripping is completed, then the temperature is reduced to 15-25 ℃, N-dimethyl-o-phenylenediamine hydrochloride is added, the temperature is raised to 120-140 ℃ for reaction, after the reaction is completed, the reaction solution is distilled under reduced pressure at 50-80 ℃ until no liquid drips out, the temperature is reduced to 10-20 ℃, the pH value is regulated by 10% sodium hydroxide solution until no solid is precipitated, the mixture is heated, stirred and filtered in a suction way, and a filter cake is dried, thus obtaining 2-N-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention directly takes 3-methyl-4-aminobenzoic acid and n-butyronitrile as initial raw materials, the raw materials are cheap and easy to obtain, other solvents and auxiliary materials used in the whole process are cheap and easy to obtain, the reaction is mild, and the total molar yield is up to more than 85 percent;
(2) The prior single imidazole preparation process needs 4-7 steps of reactions, and the key intermediate single imidazole can be prepared by the two-time one-pot reaction, so that the working hours are greatly shortened, the manufacturing cost is reduced, and the preparation method is suitable for industrial production;
(3) The invention has short process, simple operation, good stability of the related intermediate, easy operation control and preservation, and is beneficial to mass stable production and preparation;
(4) The invention avoids the preparation of bisimidazole by cyclizing polyphosphoric acid with intermediate monoimidazole, and can avoid the defects of difficult production and stirring and long high-temperature reaction time (about 10 hours) caused by too high viscosity of polyphosphoric acid.
(5) The invention has the advantages of few types of organic solvents, few waste solvents, recycling and reusing part of solvents, and being more beneficial to environmental protection and cost control.
Detailed Description
The technical scheme of the present invention is further described by the following examples, but the present invention is not limited by the examples, and any modification and/or variation of the present invention falls within the scope of the present invention.
Example 1
Preparation of 4-butyrimine-3-methylbenzoate (intermediate 1)
300G (2.0 mol) of 3-methyl-4-aminobenzoic acid is put into a 5L reaction bottle, the temperature is reduced to 10 ℃, 1500g of butyronitrile is added, 793.5g (6.0 mol) of anhydrous aluminum trichloride is added in batches, the mixture is stirred for 30min, the temperature of the system is increased to 130 ℃ for reflux reaction, the reaction is started for 4 hours, and the reaction of the raw material 3-methyl-4-aminobenzoic acid is completely stopped; cooling the system to 5 ℃, beginning to dropwise add 792mL of 2mol/L hydrochloric acid, stirring for 30min after the dropwise addition is completed, and filtering to obtain filtrate and a filter cake; at room temperature, the filter cake was slurried with 1584mL 1mol/L hydrochloric acid for 30min, filtered, and dried under reduced pressure at 50deg.C to give intermediate 1, yield 494.2g, molar yield 97.0%, HPLC:99.8%.
Layering the filtrate, drying the organic layer with anhydrous sodium sulfate, filtering, and distilling the dried butyronitrile under reduced pressure (the pressure is less than or equal to-0.08 MPa) at the temperature of 50-60 ℃ to obtain 1060g of butyronitrile with water content: 0.02 percent, and the recovery rate is 88.3 percent, and the butyronitrile is directly used.
Preparation of 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid (monoimidazole or intermediate 2)
470G (1.8 mol) of intermediate 1 is dispersed in 1410mL of water, the system is in a solid-liquid state, the system is cooled to 5-10 ℃, 1339.2g (3.6 mol) of 20% sodium hypochlorite solution is dripped at the temperature, after the dripping is finished, the reaction is continued for 0.5h at the temperature of 5-10 ℃, 720.0g (3.6 mol) of 20% sodium hydroxide solution is dripped at the temperature of 5 ℃, after the dripping is finished, the reaction is completed for 2h at the temperature of 10-15 ℃, concentrated hydrochloric acid is dripped for regulating the pH value to 4, the temperature is reduced to 0-5 ℃, the system is stirred and crystallized for more than 1 hour, the reaction bottle is subjected to suction filtration, a small amount of water is used for washing, the suction filtration is combined, a filter cake is dried at the temperature of 60 ℃ under reduced pressure, 384.0g of intermediate 2 (namely, monoimidazole and white solid) is obtained in molar yield: 96.1%, HPLC:99.7%.
Preparation of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole (abbreviated as bisimidazole)
300G (1.4 mol) of monoimidazole is added into 2400g of paraxylene, then 60ml of LDMF is added, the temperature is raised to 60 ℃, 249.8g (2.1 mol) of thionyl chloride is added dropwise, the temperature is raised to 80 ℃ after the dropwise addition is finished, the reaction is carried out for 1h, then the temperature is reduced to 15-25 ℃, 270g (2.1 mol) of N, N-dimethyl-o-phenylenediamine hydrochloride is added, the temperature is raised to 140 ℃ for reflux reaction, and the sampling and the central control are carried out until the raw material reaction is complete for 2 h; after the reaction is finished, the reaction solution is distilled under reduced pressure at the temperature of 70-80 ℃ until no liquid drips out, the temperature is reduced to 10-20 ℃, the pH is regulated by 10% sodium hydroxide solution until no solid is separated out, the mixture is stirred for 2 hours under heat preservation, suction filtration is carried out, a filter cake is dried under reduced pressure at the temperature of 70 ℃ to obtain 410.3g of bisimidazole (white-like solid), the molar yield is 92.6%, and HPLC:99.4%.
Example 2
Preparation of 4-butyrylimine-3-methylbenzoic acid (intermediate 1)
300G (2.0 mol) of 3-methyl-4-aminobenzoic acid is put into a 5L reaction bottle, the temperature is reduced to 10 ℃, 3000g of butyronitrile is added, 545.2g (4.0 mol) of zinc chloride is added in batches, the mixture is stirred for 30min, the temperature of the system is increased to 130 ℃ for reflux reaction, the central control is started for 3h, and the raw material 3-methyl-4-aminobenzoic acid is completely reacted at the moment and stops reacting; the system is cooled to 5 ℃, 528mL of 2mol/L hydrochloric acid is added dropwise, stirring is carried out for 30min after the dropwise addition is finished, and filtrate and filter cake are obtained after filtration; at room temperature, the filter cake was slurried with 528mL of 2mol/L hydrochloric acid for 30min, filtered, and dried under reduced pressure at 50deg.C to give intermediate 1 in a yield of 490.1g at a molar yield of 96.2%, HPLC:99.4%.
The filtrate was separated into layers, and the organic layer was dried over anhydrous sodium sulfate and filtered to give butyronitrile to be recovered, which was recovered as in example 1.
Preparation of 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid (monoimidazole or intermediate 2)
385.1G (1.5 mol) of intermediate 1 is dispersed in 1175mL of water, the system is in a solid-liquid state, the system is cooled to 5-10 ℃, 1116.0g (3.0 mol) of 20% sodium hypochlorite solution is dripped at the temperature, after the dripping is completed, the reaction is carried out for 1h at 5-10 ℃ under the heat preservation, 600.0g (3.0 mol) of 20% sodium hydroxide solution is dripped at the temperature of 8 ℃, after the dripping is completed, the reaction is carried out for 0.5h at 25-30 ℃, the reaction is completed, concentrated hydrochloric acid is dripped to adjust the pH value to 4, the temperature is reduced to 0-5 ℃, the temperature is above 1 hour of stirring crystallization, the reaction bottle is subjected to suction filtration, a small amount of water is used for washing, the reaction bottle is combined, the suction filtration is carried out, a filter cake is dried at 60 ℃ under reduced pressure, and 314.9g of intermediate 2 (white solid) is obtained according to the mole yield: 96.2%, HPLC:99.3%.
Preparation of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole (abbreviated as bisimidazole)
300G (1.4 mol) of monoimidazole is added into 2400g of paraxylene, the temperature is raised to 60 ℃, 321.9g (2.1 mol) of phosphorus oxychloride is added dropwise, the temperature is raised to 70 ℃ after the completion of the dropwise addition, the reaction is carried out for 3 hours, then the temperature is reduced to 15-25 ℃, 270g (2.1 mol) of N, N-dimethyl-o-phenylenediamine hydrochloride is added, the temperature is raised to 140 ℃ for reflux reaction, the sampling is started until the raw material reaction is complete, after the reaction is finished, the reaction is completed, the reaction is distilled under reduced pressure until no liquid drips out, the temperature is reduced to 10-20 ℃, the pH is regulated by 10% of sodium hydroxide solution until no solid is precipitated, the temperature is kept for 2 hours, the filtration is carried out, the filter cake is dried under reduced pressure at 70 ℃ to obtain 411.7g of bisimidazole (quasi-white solid), the molar yield is 93.2 percent, and the following HPLC:99.4%.
Example 3
Preparation of 4-butyrylimine-3-methylbenzoic acid (intermediate 1)
300G (2.0 mol) of 3-methyl-4-aminobenzoic acid is put into a 5L reaction bottle, the temperature is reduced to 20 ℃, 1500g of butyronitrile is added, 521.0g (2.0 mol) of stannic chloride is added in batches, the mixture is stirred for 30min, the temperature of the system is increased to 80 ℃ for reaction, the central control is started for 6h, and the raw material 3-methyl-4-aminobenzoic acid is completely reacted at the moment and stops reacting; cooling the system to 20 ℃, beginning to dropwise add 264mL of 2mol/L hydrochloric acid, stirring for 30min after the dropwise addition is finished, and filtering to obtain filtrate and a filter cake; at room temperature, the filter cake was slurried with 528mL 1mol/L hydrochloric acid for 30min, filtered, and the filter cake was dried under reduced pressure at 50deg.C to give intermediate 1, yield 493.1g, molar yield 94.8%, HPLC:99.5%.
The filtrate was separated into layers, and the organic layer was dried over anhydrous sodium sulfate and filtered to give butyronitrile to be recovered, which was recovered as in example 1.
Preparation of 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid (monoimidazole or intermediate 2)
385.1G (1.5 mol) of intermediate 1 is dispersed in 1925.5mL of water, the system is in a solid-liquid state, the system is cooled to 5-10 ℃, 1674g (4.5 mol) of 20% sodium hypochlorite solution is dripped at the temperature, after dripping is finished, the reaction is carried out for 0.5h at 5-10 ℃, 900.0g (4.5 mol) of 20% sodium hydroxide solution is dripped at the temperature of 10 ℃, after dripping is finished, the reaction is carried out for 2h at 10-15 ℃, concentrated hydrochloric acid is dripped to adjust the pH value to 4, the system is cooled to 0-5 ℃, the temperature is above 1 hour of stirring crystallization, the reaction bottle is subjected to suction filtration, a small amount of water is used for washing, the suction filtration is combined, a filter cake is dried at 60 ℃ under reduced pressure, 314.6g of intermediate 2 (white solid) is obtained, the molar yield: 96.1%, HPLC:99.4%.
Preparation of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole (abbreviated as bisimidazole)
300G (1.4 mol) of monoimidazole is added into 2400g of paraxylene, 60ml of LDMF is added, the temperature is raised to 50 ℃, 249.8g (2.1 mol) of thionyl chloride is added dropwise, the temperature is raised to 80 ℃ after the completion of the dropwise addition, the reaction is carried out for 1h, then the temperature is reduced to 15-25 ℃, 270g (2.1 mol) of N, N-dimethyl-o-phenylenediamine hydrochloride is added, the temperature is raised to 120 ℃ for reaction, sampling is started until the raw materials are completely reacted, after the reaction is finished, the reaction is carried out, the pressure is reduced and distilled at 70-80 ℃ until no liquid drops out, the temperature is reduced to 10-20 ℃, the pH is regulated by 10% sodium hydroxide solution until no solid is precipitated, the temperature is kept for 2h, suction filtration is carried out, a filter cake is dried at 70 ℃ under reduced pressure, and the molar yield of 418.7g of bisimidazole (quasi-white solid) is 94.5 percent, and HPLC:99.4%.
Example 4
Preparation of 4-butyrimine-3-methylbenzoate (intermediate 1)
Adding 30g (0.2 mol) of 3-methyl-4-aminobenzoic acid into a 5L reaction bottle, cooling to 0 ℃, adding 450g of butyronitrile, adding 133.3g (1.0 mol) of anhydrous aluminum trichloride in batches, stirring for 30min after the addition, heating the system to 130 ℃ for reflux reaction, and starting central control for 4h, wherein the raw material 3-methyl-4-aminobenzoic acid completely reacts, and stopping the reaction; cooling the system to 10 ℃, beginning to dropwise add 70mL 2mol/L hydrochloric acid, stirring for 1h after the dropwise addition is completed, and filtering to obtain filtrate and a filter cake; at room temperature, the filter cake was slurried with 140mL of 1mol/L hydrochloric acid for 1h, filtered, and dried under reduced pressure at 50℃to give intermediate 1 in a yield of 49.5g, molar yield of 97.1%, HPLC:99.5%.
The filtrate was separated into layers, and the organic layer was dried over anhydrous sodium sulfate and filtered to give butyronitrile to be recovered, which was recovered as in example 1.
Preparation of 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid (monoimidazole or intermediate 2)
Dispersing 47g (0.18 mol) of intermediate 1 in 141mL of water, cooling to 5-10 ℃ in a solid-liquid state, dropwise adding 133.9g (0.36 mol) of 20% sodium hypochlorite solution at the temperature, carrying out heat preservation reaction for 3h at 5-10 ℃ after the dropwise adding is completed, dropwise adding 72.0g (0.36 mol) of 20% sodium hydroxide solution at the temperature of 6 ℃, carrying out reaction for 1h at 10-15 ℃ after the dropwise adding is completed, dropwise adding concentrated hydrochloric acid to adjust the pH value to 6, cooling to 0-5 ℃ for more than 1 hour, stirring and crystallizing, carrying out suction filtration, washing a reaction bottle with a small amount of water, merging the suction filtration, and carrying out pressure reduction and drying on a filter cake at 60 ℃ to obtain 38.6g of intermediate 2 (white solid) in a molar yield: 96.5%, HPLC:99.7%.
Preparation of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole (abbreviated as bisimidazole)
30G (0.14 mol) of monoimidazole is added into 240g of paraxylene, 6ml of LDMF is added, the temperature is raised to 70 ℃, 83.3g (0.7 mol) of thionyl chloride is added dropwise, the temperature is raised to 80 ℃ for reaction for 1h after the dripping is finished, the temperature is reduced to 15-25 ℃,27 g (0.21 mol) of N, N-dimethyl-o-phenylenediamine hydrochloride is added, the temperature is raised to 80 ℃ for reaction, sampling is started until the raw materials are completely reacted, after the reaction is finished, the mixture is distilled under reduced pressure at 70-80 ℃ until no liquid drops out, the temperature is reduced to 10-20 ℃, the pH is regulated by 10% sodium hydroxide solution until no solid is precipitated, the mixture is kept at the temperature for 2h, suction filtration is carried out, a filter cake is dried under reduced pressure at 70 ℃ to obtain 40.5g of bisimidazole (off-white solid), the molar yield is 91.5 percent of HPLC:99.5%.
Example 5
Preparation of 4-butyrylimine-3-methylbenzoate (intermediate 1) (nitrile application test)
300G (2.0 mol) of 3-methyl-4-aminobenzoic acid is put into a 5L reaction bottle, the temperature is reduced to 10 ℃, 1500g of recovered butyronitrile (moisture content is 0.5%) is added, 793.5g (6.0 mol) of anhydrous aluminum trichloride is added in batches, after the addition, stirring is carried out for 30min, the temperature of the system is increased to 130 ℃ for reflux reaction, central control is carried out after 4h, the reaction of the raw material 3-methyl-4-aminobenzoic acid is complete, and the reaction is stopped; cooling the system to 0 ℃, beginning to dropwise add 792mL of 2mol/L hydrochloric acid, stirring for 30min after the dropwise addition is completed, and filtering to obtain filtrate and a filter cake; at room temperature, the filter cake was slurried with 1584mL 1mol/L hydrochloric acid for 30min, filtered, and dried under reduced pressure at 50deg.C to give intermediate 1 in a yield of 494.7g, molar yield 97.1%, HPLC:99.9%.
Layering the filtrate, drying the organic layer by using anhydrous sodium sulfate, filtering, and distilling the dried butyronitrile under reduced pressure (the pressure is less than or equal to-0.08 MPa) at the temperature of 50-60 ℃ to obtain 1050g of butyronitrile with the water content: 0.04%, recovery rate 87.5%, recovered butyronitrile direct sleeve.
Comparative example 1
Intermediate II was prepared according to the procedure of example 1 of patent CN109320461 a.
150G of ethanol hydrochloride and 250g of butyronitrile are added into a 1L reaction bottle, the temperature is controlled at 20 ℃ and maintained, 125g of anhydrous hydrogen chloride gas is slowly introduced, and the reaction is stirred for 2 hours after the completion of the aeration. 550g of xylene was added to R1 to give a nitrile solution containing intermediates V and IV, which was detected by GC and had a main peak of 79.4%.
And (2) adding 64g of sodium carbonate and 370g of water into a 1L reaction bottle, stirring until the mixture is clear, adding 1500g of dimethylbenzene, controlling the temperature to be 10 ℃ and maintaining, starting to dropwise add the sodium hydroxide solution and the nitrile salt solution obtained in the step (1) under stirring, maintaining the pH value to be 6.1, and stirring for 2 hours after the dropwise addition is completed. Separating lower water phase, transferring the material to a new 1L reaction bottle, adding 360g of absolute methanol, 200g of aminobenzoic acid and 80g of glacial acetic acid under stirring, controlling the temperature to 18 ℃ and maintaining, stirring for 1 hour, centrifuging, spin-drying to obtain intermediate II, and drying the intermediate II at 60 ℃ under reduced pressure to obtain 80.6g of off-white solid with a molar yield of 15.3 percent by HPLC:71.9%.
The inventor has found that intermediate II has low purity and low yield, and through data analysis, mainly intermediate V or IV is unstable and is easy to hydrolyze to obtain ethyl butyrate, and the ethyl butyrate is further hydrolyzed into butyric acid and ethanol with a plurality of byproducts.
Claims (9)
1. A preparation method of a telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole is characterized by comprising the following steps of: the synthetic route is as follows:
Comprising the following steps:
step (1), 3-methyl-4-aminobenzoic acid and n-butyronitrile are used as starting materials, 4-butyrylimine-3-methylbenzoic acid is prepared through a Pinner reaction one-pot method in the presence of Lewis acid, after the reaction is finished, the reaction solution is cooled to 0-20 ℃, dilute hydrochloric acid is added according to the molar ratio of HCl in 3-methyl-4-aminobenzoic acid and hydrochloric acid of 0.25:1-0.8:1, and the mixture is stirred and filtered to obtain filtrate and filter cake; adding dilute hydrochloric acid into a filter cake according to the molar ratio of 0.25:1-0.8:1 of HCl in 3-methyl-4-aminobenzoic acid to hydrochloric acid for pulping, filtering, and drying the filter cake to obtain 4-butyrylimine-3-methylbenzoic acid; the weight ratio of the butyronitrile to the 4-amino-3-methylbenzoic acid is more than or equal to 5:1; the molar ratio of the 4-amino-3-methylbenzoic acid to the Lewis acid is 1:1-1:5; the Lewis acid is one of aluminum trichloride, zinc chloride and tin tetrachloride;
Step (2), the reaction solvent is water; under the action of hypochlorite and alkali, 4-butyrylimine-3-methylbenzoic acid is subjected to cyclization by a one-pot method, after the reaction is finished, concentrated hydrochloric acid is dropwise added to adjust the pH of reaction liquid to 4-6, the temperature is reduced to 0-5 ℃, stirring and crystallization are carried out, suction filtration is carried out, and filter cakes are dried, thus obtaining 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid;
Step (3), mixing 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid with a reaction solvent, heating to 50-70 ℃, dropwise adding acid, reacting at 70-80 ℃ for 1-3H after the completion of dropwise adding, cooling to 15-25 ℃, adding N, N-dimethyl-o-phenylenediamine hydrochloride, heating to 120-140 ℃ for reacting, after the reaction is finished, distilling the reaction solution under reduced pressure at 50-80 ℃ until no liquid drips out, cooling to 10-20 ℃, regulating the pH value with 10% sodium hydroxide solution until no solid is precipitated, preserving heat, stirring, suction filtering, and drying a filter cake to obtain 2-N-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole; wherein the acid is one of thionyl chloride and phosphorus oxychloride.
2. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (1), the weight ratio of the butyronitrile to the 4-amino-3-methylbenzoic acid is 5:1-15:1.
3. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (1), the temperature of the Pinner reaction is 80-130 ℃.
4. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (1), 3-methyl-4-aminobenzoic acid and butyronitrile are mixed at the temperature of 0-20 ℃, lewis acid is added in batches, the temperature is raised to 80-130 ℃ for carrying out a Pinner reaction, after the reaction is finished, the reaction solution is cooled to 0-20 ℃, dilute hydrochloric acid is added according to the mol ratio of 0.25:1-0.8:1 of HCl in the 3-methyl-4-aminobenzoic acid and hydrochloric acid, stirring is carried out, and filtrate and filter cake are obtained; adding dilute hydrochloric acid into a filter cake according to the molar ratio of 0.25:1-0.8:1 of HCl in 3-methyl-4-aminobenzoic acid to hydrochloric acid for pulping, filtering, and drying the filter cake to obtain 4-butyrylimine-3-methylbenzoic acid; and recovering the filtrate to obtain the butyronitrile.
5. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (2), the hypochlorite is one of sodium hypochlorite or calcium hypochlorite; the alkali is one of sodium hydroxide and potassium hydroxide.
6. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (2), the molar ratio of the 4-butyrylimine-3-methylbenzoic acid, the hypochlorite and the alkali is 1:2:2-1:5:5.
7. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 6, which is characterized in that: in the step (2), the molar ratio of the 4-butyrylimine-3-methylbenzoic acid, the hypochlorite and the alkali is 1:2:2-1:3:3.
8. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (3), the reaction solvent is at least one of paraxylene and DMF.
9. The preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole according to claim 1, which is characterized in that: in the step (3), the molar ratio of the 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid to the acid is 1:1.5-1:5; the molar ratio of the 4-methyl-2-propyl-1H-benzo [ d ] imidazole-6-carboxylic acid to the N-methylphthalamide hydrochloride is 1:1.5-1:5; the temperature of the cyclization reaction is 80-140 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210897609.8A CN115466222B (en) | 2022-07-28 | 2022-07-28 | Preparation method of telmisartan intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210897609.8A CN115466222B (en) | 2022-07-28 | 2022-07-28 | Preparation method of telmisartan intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115466222A CN115466222A (en) | 2022-12-13 |
| CN115466222B true CN115466222B (en) | 2024-06-04 |
Family
ID=84367863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210897609.8A Active CN115466222B (en) | 2022-07-28 | 2022-07-28 | Preparation method of telmisartan intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115466222B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620437A (en) * | 2002-01-18 | 2005-05-25 | 贝林格尔英格海姆法玛两合公司 | Method for the production and purification of 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-benzimidazole |
| CN101024631A (en) * | 2007-03-08 | 2007-08-29 | 杭州盛美医药科技开发有限公司 | Intermediate of telmisartan, its preparation and use |
| CN101717370A (en) * | 2009-11-30 | 2010-06-02 | 常州亚邦制药有限公司 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
| CN105237457A (en) * | 2015-10-22 | 2016-01-13 | 威特(湖南)药业有限公司 | Preparation method for 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole |
| CN109320461A (en) * | 2018-12-12 | 2019-02-12 | 威海迪素制药有限公司 | A kind of preparation method of telmisartan intermediate |
-
2022
- 2022-07-28 CN CN202210897609.8A patent/CN115466222B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620437A (en) * | 2002-01-18 | 2005-05-25 | 贝林格尔英格海姆法玛两合公司 | Method for the production and purification of 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-benzimidazole |
| CN101024631A (en) * | 2007-03-08 | 2007-08-29 | 杭州盛美医药科技开发有限公司 | Intermediate of telmisartan, its preparation and use |
| CN101717370A (en) * | 2009-11-30 | 2010-06-02 | 常州亚邦制药有限公司 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
| CN105237457A (en) * | 2015-10-22 | 2016-01-13 | 威特(湖南)药业有限公司 | Preparation method for 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole |
| CN109320461A (en) * | 2018-12-12 | 2019-02-12 | 威海迪素制药有限公司 | A kind of preparation method of telmisartan intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Minh Quan Tran等.Unaromatized Tetrahydrobenzimidazole Synthesis from p-Benzoquinone and N-Arylamidines and their Cytotoxic Potential.《European Journal of Organic Chemistry》.2018,第2018卷(第42期),第5878-5884页. * |
| 石庆东 等.替米沙坦合成工艺研究.《精细与专用化学品》.2012,第20卷(第2期),第42-44页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115466222A (en) | 2022-12-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114573560B (en) | Preparation method of voronoi fumarate | |
| CN108689952B (en) | Preparation method of prothioconazole | |
| CN115466222B (en) | Preparation method of telmisartan intermediate | |
| CN100436426C (en) | Method for the production and purification of 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-benzimidazole | |
| KR101050256B1 (en) | Method of manufacturing Losartan | |
| CN117447427A (en) | Preparation method of furosemide | |
| CN102267949A (en) | New process for telmisartan preparation | |
| CN106674084A (en) | Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride | |
| CN114671859B (en) | Preparation method of rosuvastatin calcium and intermediate thereof | |
| NO317761B1 (en) | Process for the preparation of eprosartan | |
| CH645360A5 (en) | METHOD FOR PRODUCING 7-ALKOXYCARBONYL-6,8-DIMETHYL-4-HYDROXYMETHYL-1-PHTHALAZONE. | |
| CN114773270A (en) | Production and preparation method of imidocarb dipropionate | |
| CN107089972B (en) | Preparation method of candesartan cilexetil | |
| CN107827886A (en) | A kind of refined preparation technology of high-purity AVM hereinafter Batan | |
| CN113248439A (en) | Synthesis method of pyrazole disulfide | |
| CN110845405A (en) | Synthesis method of 7-chloroquinaldine | |
| CN109503343B (en) | Preparation method of photoinitiator 184 | |
| CN1258519C (en) | Method for co-production of 3-chloro-4-fluoroaniline and 2, 6-dichlorofluorobenzene | |
| DE2841644A1 (en) | 3 (TETRAZOL-5-YL) -1-AZAXANTHONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING IT | |
| CN111689903A (en) | Synthesis method of 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole | |
| CN115745959B (en) | Industrial production method of chlorantraniliprole | |
| CN111410614A (en) | Full-synthesis environment-friendly process of D-calcium pantothenate | |
| CN110938036A (en) | Preparation method of 4-iodine-1H-imidazole | |
| CN114456104B (en) | Synthesis method of torasemide key intermediate | |
| CN110563648B (en) | Method for preparing blonanserin intermediate (BN-04) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |