CN103130729B - 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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- VWBHHSJRPOSFGG-UHFFFAOYSA-N CC(Oc(c(OC)cc1ncn2)cc1c2Cl)=O Chemical compound CC(Oc(c(OC)cc1ncn2)cc1c2Cl)=O VWBHHSJRPOSFGG-UHFFFAOYSA-N 0.000 description 2
- ANGPUOTYQQFHKN-UHFFFAOYSA-N CC(Oc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OC)=O Chemical compound CC(Oc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OC)=O ANGPUOTYQQFHKN-UHFFFAOYSA-N 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N Nc(cc1)cc(Cl)c1F Chemical compound Nc(cc1)cc(Cl)c1F YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
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 medicinal chemistry art, be specifically related to the preparation method of Gefitinib intermediate 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester.
Background technology
4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester is the key intermediate of synthesis Gefitinib, and structure is such as formula shown in I:
In prior art, the preparation method of Gefitinib intermediate mainly contains following several:
The patent CN1182421A of Zeneca Limited of Britain application discloses the preparation method of Gefitinib, as shown in Scheme 1:
In this route, Gefitinib intermediate 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester adopts 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester and sulfur oxychloride and N, dinethylformamide carries out chlorination, the directly mode of steaming except sulfur oxychloride is adopted to obtain, 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester directly carries out aryl amination again and is obtained by reacting 4-(3 '-chloro-4 '-fluoroaniline)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester, and yield is only 56%.
The subject matter that the method exists is: sulfur oxychloride subtracts steaming difficulty, cannot 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 and to generate impurity more, cause yield low, the problem that product purity is low, is unfavorable for suitability for industrialized production.
WO0166099 also reports similar chloro method, and post-treating method is improved: be difficult to subtract for sulfur oxychloride and steam defect thoroughly, dissolve with toluene after adopting evaporate to dryness, the mode of being washed by saturated sodium bicarbonate aqueous solution again removes remaining sulfur oxychloride, then obtains 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester by evaporate to dryness.
The subject matter that the method exists is: adopt sodium bicarbonate aqueous solution to carry out aftertreatment, 4-chloro-7-methoxyquinazoline hydrochloride-6-the alcohol acetic ester obtained meets water unstable, decompose very fast, regenerate Compound II per, along with industrial scale increases, the prolongation of operating time, can accelerate the conversion of product further, affect yield and the purity of product, be unfavorable for realizing suitability for industrialized production.
WO2004046101 reports a kind of method of synthetic compound I, the method adopts oxalyl chloride to be chlorinating agent, take ethylene dichloride as solvent, with 3 under DMF exists, 4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester reacts, and then joins in frozen water by reaction system, destroys chlorinating agent, obtain Compound I with dichloromethane extraction is concentrated again, yield is 80%.
The method eliminates the process subtracting and steam chlorinating agent, and have employed the method for the acidic substance of the excessive chlorinating agent of water treatment and reaction generation, the method, owing to employing water, is the decomposition cannot avoiding 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 in the synthesis of present 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester.
Summary of the invention
For the defect that prior art exists, and the special property that 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester Compound I exists: except meeting water decomposition, also exist in some alkalescence (as at triethylamine, wopropyl ethyl amine, pyridine, under the alkaline matter such as sodium hydroxide exists) product degradation and ethanoyl come off under environment problem, the invention provides a kind of preparation method of 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester, the problem that the acidic substance that the mode that main employing adds solid carbonate or solid carbonic acid hydrogen salt solves chlorinating agent and reaction generation remain, greatly reduce the generation of subsequent reactions impurity, and product meets the labile defect of water in last handling process, avoid the problem that product degradation and ethanoyl come off simultaneously.The product yield that this preparation method obtains is high, and purity is high, simple to operate, is applicable to suitability for industrialized production.
In the present invention, for convenience of description by 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester referred to as Compound I; By 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester referred to as Compound II per; By 4-(3 '-chloro-4 '-fluoroaniline)-7-methoxyquinazoline hydrochloride-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 namely preparation method of 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester, step is as follows:
Added by Compound II per in organic solvent, add chlorinating agent and DMF, back flow reaction, add solid carbonate or solid carbonic acid hydrogen salt under room temperature, adjust ph, 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 namely preparation method of 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester, step is as follows:
Added by Compound II per in organic solvent, add chlorinating agent and DMF, back flow reaction 5h, add solid carbonate or solid carbonic acid hydrogen salt under room temperature, regulate pH=6 ~ 8, suction filtration, evaporate to dryness filtrate obtains Compound I.
Wherein said Compound I is 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester; Compound II per is 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester.
Wherein said organic solvent be selected from methylene dichloride or ethylene dichloride or trichloromethane or toluene or acetonitrile one or more, the wherein volume of organic solvent and Compound II per: mass ratio is 4: 1 ~ 30: 1 (ml/g), preferably, the volume of organic solvent and Compound II per: 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 II per is 1: 1 ~ 10: 1, and preferably, the mol ratio of chlorinating agent and Compound II per is 3: 1 ~ 5: 1.
Same, the volume of the DMF described in above-mentioned preparation method and Compound II per: mass ratio 1: 1 ~ 1: 30 (ml/g), preferably, the volume of DMF and Compound II per: 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, solid carbonic acid hydrogen salt is selected from sodium bicarbonate.And find further by detection, the add-on of solid carbonate or solid carbonic acid hydrogen salt is determined by pH value, as long as control reaction solution pH to 6 ~ 8.Wherein, described solid carbonate or supercarbonate purposes is in the reaction acid binding agent, for neutralizing the acidic substance of excessive chlorinating agent and reaction generation thereof.
Contriver finds after long-felt, and 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 extremely important in preparation method provided by the invention, after completion of the reaction, add solid carbonate or supercarbonate, for the acidic substance (hydrogenchloride etc.) that chlorinating agent excessive in neutralization reaction liquid and reaction thereof generate, controlling reaction solution pH is in 6 ~ 8 scopes, avoid on the one hand in prior art, adopting the mode of steaming except excessive chlorinating agent, the acidic substance (hydrogenchloride etc.) efficiently solving residual chlorinating agent and reaction generation thereof hinder the carrying out of next step amination reaction, cause raw material reaction not exclusively and to generate impurity more, cause yield low, the problem that product purity is low, overcoming prior art on the other hand adopts sodium bicarbonate aqueous solution or direct water to carry out aftertreatment to reaction solution, product 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester is caused to meet water decomposition, regenerate raw material 3, the defect of 4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester, and avoid product 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester and meet the problem that some alkaline degradation and ethanoyl come off, obtained product yield is high, purity is high, simple to operate, be applicable to suitability for industrialized production.
Why in numerous alkaline matter, choose above-mentioned each material, mainly because the present invention's product to be prepared has following constructional feature: a.4-the ethanoyl of chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester can come off under comparatively strong alkaline condition; B.4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester itself is unstable.If therefore select organic bases, as triethylamine, wopropyl ethyl amine, pyridine etc., this reaction can, because have a large amount of impurity to produce adding of these organic basess, also can cause part ethanoyl to come off; And other highly basic, ethanoyl can be caused to come off as sodium hydroxide, potassium hydroxide etc. and product is degraded, therefore inadvisable; In addition, this class reacts the aqueous solution and the organic bases of traditional aftertreatment many employings mineral alkali, is inadvisable in suitability for industrialized production.Therefore, described solid carbonate or solid carbonic acid hydrogen salt is selected better can to coordinate with product 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester.
According to the present invention, further, by obtained Compound I and the chloro-4-fluoroaniline of 3-, react in alcoholic solvent, obtain 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 problem that the acidic substance that the present invention mainly adopts the mode adding solid carbonate or solid carbonic acid hydrogen salt to solve chlorinating agent and reaction generation remain, greatly reduce the generation of subsequent reactions impurity, and product chance water easily decomposes in last handling process, product meets the defect that some alkali is easily degraded and ethanoyl comes off, the product yield that this preparation method obtains is high, reach more than 99%, purity is high, reach more than 97%, namely the Compound I obtained also can be used for next step amination reaction without the need to refining, the compound III purity obtained reaches more than 98%, two-step reaction yield reaches more than 96%, simple to operate, be applicable to suitability for industrialized production.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Methylene dichloride 400L is joined in reactor, under stirring, adds 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester 30kg (Compound II per, 128mol), 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 dry, obtain 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (Compound I) yellow solid, purity 98.21%, namely can be used for subsequent reactions without the need to refining.
The Compound I obtained by aforesaid method joins in 150L Virahol, adds 3-chloro-4-fluoroaniline 20.0kg, room temperature reaction 1h, suction filtration; Drying, obtains 4-(the chloro-4-fluoroaniline of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (compound III) 45.6kg, purity 98.36%, two step yields: 96.5%.
Embodiment 2
Trichloromethane 350m l is joined in reaction flask, under stirring, adds 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester 30.0g (Compound II per, 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 adds sodium carbonate solid, regulate pH=8, centrifugal, subtract and steam to dry, obtain 4-chloro-7-methoxyquinazoline hydrochloride-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, under stirring, adds 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester 30.0g (Compound II per, 0.128mol), add oxalyl chloride 100g (0.788mol), DMF 3ml; Finish rear temperature rising reflux reaction 5h, reaction system is down to room temperature, slowly adds bicarbonate of ammonia solid, regulate pH=6, centrifugal, subtract and steam to dry, obtain 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (Compound I) yellow solid 32.3g, purity 98.16%, yield 99.5%.
The Compound I obtained by aforesaid method joins in 150ml primary isoamyl alcohol, adds 3-chloro-4-fluoroaniline 23.0g, room temperature reaction 1h, suction filtration; Drying, obtains 4-(the chloro-4-fluoroaniline of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (compound III) 44.8g, purity 98.25%, two step yields: 96.7%.
Embodiment 4
Methylene dichloride 900ml is joined in reaction flask, under stirring, adds 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester 30.0g (Compound II per, 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 adds saleratus solid, regulate pH=7, centrifugal, subtract and steam to dry, obtain 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (Compound I) yellow solid 33.2g, purity 97.89%, yield 99.5%.
The Compound I obtained by aforesaid method joins in 150ml Virahol, adds 3-chloro-4-fluoroaniline 21.0g, room temperature reaction 1h, suction filtration; Drying, obtains 4-(the chloro-4-fluoroaniline of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (compound III) 44.5g, purity 98.12%, two step yields: 96.0%.
Comparative example 1 is prepared according to WO 0166099 preparation method
3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester 30g is joined in sulfur oxychloride 430ml, then adds DMF 8.6ml; Finish rear 90 DEG C of reaction 4h, reaction system is down to room temperature, subtract and steam removing sulfur oxychloride, add 300ml toluene, wash with 100ml saturated sodium bicarbonate, anhydrous sodium sulfate drying, suction filtration, filtrate subtracts steams to dry, obtains 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (Compound I) solid 27.1g, purity 78.36%, yield 83.7%.
Comparative example 2: be prepared according to WO2004046101 preparation method, and the technique wearing quality research having carried out the method on this basis.
By N, dinethylformamide (45ml) joins in ethylene dichloride (200m l), ice-water bath is lowered the temperature, oxalyl chloride (79ml is added under nitrogen protection, ethylene dichloride (400ml) solution 900mmol), stirring at room temperature 5min, 3 are added under stirring, 4-dihydro-7-methoxyl group-4-oxoquinazolin-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 and carries out aftertreatment, the a step operation according to WO2004046101 report, portion carries out process-tolerant Journal of Sex Research by extending the treatment time.
WO2004046101 preparation method: portion joins in 500ml mixture of ice and water, use 2.5L dichloromethane extraction immediately, aqueous phase uses the dichloromethane extraction of 250ml × 2 again, merge organic phase, anhydrous sodium sulfate drying, suction filtration, filtrate subtracts steams to dry, obtain 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (Compound I) solid 27.9g (104mmol), purity 80.76%, yield 79.6%.
Technique wearing quality research: another part joins in 500ml mixture of ice and water, after stirring 30min, use 2.5L dichloromethane extraction, aqueous phase uses the dichloromethane extraction of 250ml × 2 again, merges organic phase, anhydrous sodium sulfate drying, suction filtration, filtrate subtracts steams to dry, obtains 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester (Compound I) solid 26.4g (100mmol), purity 73.62%, yield 75.3%.
In sum, (1) product yield that obtains of this preparation method is up to more than 99%, purity is high, reach more than 97%, namely the Compound I obtained also can be used for next step amination reaction without the need to refining, the compound III purity obtained reaches more than 98%, and two-step reaction yield reaches more than 96%, the yield of visible the inventive method and purity higher than WO0166099, WO2004046101 preparation method a lot; (2) shown by the research of technique wearing quality; comparative example 2 reaction system carries out aftertreatment stir 30min in water after again; namely product purity is down to 73.62% from 80.76%; method technique poor durability in comparative example is described; because the prolongation of operating time will cause a large amount of degradeds of product in large-scale production, be therefore not suitable for large-scale production.
Claims (5)
- The preparation method of 1.4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester, is characterized in that:Step is as follows:Added by compound ii in organic solvent, add chlorinating agent and DMF, back flow reaction, add solid carbonate or solid carbonic acid hydrogen salt under room temperature, adjust ph, suction filtration, evaporate to dryness filtrate obtains chemical compounds I;Wherein said chemical compounds I is 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester; Compound ii is 3,4-dihydro-7-methoxyl group-4-oxoquinazolin-6-alcohol acetic ester;Described organic solvent be selected from methylene dichloride or ethylene dichloride or trichloromethane or toluene or acetonitrile one or more, wherein the volume of organic solvent and compound ii: quality ml/g is than being 4:1 ~ 30:1;Described chlorinating agent is selected from sulfur oxychloride or phosphorus oxychloride or oxalyl chloride, and wherein the mol ratio of chlorinating agent and compound ii is 1:1 ~ 10:1;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;Described DMF and the volume of compound ii: quality ml/g is than 1:1 ~ 1:30;Described pH value is adjusted to 6 ~ 8.
- 2. preparation method according to claim 1, is characterized in that: described reflux time is 3 ~ 7h.
- 3. preparation method according to claim 1, is characterized in that: described organic solvent and the volume of compound ii: quality ml/g are than being 10:1 ~ 15:1.
- 4. preparation method according to claim 1, is characterized in that: described chlorinating agent is sulfur oxychloride, and wherein the mol ratio of chlorinating agent and compound ii is 3:1 ~ 5:1.
- 5. preparation method according to claim 1, is characterized in that: described DMF and the volume of compound ii: quality ml/g is than 1:5 ~ 1:10.
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| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2001066099A2 (en) * | 2000-03-06 | 2001-09-13 | Astrazeneca Ab | Use of quinazoline derivatives as angiogenesis inhibitors |
| CN1733738A (en) * | 2005-08-25 | 2006-02-15 | 江苏吴中苏药医药开发有限责任公司 | Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline |
| 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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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2001066099A2 (en) * | 2000-03-06 | 2001-09-13 | Astrazeneca Ab | Use of quinazoline derivatives as angiogenesis inhibitors |
| CN1733738A (en) * | 2005-08-25 | 2006-02-15 | 江苏吴中苏药医药开发有限责任公司 | Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline |
| 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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