CN106146480A - A kind of preparation method of itraconazole - Google Patents
A kind of preparation method of itraconazole Download PDFInfo
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- CN106146480A CN106146480A CN201610566225.2A CN201610566225A CN106146480A CN 106146480 A CN106146480 A CN 106146480A CN 201610566225 A CN201610566225 A CN 201610566225A CN 106146480 A CN106146480 A CN 106146480A
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Abstract
The invention discloses the preparation method of a kind of itraconazole; use racemic modification that cheaper starting materials is easy to get (±) epoxy prapanol is raw material; by its respectively with after trityl and benzyl protection two terminal hydroxy group with 2; 4 dichlorobenzoyl chlorides are through esterification; carbonyl reduction is carbon-carbon double bond by the elimination reaction then using silylation grignard additive reaction and β silylation alcohol; again through iodine to alkene additive reaction and stereo selectivity ring-closure reaction, obtain compound 9 with triazole sodium replacement, debenzylation, introducing p-toluenesulfonyl;Carry out condensation reaction with compound 10 and generate itraconazole;Whole building-up process is not only polluted little, disposable, and by-product is few, and reaction selectivity and purity are high, and environmentally friendly, production cost is low, are suitable for industrialized production;Avoid poor selectivity of the prior art, by-product is many, yield is relatively low, avoid and use valuable catalyst and the drawback of the big reagent of environmental pollution.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, be specifically related to the preparation method of a kind of itraconazole.
Background technology
Itraconazole is that current curative effect is preferable, a kind of triazole type broad-spectrum antifungal medicine that side effect is less, its In Vitro Anti
Bacterium spectrum is relatively wide, but injection this to pulmonary infection position, be used for treating pulmonary's aspergillin infection.Its English name is
Itraconazole, the cis-4-of chinesization formal name used at school [4-[4-[4-[[-2-(2,4-Dichlorobenzene base)-2-(1H-1,2,4-triazole-1-
Ylmethyl)-1,3-dioxolanes-4-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2 ' S)-1-methyl-propyl]-1,
2,4-triazole-3-ketone.Its chemical structural formula is as follows:
Itraconazole has 3 chiral carbon atoies, has 8 kinds of optical isomers, and Clinical practice is dioxy penta in its structure
The mixture of 4 cis-isomers on alkane ring, corresponds to 2S, 4R, 2 ' R-itraconazole (A), 2S, 4R, 2 ' S-itraconazole
(C), 2R, 4S, 2 ' R-itraconazole (B) and 2R, 4S, 2 ' S-itraconazole (D), its chemical structural formula is as follows:
Research finds, biological activity and the toxic and side effects of itraconazole Isomers exist larger difference, as
The itraconazole isomer composition that discloses CN103263417A can improve the selectivity to fungus and endotheliocyte, is also simultaneously
Being to have treatment fungus and the drug candidate of relevant diseases of angiogenesis potentiality, the optical voidness itraconazole of single configuration can also show
Write and reduce hepatotoxicity, the side effect that itraconazole causes can be avoided.
The synthetic method of itraconazole has been reported:
1, document Med.Chem.Lett.2010,1,155~159 and US20130102614Al reports the more commonly used
Synthetic route, with compounds I and compound ii as starting material, first cyclization obtains dioxolanes construction unit, by control
The chirality of compound II, it is possible to obtain optically pure compound III, then be condensed to yield V optical voidness Yi Qu with optical voidness chemicals IV
Health azoles.This route is fairly simple, but this reaction critical materials compound III p-methyl benzenesulfonic acid glycerine esterification complicated component, purity and
Optical voidness satisfactory p-methyl benzenesulfonic acid glyceride generally requires customization, and production cost is the highest, is difficult to industrialization.
2, CN201510104731.5 discloses the synthesis technique of optical voidness itraconazole: compounds I and compound VI-a
Or compound VI-b carries out aldol reaction under the effect under Catalyzed by p-Toluenesulfonic Acid, obtaining cis is in the middle of main key
Body compound VII-a or VII-b, with sodium benzoate generation substitution reaction, basic hydrolysis, reacts with paratoluensulfonyl chloride, at highly basic
Catalysis under carry out condensation reaction, obtain optical voidness itraconazole.Though compound VII-a or VII-b synthesis technique be simple light
Learn purity relatively low (78-85%), possibly together with substantial amounts of transisomer impurity, need chiral separation.
3, in patent US4101665, US5998413, EP0402989, US4267179 and document J.Med.chem, 1983,
26,611~613 and J.Med.chem, it is disclosed in 1984,27,894~900, wherein typical compound sulphonic acid ester
Synthetic route is:
Above-mentioned synthetic method exists following not enough: (1) complex operation is loaded down with trivial details, needs to prepare triazole through first
Sodium, then with cis-bromic ester N-alkylation, after through three steps synthesis triazole compounds such as sodium hydroxide alkali hydrolysis, production cycle
Long.(2) raw material cis-bromic ester is expensive.(3) yield relatively low only 50%~60%, isomer impurities content is higher,
About 15%, isomer impurities too high levels can cause the relevant content of material of itraconazole finished product the highest, even exceeds standard, seriously
Have impact on the Control of Internal Quality to itraconazole product.
Summary of the invention
For solving the above-mentioned technical problem that prior art exists, the invention provides the preparation method of a kind of itraconazole,
Which obviate the disadvantages such as poor selectivity of the prior art, by-product is many, yield is relatively low.
Technical scheme is as follows:
The preparation method of a kind of itraconazole, it is characterised in that comprise the steps:
1) with (±)-epoxy prapanol as raw material, with trityl chloride protection hydroxyl after obtain (±) trityl shrink sweet
Oil ether (1);
2) (±) trityl glycidyl ether (1) carries out epoxy addition reaction with benzyl alcohol under the effect of alkali
Compound 2;
3) compound 2 and 2,4 dichlorobenzyl chloride occur esterification to obtain chemical combination under the effect of alkali and organic solvent
Thing 3;
4) compound 3 carries out silylation grignard additive reaction and obtains compound 4;
5) compound 4 carry out β-silylation alcohol elimination reaction and removing trityl-protecting group obtain compound 5;
6) compound 5 carries out iodine and alkene additive reaction and stereo selectivity ring-closure reaction is obtained compound 6;
7) compound 6 and triazole sodium generation substitution reaction obtain compound 7;
8) compound 7 carries out debenzylation and obtains compound 8;
9) compound 8 introduces p-toluenesulfonyl and obtains compound 9;
10) compound 9 generates itraconazole with compound 10 reaction;Its synthetic route is as follows:
As preferably, step 1) in, (±)-epoxy prapanol carries out in catalyst and triethylamine with trityl chloride,
Described catalyst is 4-dimethylamino pyridine (DMAP), and reaction dissolvent is chloroform or dichloromethane;(±)-epoxy prapanol and triphen
The mol ratio of methyl chloride is 1:1-1.1.
As preferably, step 2) in, described alkali is NaH or NaOH;Reaction dissolvent be dimethylformamide (DMF), two
Methylacetamide, dimethyl sulfoxide or oxolane, reaction temperature 15 DEG C-40 DEG C, 12-18 hour response time.
As preferably, step 3) in, described alkali is pyridine, triethylamine, DMA, N, N-dimethylamino pyrrole
Pyridine, tetramethylethylenediamine or sodium carbonate;Described organic solvent is DCM, THF, toluene or DMF;Compound 2,2,4 dichloro benzene first
The mol ratio of acyl chlorides and alkali is 1:1-1.2:1-3.
As preferably, step 4) in, chloromethyl trimethyl silane is generated Grignard reagent with magnesium generation grignard reaction, will
The Grignard reagent obtained and compound 3 occur additive reaction to generate compound 4;Described grignard reaction uses and is dissolved in methyl-tert fourth
Iodine grain in base ether is as initiator;Described grignard reaction and additive reaction are to enter in the dicyandiamide solution of methyl tertiary butyl ether(MTBE)
OK.
As preferably, step 5) in, compound 4 is dissolved in MTBE, adds concentrated sulphuric acid and disappear in temperature 40~60 DEG C
Except reaction and removing trityl-protecting group generate compound 5.
As preferably, step 6) in, reaction dissolvent is acetonitrile, ethanol or THF;Reaction temperature is-20 DEG C~-10 DEG C.
As preferably, step 7) in, reaction dissolvent is DMSO;Reaction temperature is 80 DEG C~100 DEG C;Compound 6 and three
The mol ratio of nitrogen azoles sodium is 1:1~6.
As preferably, step 8) in, use palladium charcoal catalytic hydrogenation to make compound 7 slough benzyl and obtain compound 8;Chemical combination
Thing 7, the mass ratio of catalyst are 1:0.05-0.1, preferably 1:0.1;Reaction dissolvent be methanol, ethanol, isopropanol one or both
Above, preferred methanol.
Relative to prior art, the present invention has a following beneficial effect:
1) novelty of the present invention use that cheaper starting materials is easy to get (±)-epoxy prapanol, benzyl alcohol and 2,4 dichloro benzene first
Acyl chlorides is raw material, carries out the itraconazole key intermediate sulfonic acid ester i.e. synthesis of compound 9: with racemic modification (±)-epoxy third
Alcohol is raw material, by its respectively with after trityl and benzyl protection two terminal hydroxy group with 2,4-dichlorobenzoyl chloride is through esterificationization
Compound 3;Carbonyl reduction is carbon carbon by the elimination reaction using silylation grignard additive reaction and β-silylation alcohol then innovated
Double bond obtains compound 5;Through iodine, alkene additive reaction and stereo selectivity ring-closure reaction are obtained compound 6 again;With triazole
Sodium replacement, debenzylation, introducing p-toluenesulfonyl obtain compound 9;Whole building-up process is not only polluted little, disposable, by-product
Thing is few, and reaction selectivity and purity are high, and environmentally friendly, production cost is low, are suitable for industrialized production;Avoid in prior art
Poor selectivity, by-product is many, yield is relatively low, avoid and use valuable catalyst and the fraud of the big reagent of environmental pollution
End.
2) in the synthesis of compound 5, reacting with the elimination of silylation grignard reaction and β-silylation alcohol, carbonyl is turned
Chemical conversion carbon-carbon double bond, economic and environment-friendly, post processing is simple, meets the principle of Green Chemistry.The present invention selects chloromethyl trimethyl silicane
Alkane prepares Grignard reagent, the silica-based hydroxyl effect being prone to ortho position of the trimethyl of the compound 4 of generation so that eliminate product
The purity of 5 is higher, and product silanol has preferable stability.
3) step 6) in iodine cyclization, substrate in the basic conditions with elemental iodine effect, lured by substrate S or R configuration
Lead, generate a new S or R configuration iodine methylene structured product compound 6.Iodine replaces carbon atom on the dioxolanes of side
Chiral selectivity is substantially unaffected, diastereo-isomerism body burden≤1.5%.And when temperature is-20 DEG C~-10 DEG C, product
Purity higher, non-corresponding isomer products is less.
Detailed description of the invention
In order to be better understood from present disclosure, it is described further below in conjunction with specific embodiment, but specifically
Embodiment be not the restriction that present disclosure is done.
Embodiment 1-1: trityl-glycidyl ether (1) synthesis
Trityl chloride (139.4g, 0.5mol) dissolves in 5000mL dichloromethane, add 4-diamino-pyridine (DMAP, 3g,
25mmol) and triethylamine (100mL), stir lower (±) dichloromethane solution of-epoxy prapanol (37g, 0.5mol)
(500mL), room temperature reaction 3 hours;Separating out a large amount of white solid, leach solid, solution saturated nacl aqueous solution (300mL) is washed
Washing, anhydrous sodium sulfate is dried, and uses dehydrated alcohol recrystallization after concentration, is dried to obtain white solid (109.6g, 1), productivity 69.3%.
Embodiment 1-2: trityl-glycidyl ether (1) synthesis
Trityl chloride (153.3g, 0.55mol) dissolves in 5000mL chloroform, add 4-diamino-pyridine (DMAP, 3g,
25mmol) and triethylamine (120mL), stir lower (±) chloroformic solution (500mL) of-epoxy prapanol (37g, 0.5mol), room
Temperature reaction 5 hours;Separating out a large amount of white solid, leach solid, solution saturated nacl aqueous solution (300mL) washs, anhydrous sulfur
Acid sodium is dried, and uses dehydrated alcohol recrystallization after concentration, is dried to obtain white solid (119.0g, 1), productivity 75.2%.
Embodiment 2-1: the preparation of compound 2
Sodium hydride (50% is dispersed in mineral oil, 0.7mol) is washed twice with the hexane of 1 liter, is dried the most under a nitrogen.
Add the dimethylformamide (0.5L) being dried.Then less than 50 DEG C are maintained the temperature at, with certain speed dropping benzylalcohol
(140mL), drip in 2 hours.Recombination thing 1 (110.7g, 0.35mol) drips 0.5 hour, cools down to keep temperature to be less than
40 DEG C, stir 16 hours at temperature 20 DEG C, then stir 2.5 hours at 50 DEG C.Carry out being evaporated under reduced pressure and remove dimethyl formyl
Amine, with 1L ether dissolution oiliness residue, organic solution respectively with the water of 0.5L, the hydrochloric acid solution of the 2% of 0.5L, 0.5L's
The sodium bicarbonate solution of 1%, and the saline washing of 0.35L, anhydrous sodium sulfate is dried, and is concentrated to give brown oil (compound
2,104.5g), productivity 70.5%.
Embodiment 2-2: the preparation of compound 2
The dimethyl sulfoxide (0.5L) being dried adds sodium hydroxide (32g, 0.8mol) heating makes dissolving.Then temperature is kept
Below 50 DEG C, with certain speed dropping benzylalcohol (140mL), drip in 2 hours.Recombination thing 1 (110.7g,
0.35mol) drip 0.5 hour, cool down to keep temperature less than 40 DEG C, stir 18 hours at temperature 30 DEG C, then at 50 DEG C
Stir 2.5 hours.Carrying out being evaporated under reduced pressure and remove dimethyl sulfoxide, with 1L ether dissolution oiliness residue, organic solution is used respectively
The saline washing of the water of 0.5L, the hydrochloric acid solution of the 2% of 0.5L, the sodium bicarbonate solution of the 1% of 0.5L, and 0.35L, anhydrous sulfur
Acid sodium is dried, and is concentrated to give brown oil (compound 2,112.4g), productivity 75.8%.
Embodiment 3-1: the preparation of compound 3
Under the conditions of being stirred at room temperature, to 1000mL dichloromethane, compound 2 (110.1g, 0.26mol) and 70mL triethylamine
(0.5mol) dripping 54.5g2,4-dichlorobenzoyl chloride (0.26mol) in mixture, about 30min adds, and is warming up to 50 DEG C,
Continue stirring 30min.Being subsequently adding 500mL water, separate organic layer, be dried, decompression removes dichloromethane, obtains compound 3
(147.6g), yield 95.2%.
Embodiment 3-2: the preparation of compound 3
Under the conditions of being stirred at room temperature, to 1000mL toluene, compound 2 (110.1g, 0.26mol) and 63mL pyridine
(0.78mol) dripping 65.4g2,4-dichlorobenzoyl chloride (0.312mol) in mixture, about 30min adds, and is warming up to 50
DEG C, continue stirring 30min.Being subsequently adding 500mL water, separate organic layer, be dried, decompression removes dichloromethane, obtains compound 3
(154.3g), yield 99.5%.
Embodiment 4: the preparation of compound 5
N2It is dried in there-necked flask the methyl tertiary butyl ether(MTBE) adding magnesium powder (14.6g, 0.6mol) and being dried to 1L under protection
(MTBE, 100mL), is heated to backflow.Add iodine grain (1.27g, 5mmol), in reactant liquor, drip chloromethyl trimethyl silane
(6mL, 0.05mol)/MTBE (20mL) solution.After reaction to be determined causes, continuation dropping chloromethyl trimethyl silane (50mL,
0.4mol)/MTBE (150mL) solution.Drip and finish, at 0~56 DEG C, react 2h.It is cooled to-10~0 DEG C, droppingization in reaction bulb
Compound 3 (150.0g, 0.2mol)/MTBE (100mL) solution, drips process temperature control-10 DEG C~10 DEG C, after dropping, and transfer
After reacting 5h, TLC (developing solvent: PE) monitoring raw material reaction at 10~30 DEG C, add 4N hydrochloric acid (1500mL) and terminate anti-
Should, stirring 30min, stand 10min, extraction, aqueous phase MTBE (200mL) extracts, and merges MTBE layer, concentrates, obtains g light yellow liquid
Body compound 4, direct plunges into next step reaction.
Above-mentioned prepared compound 4 is dissolved in MTBE (0.5L), dropping concentrated sulphuric acid (55mL, 1mol), temperature control 25~30
DEG C, drip complete, be warming up to 40~60 DEG C, after reaction 3.5h, TLC monitoring raw material reaction, be cooled to 20 DEG C, add water
(400mL) terminating reaction, after separatory, organic layer uses 9%NaHCO successively3(200mL) solution, water (200mL), saturated aqueous common salt
(200mL) washing, is dried, and at 40~45 DEG C, concentrating under reduced pressure obtains 54.5g dark red solution compound 5, and yield is 80.5%.
Embodiment 5-1: the preparation of compound 6
Being sequentially added into compound 5 (50.7g, 0.15mol) and EA (400mL) in 1L there-necked flask, stirring is cooled to-15
~-20 DEG C, add I2(114.2g, 0.45mol), NaHCO3(33.6g, 0.4mol), reacts 5~6h, TLC (PE/EA=3:1)
Monitoring raw material reaction is complete.Dropping 10%Na2SO3(500mL) stopped reaction, separatory, aqueous phase EA (200mL) extracts, and merges EA,
Use 10%Na2SO3Solution (200mL), H2O (200mL) respectively washed once, and concentrates, and is dried, and obtains 60.9g orange-yellow oily materialization and closes
Thing 6, productivity 86.8%, purity 99.3%, non-corresponding isomer impurities is less than 0.5%.
Following instance operation is identical with embodiment 5-1, reaction raw materials is identical, reaction dissolvent, the response time, reaction temperature etc.
Variant, experimental result see table:
Sequence | Solvent | Reaction temperature | Non-corresponding isomer | Purity | Yield |
Embodiment 5-2 | Ethanol | -20~-25 DEG C | 2.4% | 96.6% | 83.1% |
Embodiment 5-3 | Ethanol | -10~-15 DEG C | 0.6% | 99.2% | 88.4% |
Embodiment 5-4 | Ethanol | -5~-10 DEG C | 2.3% | 97.1% | 74.5% |
Embodiment 5-5 | Acetonitrile | -10~-15 DEG C | 0.5% | 98.9% | 87.2% |
Embodiment 5-6 | THF | -15~-20 DEG C | 0.8% | 98.6% | 85.3% |
Embodiment 6-1: the preparation of compound 7
Compound 6 (55.7g, 0.12mol) and dry DMSO (400mL), triazole sodium is added in 500mL there-necked flask
(45.5g, 0.5mol), stirs 1h under room temperature, be warming up to 80-100 DEG C of reaction 24h, HPLC and detect the complete (< of raw material reaction
1.5%).Reactant liquor adds saturated brine ice (600mL) after being cooled to room temperature, stirring, extracts with EA (250mL × 2), water
(250mL) wash, concentrated by rotary evaporation, obtain 45.9g yellow oily compounds 7, yield 92.8%, purity 98.6%.
Embodiment 6-2: the preparation of compound 7
Compound 6 (55.7g, 0.12mol) and dry DMSO (400mL), triazole sodium is added in 500mL there-necked flask
(22.8g, 0.25mol), stirs 1h under room temperature, be warming up to 80-100 DEG C of reaction 24h, HPLC and detect the complete (< of raw material reaction
1.5%).Reactant liquor adds saturated brine ice (600mL) after being cooled to room temperature, stirring, extracts with EA (250mL × 2), water
(250mL) wash, concentrated by rotary evaporation, obtain 43.0g yellow oily compounds 7, yield 86.8%, purity 98.3%.
Embodiment 7: the preparation of compound 8
By compound 7 (40.6g, 0.1mol), palladium carbon catalyst Pd-C4.0g, refrigerated methanol 350mL, concentrated hydrochloric acid 8.4mL,
Put in high pressure resistant bottle successively, be evacuated to-0.08Mpa, be flushed with hydrogen gas to 0.2Mpa, room temperature reaction 18 hours, filtration, filtrate
45 DEG C of dense doing of reducing pressure, add pure water 36.5mL, isopropanol 36.5mL, and stirring intensification is molten clearly, filtration, filtrate temperature control 60~70 DEG C
Add isopropanol 164.3mL, drip off slow cooling, separate out white solid, be cooled to-10 DEG C of sucking filtration, 50 DEG C of decompression dryings of filter cake
30.3g obtains compound 8, yield 95.3%, purity 99.4%.
Embodiment 8: the preparation of compound 9
In 250mL there-necked flask add compound 8 (25.3g, 0.08mol), DCM (250mL), stir molten clearly.Reactant liquor
It is cooled to-15~0 DEG C, is slowly added dropwise triethylamine (15.2g, 0.15mol), TsCl (15.3g, 0.08mol), 10~30 DEG C of stirrings
20min, is warming up to backflow, and reaction 24h, TLC detection (DCM:MeOH=25:1) raw material reacts completely.Add 10% hydrochloric acid
(50mL), 9%NaHCO3(50mL), water (50mL) washing, separatory obtains organic facies, is concentrated to give faint yellow solid.In concentrated solution
Add DCM (20mL), dropping normal heptane (180mL), 0 DEG C of crystallization 1h, filter, vacuum drying, obtain 30.5g compound as white solid
9, yield 80.6%, purity 99.5%.
Embodiment 10: the synthesis of itraconazole
With stirring, air inlet pipe, thermometer, condensing tube four-hole bottle in, at N2Protection under add 20g4-[4-[4-
(hydroxy phenyl)-1-piperazinyl] phenyl]-2,4-dihydro-2-(1-methyl-propyl)-3H-l, 2,4-triazole-one (compound 10,
0.05mol), 2.6g sodium hydrate solid, 0.3mL80% hydrazine hydrate and 150mLDMF.Stirring is warming up to 40 DEG C and reacts 40 minutes,
Being subsequently adding 23.6g compound 9 (0.05mol), and be heated to 60 DEG C, react 1.5 hours, TLC monitors without piperazine oxazolone
It is reaction end.After reaction terminates, it is cooled to 20 DEG C, reactant liquor is poured in 200mL10% sodium hydroxide solution, add
300mL dichloromethane is also layered in separatory funnel, and organic layer 200mL10% sodium hydroxide solution is washed, be washed with water in
Property, anhydrous magnesium sulfate is dried, and filters, and drains, filter cake 10mL eluent methylene chloride, concentrates the filtrate to do, obtains crude product.Then
Adding 100mL toluene, intensification stirring and dissolving, add 50mL ethyl acetate, slowly cooling separates out 32g solid itraconazole, yield
90.5%, purity 99.8%, quality meets European Pharmacopoeia standard.
Claims (9)
1. the preparation method of an itraconazole, it is characterised in that comprise the steps:
1) with (±)-epoxy prapanol as raw material, with trityl chloride protection hydroxyl after obtain (±) trityl glycidyl ether
(1);
2) (±) trityl glycidyl ether (1) carries out epoxy addition under the effect of alkali and react and obtain compound with benzyl alcohol
2;
3) compound 2 and 2,4 dichlorobenzyl chloride occur esterification to obtain compound 3 under the effect of alkali and organic solvent;
4) compound 3 carries out silylation grignard additive reaction and obtains compound 4;
5) compound 4 carry out β-silylation alcohol elimination reaction and removing trityl-protecting group obtain compound 5;
6) compound 5 carries out iodine and alkene additive reaction and stereo selectivity ring-closure reaction is obtained compound 6;
7) compound 6 and triazole sodium generation substitution reaction obtain compound 7;
8) compound 7 carries out debenzylation and obtains compound 8;
9) compound 8 introduces p-toluenesulfonyl and obtains compound 9;
10) compound 9 and compound 10 carry out condensation reaction generation itraconazole;Its synthetic route is as follows:
2. preparation method as claimed in claim 1, it is characterised in that: step 1) in, (±)-epoxy prapanol and trityl chloride
Carrying out in catalyst and triethylamine, described catalyst is 4-dimethylamino pyridine (DMAP), and reaction dissolvent is chloroform or dichloro
Methane;(±)-epoxy prapanol is 1:1-1.1 with the mol ratio of trityl chloride.
3. preparation method as claimed in claim 2, it is characterised in that: step 2) in, described alkali is NaH or NaOH;React molten
Agent is dimethylformamide (DMF), dimethyl acetylamide, dimethyl sulfoxide or oxolane, reaction temperature 15 DEG C-40 DEG C, instead
Between Ying Shi 12-18 hour.
4. preparation method as claimed in claim 2, it is characterised in that: step 3) in, described alkali is pyridine, triethylamine, N, N-
Dimethylaniline, N, N-dimethylamino naphthyridine, tetramethylethylenediamine or sodium carbonate;Described organic solvent is DCM, THF, toluene or
DMF;The mol ratio of compound 2,2,4 dichlorobenzyl chloride and alkali is 1:1-1.2:1-3.
5. preparation method as claimed in claim 1, it is characterised in that: step 4) in, chloromethyl trimethyl silane is sent out with magnesium
Raw grignard reaction generates Grignard reagent, occurs additive reaction to generate compound 4 Grignard reagent obtained and compound 3;Described
Grignard reaction uses the iodine grain being dissolved in methyl tertiary butyl ether(MTBE) as initiator;Described grignard reaction and additive reaction are in first
The dicyandiamide solution of base tertbutyl ether is carried out.
6. preparation method as claimed in claim 1, it is characterised in that: step 5) in, compound 4 is dissolved in MTBE, enriching
Sulphuric acid occurs to eliminate reaction and removing trityl-protecting group generation compound 5 in temperature 40~60 DEG C.
7. preparation method as claimed in claim 6, it is characterised in that: step 6) in, reaction dissolvent is acetonitrile, ethanol or THF;
Reaction temperature is-20 DEG C~-10 DEG C.
8. preparation method as claimed in claim 1, it is characterised in that: step 7) in, reaction dissolvent is DMSO;Reaction temperature is
80 DEG C~100 DEG C;Compound 6 is 1:1~6 with the mol ratio of triazole sodium.
9. preparation method as claimed in claim 1, it is characterised in that: in step step 8), use palladium charcoal catalytic hydrogenation to make chemical combination
Thing 7 is sloughed benzyl and is obtained compound 8;Compound 7, the mass ratio of catalyst are 1:0.05-0.1, preferably 1:0.1;Reaction dissolvent
For methanol, ethanol, isopropanol one or more, preferably methanol.
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