CN103130729A - Preparation method of 4-chloro-7-methoxyl quinazoline-6-alchol acetate - Google Patents
Preparation method of 4-chloro-7-methoxyl quinazoline-6-alchol acetate Download PDFInfo
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Abstract
The invention relates to the field of organic chemistry and medicinal chemistry, in particular to a preparation method of gefitinib intermediate 4-chloro-7-methoxyl quinazoline-6-alchol acetate. The method comprises the steps of adding 3, 4-dihydro-7-methoxyl-4-oxygen generation quinazoline-6-alchol acetate to organic solvents, adding chloro regents and N, N- dimethylformamide, reacting 5h in a backflow mode, adding solid carbonate or solid bicarbonate under room temperature, adjusting potential of hydrogen (PH) which is equal to 6-8, carrying out suction filtration, and evaporating and drying filtrate to obtain the 4-chloro-7-methoxyl quinazoline-6-alchol acetate. According to the method, the solid carbonate or solid bicarbonate is added, the problem that the chloro regents or acidic materials generated by reaction are remained is solved, generation of following reaction impurities is largely reduced, and meanwhile the defect that products are easy dissolve when meeting water in a post-processing process and the problem that certain alkaline conditions cause degradation of the products and falling-off of acetyl are solved. The preparation method is high in product yield, high in purity, simple in operation and suitable for commercial production.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, be specifically related to the preparation method of Gefitinib intermediate 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester.
Background technology
4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester is the key intermediate of synthetic Gefitinib, and structure is suc as formula shown in I:
In prior art, the preparation method of Gefitinib intermediate mainly contains following several:
The patent CN1182421A of Britain Zeneca Limited application discloses the preparation method of Gefitinib, as shown in Scheme 1:
Gefitinib intermediate 4-chloro-7-methoxyl group quinazoline in this route-6-alcohol acetic ester adopts 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester and sulfur oxychloride and N, dinethylformamide carries out chlorination, adopt the mode of directly steaming except the chlorination sulfoxide to obtain, 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester directly carries out the aryl amination reaction again and obtains 4-(3 '-chloro-4 '-fluoroaniline)-7-methoxyl group quinazoline-6-alcohol acetic ester, and yield is only 56%.
The method Main Problems is: sulfur oxychloride subtracts the steaming difficulty, thorough evaporate to dryness, the acidic substance (hydrogenchloride etc.) that residual chlorinating agent and reaction thereof generate can affect the carrying out of next step amination reaction, cause raw material reaction not exclusively to reach generation impurity more, cause yield low, the problem that product purity is low is unfavorable for suitability for industrialized production.
WO0166099 has also reported similar chloro method, and post-treating method is improved: be difficult to subtract for sulfur oxychloride and steam defective thoroughly, dissolve with toluene after adopting evaporate to dryness, the mode of washing by saturated sodium bicarbonate aqueous solution is again removed remaining sulfur oxychloride, then obtains 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester by evaporate to dryness.
The method Main Problems is: adopt sodium bicarbonate aqueous solution to carry out aftertreatment, the 4-chloro that obtains-7-methoxyl group quinazoline-6-alcohol acetic ester is met water unstable, decompose very fast, regenerate Compound I I, along with industrial scale increases, the conversion of product can be further accelerated in the prolongation of operating time, affect yield and the purity of product, be unfavorable for realizing suitability for industrialized production.
WO2004046101 has reported the method for synthetic compound I a kind of, it is chlorinating agent that the method adopts oxalyl chloride, take ethylene dichloride as solvent, under DMF exists with 3, then 4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester reaction joins reaction system in frozen water, destroys chlorinating agent, obtain Compound I with dichloromethane extraction is concentrated again, yield is 80%.
The method has been removed and has been subtracted the process of steaming chlorinating agent, has adopted the method for the acidic substance of the excessive chlorinating agent of water treatment and reaction generation, and the method owing to having used water, is the decomposition that can't avoid product, is unfavorable for equally realizing suitability for industrialized production.
Therefore how solving the series of problems that chlorinating agent brings, is a great problem during present 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester synthesizes.
Summary of the invention
defective for the prior art existence, and the special property of 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester Compound I existence: except meeting water decomposition, also exist in some alkalescence (as at triethylamine, sec.-propyl ethamine, pyridine, under the alkaline matters such as sodium hydroxide exist) product degradation and ethanoyl come off under environment problem, the invention provides the preparation method of a kind of 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester, the main residual problem of acidic substance that adopts the mode that adds solid carbonate or solid carbonic acid hydrogen salt to solve chlorinating agent and reaction generation, greatly reduced the generation of subsequent reactions impurity, and in last handling process, product is met the labile defective of water, the problem of having avoided simultaneously product degradation and ethanoyl to come off.The product yield that this preparation method makes is high, and purity is high, and is simple to operate, is fit to suitability for industrialized production.
In the present invention, for convenience of description with 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester referred to as Compound I; With 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester referred to as Compound I I; With 4-(3 '-chloro-4 '-fluoroaniline)-7-methoxyl group quinazoline-6-alcohol acetic ester referred to as compound III.
Concrete preparation process disclosed in this invention is as follows:
A kind of Compound I, the preparation method of 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester namely, step is as follows:
Compound I I is added in organic solvent, add chlorinating agent and DMF, add solid carbonate or solid carbonic acid hydrogen salt under back flow reaction, room temperature, regulate the pH value, suction filtration, evaporate to dryness filtrate obtains Compound I;
Wherein said reflux time is 3～7h, and preferably, reflux time is 5h.
Particularly, a kind of Compound I, the preparation method of 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester namely, step is as follows:
Compound I I is added in organic solvent, add chlorinating agent and DMF, back flow reaction 5h adds solid carbonate or solid carbonic acid hydrogen salt under room temperature, regulates pH=6～8, suction filtration, and evaporate to dryness filtrate obtains Compound I.
Wherein said Compound I is 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester; Compound I I is 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester.
Wherein said organic solvent is selected from one or more in methylene dichloride or ethylene dichloride or trichloromethane or toluene or acetonitrile, the volume of organic solvent and Compound I I wherein: mass ratio is 4: 1～30: 1 (ml/g), preferably, the volume of organic solvent and Compound I I: mass ratio is 10: 1～15: 1 (ml/g).
And the chlorinating agent described in above-mentioned preparation method is selected from sulfur oxychloride or phosphorus oxychloride or oxalyl chloride, wherein be preferably sulfur oxychloride, wherein the mol ratio of chlorinating agent and Compound I I is 1: 1～10: 1, and preferably, the mol ratio of chlorinating agent and Compound I I is 3: 1～5: 1.
Same, the volume of DMF described in above-mentioned preparation method and Compound I I: mass ratio 1: 1～1: 30 (ml/g), preferably, the volume of DMF and Compound I I: mass ratio 1: 5～1: 10 (ml/g).
Wherein said solid carbonate is selected from sodium carbonate, salt of wormwood, volatile salt or cesium carbonate, and preferably, solid carbonate is selected from sodium carbonate; Described solid carbonic acid hydrogen salt is selected from sodium bicarbonate, saleratus or bicarbonate of ammonia, and preferably, the solid carbonic acid hydrogen salt is selected from sodium bicarbonate.And further find by detection, the add-on of solid carbonate or solid carbonic acid hydrogen salt is determined by the pH value, as long as control reaction solution pH to 6～8.Wherein, described solid carbonate or the supercarbonate purposes in reaction is acid binding agent, for the acidic substance of neutralize excessive chlorinating agent and reaction generation thereof.
Find after contriver's process long-felt, solid carbonate or solid carbonic acid hydrogen salt are selected from sodium bicarbonate or saleratus or bicarbonate of ammonia or volatile salt or sodium carbonate or salt of wormwood or cesium carbonate, preferably adopt sodium bicarbonate or sodium carbonate.
the preparation method of Compound I provided by the invention, the selection of solid carbonate or solid carbonic acid hydrogen salt and consumption are extremely important in preparation method provided by the invention, after reaction is complete, add solid carbonate or supercarbonate, be used for the acidic substance (hydrogenchloride etc.) that the excessive chlorinating agent of neutralization reaction liquid and reaction thereof generate, controlling reaction solution pH is in 6～8 scopes, avoid on the one hand available technology adopting to steam the mode of removing excessive chlorinating agent, the acidic substance (hydrogenchloride etc.) that efficiently solve residual chlorinating agent and reaction generation thereof hinder the carrying out of next step amination reaction, cause raw material reaction not exclusively to reach generation impurity more, cause yield low, the problem that product purity is low, having overcome on the other hand prior art adopts sodium bicarbonate aqueous solution or direct water to carry out aftertreatment to reaction solution, cause product 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester to meet water decomposition, regenerate raw material 3, the defective of 4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester, and avoided product 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester to meet the problem that some alkaline degradation and ethanoyl come off, the product yield that makes is high, purity is high, simple to operate, be fit to suitability for industrialized production.
Why choosing each above-mentioned material in numerous alkaline matters, is mainly because the present invention's product to be prepared has following constructional feature: a.4-the ethanoyl of chloro-7-methoxyl group quinazoline-6-alcohol acetic ester is than coming off under strong alkaline condition; B.4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester itself is unstable.If therefore select organic bases, as triethylamine, sec.-propyl ethamine, pyridine etc., this reaction meeting also can cause the part ethanoyl to come off because adding of these organic basess has a large amount of impurity to produce; And other highly basic can cause ethanoyl to come off and make the product degraded as sodium hydroxide, potassium hydroxide etc., and is therefore inadvisable; In addition, the aqueous solution and the organic bases of mineral alkali adopted in the traditional aftertreatment of this class reaction more, is inadvisable in suitability for industrialized production.Therefore, select described solid carbonate or solid carbonic acid hydrogen salt better to coordinate with product 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester.
According to the present invention, further, Compound I and 3-chloro-4-fluoroaniline with making react in alcoholic solvent, get compound III,
Alcoholic solvent described in above-mentioned reaction is selected from methyl alcohol or ethanol or Virahol or primary isoamyl alcohol, is preferably Virahol.
in sum, the present invention mainly adopts the mode that adds solid carbonate or solid carbonic acid hydrogen salt to solve the residual problem of acidic substance of chlorinating agent and reaction generation, greatly reduced the generation of subsequent reactions impurity, and in last handling process, product chance water easily decomposes, product is met the defective that some alkali is easily degraded and ethanoyl comes off, the product yield that this preparation method makes is high, reach more than 99%, purity is high, reach more than 97%, the Compound I that obtains also can need not refining next step amination reaction that namely can be used for, the compound III purity that obtains reaches more than 98%, the two-step reaction yield reaches more than 96%, simple to operate, be fit to suitability for industrialized production.
Embodiment
The embodiment of form, be described in further detail foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Methylene dichloride 400L is joined in reactor, add 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester 30kg (Compound I I, 128mol) under stirring, add sulfur oxychloride 60kg (504mol), DMF 3L; Finish rear temperature rising reflux reaction 3h, reaction system is down to room temperature, slowly add sodium bicarbonate solid, regulate pH=6.5, centrifugal, subtract and steam to doing, obtain 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) yellow solid, purity 98.21% need not the refining subsequent reactions that namely can be used for.
The Compound I that aforesaid method is obtained joins in the 150L Virahol, adds 3-chloro-4-fluoroaniline 20.0kg, room temperature reaction 1h, suction filtration; Drying obtains 4-(3-chloro-4-fluoroaniline)-7-methoxyl group quinazoline-6-alcohol acetic ester (compound III) 45.6kg, 98.36%, two step of purity yield: 96.5%.
Embodiment 2
Trichloromethane 350m l is joined in reaction flask, add 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester 30.0g (Compound I I under stirring, 0.128mol), add phosphorus oxychloride 180g (1.174mol), DMF 5ml; Finish rear temperature rising reflux reaction 6h, reaction system is down to room temperature, slowly add the sodium carbonate solid, regulate pH=8, centrifugal, subtract and steam to doing, obtain 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) yellow solid 32.3g, purity 97.52%, yield 99.8%.
Embodiment 3
Toluene 400ml is joined in reaction flask, add 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester 30.0g (Compound I I, 0.128mol) under stirring, add oxalyl chloride 100g (0.788mol), DMF 3ml; Finish rear temperature rising reflux reaction 5h, reaction system is down to room temperature, slowly add the bicarbonate of ammonia solid, regulate pH=6, centrifugal, subtract and steam to doing, obtain 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) yellow solid 32.3g, purity 98.16%, yield 99.5%.
The Compound I that aforesaid method is obtained joins in the 150ml primary isoamyl alcohol, adds 3-chloro-4-fluoroaniline 23.0g, room temperature reaction 1h, suction filtration; Drying obtains 4-(3-chloro-4-fluoroaniline)-7-methoxyl group quinazoline-6-alcohol acetic ester (compound III) 44.8g, 98.25%, two step of purity yield: 96.7%.
Embodiment 4
Methylene dichloride 900ml is joined in reaction flask, add 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester 30.0g (Compound I I under stirring, 0.128mol), add sulfur oxychloride 30g (0.252mol), DMF 6ml; Finish rear temperature rising reflux reaction 7h, reaction system is down to room temperature, slowly add the saleratus solid, regulate pH=7, centrifugal, subtract and steam to doing, obtain 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) yellow solid 33.2g, purity 97.89%, yield 99.5%.
The Compound I that aforesaid method is obtained joins in the 150ml Virahol, adds 3-chloro-4-fluoroaniline 21.0g, room temperature reaction 1h, suction filtration; Drying obtains 4-(3-chloro-4-fluoroaniline)-7-methoxyl group quinazoline-6-alcohol acetic ester (compound III) 44.5g, 98.12%, two step of purity yield: 96.0%.
Comparative example 1 is prepared according to WO 0166099 preparation method
3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester 30g is joined in sulfur oxychloride 430ml, then add DMF 8.6ml; Finish rear 90 ℃ of reaction 4h, reaction system is down to room temperature, subtract to steam and remove sulfur oxychloride, add 300ml toluene, with the washing of 100ml saturated sodium bicarbonate, anhydrous sodium sulfate drying, suction filtration, filtrate subtract to steam extremely to be done, and obtains 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) solid 27.1g, purity 78.36%, yield 83.7%.
Comparative example 2: be prepared according to the WO2004046101 preparation method, and carried out on this basis the technique wearing quality research of the method.
with N, dinethylformamide (45ml) joins in ethylene dichloride (200m l), the ice-water bath cooling, add oxalyl chloride (79ml under nitrogen protection, ethylene dichloride 900mmol) (400ml) solution, stirring at room 5min, add 3 under stirring, 4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester 65g (280mmol), temperature rising reflux reaction 3h, reaction system is down to room temperature, reaction system is divided into two parts carries out aftertreatment, a step operation according to the WO2004046101 report, portion carries out the technique tolerance studies by extending the treatment time.
The WO2004046101 preparation method: portion joins in the 500ml mixture of ice and water, use immediately the 2.5L dichloromethane extraction, water is used the dichloromethane extraction of 250ml * 2 again, merge organic phase, anhydrous sodium sulfate drying, suction filtration, filtrate subtracts steams to doing, obtain 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) solid 27.9g (104mmol), purity 80.76%, yield 79.6%.
The research of technique wearing quality: another part joins in the 500ml mixture of ice and water, after stirring 30min, use the 2.5L dichloromethane extraction, water is used the dichloromethane extraction of 250ml * 2 again, merges organic phase, anhydrous sodium sulfate drying, suction filtration, filtrate subtract to steam extremely to be done, and obtains 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester (Compound I) solid 26.4g (100mmol), purity 73.62%, yield 75.3%.
In sum, (1) product yield that makes of this preparation method is up to more than 99%, purity is high, reach more than 97%, the Compound I that obtains also can need not refining next step amination reaction that namely can be used for, the compound III purity that obtains reaches more than 98%, and the two-step reaction yield reaches more than 96%, and the yield of visible the inventive method and purity are high more a lot of than WO0166099, WO2004046101 preparation method; (2) studies show that by the technique wearing quality; comparative example 2 reaction systems are carried out aftertreatment stir 30min in water after again; product purity namely is down to 73.62% from 80.76%; method technique poor durability in comparative example is described; will cause a large amount of degradeds of product due to the prolongation of operating time in large-scale production, therefore be not suitable for large-scale production.
Claims (10)
1.4-the preparation method of chloro-7-methoxyl group quinazoline-6-alcohol acetic ester is characterized in that:
Step is as follows:
Compound I I is added in organic solvent, add chlorinating agent and DMF, add solid carbonate or solid carbonic acid hydrogen salt under back flow reaction, room temperature, regulate the pH value, suction filtration, evaporate to dryness filtrate obtains Compound I;
Wherein said Compound I is 4-chloro-7-methoxyl group quinazoline-6-alcohol acetic ester; Compound I I is 3,4-dihydro-7-methoxyl group-4-oxo quinazoline-6-alcohol acetic ester.
2. preparation method according to claim 1, it is characterized in that: described organic solvent is selected from one or more in methylene dichloride or ethylene dichloride or trichloromethane or toluene or acetonitrile, the wherein volume of organic solvent and Compound I I: mass ratio is 4: 1～30: 1 (ml/g).
3. preparation method according to claim 1, it is characterized in that: described chlorinating agent is selected from sulfur oxychloride or phosphorus oxychloride or oxalyl chloride, and wherein the mol ratio of chlorinating agent and Compound I I is 1: 1～10: 1.
4. preparation method according to claim 1, is characterized in that: the volume of described DMF and Compound I I: mass ratio 1: 1～1: 30 (ml/g).
5. preparation method according to claim 1, it is characterized in that: described solid carbonate is selected from volatile salt or sodium carbonate or salt of wormwood or cesium carbonate; Described solid carbonic acid hydrogen salt is selected from sodium bicarbonate or saleratus or bicarbonate of ammonia.
6. preparation method according to claim 1, it is characterized in that: described pH value is adjusted to 6～8.
7. preparation method according to claim 1, it is characterized in that: described reflux time is 3～7h.
8. preparation method according to claim 2, it is characterized in that: the volume of described organic solvent and Compound I I: mass ratio is 10: 1～15: 1 (ml/g).
9. preparation method according to claim 3, it is characterized in that: described chlorinating agent is sulfur oxychloride, wherein the mol ratio of chlorinating agent and Compound I I is 3: 1～5: 1.
10. preparation method according to claim 4, is characterized in that: the volume of described DMF and Compound I I: mass ratio 1: 5～1: 10 (ml/g).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108314657A (en) * | 2018-05-16 | 2018-07-24 | 沈阳感光化工研究院有限公司 | A kind of synthetic method of quinazoline ditosylate salt antitumor drug intermediate |
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| CN101878203A (en) * | 2007-10-29 | 2010-11-03 | 纳科法尔马有限公司 | Novel 4-(tetrazol-5-yl)-quinazoline derivatives as anti cancer agents |
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Effective date of registration: 20170419 Address after: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 317 250100 Co-patentee after: Qilu (Linyi) Pharmaceutical Co., Ltd. Patentee after: Qilu Pharmaceutical Co., Ltd. Address before: Industrial Road Licheng District, Ji'nan city of Shandong Province, No. 243 250100 Patentee before: Qilu Pharmaceutical Co., Ltd. |
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