CN106397414A - Preparation method for hetero-spiro-ketone indole derivative - Google Patents
Preparation method for hetero-spiro-ketone indole derivative Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The invention relates to a novel preparation method for a hetero-spiro-ketone indole derivative. According to the method, the disadvantages in the prior art that the reaction route is long, the yield is relatively low during the bromination of methyl, the overall yield is low, and the like are overcome, and the overall yield is increased to about 43% from about 28%, so that the method has important practical significance and scientific research value and has a great application prospect in the field of pharmacy and the fields of chemistry and chemical industry.
Description
Technical field
The present invention relates to a kind of new preparation method of a class miscellaneous spirocyclic ketone indole derivativeses, such compound can effectively prevent and
The heart brain and kidney blood vessel diseases such as treatment hypertension, coronary heart disease, migraine, pulmonary hypertension, belong to organic chemical synthesis field.
Background technology
Miscellaneous spirocyclic ketone indole derivativeses are the new compounds that a class has higher medical value, to hypertension, coronary heart disease, the heart
The diseases such as brain renal vascular, migraine, pulmonary hypertension are respectively provided with preferable prevention or therapeutical effect, have boundless
DEVELOPMENT PROSPECT.
At present its synthetic method is typically adopted with 4 or 5- methylindole as initiation material, with benzoyl protection indole ring
Nitrogen, then carries out bromination to methyl；Then there is substitution reaction with miscellaneous spirocyclic ketone compound in the basic conditions；Take off benzoyl
Base protection group；React with o Flurobenzonitrile again, finally make cyano group tetrazole obtain miscellaneous spirocyclic ketone indole derivatives.This team is special
The patent of sharp ZL201010112044.5 and Application No. 201210278805.3 had report to the synthetic method of such compound
Lead.
So far, there are some defects in this method, such as：
(1), reaction scheme is long, complex operation., if first directly reacting with fluorobenzonitril, then carry out bromine taking 4- methylindole as a example
When changing reaction, on indole ring, C2 and C3 position can react, thus cannot get target compound monomethyl brominated product (specially
Sharp US 5374615) it is therefore desirable to bromination again after first 4- methylindole being protected.After introducing blocking group, subsequent reactions
In slough blocking group again, this not only extends reaction scheme, increased the fussy degree of operation, also reduces that reaction is total to receive
Rate.Reaction is as follows：
(2) when, carrying out bromination to methyl, yield is relatively low, and by-product is relatively more, separates difficult., use taking 4- methylindole as a example
After benzoyl protection, when carrying out bromination reaction to methyl, the synthetic method of employing is in carbon tetrachloride, with NBS (N- bromine
For butanimide) the 4- methylindole protected with benzoyl with AIBN (azodiisobutyronitrile) reacted.This reaction
For radical reaction, there is the shortcomings of reaction is uncontrollable, by-product is many.And the target product obtaining is close with by-product property,
It is difficult to isolate and purify.This reaction needs to use the stronger solvent carbon tetrachloride of toxicity, big to environmental hazard.In addition in operation
When, NBS and AIBN needs to add in batches and somewhat could improve yield, and before adding every time, needs reactant liquor from backflow
State is cooled to room temperature, and this makes in commercial production, very inconvenient, and wastes the energy.Reaction is as follows：
(3), gross production rate is low.The gross production rate ratio of this area is relatively low at present, about 25% about (patent ZL201010112044.5；
The patent of Application No. 201210278805.3) it is difficult to be used for industrialized production.
Therefore, research and develop the new synthetic method of miscellaneous spirocyclic ketone indole derivativeses, there is important scientific theory meaning and using value,
In pharmaceutical field and chemical field, also there is huge application prospect.
Content of the invention
In view of this, in order to solve such as reaction scheme length present in above-mentioned prior art, methyl carried out yield during bromination relatively low,
The low defect of gross production rate, the present inventor has made intensive studies to the preparation method of miscellaneous spirocyclic ketone indole derivativeses, a large amount of paying
After creative work, complete the present invention.
The present invention relates to a kind of preparation method of miscellaneous spirocyclic ketone indole derivativeses.The method includes the bar existing in organic solvent and alkali
Under part, make substituted benzazolyl compounds, with o Flurobenzonitrile, substitution reaction occur, then with go back original reagent, reduction reaction occurs, then
The hydroxy compounds producing after reduction are activated, then so that activation products is taken with miscellaneous spirocyclic ketone compound in the basic conditions
Generation reaction, finally makes cyano group tetrazole thus obtaining miscellaneous spirocyclic ketone indole derivativeses.
Specifically, the invention provides the synthetic method of miscellaneous spirocyclic ketone indole derivativeses shown in a kind of formula (I).
Wherein, R1For n-pro-pyl, normal-butyl, n-pentyl and n-hexyl.In above-claimed cpd, at miscellaneous spirocyclic ketone N-methyl group
On 4 or 5 of indole.
Methods described includes：In the presence of a base, formula (II) compound and formula (III) compound are made in nitrogen atmosphere organic
React in solvent, generate formula (IV) compound；Formula (IV) compound is reacted with go back original reagent in organic solvent, production
(V) compound；Formula (V) compound is reacted from various different activating reagents in organic solvent, generates formula (VI) compound；
In the presence of a base, formula (VI) compound and miscellaneous spirocyclic ketone compound react in organic solvent, generate formula (VII)
Compound；Formula (VII) compound in a solvent with tetrazole reagent reacting, generate formula (I) miscellaneous spirocyclic ketone indole derivativeses.
Wherein, R1For n-pro-pyl, normal-butyl, n-pentyl, n-hexyl；R2For halogen, mesyloxy；R3For aldehyde radical, first
Oxygen carbonyl, carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, tertbutyloxycarbonyl, butoxy carbonyl, benzyloxycarbonyl group.
Wherein ,-CH2OH、-CH2R2、R3Group, miscellaneous spirocyclic ketone N-methyl group are on 4 or 5 of indole.
In the method for the invention, formula (II) and (III) reacted alkali used be potassium carbonate, sodium carbonate, potassium bicarbonate,
Sodium bicarbonate, triethylamine, diisopropylethylamine, pyridine, Sodium Acetate Trihydrate, potassium acetate, potassium phosphate, sodium phosphate, sodium hydroxide,
Potassium hydroxide, Lithium hydrate, sodium hydrogen, Feldalat KM, Feldalat NM, potassium ethoxide, Sodium ethylate, normal propyl alcohol potassium, normal propyl alcohol sodium, different
Any one in potassium propoxide, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide etc. or arbitrarily multiple mixture.
In the method for the invention, it is Isosorbide-5-Nitrae-dioxane, oxolane that formula (II) and (III) are reacted organic solvent used
(THF), toluene, dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, DMF (DMF), dimethyl are sub-
Sulfone (DMSO), HMPA (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyltetrahydrofuran,
In the positive butyl oxide of dichloromethane, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol, methyl tert-butyl ether etc.
Any one or arbitrarily multiple mixture.
In the method for the invention, reaction temperature when formula (II) and (III) are reacted is 40-160 DEG C, and the response time is 1
-3h.
In the method for the invention, when formula (IV) reaction generates formula V go back original reagent used be sodium borohydride, potassium borohydride,
Lithium borohydride, reduced iron powder-dilute hydrochloric acid, zinc-dilute hydrochloric acid, Raney's nickel-hydrazine hydrate, hydrogen-palladium carbon, Lithium Aluminium Hydride, hydroboration
Any one in potassium-lithium chloride, potassium borohydride-copper chloride etc. or arbitrarily multiple mixture.
In the method for the invention, it is Isosorbide-5-Nitrae-dioxane, tetrahydrochysene furan that formula (IV) reaction generates organic solvent used during formula V
Mutter (THF), ethyl acetate, 2- methyltetrahydrofuran, dichloromethane, chloroform, dichloroethanes, ether, glycol dinitrate
In ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether methanol, ethanol, normal propyl alcohol, ethylene glycol, glycerol etc. any one or appoint
The multiple mixture of meaning.
In the method for the invention, the reaction temperature that formula (IV) reaction generates during formula V is -10-25 DEG C, and the response time is 0.5-
4h.
In the method for the invention, when formula (V) reaction generates formula (VI), activating reagent used is hydrogen bromide acetic acid solution, chlorination
Sulfoxide, mesyl chloride, phosphorus tribromide, Phosphorous chloride., phosphorus pentachloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, hydrogen chloride
Ethanol solution.
In the method for the invention, it is Isosorbide-5-Nitrae-dioxane, tetrahydrochysene furan that formula (V) reaction generates organic solvent used during formula (VI)
Mutter (THF), toluene, dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyl
Oxolane, dichloromethane, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl
Any one in tertiary butyl ether etc. or arbitrarily multiple mixture.
In the method for the invention, the temperature that formula (V) reaction generates during formula (VI) is 0-40 DEG C, and the response time is 0.5-4h.
In the method for the invention, when formula (VI) reaction generates formula (VII) alkali used be potassium carbonate, sodium carbonate, potassium bicarbonate,
Sodium bicarbonate, triethylamine, diisopropylethylamine, pyridine, Sodium Acetate Trihydrate, potassium acetate, potassium phosphate, sodium phosphate, sodium hydroxide,
Potassium hydroxide, Lithium hydrate, sodium hydrogen, Feldalat KM, Feldalat NM, potassium ethoxide, Sodium ethylate, potassium propoxide, sodium propoxide, isopropanol
Any one in potassium, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide etc. or arbitrarily multiple mixture.
In the method for the invention, it is Isosorbide-5-Nitrae-dioxane, tetrahydrochysene that formula (VI) reaction generates organic solvent used during formula (VII)
Furan (THF), toluene, dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, DMF (DMF), dimethyl
Sulfoxide (DMSO), HMPA (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyltetrahydrofuran,
In dichloromethane, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether etc.
Any one or arbitrarily multiple mixture.
In the method for the invention, the reaction temperature that formula (VI) reaction generates during formula (VII) is 25-160 DEG C, and the response time is
0.5-24h.
In the method for the invention, it is Hydrazoic acid,sodium salt and three fourths that formula (VII) reaction generates tetrazole reagent used during formula (I)
Base stannic chloride.
In the method for the invention, it is Isosorbide-5-Nitrae-dioxane, oxolane that formula (VII) reaction generates organic solvent used during formula (I)
(THF), toluene, dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, DMF (DMF), dimethyl sulfoxide
(DMSO), HMPA (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyltetrahydrofuran, two
In chloromethanes, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether etc.
Any one or arbitrarily multiple mixture.
In the method for the invention, the reaction temperature that formula (VII) reaction generates during formula (I) is 40-200 DEG C, and the response time is 0.5-
48h.
In the method for the invention, there is no particular limitation for post processing, for example, can be：After reaction terminates, to reactant mixture
Middle addition water, is extracted with ethyl acetate 2-4 time, merges organic faciess；Organic faciess saturated common salt water washing 2-4 time, anhydrous
Magnesium sulfate is dried, and filters, filtrate reduced in volume；By concentrate recrystallization, obtain target product formula (I) compound.
In sum, the invention provides a kind of new synthetic route of preparation formula (I) compound and method.The process employs
Specific chemical reagent and suitable organic solvent, have the advantages that simple to operate, product yield and purity are higher, are synthesis
The effective ways of miscellaneous spirocyclic ketone indole derivativeses, have important scientific theory meaning and using value, in pharmaceutical field and chemistry
Chemical field has huge application prospect.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and purpose are only
Be used for enumerating the present invention, not the real protection scope of the present invention constituted with any type of any restriction, more non-by the present invention's
Protection domain is confined to this.
【Embodiment 1】
Compound 3- ((1- (2- (1H- tetrazole -5- base) phenyl) -1H- indole -5- base) methyl -2- butyl -1,3- diaza spiro in formula (I)
The preparation method of ring [4,4] nonyl- 1- alkene -4- ketone specifically includes following steps：
Step 1：The synthesis of N- neighbour's cyano-phenyl -1H- indole-4-methanal：
Indole-4-methanal (10.00g, 68.97mmol) is dissolved in DMF (150mL), adds adjacent fluorine
Cyanophenyl (8.40mL, 75.86mmol) and potassium carbonate (19.03g, 137.94mmol), are stirred at reflux about 2h, and TLC supervises
Survey to reaction completely.After question response liquid temp is reduced to room temperature, filter, filter cake washs three times with dichloromethane (20mL × 3).
Merging filtrate, adds 200mL dichloromethane and 200mL water in filtrate, divides and takes organic faciess, aqueous phase dichloromethane (150
ML × 3) extraction, merge organic faciess.Organic faciess saturated aqueous common salt (300mL × 4) is washed, and anhydrous magnesium sulfate is dried, and filters,
Filtrate decompression is evaporated off solvent, obtains Tan solid.This solid is recrystallized to give product as off-white solid about 16g (yield
About 94.3%).1HNMR (400MHz, CDCl3)δ：10.32 (s, 1H), 7.91 (d, 1H), 7.81 (t, 1H), 7.76 (d, 1H), 7.61-
7.56 (m, 5H), 7.42 (t, 1H).MS(ESI)m/z：247.2[M+H]+, 269.2 [M+Na]+.
Step 2：The synthesis of N- neighbour's cyano-phenyl -4- methylol -1H- indole：
N- neighbour's cyano-phenyl indole-4-methanal (10g, 40.65mmol) is dissolved in ethanol (100mL) and oxolane (50mL)
Mixed liquor in, under ice bath stir.It is slowly added to sodium borohydride (386mg, 10.16mmol) while stirring, interpolation finishes
Stirring reaction at room temperature afterwards.After TLC monitoring reaction completely, add 200mL water terminating reaction.With ethyl acetate (100mL
× 3) extract, merge organic faciess, be dried with anhydrous magnesium sulfate, filter, remove solvent under reduced pressure, obtain faint yellow solid.Should
Solid is recrystallized to give pale solid about 10g (99.2%).1HNMR (400MHz, CDCl3)δ：7.88 (d, 1H), 7.78 (t,
1H), 7.63 (d, 1H), 7.54 (t, 1H), 7.46 (d, 1H), 7.32-7.26 (m, 3H), 6.94 (d, 1H), 5.06 (s, 2H).
MS(ESI)m/z：249.2[M+H]+, 271.2 [M+Na]+.
Step 3：The synthesis of N- neighbour's cyano-phenyl -4- bromomethyl -1H- indole
N- neighbour's cyano-phenyl -4- skatoxyl (500mg, 2.02mmol) is dissolved in 100mL anhydrous methylene chloride, in
Stir under ice bath, slowly slow Deca contains the acetum (0.5mL) of 35% about hydrogen bromide.Drip and finish, under ice bath, stir 1-2h.
Add 50mL dichloromethane and 150mL water toward in reactant liquor, take organic faciess；With dichloromethane (100mL × 3) extraction water
Xiang Sanci, merges organic faciess.Organic faciess are washed three times with saturated aqueous common salt (100mL × 3), and anhydrous magnesium sulfate is dried, mistake
Filter, filtrate decompression is evaporated off solvent, obtains gray solid.Gained solid is carried out be recrystallized to give product as off-white solid about 500
Mg (yield about 80.0%).1HNMR (400MHz, CDCl3)δ：7.88 (d, 1H), 7.79 (t, 1H), 7.63 (d, 1H), 7.57-7.51
(m, 2H), 7.33-7.22 (m, 3H), 6.97 (d, 1H), 4.89 (s, 2H).MS(ESI)m/z：311.0[M+H]+, 313.0 [M+2+H]+.
Step 4：3- (1- ((2- cyano group) phenyl) -1H- indole -5- base) methyl -2- butyl -1,3- diazaspiracyclic [4,4] nonyl- 1- alkene -4- ketone
Synthesis：
Miscellaneous spirocyclic ketone compound (500mg, 2.58mmol) is dissolved in 20mLN, in dinethylformamide, adds sodium hydrogen (124
Mg, 5.16mmol), stir 30min at room temperature.Be slowly added dropwise containing N- neighbour cyano-phenyl -4- bromomethyl indole (960mg,
DMF solution (10mL) 3.1mmol), continues stir about 2h under room temperature, TLC monitors to reaction completely.
Filter, filter cake is washed three times with dichloromethane (10mL × 3), in filtrate, add 200mL dichloromethane and 200mL water,
Divide and take organic faciess；With dichloromethane (150mL × 3) aqueous phase extracted three times, merge organic faciess.Organic faciess saturated aqueous common salt
(300mL × 4) wash four times, and anhydrous magnesium sulfate is dried, and filter.Filtrate decompression is evaporated off solvent, obtains Tan solid.
This solid is recrystallized to give product as off-white solid about 750mg (yield about 68.6%).1H NMR (400MHz, CDCl3)δ：
7.83 (m, 1H), 7.73 (m, 1H), 7.56 (d, 1H), 7.51 (m, 2H), 7.41 (m, 1H), 7.28 (m, 1H), 7.07 (m, 1H),
6.71 (d, 1H), 4.79 (s, 2H), 1.30-2.38 (m, 14H), 0.85 (t, 3H) .MS (ESI) m/z：425.4[M+1]+.
Step 5：3- (1- (2- (1H- tetrazole -5- base) phenyl) -1H- indole -5- base) methyl -2- butyl -1,3- diazaspiracyclic [4,4] nonyl
The synthesis of -1- alkene -4- ketone
Miscellaneous spirocyclic ketone indole cyanophenyl compound (437mg, 1.0mmol) is dissolved in the DMF of 8mL, plus
Enter NaN3(102mg, 6.0mmol) and Bu3SnCl (2.4mL, 6.0mmol), N2Under protection, it is stirred at reflux about 24h.Will be anti-
Answer liquid to pour in 10mL frozen water, with 1mol/L HCl solution, pH value is adjusted to 5-6.Extract (30mL × 3) with dichloromethane
Three times, merge organic faciess.Organic phases washed with water five times (20mL × 5), saturated common salt is washed once (30mL), anhydrous magnesium sulfate
Organic faciess are dried, filter.Filtrate decompression is evaporated off solvent, gained residue is carried out column chromatography (eluent, DCM: CH3OH
=60: 1), obtain white solid product about 400mg (yield about 83.2%).1H NMR (400MHz, DMSO)：δ 16.43 (s,
1H), 7.91 (d, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 6.86 (m, 2H),
6.56 (d, 1H), 4.69 (s, 2H), 0.73-2.29 (m, 17H).MS(ESI)m/z：468.5[M+1]+.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the scope of the invention.Additionally,
It will also be appreciated that after the technology contents having read the present invention, those skilled in the art can make various changes, repair to the present invention
Change and/or modification, all these equivalent form of value equally falls within the protection domain that the application appended claims are limited.
Claims (6)
1. the miscellaneous spirocyclic ketone indole derivatives shown in formula (I), its synthetic method includes：
Wherein, R1For n-pro-pyl, normal-butyl, n-pentyl, n-hexyl；R2For halogen, mesyloxy；R3For aldehyde radical, first
Oxygen carbonyl, carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, tertbutyloxycarbonyl, butoxy carbonyl, benzyloxycarbonyl group.
Wherein ,-CH2OH、-CH2R2、R3Group, miscellaneous spirocyclic ketone N-methyl group are on 4 or 5 of indole.
Methods described includes：In the presence of a base, formula (II) compound is made to have with formula (III) compound in nitrogen atmosphere
React in machine solvent, generate formula (IV) compound；Formula (IV) compound is reacted with go back original reagent in organic solvent, generates
Formula (V) compound；Formula (V) compound is reacted from various different activating reagents in organic solvent, generates formula (VI) compound；
In the presence of a base, formula (VI) compound and miscellaneous spirocyclic ketone compound react in organic solvent, generate formula (VII)
Compound；Formula (VII) compound in a solvent with tetrazole reagent reacting, generate formula (I) miscellaneous spirocyclic ketone indole derivatives.
In the method for the invention, there is no particular limitation for the post processing of reaction, for example, can be：After reaction terminates, to reaction
Add water in mixture, be extracted with ethyl acetate 2-4 time, merge organic faciess.Organic faciess saturated common salt water washing 2-4
Secondary, anhydrous magnesium sulfate is dried, and filters, filtrate reduced in volume carries out recrystallization to concentrate, obtains target product formula (I) and changes
Compound.
2. the method for claim 1 it is characterised in that：Alkali when formula (II) and (III) are reacted is potassium carbonate,
Sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, pyridine, Sodium Acetate Trihydrate, potassium acetate, potassium phosphate,
Sodium phosphate, sodium hydroxide, potassium hydroxide, Lithium hydrate, sodium hydrogen, Feldalat KM, Feldalat NM, potassium ethoxide, Sodium ethylate, positive third
In potassium alcoholate, normal propyl alcohol sodium, potassium isopropoxide, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide etc. any one or arbitrarily multiple
Mixture；Organic solvent when formula (II) and (III) are reacted is Isosorbide-5-Nitrae-dioxane, oxolane (THF), toluene, diformazan
Benzene, normal hexane, hexamethylene, ethyl acetate, DMF (DMF), dimethyl sulfoxide (DMSO), hempa
Acyl triamine (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyltetrahydrofuran, dichloromethane, chloroform,
In dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether etc. any one or arbitrarily multiple
Mixture；Reaction temperature when formula (II) and (III) are reacted is 40-160 DEG C, and the response time is 1-3h.
3. the method for claim 1 it is characterised in that：It is boron that formula (IV) reaction generates go back original reagent used during formula V
Sodium hydride, potassium borohydride, lithium borohydride, reduced iron powder-dilute hydrochloric acid, zinc-dilute hydrochloric acid, Raney's nickel-hydrazine hydrate, hydrogen-palladium carbon,
Any one in Lithium Aluminium Hydride, potassium borohydride-lithium chloride, potassium borohydride-copper chloride etc. or arbitrarily multiple mixture；Formula (IV)
Reaction generate formula V when organic solvent be Isosorbide-5-Nitrae-dioxane, oxolane (THF), ethyl acetate, 2- methyltetrahydrofuran,
Dichloromethane, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether, first
Any one in alcohol, ethanol, normal propyl alcohol, ethylene glycol, glycerol etc. or arbitrarily multiple mixture；Formula (IV) reaction generates formula V
When reaction temperature be -10-25 DEG C, the response time be 0.5-4h.
4. the method for claim 1 it is characterised in that：It is bromine that formula (V) reaction generates activating reagent used during formula (VI)
Change acetate hydrogen solution, thionyl chloride, mesyl chloride, phosphorus tribromide, Phosphorous chloride., phosphorus pentachloride, phosphorus oxychloride, tetrabormated
Carbon-triphenylphosphine, ethanol solution of hydrogen chloride；When formula (V) reaction generates formula (VI) organic solvent used be Isosorbide-5-Nitrae-dioxane,
Oxolane (THF), toluene, dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, carbon tetrachloride, acetone, benzene, chlorobenzene,
2- methyltetrahydrofuran, dichloromethane, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether,
Any one in methyl tert-butyl ether etc. or arbitrarily multiple mixture；The reaction temperature that formula (V) reaction generates during formula (VI) is 0-
40 DEG C, the response time is 0.5-4h.
5. the method for claim 1 it is characterised in that：When formula (VI) reaction generates formula (VII) alkali used be potassium carbonate,
Sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, pyridine, Sodium Acetate Trihydrate, potassium acetate, potassium phosphate,
Sodium phosphate, sodium hydroxide, potassium hydroxide, Lithium hydrate, sodium hydrogen, Feldalat KM, Feldalat NM, potassium ethoxide, Sodium ethylate, positive third
In potassium alcoholate, normal propyl alcohol sodium, potassium isopropoxide, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide etc. any one or arbitrarily multiple
Mixture；When formula (VI) reaction generates formula (VII) organic solvent used be Isosorbide-5-Nitrae-dioxane, oxolane (THF), toluene,
Dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, DMF (DMF), dimethyl sulfoxide (DMSO), six
Methyl phosphoric triamide (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyltetrahydrofuran, dichloromethane, trichlorine
In methane, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether etc. any one or appoint
The multiple mixture of meaning；The reaction temperature that formula (VI) reaction generates during formula (VII) is 25-160 DEG C, and the response time is 0.5-24
h.
6. the method for claim 1 it is characterised in that：Formula (VII) reaction generates tetrazole reagent used during formula (I)
For Hydrazoic acid,sodium salt and tributyltin chloride；It is Isosorbide-5-Nitrae-dioxane, tetrahydrochysene furan that formula (VII) reaction generates organic solvent used during formula (I)
Mutter (THF), toluene, dimethylbenzene, normal hexane, hexamethylene, ethyl acetate, DMF (DMF), dimethyl is sub-
Sulfone (DMSO), HMPA (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2- methyltetrahydrofuran, two
In chloromethanes, chloroform, dichloroethanes, ether, glycol dimethyl ether, ethylene glycol bisthioglycolate n-butyl ether, methyl tert-butyl ether etc.
Any one or arbitrarily multiple mixture；The reaction temperature that formula (VII) reaction generates during formula (I) is 40-200 DEG C, the response time
For 0.5-48h.
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| CN (1) | CN106397414A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061224A (en) * | 1990-10-31 | 1992-05-20 | E·R·斯奎布父子公司 | The imidazoles that indoles and benzoglyoxaline replace and the preparation method of benzimidizole derivatives |
| CN1101908A (en) * | 1992-06-03 | 1995-04-26 | 伊莱利利公司 | Angiotensin II antagonists |
| CN102796083A (en) * | 2012-08-07 | 2012-11-28 | 陈志龙 | Spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields |
| CN103965167A (en) * | 2013-01-29 | 2014-08-06 | 通化济达医药有限公司 | Imidazole carboxylic acid derivative |
-
2015
- 2015-08-14 CN CN201510500220.5A patent/CN106397414A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061224A (en) * | 1990-10-31 | 1992-05-20 | E·R·斯奎布父子公司 | The imidazoles that indoles and benzoglyoxaline replace and the preparation method of benzimidizole derivatives |
| CN1101908A (en) * | 1992-06-03 | 1995-04-26 | 伊莱利利公司 | Angiotensin II antagonists |
| CN102796083A (en) * | 2012-08-07 | 2012-11-28 | 陈志龙 | Spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields |
| CN103965167A (en) * | 2013-01-29 | 2014-08-06 | 通化济达医药有限公司 | Imidazole carboxylic acid derivative |
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