CN102603718A - Synthesis method of cediranib - Google Patents
Synthesis method of cediranib Download PDFInfo
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- CN102603718A CN102603718A CN2012100274093A CN201210027409A CN102603718A CN 102603718 A CN102603718 A CN 102603718A CN 2012100274093 A CN2012100274093 A CN 2012100274093A CN 201210027409 A CN201210027409 A CN 201210027409A CN 102603718 A CN102603718 A CN 102603718A
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Abstract
The invention discloses a preparation method of cediranib, which comprises the following steps of using trifluoro-nitrobenzene as a raw material and performing acetyl methyl adding, substitution, cyclization and protection to obtain a segment 1; and then using methyl vanillate as the raw material, performing benzyl bromine protection, nitro adding, reduction, unique cyclization and chlorination to obtain a segment 2; and performing nucleophilic substitution and deprotection on the two segments to obtain the final product cediranib. Compared with other methods, the preparation method of the cediranib has the advantages of mild reaction condition, high yield and scale amplification, and raw materials can be obtained easily.
Description
Technical field
The present invention relates to the preparation of west ground Buddhist nun's cloth (Cediranib), belong to the synthetic field of pharmaceutical chemistry.
Background technology
Cediranib (tentative trade name Recentin) is also referred to as AZD2171, is the potent inhibitor of a kind of general VEGF (pan-VEGF) receptor tyrosine kinase.This is a kind of oral chemotherapeutics that possibly be used to treat cancer that Astrazeneca AB is developing.
In antineoplaston, chemotherapy is to use whole body therapeutic more widely, both can use separately, again can with the additive method combined utilization, even in the treatment that can't undergo surgery, TCA still can treat.In recent years; Chemotherapeutic Neo-Confucianism and cellular elements biology develop rapidly; Chemotherapeutics is just excessive to the new type anticancer medicine of too many levels, novel targets by traditional cytotoxic drug, methods such as cancer cells differentiating inducer, telomerase inhibitor, therapy of tumor occurred.The transfer of tumour is the process of a complicacy, but formation that great majority shift and development all need rely on the formation of blood vessel.Therefore suppress tumor vessel and form, cut off tumor growth and shift " lifeblood " that is relied on, become important anticancer strategy.Referring to Volkmann. through attacking its blood supply system beat cancer. U.S. science .1996,2-5. (Folkman, J. Fighting Cancer by Attacking its Blood Supply. Sci. Am. 1996,2-5.).
The mechanism of action of Cediranib mainly also is through suppressing VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR.Discover that it can suppress the activity of 3 kinds of factors simultaneously, the restraining effect of VEGFR-2 acceptor that angiogenic growth is accounted for critical role is stronger.Carrying out first phase or phase ii clinical trials such as cerebral glioma, lung cancer, mammary cancer, liver cancer, colorectal carcinoma, prostate cancer at present, it is said that transfer also produces effect to brain.But Astrazeneca AB abandons submitting the new drug application of cediranib (Recentin) as colorectal carcinoma first-line treatment medicine in the recent period surely.Compared these article combined chemotherapy and single curative effect with chemotherapy because this key name is the clinical study of HORIZON II, the result shows that these article combined chemotherapy can prolong patient disease and get nowhere lifetime, but the patient is single with not improvement of chemotherapy group overall lifetime.
Although on the colorectal carcinoma first-line treatment, meet with setback, these article are still carrying out the treatment information of other cancer kind.Http:// clinicaltrials.gov/ct2/resultsterm=AZD2171 can see the clinical information of a lot of these medicines in the website; For example carrying out a first phase test of shifting with full brain radiotherapy contrast therapy brain, seeing: http://clinicaltrials.gov/ct2/show/NCT00937482.Also have one to be the pharmacokinetics test http://clinicaltrials.gov/ct2/sh that presides over by Sun Yan academician in China ...=AZD2171&rank=7.
Preparation about this compound; Patent WO2000047212 has narrated the synthetic 4-fluoro-2-methyl isophthalic acid H-5-oxyindole of the guard method of using trimethyl orthoformate to form ketal; The step of many protections and deprotection; And need purify and separate the midbody of multistep in the method, therefore cause difficulty in process and productive rate to reduce relatively.WO2004009542 has proposed another method: utilize the sodium methylate nucleophilic substitution, after remove methyl method introduce hydroxyl, arts demand could be accomplished in 180 ℃ of long-time reactions of high temperature, energy expenditure is higher; Perhaps introduce hydroxyl, remove benzyl in the time of cyclization, obtain 4-fluoro-2-methyl isophthalic acid H-5-oxyindole with benzylalcohol.Patent WO2008053221 has narrated the method for employing Triton B (N, N, N-Three methyl Benzene first ammonium oxyhydroxide) and has introduced hydroxyl, and SODIUM HYDROSULPHITE sodium reduction nitro is adopted in the back, and cyclization simultaneously obtains key intermediate 4-fluoro-2-methyl isophthalic acid H-5-oxyindole.What in the technology of hydrolysis and decarboxylation, use is aqueous sulfuric acid, and the situation of carbonization takes place down high temperature easily.
The preparation of another crucial midbody 7-benzyloxy-4-chloro-6-methoxyl group quinazoline: (J.Med.Chem. 2003 for document; 46; Be raw material with the vanillic acid 4910-4925), behind benzyl protection, with nitro on nitrosonitric acid and the acetic anhydride; And use zinc powder reduction, methane amide obtains product for cyclization reagent.The zinc powder reduction that this method is used, aftertreatment is difficult and produce a large amount of solid residues, and making cyclization reagent with methane amide needs the long-time reaction of high temperature (190 ℃), makes the product carbonization produce impurity easily.WO2006117552A1 adopts iron powder to reduce, and is that the employing methane amide is a cyclization reagent equally, all can cause aftertreatment difficulty and product to be not easy purifying.
Summary of the invention
For remedying the deficiency of prior art, the invention reside in the compound method that a kind of west ground Buddhist nun's cloth (Cediranib) is provided, this method productive rate is higher, and cost is lower, is fit to suitability for industrialized production.
Technical scheme provided by the invention is:
The compound method of ground, west Buddhist nun's cloth, its synthesis step is following:
1) with the sodium ethylate be basic catalyst, THF is a solvent, and methyl aceto acetate and trifluoronitrobenzene (both molar ratios are 1-3:1) obtained 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate in 2 ~ 8 hours in 0 ~ 40 ℃ of reaction.
2) 2-(2; 3-two fluoro-6-nitrophenyls)-(volume ratio is under 0.5 ~ 1.5:1) condition to the 3-methyl aceto acetate at the nitration mixture of concentrated hydrochloric acid (20%-36%) and Glacial acetic acid min. 99.5 composition; 60 ~ 120 ℃ were reacted 10 ~ 20 hours, and obtained 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone.The ratio of 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate and mixing acid is 1mol:1-2L;
3) 1-(2; 3-two fluoro-6-nitrophenyls) propyl group-2 ketone and benzylalcohol (both mol ratios are 1:2-4); At sodium hydroxide is under the effect of basic catalyst, in 80 ~ 120 ℃ of reaction 2-4h, obtains 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone;
4) 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone is dissolved in ethanol; Adding concentration then is the SODIUM HYDROSULPHITE sodium water solution of 1-3mol/L; In the presence of wet chemical (5-10mol/L) catalysis; Under 0-40 ℃ of condition, reacted 4 ~ 10 hours, obtain 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole.Wherein the molar ratio of 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone, V-Brite B and salt of wormwood is 1:2-4:3-5;
5) with methyl alcohol be solvent, under the Pd/C katalysis, 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole atmospheric hydrogenation deprotection obtains 4-fluoro-2-methyl isophthalic acid H-5-oxyindole.Wherein said Pd/C catalyzer is 10wt%Pd/C; The Pd/C catalyst levels is the 0.5-2wt% of 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole
6) vanillic acid methyl esters is used dissolve with ethanol, adds benzyl bromine (mol ratio of vanillic acid methyl esters and benzyl bromine is 1:1-1.5) then, and in the presence of basic catalyst sodium hydroxide, 0-40 ℃ was reacted 4-8 hour, and obtained 4-benzyloxy-3-methoxyl methyl benzoate;
7) 4-benzyloxy-3-methoxyl methyl benzoate adds excessive concentrated nitric acid (mass concentration is 65%-68%) and is warming up to 50-80 ℃ in the Glacial acetic acid min. 99.5 solvent, reacts 0.5 ~ 2 hour, obtains 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters.The molar ratio of 4-benzyloxy-3-methoxyl methyl benzoate and concentrated nitric acid is 1:2-5;
8) wet chemical (5-10mol/L) is made basic catalyst; 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters is dissolved in the ethanol; Add SODIUM HYDROSULPHITE sodium water solution (concentration is 1-3mol/L); Normal-temperature reaction 2-8 hour, obtain 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate; The molar ratio of 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters, V-Brite B and salt of wormwood is 1:2-4:3-5;
9) 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate and FORMAMIDINE ACETATE (both molar ratios are 1:1-2) are in isopropanol solvent, and 60 ~ 100 ℃ were reacted 4 ~ 8 hours down, obtain 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone;
10) 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone obtains 7-benzyloxy-4-chloro-6-methoxyl group quinazoline in 90-110 ℃ of dehydration reaction under the POCl3 effect; The amount ratio of 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone and POCl3 is 1g:2-4ml;
11) 7-benzyloxy-4-chloro-6-methoxyl group quinazoline and 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (both molar ratios are 1-1.5:1) are at DMF (N; Dinethylformamide) in the solvent; Basic catalyst salt of wormwood exists down; Lucifuge and nitrogen protection in 60 ~ 100 ℃ of reactions 10 ~ 20 hours, generate 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline;
12) 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline is in N-Methyl pyrrolidone, and palladium carbon shortening deprotection obtains 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline; Wherein said Pd/C catalyzer is 10wt%Pd/C; The Pd/C catalyst consumption is the 5-10% of 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline weight.
13) N-(3-chloropropyl) tetrahydro pyrrolidine is made by laxative remedy: be solvent with toluene; 1-bromo-3 chloropropanes and Pyrrolidine 40-60 ℃ was reacted 2 ~ 8 hours; Obtain N-(3-chloropropyl) tetrahydro pyrrolidine, the equivalence ratio of 1-bromo-3 chloropropanes and Pyrrolidine is 1:2-3.
14) 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline and N-(3-chloropropyl) tetrahydro pyrrolidine (both molar ratios are 1:1-1.5); In the presence of basic catalyst salt of wormwood; Be warming up to 60-100 ℃ of reaction 2-4 hour, obtain title product 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-[3-(tetramethyleneimine-1-yl) propoxy-] quinazoline.
In above-mentioned steps 3) in the reaction 2h be termination reaction; Aftertreatment adopts the volume ratio of methylene dichloride: sherwood oil=1:0.5 ~ 2 high yield to separate out solid phase prod.
Preferred concrete steps in the face of above-mentioned compound method describe respectively down.
1) chemosynthesis of 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate (X1)
THF was made solvent, and sodium ethylate is a basic catalyst, and the mol ratio of methyl aceto acetate and trifluoronitrobenzene is 1-3:1, in 0 ~ 40 ℃ of reaction 2 ~ 8 hours.Diluted hydrochloric acid aqueous solution destroys, ethyl acetate extraction, and drying, revolving desolvates can obtain 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate (X1).
Reaction equation is:
2) chemosynthesis of 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone (X2)
2-(2; 3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate (X1) is at concentrated hydrochloric acid and Glacial acetic acid min. 99.5 (under the mixed solvent condition that volume ratio 0.5 ~ 1.5:1) is formed; Obtained 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone (X2) in 10 ~ 20 hours in 60 ~ 120 ℃ of reactions.
Reaction equation is:
3) chemosynthesis of 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3)
Sodium hydroxide is basic catalyst, and 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone (X2) and benzylalcohol (2-4eq) under the condition of no solvent, and react 2-4h under 80 ~ 120 ℃ of temperature.After the washing of product diluted hydrochloric acid aqueous solution, adopt methylene dichloride: the ratio of sherwood oil (volume ratio)=1:0.5 ~ 2 is separated out solid phase prod-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3).
Reaction equation is:
4) chemosynthesis of 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole (X4)
Wet chemical is made basic catalyst; 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3) is used dissolve with ethanol, drips the aqueous solution of V-Brite B (3-8eq), reacts 4 ~ 10 hours under the 0-40 ℃ of condition; Spin off ethanol; Ethyl acetate extraction, drying, revolving desolvates obtains reducing and 5-(the benzyloxy)-4-fluoro-2-Methyl-1H-indole (X4) of cyclisation.
Reaction equation is:
5) chemosynthesis of 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5)
5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole (X4) is in solvent methanol; (10%Pd)/C makees catalyzer; The atmospheric hydrogenation deprotection obtains 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5); Thick product is used activated carbon decolorizing in alcohol solvent, sherwood oil and ethanol are done the mixed solvent recrystallization and obtained the white needle-like crystals product.
Reaction equation is:
6) chemosynthesis of 4-benzyloxy-3-methoxyl methyl benzoate (Y1)
Sodium hydroxide is made basic catalyst, and the dissolve with ethanol vanillic acid methyl esters drips benzyl bromine (mol ratio of vanillic acid methyl esters and benzyl bromine is 1:1-1.5), reacts the 4-benzyloxy-3-methoxyl methyl benzoate (Y1) that obtains benzyl protection under the 0-40 ℃ of condition.The sherwood oil recrystallization obtains the pure article of white crystal.
Reaction equation is:
7) chemosynthesis of 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters (Y2)
4-benzyloxy-3-methoxyl methyl benzoate (Y1) drips excessive concentrated nitric acid and is warming up to 50-80 ℃ in the Glacial acetic acid min. 99.5 solvent, reacts 0.5 ~ 2 hour.Obtain light yellow solid 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters (Y2).
Reaction equation is:
8) chemosynthesis of 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3)
Salt of wormwood is made basic catalyst, and the mixed system of second alcohol and water is a solvent, and 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters (Y2) and V-Brite B (3-8eq) normal-temperature reaction 2-8 hour obtain lurid solid
4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3).
Reaction equation is:
9) chemosynthesis of 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone (Y4)
4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) and FORMAMIDINE ACETATE (1-2eq) in isopropanol solvent, are warming up to 60 ~ 100 ℃ and reacted 4 ~ 8 hours down, and reaction is closed ring and obtained 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone (Y4).
Reaction equation is:
10) chemosynthesis of 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (Y5)
7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone (Y4) is under the effect of excessive POCl3, and the temperature rising reflux reaction obtains 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (Y5).
Reaction equation is:
11) chemosynthesis of 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X6)
7-benzyloxy-4-chloro-6-methoxyl group quinazoline (Y5) and 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5) (mol ratio is 1-1.5:1) are in the DMF solvent; Salt of wormwood is made basic catalyst; Lucifuge and nitrogen protection; In 60 ~ 100 ℃ of nucleophilic substitution reactions 10 ~ 20 hours, generate white solid product 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X6).
Reaction equation is:
7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X6) is in N-Methyl pyrrolidone; Under 10% the palladium charcoal catalysis, normal temperature and pressure hydrogenation deprotection obtains 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X7).
Reaction equation is:
13) chemosynthesis of 1-(3-chloropropyl) Pyrrolidine
1-bromo-3 chloropropanes are in toluene system, and 40-60 ℃ of Pyrrolidine (2-3eq) intensification reaction 2 ~ 8 hours, obtain 1-(3-chloropropyl) Pyrrolidine.
Reaction equation is:
14) chemosynthesis of title product 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-[3-(tetramethyleneimine-1-yl) propoxy-] quinazoline (X8)
7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X7) and 1-(3-chloropropyl) tetrahydro pyrrolidine (2-10eq) for preparing; At salt of wormwood is under the condition of basic catalyst; Be warming up to 60-100 ℃ of reaction 2-4 hour, finally obtain the khaki color title product.
Reaction equation is:
Technique effect of the present invention:
The present invention changes and has optimized the compound method of western ground Buddhist nun's cloth, and reaction process does not have harsh reaction conditions, and raw material is easy to get, and the place, back is easy.For example: step avoids the use of the vitriol oil in (2), has alleviated carbonization and environmental pollution; Step (3) product is clamminess and is difficult for purifying, and has saved the step of crossing post, controls the accurate ratio of sherwood oil and methylene dichloride, can make things convenient for the product that obtains of high yield; Step (4) and step (8) have avoided using iron powder, zinc powder in the presence of hydrochloric acid, to reduce the high pollution of nitro and the method that is difficult to aftertreatment, have been convenient to use V-Brite B normal-temperature reaction high yield and have obtained product; Step has adopted FORMAMIDINE ACETATE rather than methane amide in (9), and it is low to have temperature of reaction, and productive rate is high, the characteristics that product colour is good.The productive rate of the midbody compound 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5) of two keys and 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (Y5) is increased to 44% and 72%, and the productive rate of end product also is increased to 75%.The present invention is fit to the mass-producing amplification of ground, west Buddhist nun's cloth and becomes to produce.
Embodiment
Embodiment 1:
1) chemosynthesis of 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate (X1)
Sodium ethylate 68g (1mol) is dissolved in anhydrous tetrahydro furan 300ml, and mechanical stirring is cooled to 10 ℃, adds methyl aceto acetate 130g (1mol), dropwises in about 1 hour, and temperature control is lower than 35 ℃.With 1,2,3-three fluoro-4-oil of mirbane 88.5g (0.5mol) are dissolved in 200mlTHF, drip under the condition of ice bath to get in the above-mentioned reaction soln.Naturally rise to stirring at room reaction 5h, the TLC monitoring reaction finishes.
Pour the aqueous hydrochloric acid cancellation of 500ml1N into, ETHYLE ACETATE (1L*3) extraction merges organic phase, and saturated common salt water washing organic phase is revolved dried 241g product, productive rate: 84%.
Product structure confirms through nuclear-magnetism:
1H?NMR?Spectrum(CDCl
3):?δppm?13.21(s,1H),7.87(m,1H),7.30(t,1H),4.2(m,1H),4.0(m,1H),1.885(s,3H),1.13(t,3H).
2) chemosynthesis of 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone (X2)
With 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate (X1) 201g (0.70mol), be added in the mixing acid of forming by concentrated hydrochloric acid (0.8L) and Glacial acetic acid min. 99.5 (0.8L), rise to 100 ℃ of reactions 12 hours, the TLC monitoring reaction finishes.
Revolve and reclaim most concentrated hydrochloric acid and Glacial acetic acid min. 99.5, it is 6 that remaining product uses sodium bicarbonate aqueous solution to regulate PH, ethyl acetate extraction three times; Merge organic phase, washing, saturated common salt water washing organic phase; Anhydrous magnesium sulfate drying, filtration is revolved dried, obtains light yellow mucus 1-(2; 3-two fluoro-6-nitrophenyls) propyl group-2 ketone (X2) becomes pale yellow crystal 118g after the cooling.Productive rate: 78%.
Product structure confirms through mass spectrometric detection: m/z:212 (M-H)
-
Confirm through nuclear-magnetism:
1H?NMR?Spectrum(CDCl
3):?δppm
7.85（m，1H）,7.12(m,1H),3.90(d,2H),2.32(s,3H).
3) chemosynthesis of 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3)
With 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone (X2) 38g (176mmol), benzylalcohol 28.5g (264mmol) and sodium hydroxide 11.3g (283mmol) mix, and oil bath rises under 110 ℃ of temperature reacts 3h.
Be cooled to room temperature, add the 120ml methylene dichloride, diluted hydrochloric acid aqueous solution washed twice organic phase; Organic phase adds sherwood oil (180ml); Separate out yellow solid product-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3), dry back 42.3g, productive rate 79.3%.
Product structure confirms through mass spectrometric detection: m/z:302 (M-H)
-
4) chemosynthesis of 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole (X4)
Salt of wormwood 38g (0.28mol) is dissolved in the 40ml water; 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3) 26g (0.086mol) uses the 200ml dissolve with ethanol; Drip the 150ml aqueous solution of V-Brite B 52g (0.3mol), stirring reaction is 4 hours under 25 ℃ of conditions.Spin off most of ethanol, ethyl acetate extraction, drying, revolving desolvates obtains pale yellow liquid 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole (X4) 25.6g, productive rate: 98%.
Product structure confirms through mass spectrometric detection: m/z:254 (M-H)
-
5) chemosynthesis of 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5)
5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole (X4) 23.6g (0.092mol) is dissolved in the 200ml methyl alcohol; Add 0.3g (10%Pd)/C and make catalyzer; Atmospheric hydrogenation reacted 15 hours, obtained 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5) bullion of deprotection.Thick product activated carbon decolorizing in alcohol solvent revolves driedly, and sherwood oil and ethanol (volume ratio 6:1) mixed solvent recrystallization obtains white needle-like crystals product 13.2g, productive rate 87%.
Product structure confirms through mass spectrometric detection: m/z:166 (M+H)
+
Confirm through nuclear-magnetism:
1H?NMR?Spectrum(DMSO-d
6):?δppm
10.86(br,s,1H),8.75(s,1H),6.86(d,1H),6.65(t,1H),6.04(m,1H),2.25(s,3H).
6) chemosynthesis of 4-benzyloxy-3-methoxyl methyl benzoate (Y1)
Vanillic acid methyl esters 150g (0.823mol) is dissolved in 700ml ethanol, adds sodium hydroxide 44g, drips benzyl bromine 117ml (mol ratio of vanillic acid methyl esters and benzyl bromine is 1:1.2), and stirring reaction is 6 hours under 25 ℃ of conditions.
Add 1L water, ethyl acetate extraction, the washing organic phase, anhydrous magnesium sulfate drying revolves the dried pale yellow liquid that obtains.The sherwood oil recrystallization obtains the 4-benzyloxy-3-methoxyl methyl benzoate (Y1) of 213g benzyl protection, white crystal, productive rate 95%.
Product structure confirms through mass spectrometric detection: m/z:273 (M+H)
+
7) chemosynthesis of 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters (Y2)
4-benzyloxy-3-methoxyl methyl benzoate (Y1) 8g (0.0294mol) is dissolved in the 50ml Glacial acetic acid min. 99.5, drips the 7ml concentrated nitric acid, is warming up to 60 ℃, stirring reaction 1 hour.
Pour in the 300ml water, dichloromethane extraction, the sodium bicarbonate aqueous solution washing, anhydrous magnesium sulfate drying filters, and revolves dried light yellow solid 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters (Y2) 8.9g, the productive rate: 95.4% of obtaining.
Product structure confirms through mass spectrometric detection: m/z:318 (M+H)
+
8) chemosynthesis of 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3)
4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters (Y2) 6g (0.0189mol) is dissolved in the 40ml ethanol; Add salt of wormwood 13.1g; V-Brite B 13.2g (4eq); Stirring at normal temperature was reacted 6 hours, obtained 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) of lurid solid 5.1 g, productive rate 93%.
Product structure confirms through mass spectrometric detection: m/z:288 (M+H)
+
9) chemosynthesis of 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone (Y4)
4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) 4.38g (15.2mmol), FORMAMIDINE ACETATE 3g (28.8mmol) is dissolved among the Virahol 35ml; Being warming up to 98 ℃ reacted 6 hours down. reduce to room temperature; Filter, the washed with isopropyl alcohol solid product obtains crystal 7-benzyloxy-6-methoxyl group quinazoline-4 (the 3H)-ketone (Y4) of beige; Be total to 3.82g, productive rate 89%.
Product structure confirms through mass spectrometric detection: m/z:283 (M+H)
+
10) chemosynthesis of 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (Y5)
7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone (Y4) 1.6g (5.7mmol) adds the 5ml POCl3, temperature rising reflux reaction 3 hours; Be chilled to room temperature, spin off unnecessary POCl3, pour in the dilute sodium hydroxide aqueous solution; Filter; Obtain the cotton-shaped product of yellow-white, be total to 1.64g, productive rate: 96%.
Product structure confirms through mass spectrometric detection: m/z:301 (M+H)
+
Confirm through nuclear-magnetism:
1H?NMR?Spectrum(CDCl
3):?δppm
8.66(s,1H),7.35-7.50(m,7H),5.34(s,2H),4.08(s,3H).
11) chemosynthesis of 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X6)
7-benzyloxy-4-chloro-6-methoxyl group quinazoline (Y5) 6.6g (0.04mol) is dissolved among the 40mlDMF, adds 27.6g salt of wormwood, the protection of lucifuge inflated with nitrogen.4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5) 12g (0.04mol) is dissolved among the 30mlDMF, rises to 80 ℃ of reactions 16 hours.Pour in the 400ml water and destroy, EA extraction, revolve dried, dissolve with ethanol, activated carbon decolorizing revolves dried white solid product 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X6) 15.7g altogether, the productive rate: 91.4% of obtaining.
Product structure confirms through mass spectrometric detection: m/z:428 (M-H)
-
Product structure confirms through mass spectrometric detection: m/z:430 (M+H)
+
12) chemosynthesis of 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X7)
7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X6) 14.4g (33.5mmol) is dissolved in the 80mlN-SL 1332; The palladium charcoal that adds 1g10%; Normal temperature and pressure hydrogenation reaction 5 hours; Filter out palladium carbon catalyst, little amount of N-SL 1332 washing back merges, and the N-Methyl pyrrolidone that obtains 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X7) is subsequent use.
Product structure confirms through mass spectrometric detection: m/z:338 (M-H)
-
13) chemosynthesis of 1-(3-chloropropyl) Pyrrolidine
1-bromo-3 chloropropane 6.3g (0.04mol) are dissolved in the 30ml toluene, drip Pyrrolidine 6.3g (0.088mol), and 40 ℃ of reactions 2 ~ 8 hours heat up.Reduce to room temperature, add 50ml water, it is 8 that Hydrogen chloride is regulated PH, separatory, and the water washing organic phase is once.The aqueous hydrochloric acid of the about 100ml2N of preparation, twice extracted organic phase merges water, adds sodium hydroxide and regulates PH to 11, and MTBE extraction three times obtains lurid 1-(3-chloropropyl) Pyrrolidine solution for standby.
14) chemosynthesis of 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-[3-(tetramethyleneimine-1-yl) propoxy-] quinazoline (X8)
In the N-Methyl pyrrolidone solution of 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline (X7); Add 4.1g salt of wormwood; Stirring is warming up to 80 ℃; The 1-that dropping prepares (3-chloropropyl) tetrahydro pyrrolidine (1.2eq) solution reacted 2 hours, and the TLC detection reaction finishes.Pour in the 200ml water, filter, vacuum-drying finally obtains yellow powder powder product 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-[3-(tetramethyleneimine-1-yl) propoxy-] quinazoline (X8), is total to 12.5g, last two step overall yields: 82.8%.
Product structure confirms through mass spectrometric detection: m/z:451 (M+H)
+
1H?NMR?Spectrum(DMSO-d
6):?δppm
11.34(s,1H),?8.52(s,1H),?7.61(s,1H),?7.39(s,1H),?7.16(d,1H),?6.70(dd,1H),?6.24(s,1H),?4.25(t,2H),4?.00(s,3H),2.57(t,2H),2.44-2.49(m,4H),2.42(s,3H),1.95-2.03(m,2H),1.67-1.74(m,4H).
Embodiment 2:
Of embodiment 1, different is that step (1) adopts sodium hydride, and the molar ratio of reaction mass is all identical, and reaction obtains the 125g product, and productive rate is: 44%.
Embodiment 3:
Of embodiment 1, different is that step (1) adopts potassium tert.-butoxide, and the molar ratio of reaction mass is all identical, and reaction obtains the 153g product, and productive rate is: 54%.
Embodiment 4:
Of embodiment 1; Different is that the decarboxylation condition is different in the step (2): 2-(2; 3-two fluoro-6-nitrophenyls)-and 3-methyl aceto acetate (X1) 200g (0.70mol), add the 240ml Glacial acetic acid min. 99.5,240ml water; The 240ml vitriol oil, heating up 110 ℃ still had big content of starting materials unreacted to finish in 24 hours.Behind the purifying, productive rate is merely 35%.
Embodiment 5:
Of embodiment 1; Different is that the decarboxylation condition is different in the step (2): 2-(2; 3-two fluoro-6-nitrophenyls)-and 3-methyl aceto acetate (X1) 200g (0.70mol), add the 250ml Glacial acetic acid min. 99.5, the 250ml vitriol oil; Still had big content of starting materials unreacted to finish in 20 hours to 80 ℃ of reactions, and system carbonization blackout.Behind the purifying, productive rate is merely 24%.
Embodiment 6:
Of embodiment 1, different is that the reaction times changes 4h in the step (3), detect to produce an impure point, and be 2-position benzyloxy substitution product through separation detection.Cross post separation back title product productive rate and be merely 52%.
Embodiment 7:
Of embodiment 1; Different is step (3) and step (4); Adopt the catalytic method of palladium charcoal to attempt to obtain 4-fluoro-2-methyl isophthalic acid H-5-oxyindole (X5) by 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone (X3) step; The impurity of finding the reaction generation is a lot, needs post to separate, and the back two steps overall yield of purifying is merely 36%.
Embodiment 8:
Of embodiment 1; Different is the synthetic of 4-benzyloxy in the step (8)-3-methoxyl group-2-Methyl anthranilate (Y3), and the reductive agent of employing is a reduced iron powder, can obtain product smoothly equally; But reaction produces a large amount of iron mud; Bad filtration, and the product color is Dark grey, the back productive rate of purifying is 65%.
Embodiment 9:
Of embodiment 1, different is in the step (9), and 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) 5g (17.7mmol) is dissolved in the 50ml methane amide, is heated to 190 ℃, stirring reaction 4h.Reactant is poured in the saturated aqueous common salt, sedimentation and filtration, washing obtains grey crystallite product, productive rate 62% after the drying.
Claims (6)
1. the compound method of west ground Buddhist nun cloth, its synthesis step is following:
1) with the THF be solvent, methyl aceto acetate and trifluoronitrobenzene obtained 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate in 2 ~ 8 hours in 0 ~ 40 ℃ of reaction in the presence of basic catalyst; The mol ratio of methyl aceto acetate and trifluoronitrobenzene is 1-3:1;
2) 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate is under the nitration mixture condition of 0.5 ~ 1.5:1 in the volume ratio of concentrated hydrochloric acid and Glacial acetic acid min. 99.5 composition, and 60 ~ 120 ℃ were reacted 10 ~ 20 hours, and obtained 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone; The ratio of 2-(2,3-two fluoro-6-nitrophenyls)-3-methyl aceto acetate and mixing acid is 1mol:1-2L;
3) 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone and benzylalcohol under the effect of basic catalyst sodium hydroxide, in 80 ~ 120 ℃ of reaction 2-4h, obtains 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone; The mol ratio of 1-(2,3-two fluoro-6-nitrophenyls) propyl group-2 ketone and benzylalcohol is 1:2-4;
4) 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone is dissolved in ethanol; Adding concentration then is the SODIUM HYDROSULPHITE sodium water solution of 1-3mol/L; In the presence of 5-10mol/L wet chemical catalyzer; Under 0-40 ℃ of condition, reacted 4 ~ 10 hours, obtain 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole; Wherein the molar ratio of 1-(3-(benzyloxy)-2-fluoro-6-nitrophenyl) propyl group-2-ketone, V-Brite B and salt of wormwood is 1:2-4:3-5;
5) with methyl alcohol be solvent, under the Pd/C katalysis, 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole atmospheric hydrogenation deprotection obtains 4-fluoro-2-methyl isophthalic acid H-5-oxyindole;
6) vanillic acid methyl esters is used dissolve with ethanol, adds the benzyl bromine then, and in the presence of basic catalyst sodium hydroxide, 0-40 ℃ was reacted 4-8 hour, and obtained 4-benzyloxy-3-methoxyl methyl benzoate; The mol ratio of vanillic acid methyl esters and benzyl bromine is 1:1-1.5;
7) 4-benzyloxy-3-methoxyl methyl benzoate is in the Glacial acetic acid min. 99.5 solvent, and to add excessive mass concentration be the 65%-68% concentrated nitric acid and be warming up to 50-80 ℃, reacted 0.5 ~ 2 hour, obtains 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters; The molar ratio of 4-benzyloxy-3-methoxyl methyl benzoate and concentrated nitric acid is 1:2-5;
8) the 5-10mol/L wet chemical is made basic catalyst; 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters is dissolved in the ethanol; Adding concentration is 1-3mol/L SODIUM HYDROSULPHITE sodium water solution, normal-temperature reaction 2-8 hour, obtains 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate; The molar ratio of 4-benzyloxy-3-methoxyl group-2-nitrobenzoic acid methyl esters, V-Brite B and salt of wormwood is 1:2-4:3-5;
9) 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate and FORMAMIDINE ACETATE are in isopropanol solvent, and 60 ~ 100 ℃ were reacted 4 ~ 8 hours down, obtain 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone; The mol ratio of 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate and FORMAMIDINE ACETATE is 1:1-2;
10) 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone obtains 7-benzyloxy-4-chloro-6-methoxyl group quinazoline in 90-110 ℃ of dehydration reaction under the POCl3 effect; The amount ratio of 7-benzyloxy-6-methoxyl group quinazoline-4 (3H)-ketone and POCl3 is 1g:2-4ml;
11) 7-benzyloxy-4-chloro-6-methoxyl group quinazoline and 4-fluoro-2-methyl isophthalic acid H-5-oxyindole are in the DMF solvent; Basic catalyst salt of wormwood exists down; Lucifuge and nitrogen protection; In 60 ~ 100 ℃ of reactions 10 ~ 20 hours, generate 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline; The mol ratio of benzyloxy-4-chloro-6-methoxyl group quinazoline and 4-fluoro-2-methyl isophthalic acid H-5-oxyindole is 1-1.5:1;
12) 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline is in N-Methyl pyrrolidone, and Pd/C shortening deprotection obtains 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline;
13) N-(3-chloropropyl) tetrahydro pyrrolidine is made by laxative remedy: be solvent with toluene, 1-bromo-3 chloropropanes and Pyrrolidine 40-60 ℃ was reacted 2 ~ 8 hours, obtained N-(3-chloropropyl) tetrahydro pyrrolidine, and the equivalence ratio of 1-bromo-3 chloropropanes and Pyrrolidine is 1:2-3;
14) 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline and N-(3-chloropropyl) tetrahydro pyrrolidine; In the presence of basic catalyst salt of wormwood; Be warming up to 60-100 ℃ of reaction 2-4 hour, obtain title product 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-[3-(tetramethyleneimine-1-yl) propoxy-] quinazoline; The mol ratio of 7-hydroxyl-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline and N-(3-chloropropyl) tetrahydro pyrrolidine is 1:1-1.5.
2. compound method as claimed in claim 1 is characterized in that, in the said step 1), basic catalyst is a sodium ethylate.
3. compound method as claimed in claim 1 is characterized in that, said step 2) the concentration of concentrated hydrochloric acid be 20wt%-36wt%.
4. compound method as claimed in claim 1 is characterized in that, reaction 2h is a termination reaction in the step 3); Aftertreatment adopts the volume ratio of methylene dichloride: sherwood oil=1:0.5 ~ 2 high yield to separate out solid phase prod.
5. compound method as claimed in claim 1 is characterized in that, the said Pd/C catalyzer of step 5) is 10wt%Pd/C; The Pd/C catalyst levels is the 0.5-2wt% of 5-(benzyloxy)-4-fluoro-2-Methyl-1H-indole.
6. compound method as claimed in claim 1 is characterized in that, the said Pd/C catalyzer of step 12) is 10wt%Pd/C; The Pd/C catalyst consumption is the 5-10% of 7-benzyloxy-4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-methoxyl group quinazoline weight.
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| CN105801443A (en) * | 2016-05-05 | 2016-07-27 | 成都东电艾尔科技有限公司 | Synthesis method of dicloxacillin drug intermediate 2-amino-6-chlorobenzoic acid |
| CN106831729A (en) * | 2016-12-19 | 2017-06-13 | 浙江工业大学 | A kind of purification process of AZD2171 |
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| CN110629246A (en) * | 2019-11-15 | 2019-12-31 | 湖南大学 | Vantanib and analogue intermediate electro-reduction preparation method thereof |
| CN110629246B (en) * | 2019-11-15 | 2021-03-16 | 湖南大学 | Vantanib and analogue intermediate electro-reduction preparation method thereof |
| CN112939897A (en) * | 2021-03-04 | 2021-06-11 | 上海珈睿医药科技有限公司 | Preparation method and application of broad-spectrum anti-cancer drug enrotinib intermediate |
| CN115403506A (en) * | 2022-09-21 | 2022-11-29 | 江西亚太科技发展有限公司 | Preparation method of indole-2-carboxylic acid derivatives |
| CN115403506B (en) * | 2022-09-21 | 2024-02-13 | 江西亚太科技发展有限公司 | Preparation method of indole-2-carboxylic acid derivative |
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