CN102603718B - Synthesis method of cediranib - Google Patents
Synthesis method of cediranib Download PDFInfo
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- CN102603718B CN102603718B CN201210027409.3A CN201210027409A CN102603718B CN 102603718 B CN102603718 B CN 102603718B CN 201210027409 A CN201210027409 A CN 201210027409A CN 102603718 B CN102603718 B CN 102603718B
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- 0 CC(C[C@](C=*F)OCC1=C=C=C*C1C)Cc1c(C)cc(C)[n]1 Chemical compound CC(C[C@](C=*F)OCC1=C=C=C*C1C)Cc1c(C)cc(C)[n]1 0.000 description 2
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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 AZD2171 (Cediranib), belong to the synthetic field of pharmaceutical chemistry.
Background technology
Cediranib(fixes tentatively trade name Recentin), also referred to as AZD2171, be the potent inhibitor of a kind of general vascular endothelial growth factor (pan-VEGF) receptor tyrosine kinase.A kind of oral chemotherapeutics that may be used for the treatment of cancer that Zhe Shi Astrazeneca AB is developing.
In antineoplaston, chemotherapy is to apply whole body therapeutic more widely, both can apply separately, again can with additive method combined utilization, even to cannot carry out operative treatment in, terminal cancer 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, has occurred the methods such as Carcinoma cell differentiation inductor, telomerase inhibitor, therapy of tumor.The transfer of tumour is a complicated process, but the formation that great majority shift and development all need to rely on the formation of blood vessel.Therefore suppress tumor vessel and form, cut off " lifeblood " that growth and metastasis of tumours relies on, become important anticancer strategy.Referring to Volkmann. by 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 is also mainly by suppressing VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR.Research finds that it can suppress the activity of 3 kinds of factors simultaneously, and the restraining effect of VEGFR-2 acceptor that angiogenic growth is accounted for to critical role is stronger.Carrying out first phase or the phase ii clinical trials such as cerebral glioma, lung cancer, mammary cancer, liver cancer, colorectal carcinoma, prostate cancer at present, it is said brain is shifted and also produced effect.But Astrazeneca AB abandons submitting cediranib(Recentin in the recent period surely) as the new drug application of colorectal carcinoma first-line treatment medicine.Because this key name is the clinical study of HORIZON II, compared the curative effect of this product combined chemotherapy and alone chemotherapy, result shows that this product combined chemotherapy can extend the patient disease Progression free survival phase, but overall lifetime of patient, more alone chemotherapy group was not improved.
Although meet with setback on colorectal carcinoma first-line treatment, this product is still being carried out the treatment information of other cancer kind.At website http://clinicaltrials.gov/ct2/resultsterm=AZD2171, can see the clinical information of a lot of these medicines, 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 being presided over by Sun Yan academician in China ...=AZD2171 & rank=7.
Preparation about this compound; patent WO2000047212 has narrated the synthetic fluoro-2-methyl isophthalic acid of the 4-H-5-oxyindole of the guard method of using trimethyl orthoformate to form ketal; the step of many protections and deprotection; and in method, need the intermediate of multistep to purify with separated, therefore cause difficulty in process and productive rate relatively to reduce.WO2004009542 has proposed another method: utilize sodium methylate nucleophilic substitution, after remove methyl method introduce hydroxyl, technique need to just can complete in 180 ℃ of long-time reactions of high temperature, energy expenditure is higher; Or with benzylalcohol, introduce hydroxyl, in the time of cyclization, remove benzyl, obtain the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole.Patent WO2008053221 has narrated employing Triton B(N, N, N-Three methyl Benzene first ammonium oxyhydroxide) method introduce hydroxyl, rear employing SODIUM HYDROSULPHITE sodium reduction nitro, cyclization simultaneously, obtains the fluoro-2-methyl isophthalic acid of key intermediate 4-H-5-oxyindole.What in the technique of hydrolysis decarboxylation, use is aqueous sulfuric acid, and the situation of carbonization easily occurs under high temperature.
The preparation of the chloro-6-methoxyl group of the intermediate 7-benzyloxy-4-quinazoline that another is crucial: (J.Med.Chem. 2003 for document; 46; 4910-4925), take vanillic acid as raw material; after benzyl protection; with nitro on nitrosonitric acid and acetic anhydride; and with zinc powder reduction, methane amide is that cyclization reagent obtains product.The zinc powder reduction that this method is used, aftertreatment is difficult and produce a large amount of solid residues, and with methane amide, making cyclization reagent needs high temperature (190 ℃) to react for a long time, easily makes product carbonization produce impurity.WO2006117552A1 adopts iron powder to reduce, and is that employing methane amide is cyclization reagent equally, all can cause aftertreatment difficulty and product to be not easy purifying.
Summary of the invention
For making up the deficiencies in the prior art, the invention reside in the synthetic method that a kind of AZD2171 (Cediranib) is provided, the method productive rate is higher, and cost is lower, is applicable to suitability for industrialized production.
Technical scheme provided by the invention is:
The synthetic method of AZD2171, its synthesis step is as follows:
1) take sodium ethylate as basic catalyst, tetrahydrofuran (THF) is solvent, and methyl aceto acetate and trifluoronitrobenzene (both molar ratios are 1-3:1) obtain 2-(2, the fluoro-6-nitrophenyl of 3-bis-for 2 ~ 8 hours in 0 ~ 40 ℃ of reaction)-3-methyl aceto acetate.
2) 2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate is under nitration mixture (volume ratio the is 0.5 ~ 1.5:1) condition of concentrated hydrochloric acid (20%-36%) and Glacial acetic acid composition, 60 ~ 120 ℃ are reacted 10 ~ 20 hours, obtain 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone.2-(2, the fluoro-6-nitrophenyl of 3-bis-) ratio of-3-methyl aceto acetate and mixing acid is 1mol:1-2L;
3) 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone and benzylalcohol (both mol ratios are 1:2-4), under the effect that is basic catalyst at sodium hydroxide, in 80 ~ 120 ℃ of reaction 2-4h, obtain 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) propyl group-2-ketone;
4) 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) propyl group-2-ketone is dissolved in ethanol, then adding concentration is the SODIUM HYDROSULPHITE sodium water solution of 1-3mol/L, under wet chemical (5-10mol/L) catalysis exists, under 0-40 ℃ of condition, react 4 ~ 10 hours, obtain 5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-.1-(3-(benzyloxy wherein) the fluoro-6-nitrophenyl of-2-) molar ratio of propyl group-2-ketone, V-Brite B and salt of wormwood is 1:2-4:3-5;
5) take methyl alcohol as solvent, under Pd/C katalysis, 5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-atmospheric hydrogenation deprotection obtains the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole.Wherein said Pd/C catalyzer is 10wt%Pd/C; Pd/C catalyst levels is 5-(benzyloxy) 0.5-2wt% of the fluoro-2-Methyl-1H-indole of-4-
6) vanillic acid methyl esters dissolve with ethanol, then adds benzyl bromine (mol ratio of vanillic acid methyl esters and benzyl bromine is 1:1-1.5), and under basic catalyst sodium hydroxide exists, 0-40 ℃ of reaction 4-8 hour, obtains 4-benzyloxy-3-methoxyl methyl benzoate;
7) 4-benzyloxy-3-methoxyl methyl benzoate, in Glacial acetic acid solvent, adds excessive concentrated nitric acid (mass concentration is 65%-68%) and is warming up to 50-80 ℃, reacts 0.5 ~ 2 hour, obtains 4-benzyloxy-3-methoxyl group-2-nitrobenzene methyl.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-nitrobenzene methyl is dissolved in ethanol, add SODIUM HYDROSULPHITE sodium water solution (concentration is 1-3mol/L), 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-nitrobenzene methyl, 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) be in isopropanol solvent, reacts 4 ~ 8 hours at 60 ~ 100 ℃, obtains 7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one;
10) 7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one obtains the chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline in 90-110 ℃ of dehydration reaction under phosphorus oxychloride effect; 7-benzyloxy-6-methoxyl group quinazoline-4(3H) amount ratio of-one and phosphorus oxychloride is 1g:2-4ml;
11) 7-benzyloxy-4-chloro-6-methoxyl group quinazoline and the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (both molar ratios are 1-1.5:1) are at DMF(N, dinethylformamide) in solvent, under basic catalyst salt of wormwood exists, lucifuge nitrogen protection, in 60 ~ 100 ℃ of reactions 10 ~ 20 hours, generate the fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline;
12) the fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline is in N-Methyl pyrrolidone, and palladium carbon shortening deprotection obtains the fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base)-6-methoxyl group quinazoline; Wherein said Pd/C catalyzer is 10wt%Pd/C; The consumption of Pd/C catalyzer is the fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base) 5-10% of-6-methoxyl group quinazoline weight.
13) N-(3-chloropropyl) tetrahydro pyrrolidine is made by laxative remedy: take toluene as solvent, bromo-3 chloropropanes of 1-and Pyrrolidine 40-60 ℃ reaction 2 ~ 8 hours, obtain N-(3-chloropropyl) tetrahydro pyrrolidine, the equivalence ratio of bromo-3 chloropropanes of 1-and Pyrrolidine is 1:2-3.
14) the fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base)-6-methoxyl group quinazoline and N-(3-chloropropyl) tetrahydro pyrrolidine (both molar ratios are 1:1-1.5), under basic catalyst salt of wormwood exists, be warming up to 60-100 ℃ of reaction 2-4 hour, obtain target product 4-(the fluoro-2 methyl indole-5-of 4-base oxygen base)-6-methoxyl group-7-[3-(pyrrolidin-1-yl) propoxy-] quinazoline.
In above-mentioned steps 3) in reaction 2h be termination reaction; Aftertreatment adopts methylene dichloride: the volume ratio of sherwood oil=1:0.5 ~ 2 can high yield be separated out solid phase prod.
Below the preferred concrete steps of above-mentioned synthetic method are described respectively.
1) 2-(2, the fluoro-6-nitrophenyl of the 3-bis-) chemosynthesis of-3-methyl aceto acetate (X1)
Tetrahydrofuran (THF) was made solvent, and sodium ethylate is 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, and ethyl acetate extraction is dry, revolves desolventizing and can obtain 2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate (X1).
Reaction equation is:
2) 1-(2, the fluoro-6-nitrophenyl of the 3-bis-) chemosynthesis of propyl group-2 ketone (X2)
2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate (X1) is under the mixed solvent condition of concentrated hydrochloric acid and Glacial acetic acid (volume ratio 0.5 ~ 1.5:1) composition, in 60 ~ 120 ℃ of reactions, within 10 ~ 20 hours, obtain 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone (X2).
Reaction equation is:
3) 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) chemosynthesis of propyl group-2-ketone (X3)
Sodium hydroxide is basic catalyst, 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone (X2) and benzylalcohol (2-4eq), under condition of no solvent, and react 2-4h at 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 the fluoro-6-nitrophenyl of solid phase prod-(3-(benzyloxy)-2-) propyl group-2-ketone (X3).
Reaction equation is:
4) the 5-(benzyloxy) chemosynthesis of the fluoro-2-Methyl-1H-indole of-4-(X4)
Wet chemical is made basic catalyst, 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) dissolve with ethanol for propyl group-2-ketone (X3), drip the aqueous solution of V-Brite B (3-8eq), under 0-40 ℃ of condition, react 4 ~ 10 hours, spin off ethanol, ethyl acetate extraction, dry, revolve the 5-(benzyloxy that desolventizing obtains reduction cyclisation) the fluoro-2-Methyl-1H-indole of-4-(X4).
Reaction equation is:
5) chemosynthesis of the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5)
5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-(X4) is in solvent methanol; (10%Pd)/C makees catalyzer; atmospheric hydrogenation deprotection obtains the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5); thick product is with activated carbon decolorizing in alcohol solvent, and sherwood oil and ethanol are done mixed solvent recrystallization and obtained 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 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), and under 0-40 ℃ of condition, reaction obtains 4-benzyloxy-3-methoxyl methyl benzoate (Y1) of benzyl protection.Sherwood oil recrystallization, obtains white crystal sterling.
Reaction equation is:
7) chemosynthesis of 4-benzyloxy-3-methoxyl group-2-nitrobenzene methyl (Y2)
4-benzyloxy-3-methoxyl methyl benzoate (Y1), in Glacial acetic acid solvent, drips excessive concentrated nitric acid and is warming up to 50-80 ℃, reacts 0.5 ~ 2 hour.Obtain light yellow solid 4-benzyloxy-3-methoxyl group-2-nitrobenzene methyl (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 solvent, and 4-benzyloxy-3-methoxyl group-2-nitrobenzene methyl (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) the 7-benzyloxy-6-methoxyl group quinazoline-4(3H) chemosynthesis of-one (Y4)
4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) and FORMAMIDINE ACETATE (1-2eq), in isopropanol solvent, be warming up at 60 ~ 100 ℃ and react 4 ~ 8 hours, reaction is closed ring and is obtained 7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one (Y4).
Reaction equation is:
10) chemosynthesis of the chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline (Y5)
7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one (Y4) is under the effect of excessive phosphorus oxychloride, and temperature rising reflux reaction obtains the chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline (Y5).
Reaction equation is:
11) the fluoro-2-Methyl-1H-indole-5-of the 7-benzyloxy-4-(4-base oxygen base) chemosynthesis of-6-methoxyl group quinazoline (X6)
The chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline (Y5) and the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5) (mol ratio is 1-1.5:1) are in DMF solvent; salt of wormwood is made basic catalyst; lucifuge nitrogen protection; in 60 ~ 100 ℃ of nucleophilic substitution reactions 10 ~ 20 hours, generate the fluoro-2-Methyl-1H-indole-5-of white solid product 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline (X6).
Reaction equation is:
The fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline (X6) is in N-Methyl pyrrolidone; under 10% palladium charcoal catalysis, normal temperature and pressure hydrogenation deprotection obtains the fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base)-6-methoxyl group quinazoline (X7).
Reaction equation is:
13) the 1-(3-chloropropyl) chemosynthesis of Pyrrolidine
Bromo-3 chloropropanes of 1-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) target product 4-(the fluoro-2 methyl indole-5-of 4-base oxygen base)-6-methoxyl group-7-[3-(pyrrolidin-1-yl) propoxy-] chemosynthesis of quinazoline (X8)
The fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base)-6-methoxyl group quinazoline (X7) and 1-(3-chloropropyl) tetrahydro pyrrolidine (2-10eq) for preparing, under the condition that is basic catalyst at salt of wormwood, be warming up to 60-100 ℃ of reaction 2-4 hour, finally obtain khaki color target product.
Reaction equation is:
technique effect of the present invention:
The present invention has changed and has optimized the synthetic method of AZD2171, and reaction process does not have harsh reaction conditions, and raw material is easy to get, and rear place is easy.For example: step avoids using 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 facilitate the product that obtains of high yield; Step (4) and step (8) have avoided using iron powder, zinc powder under hydrochloric acid exists, 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), has temperature of reaction low, and productive rate is high, the feature that product colour is good.The productive rate of two the crucial fluoro-2-methyl isophthalic acid of midbody compound 4-H-5-oxyindoles (X5) and the chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline (Y5) is increased to 44% and 72%, and the productive rate of end product is also increased to 75%.The present invention is applicable to the mass-producing of AZD2171 and amplifies and become to produce.
Embodiment
Embodiment 1:
1) 2-(2, the fluoro-6-nitrophenyl of the 3-bis-) chemosynthesis of-3-methyl aceto acetate (X1)
Sodium ethylate 68g(1mol) be dissolved in anhydrous tetrahydro furan 300ml, mechanical stirring is cooled to 10 ℃, adds methyl aceto acetate 130g(1mol), dropwise in about 1 hour, temperature control is lower than 35 ℃.By the fluoro-4-oil of mirbane of 1,2,3-tri-88.5g(0.5mol) be dissolved in 200mlTHF, under condition of ice bath, drip and enter in above-mentioned reaction soln.Naturally rise to stirring at room reaction 5h, TLC monitoring reaction is complete.
Pour the aqueous hydrochloric acid cancellation of 500ml1N into, ethyl acetate (1L*3) extraction, merges organic phase, and saturated common salt water washing organic phase, is spin-dried for to obtain 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) 1-(2, the fluoro-6-nitrophenyl of the 3-bis-) chemosynthesis of propyl group-2 ketone (X2)
By 2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate (X1) 201g(0.70mol), be added in the mixing acid being formed by concentrated hydrochloric acid (0.8L) and Glacial acetic acid (0.8L), rise to 100 ℃ of reactions 12 hours, TLC monitoring reaction is complete.
Revolve and reclaim most concentrated hydrochloric acid and Glacial acetic acid, it is 6 that remaining product regulates PH with sodium bicarbonate aqueous solution, ethyl acetate extraction three times, merges organic phase, washing, saturated common salt water washing organic phase, anhydrous magnesium sulfate drying, filtration is spin-dried for, and obtains light yellow mucus 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone (X2), becomes pale yellow crystal 118g after cooling.Productive rate: 78%.
Product structure confirms through mass spectrometric detection: m/z:212 (M-H)
-
Through nuclear-magnetism, confirm:
1H?NMR?Spectrum(CDCl
3):?δppm
7.85（m，1H）,7.12(m,1H),3.90(d,2H),2.32(s,3H).
3) 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) chemosynthesis of propyl group-2-ketone (X3)
By 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone (X2) 38g(176mmol), benzylalcohol 28.5g(264mmol), and sodium hydroxide 11.3g(283mmol) mix, oil bath rises at 110 ℃ of temperature reacts 3h.
Be cooled to room temperature, add 120ml methylene dichloride, diluted hydrochloric acid aqueous solution washed twice organic phase, organic phase adds sherwood oil (180ml), separate out the fluoro-6-nitrophenyl of yellow solid product-(3-(benzyloxy)-2-) propyl group-2-ketone (X3), dry rear 42.3g, productive rate 79.3%.
Product structure confirms through mass spectrometric detection: m/z:302 (M-H)
-
4) the 5-(benzyloxy) chemosynthesis of the fluoro-2-Methyl-1H-indole of-4-(X4)
Salt of wormwood 38g(0.28mol) be dissolved in 40ml water, 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) propyl group-2-ketone (X3) 26g(0.086mol) use 200ml dissolve with ethanol, dropping V-Brite B 52g(0.3mol) the 150ml aqueous solution, under 25 ℃ of conditions, stirring reaction is 4 hours.Spin off most of ethanol, ethyl acetate extraction, dry, revolve desolventizing and obtain pale yellow liquid 5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-(X4) 25.6g, productive rate: 98%.
Product structure confirms through mass spectrometric detection: m/z:254 (M-H)
-
5) chemosynthesis of the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5)
5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-(X4) 23.6g(0.092mol) be dissolved in 200ml methyl alcohol; adding 0.3g(10%Pd)/C makees catalyzer; atmospheric hydrogenation reacts 15 hours, obtains the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5) crude product of deprotection.Thick product activated carbon decolorizing in alcohol solvent, is spin-dried for, 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)
+
Through nuclear-magnetism, confirm:
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) be dissolved in 700ml ethanol, add sodium hydroxide 44g, the mol ratio that drips benzyl bromine 117ml(vanillic acid methyl esters and benzyl bromine is 1:1.2), under 25 ℃ of conditions, stirring reaction is 6 hours.
Add 1L water, ethyl acetate extraction, washing organic phase, anhydrous magnesium sulfate drying, is spin-dried for and obtains pale yellow liquid.Sherwood oil recrystallization, obtains 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-nitrobenzene methyl (Y2)
4-benzyloxy-3-methoxyl methyl benzoate (Y1) 8g(0.0294mol) be dissolved in 50ml Glacial acetic acid, drip 7ml concentrated nitric acid, be warming up to 60 ℃, stirring reaction 1 hour.
Pour in 300ml water, dichloromethane extraction, sodium bicarbonate aqueous solution washing, anhydrous magnesium sulfate drying, filters, and is spin-dried for and obtains light yellow solid 4-benzyloxy-3-methoxyl group-2-nitrobenzene methyl (Y2) 8.9g, productive rate: 95.4%.
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-nitrobenzene methyl (Y2) 6g(0.0189mol) be dissolved in 40ml ethanol, add salt of wormwood 13.1g, V-Brite B 13.2g(4eq), stirring at normal temperature reaction 6 hours, obtain 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) the 7-benzyloxy-6-methoxyl group quinazoline-4(3H) chemosynthesis of-one (Y4)
4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) 4.38g(15.2mmol), FORMAMIDINE ACETATE 3g(28.8mmol), be dissolved in Virahol 35ml, be warming up at 98 ℃ and react 6 hours. be down to room temperature, filter, washed with isopropyl alcohol solid product, obtains crystal 7-benzyloxy-6-methoxyl group quinazoline-4(3H of beige)-one (Y4), be total to 3.82g, productive rate 89%.
Product structure confirms through mass spectrometric detection: m/z:283 (M+H)
+
10) chemosynthesis of the chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline (Y5)
7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one (Y4) 1.6g(5.7mmol), add 5ml phosphorus oxychloride, temperature rising reflux reaction 3 hours, be chilled to room temperature, spin off unnecessary phosphorus oxychloride, pour in 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)
+
Through nuclear-magnetism, confirm:
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) the fluoro-2-Methyl-1H-indole-5-of the 7-benzyloxy-4-(4-base oxygen base) chemosynthesis of-6-methoxyl group quinazoline (X6)
The chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline (Y5) 6.6g(0.04mol) be dissolved in 40mlDMF, add 27.6g salt of wormwood, the protection of lucifuge inflated with nitrogen.By the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5) 12g(0.04mol) be dissolved in 30mlDMF, rise to 80 ℃ of reactions 16 hours.Pour in 400ml water and destroy, EA extraction, is spin-dried for, dissolve with ethanol, activated carbon decolorizing, is spin-dried for and obtains the fluoro-2-Methyl-1H-indole-5-of white solid product 7-benzyloxy-4-(4-base oxygen base) and the common 15.7g of-6-methoxyl group quinazoline (X6), productive rate: 91.4%.
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) the fluoro-2-Methyl-1H-indole-5-of the 7-hydroxyl-4-(4-base oxygen base) chemosynthesis of-6-methoxyl group quinazoline (X7)
The fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline (X6) 14.4g(33.5mmol) be dissolved in 80mlN-methyl-2-pyrrolidone, the palladium charcoal that adds 1g10%, normal temperature and pressure hydrogenation reaction 5 hours, filter out palladium carbon catalyst, after a small amount of N-Methyl pyrrolidone washing, merging, obtain the fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base) N-Methyl pyrrolidone of-6-methoxyl group quinazoline (X7) is standby.
Product structure confirms through mass spectrometric detection: m/z:338 (M-H)
-
13) the 1-(3-chloropropyl) chemosynthesis of Pyrrolidine
The bromo-3 chloropropane 6.3g(0.04mol of 1-) be dissolved in 30ml toluene, drip Pyrrolidine 6.3g(0.088mol), heat up 40 ℃ and react 2 ~ 8 hours.Be down to room temperature, add 50ml water, it is 8 that dilute hydrochloric acid regulates PH, separatory, and water washing organic phase is once.Prepare the aqueous hydrochloric acid of about 100ml2N, twice extracted organic phase, merges water, adds sodium hydroxide to regulate PH to 11, and methyl tertiary butyl ether extraction three times, obtains lurid 1-(3-chloropropyl) Pyrrolidine solution for standby.
14) 4-(the fluoro-2 methyl indole-5-of 4-base oxygen base)-6-methoxyl group-7-[3-(pyrrolidin-1-yl) propoxy-] chemosynthesis of quinazoline (X8)
The fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base) in the N-Methyl pyrrolidone solution of-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, react 2 hours, TLC detection reaction is complete.Pour in 200ml water, filter, vacuum-drying finally obtains yellow powder powder product 4-(the fluoro-2 methyl indole-5-of 4-base oxygen base)-6-methoxyl group-7-[3-(pyrrolidin-1-yl) propoxy-] quinazoline (X8), be total to 12.5g, the last two steps overall yield: 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:
As described in Example 1, difference is that step (1) adopts sodium hydride, and the molar ratio of reaction mass is all identical, and reaction obtains 125g product, and productive rate is: 44%.
Embodiment 3:
As described in Example 1, difference is that step (1) adopts potassium tert.-butoxide, and the molar ratio of reaction mass is all identical, and reaction obtains 153g product, and productive rate is: 54%.
Embodiment 4:
As described in Example 1, difference is that in step (2), decarboxylation condition is different: 2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate (X1) 200g (0.70mol), add 240ml Glacial acetic acid, 240ml water, the 240ml vitriol oil, heats up 110 ℃ and within 24 hours, still has large content of starting materials unreacted complete.After purifying, productive rate is only 35%.
Embodiment 5:
As described in Example 1, difference is that in step (2), decarboxylation condition is different: 2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate (X1) 200g (0.70mol), add 250ml Glacial acetic acid, the 250ml vitriol oil, within 20 hours, still have large content of starting materials unreacted complete to 80 ℃ of reactions, and system carbonization blackout.After purifying, productive rate is only 24%.
Embodiment 6:
As described in Example 1, difference is that in step (3), the reaction times changes 4h into, detect and produce an impure point, and through separation detection, be 2-position benzyloxy substitution product.Crossing target product productive rate after post separation is only 52%.
Embodiment 7:
As described in Example 1, difference is step (3) and step (4), adopt the method for palladium charcoal catalysis to attempt the benzyloxy by 1-(3-() the fluoro-6-nitrophenyl of-2-) propyl group-2-ketone (X3) step obtains the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole (X5), the impurity of finding reaction generation is a lot, needed post separated, after purifying, two step overall yields are only 36%.
Embodiment 8:
As described in Example 1, difference is the synthetic of 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) in step (8), the reductive agent adopting is reduced iron powder, can obtain smoothly product equally, but reaction produces a large amount of iron mud, bad filtration, and product color is Dark grey, after purifying, productive rate is 65%.
Embodiment 9:
As described in Example 1, difference is in step (9), by 4-benzyloxy-3-methoxyl group-2-Methyl anthranilate (Y3) 5g(17.7mmol) be dissolved in 50ml methane amide, be heated to 190 ℃, stirring reaction 4h.Reactant is poured in saturated aqueous common salt, sedimentation and filtration, washing, obtains grey crystallite product, productive rate 62% after being dried.
Claims (4)
1. the synthetic method of AZD2171, its synthesis step is as follows:
1) take tetrahydrofuran (THF) as solvent, methyl aceto acetate and trifluoronitrobenzene, under basic catalyst sodium ethylate exists, obtain 2-(2, the fluoro-6-nitrophenyl of 3-bis-for 2 ~ 8 hours in 0 ~ 40 ℃ of reaction)-3-methyl aceto acetate; The mol ratio of methyl aceto acetate and trifluoronitrobenzene is 1-3:1;
2), under the nitration mixture condition that the volume ratio that 2-(2, the fluoro-6-nitrophenyl of 3-bis-)-3-methyl aceto acetate forms at concentrated hydrochloric acid and Glacial acetic acid is 0.5 ~ 1.5:1,60 ~ 120 ℃ of reactions 10 ~ 20 hours, obtain 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone; 2-(2, the fluoro-6-nitrophenyl of 3-bis-) ratio of-3-methyl aceto acetate and mixing acid is 1mol:1-2L;
3) 1-(2, the fluoro-6-nitrophenyl of 3-bis-) propyl group-2 ketone and benzylalcohol, under the effect of basic catalyst sodium hydroxide, are termination reaction in 80 ~ 120 ℃ of reaction 2-4h; Aftertreatment adopts methylene dichloride: the volume ratio of sherwood oil=1:0.5 ~ 2 gets final product high yield and separates out solid phase prod 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) propyl group-2-ketone; 1-(2, the fluoro-6-nitrophenyl of 3-bis-) mol ratio of propyl group-2 ketone and benzylalcohol is 1:2-4;
4) 1-(3-(benzyloxy) the fluoro-6-nitrophenyl of-2-) propyl group-2-ketone is dissolved in ethanol, then adding concentration is the SODIUM HYDROSULPHITE sodium water solution of 1-3mol/L, under 5-10mol/L wet chemical catalyzer exists, under 0-40 ℃ of condition, react 4 ~ 10 hours, obtain 5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-; 1-(3-(benzyloxy wherein) the fluoro-6-nitrophenyl of-2-) molar ratio of propyl group-2-ketone, V-Brite B and salt of wormwood is 1:2-4:3-5;
5) take methyl alcohol as solvent, under Pd/C katalysis, 5-(benzyloxy) the fluoro-2-Methyl-1H-indole of-4-atmospheric hydrogenation deprotection obtains the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole;
6) vanillic acid methyl esters dissolve with ethanol, then adds benzyl bromine, and under basic catalyst sodium hydroxide exists, 0-40 ℃ of reaction 4-8 hour, obtains 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 Glacial acetic acid solvent, and to add excessive mass concentration be 65%-68% concentrated nitric acid and be warming up to 50-80 ℃, reacts 0.5 ~ 2 hour, obtains 4-benzyloxy-3-methoxyl group-6-nitrobenzene methyl; The molar ratio of 4-benzyloxy-3-methoxyl methyl benzoate and concentrated nitric acid is 1:2-5;
8) 5-10mol/L wet chemical is made basic catalyst, 4-benzyloxy-3-methoxyl group-6-nitrobenzene methyl is dissolved in ethanol, adding concentration is 1-3mol/L SODIUM HYDROSULPHITE sodium water solution, and normal-temperature reaction 2-8 hour obtains 4-benzyloxy-3-methoxyl group-6-Methyl anthranilate; The molar ratio of 4-benzyloxy-3-methoxyl group-6-nitrobenzene methyl, V-Brite B and salt of wormwood is 1:2-4:3-5;
9) 4-benzyloxy-3-methoxyl group-6-Methyl anthranilate and FORMAMIDINE ACETATE be in isopropanol solvent, reacts 4 ~ 8 hours at 60 ~ 100 ℃, obtains 7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one; The mol ratio of 4-benzyloxy-3-methoxyl group-6-Methyl anthranilate and FORMAMIDINE ACETATE is 1:1-2;
10) 7-benzyloxy-6-methoxyl group quinazoline-4(3H)-one obtains the chloro-6-methoxyl group of 7-benzyloxy-4-quinazoline in 90-110 ℃ of dehydration reaction under phosphorus oxychloride effect; 7-benzyloxy-6-methoxyl group quinazoline-4(3H) amount ratio of-one and phosphorus oxychloride is 1g:2-4ml;
11) 7-benzyloxy-4-chloro-6-methoxyl group quinazoline and the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole are in DMF solvent, under basic catalyst salt of wormwood exists, lucifuge nitrogen protection, in 60 ~ 100 ℃ of reactions 10 ~ 20 hours, generate the fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline; The mol ratio of benzyloxy-4-chloro-6-methoxyl group quinazoline and the fluoro-2-methyl isophthalic acid of 4-H-5-oxyindole is 1-1.5:1;
12) the fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base)-6-methoxyl group quinazoline is in N-Methyl pyrrolidone, and Pd/C shortening deprotection obtains the fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base)-6-methoxyl group quinazoline;
13) N-(3-chloropropyl) tetrahydro pyrrolidine is made by laxative remedy: take toluene as solvent, bromo-3 chloropropanes of 1-and Pyrrolidine 40-60 ℃ reaction 2 ~ 8 hours, obtain N-(3-chloropropyl) tetrahydro pyrrolidine, the equivalence ratio of bromo-3 chloropropanes of 1-and Pyrrolidine is 1:2-3;
14) the fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base)-6-methoxyl group quinazoline and N-(3-chloropropyl) tetrahydro pyrrolidine, under basic catalyst salt of wormwood exists, be warming up to 60-100 ℃ of reaction 2-4 hour, obtain target product 4-(the fluoro-2 methyl indole-5-of 4-base oxygen base)-6-methoxyl group-7-[3-(pyrrolidin-1-yl) propoxy-] quinazoline; The fluoro-2-Methyl-1H-indole-5-of 7-hydroxyl-4-(4-base oxygen base) mol ratio of-6-methoxyl group quinazoline and N-(3-chloropropyl) tetrahydro pyrrolidine is 1:1-1.5.
2. synthetic method as claimed in claim 1, is characterized in that, described step 2) the concentration of concentrated hydrochloric acid be 20wt%-36wt%.
3. synthetic method as claimed in claim 1, is characterized in that, Pd/C catalyzer is 10wt%Pd/C described in step 5); Pd/C catalyst levels is 5-(benzyloxy) 0.5-2wt% of the fluoro-2-Methyl-1H-indole of-4-.
4. synthetic method as claimed in claim 1, is characterized in that, Pd/C catalyzer is 10wt%Pd/C described in step 12); The consumption of Pd/C catalyzer is the fluoro-2-Methyl-1H-indole-5-of 7-benzyloxy-4-(4-base oxygen base) 5-10% of-6-methoxyl group quinazoline weight.
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| CN1665817A (en) * | 2002-07-19 | 2005-09-07 | 百时美施贵宝公司 | Process for preparing certain pyrrolotriazine compounds |
| CN101528688A (en) * | 2006-11-02 | 2009-09-09 | 阿斯利康(瑞典)有限公司 | Chemical process |
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| CN1665817A (en) * | 2002-07-19 | 2005-09-07 | 百时美施贵宝公司 | Process for preparing certain pyrrolotriazine compounds |
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