CN106632090B - A kind of method that one-step method prepares hydrochloric acid Erlotinib - Google Patents
A kind of method that one-step method prepares hydrochloric acid Erlotinib Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Abstract
The invention discloses a kind of methods that one-step method prepares hydrochloric acid Erlotinib, this method is with 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is starting material, condensation reaction is carried out with 3- amino phenylacetylene again after simple activated carbon adsorption with after chlorinating agent progress chlorination, when carrying out condensation reaction, directly react with Erlotinib disposably obtaining hydrochloric acid product salt hydrochloric acid Erlotinib in reaction using the hydrogen chloride generated.The preparation method technical process is simple, and easy to operation, production cost is low, and whole route high income, by-product is few, and product purity is high, and stable reaction is controllable, and post-processing is simple, is able to achieve industrialization continuous production.
Description
Technical field
The present invention relates to field of medicine preparing technology, and in particular to a kind of method that one-step method prepares hydrochloric acid Erlotinib.
Background technique
Hydrochloric acid Erlotinib (Erlotinib Hydrochloride), is total to by tri- company of Genetech, OSI, Roche
It with exploitation, is produced by Roche (Roche Holding Ag), is for treating Locally Advanced or transfer to the failure of at least one chemotherapy regimen
The original new drug of property non-small cell lung cancer (NSCLC).U.S. FDA approval is obtained in November, 2004, and obtains Europe in September, 2005
Alliance's approval listing, in April, 2006 in Discussion on Chinese Listed.FDA2005 also has approved Erlotinib and combines use with gemcitabine
In the treatment of advanced pancreatic cancer, become approved advanced pancreatic cancer therapeutic agent first in the past 10 years.
Hydrochloric acid Erlotinib is epidermal growth factor recipient tyrosine kinase inhibitor (EGFR-TK).It passes through in cell
The interior intracellular region catalysed partial with atriphos competitive binding receptor tyrosine kinase, inhibits phosphorylation reaction, to block
Downstream proliferation signal conducts, and inhibits tumour cell ligand-dependent or the activity with the HER-1/EG-FR relied in vitro, reaches suppression
Cancer cell multiplication effect processed
The synthesis of hydrochloric acid Erlotinib mainly passes through chloro- bis--(2- methoxy ethoxy) quinazoline of 6,7- of 4- and ammonia
Base phenylacetylene reacts.
United States Patent (USP) US5747498 is disclosed in the synthesis of hydrochloric acid Erlotinib, (the 2- methoxy of 6,7- bis- as intermediate
Base oxethyl) quinazoline-4-one, and disclose the synthetic method that hydrochloric acid Erlotinib is prepared by the intermediate.Currently, hydrochloric acid is in distress
Sieve mainly uses institute's report method in above-mentioned two patents for the synthetic route of Buddhist nun, and general synthetic routes are as follows:
Above-mentioned route is first reacted with Bromoethyl methyl ether, is then nitrified, restore using 3,4-Dihydroxybenzoic acid ethyl ester as raw material
Nitro is amino, cyclisation, chloro, and in the presence of acid binding agent and 3- acetylenylaniline reacts to obtain Erlotinib, obtains salt after acidification
Sour Erlotinib.
Patent CN101463013A, it was recently reported that another synthetic route:
Both the above route passes through chloro- bis--(2- methoxy ethoxy) quinazoline of 6,7- of 4- and 3-aminophenylacetylene is anti-
Erlotinib should be obtained, is then acidified to obtain hydrochloric acid Erlotinib.In process of production, chloro- 6, the 7- of usually 4- bis--
After (2- methoxy ethoxy) quinazoline and 3-aminophenylacetylene carry out condensation reaction, Erlotinib is extracted and is crystallized
Purification process, gained Erlotinib are reacted to hydrochloric acid product salt hydrochloric acid Erlotinib with hydrochloric acid again.This complex technical process, at
This rising.It has passed through multiple purifying, yield decline.When carrying out condensation reaction, impurity content is larger, brings pressure to subsequent purifying
Power.
Summary of the invention
To overcome the shortcomings of background technique, the object of the present invention is to provide the sides that a kind of one-step method prepares hydrochloric acid Erlotinib
Method, the preparation method technical process is simple, easy to operation, production cost is low, is suitable for large-scale industrial production.
A kind of method that one-step method prepares hydrochloric acid Erlotinib, specifically includes the following steps:
(1) it with 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one for starting material, is carried out with chlorinating agent
Reaction solution I is obtained after chlorination；
(2) reaction solution I is poured into ice water, is removed under reduced pressure after organic phase is separated, solvent is added into vinasse, is stirred
It mixes and is warming up to solid dissolved clarification, active carbon is added, obtains filtrate II after stirring, filtering；
(3) 3- amino phenylacetylene is added in filtrate II, reaction solution III is obtained after condensation reaction；
(4) reaction solution III is after cooling, stirring, centrifugation, drying up to hydrochloric acid Erlotinib.
In above-mentioned preparation route, the concrete technology condition of each step is as follows:
(1) in step (1):
The chlorinating agent be selected from oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, preferably three
Chlorethoxyfos；
The molar ratio of the chlorinating agent and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 0.8~4:
1；Preferably, the chlorinating agent and 6, the molar ratio of 7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 1.3
~1.7:1；In this preferred scope, raw material 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one can convert completely
For required midbody compound, also it is not using excessive chlorination reagent；
Solvent used is selected from atent solvents or the mixed solvents such as methylene chloride, toluene, thiacyclohexane, normal heptane；As
It is preferred that solvent used is methylene chloride；
According to reactivity difference, the temperature of the chlorination is 0~50 DEG C；Preferably, the chlorination
Temperature is 20~30 DEG C；The temperature of chlorination is lower than 20 DEG C, and reaction speed slows down, and needing the longer reaction time just can make instead
It should be complete；Temperature is higher than 30 DEG C, and side reaction increases, and impurity content in product is caused to rise, yield decline；
During chlorination, the impurity A for being difficult to remove can be generated, chemical structure is as follows with formation mechanism:
In order to avoid the generation of impurity A, key is that the addition side of n,N-Dimethylformamide and chlorinating agent is added
Formula, preferably, after mixing, N, N- is added in (2- methoxy ethoxy)-quinazoline -4 (3H) -one of 7- bis- and solvent by 6
Dimethylformamide, the temperature for controlling mixed solution in reaction kettle is 0~50 DEG C, and then property rapidly joins chloro examination again
Agent, the feed way can effectively avoid the generation of impurity A, and the addition of n,N-Dimethylformamide can effectively increase raw material 6,
Solubility of 7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one in reaction solution, while n,N-Dimethylformamide energy
It is acted on chlorinating agent, enhances the reactivity of chlorinating agent, promote the speed of chlorination, keep raw material dense in reaction solution
Rapid decrease is spent, the condensation of raw material and chloro-product is reduced, that is, reduces the production quantity of impurity A；
Preferably, the throwing of n,N-Dimethylformamide and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one
Material molar ratio is 0.5~3:1；Further preferably, n,N-Dimethylformamide and 6,7- bis- (2- methoxy ethoxy)-quinoline azoles
The molar ratio of quinoline -4 (3H) -one is 1.0~1.5:1, and in this preferred scope, content of the impurity A in reaction solution can be effectively
Within 0.3%, the dosage of n,N-Dimethylformamide is too low for control, then the content of impurity A rises, the excessively high then N of dosage,
Dinethylformamide no longer can be such that the content of impurity A is decreased obviously；
The time of the chlorination is 2~10 hours；Preferably, the time of the chlorination is 3~5 hours；
Reaction time, not exclusively, product yield declined for reaction, and raw material residual quantity increases in product less than 3 hours；Reaction time is small up to 5
When, fully reacting；Reaction continues to extend the time, does not influence product quality and yield.
(2) in step (2):
Preferably, the process control temperature of reaction kettle removed under reduced pressure is no more than 40 DEG C, vacuum degree≤- 0.06MPa；
The solvent is methanol, ethyl alcohol, isopropanol or isobutanol.Preferably, the solvent is methanol；
The dosage of the active carbon be 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one dosage 0~
5%；Preferably, the dosage of the active carbon is 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one dosage
0.5~5%, after carrying out chlorination described in step (1), the presence of impurity A can bring pressure to the purifying of subsequent product,
The present invention has been simply and effectively reduced impurity A in product before carrying out condensation reaction, using the method for active carbon decolorization filtering
Content.
(3) in step (3):
When the present invention carries out condensation reaction, directly carry out reacting primary with Erlotinib using the hydrogen chloride generated in reaction
Property obtain hydrochloric acid product salt hydrochloric acid Erlotinib, do not need to isolate intermediate, this technical process is simple, without purification can obtain
The product of high-purity；
The molar ratio of the 3- amino phenylacetylene and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 0.8
~1.5:1；Preferably, the 3- amino phenylacetylene and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is rubbed
You are than being 0.95~1.05:1；3- amino phenylacetylene dosage is very few, and not exclusively, product yield declines for chloride reaction；3- amino
Phenylacetylene dosage is excessively high, then there may be excessive 3- amino phenylacetylenes in product, this influences the purity of product, i.e. influence product
Quality.
The temperature of the condensation reaction is 20 DEG C or more, below solvent reflux temperature；Preferably, the condensation reaction
Temperature is 65 DEG C or more, below solvent reflux temperature；Condensation temp is lower than 65 DEG C, and reaction speed is slow, on product impurity content
It rises；
The time of the condensation reaction is 2~10 hours；Preferably, the time of the condensation reaction is 3~4 hours；
Reaction time is lower than 3 hours, and reaction is incomplete；Reaction time is higher than 4 hours, does not generate obvious shadow to product quality and yield
It rings.
Compared with prior art, the invention has the following advantages:
(1) when carrying out chlorination reaction, by strict control process conditions, reduce the generation of impurity A；
(2) content of impurity A is reduced, using the method for active carbon decoloring before condensation reaction to mitigate the pressure of subsequent purification
Power simplifies processing step；
(3) it after the completion of chlorination, does not need to isolate and purify chloro thing, directly progress subsequent reactions, simplifies work
Skill step decreases Crystallization Separation and goes out the loss that intermediate generates intermediate；
(4) it when carrying out condensation reaction, directly carries out reacting disposable with Erlotinib using the hydrogen chloride generated in reaction
Hydrochloric acid product salt hydrochloric acid Erlotinib is obtained, does not need to isolate intermediate, this technical process is simple, can obtain without purification high
The product of purity；
(5) reaction condition is mild, and production cost is low, and whole route high income, by-product is few, and product purity is high, and reaction is steady
Fixed controllable, post-processing is simple, is able to achieve industrialization continuous production.
Detailed description of the invention
Fig. 1 is impurity A1H NMR spectra.
Specific embodiment
The present invention is further explained combined with specific embodiments below, it should be appreciated that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.
Embodiment 1
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
After mixing 7.3Kg n,N-Dimethylformamide is added, reacting liquid temperature is 10~30 in control reaction kettle in 4 (3H) -one
DEG C, 23.5Kg phosphorus oxychloride is disposably rapidly joined, after dripping off, reaction solution is warming up to back flow reaction 3h in reaction kettle, must react
Liquid I, through detecting, in reaction solution I, the content of impurity A is 0.2% hereinafter, impurity A1H NMR spectra is as shown in Figure 1.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.471Kg methanol is added into vinasse, solid dissolved clarification is warming up under stirring.0.6Kg active carbon is added, stirs
Filtrate II is obtained after mixing, filtering, and impurity A is not detected in filtrate II.
(3) 11.9Kg 3- amino phenylacetylene is added in filtrate II, is warming up to back flow reaction 3h, obtains reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
(5) 55~65 DEG C of boiler temperature are controlled, vacuum degree≤- 0.09MPa, gained is centrifuged the dry 8h of wet product, rewinding, packet
Dress is to get product hydrochloric acid Erlotinib, yield 95.1%.It is detected through HPLC, product purity is 99.0% or more.
Embodiment 2
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
After mixing 10.9Kg n,N-Dimethylformamide is added, reacting liquid temperature is 0~10 in control reaction kettle in 4 (3H) -one
DEG C, 20.3Kg phosphorus oxychloride is disposably rapidly joined, after dripping off, reaction solution is warming up to 25 DEG C of reaction 5h in reaction kettle, must react
Liquid I, through detecting, in reaction solution I, the content of impurity A is 0.3%.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.471Kg methanol is added into vinasse, solid dissolved clarification is warming up under stirring.0.4Kg active carbon is added, stirs
Filtrate II is obtained after mixing, filtering, and impurity A is not detected in filtrate II.
(3) 10.5Kg 3- amino phenylacetylene is added in filtrate II, is warming up to 60 DEG C of reaction 7h, obtains reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
55~65 DEG C of boiler temperature of control, vacuum degree≤- 0.09MPa, gained are centrifuged the dry 8h of wet product, and rewinding is packed,
Up to product hydrochloric acid Erlotinib, yield 94.5%.It is detected through HPLC, product purity is 99.0% or more.
Embodiment 3
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
4 (3H) -one, after mixing, 7.3Kg n,N-Dimethylformamide is added, control in reaction kettle reacting liquid temperature 20~
30 DEG C, 15.6Kg phosphorus oxychloride is disposably rapidly joined, after dripping off, reaction solution maintains the temperature at 10 DEG C of reaction 7h in reaction kettle,
Reaction solution I is obtained, through detecting, in reaction solution I, the content of impurity A is 0.6%.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.471Kg methanol is added into vinasse, solid dissolved clarification is warming up under stirring.0.2Kg active carbon is added, stirs
Filtrate II is obtained after mixing, filtering, and impurity A is not detected in filtrate II.
(3) 9.8Kg 3- amino phenylacetylene is added in filtrate II, is warming up to back flow reaction 2h, obtains reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
55~65 DEG C of boiler temperature of control, vacuum degree≤- 0.09MPa, gained are centrifuged the dry 8h of wet product, and rewinding is packed,
Up to product hydrochloric acid Erlotinib, yield 88.2%.It is detected through HPLC, product purity is 99.0% or more.
Embodiment 4
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
21.9Kg n,N-Dimethylformamide is added after mixing in 4 (3H) -one, control in reaction kettle reacting liquid temperature 10~
20 DEG C, 23.8Kg thionyl chloride is disposably rapidly joined, after dripping off, reaction solution maintains the temperature at 35 DEG C of reaction 4h in reaction kettle,
Reaction solution I is obtained, through detecting, in reaction solution I, the content of impurity A is 0.2% or less.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.471Kg methanol is added into vinasse, solid dissolved clarification is warming up under stirring.0.9Kg active carbon is added, stirs
Filtrate II is obtained after mixing, filtering, and impurity A is not detected in filtrate II.
(3) 12.5Kg 3- amino phenylacetylene is added in filtrate II, heats up 70 DEG C and reacts 4h, obtain reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
55~65 DEG C of boiler temperature of control, vacuum degree≤- 0.09MPa, gained are centrifuged the dry 8h of wet product, and rewinding is packed,
Up to product hydrochloric acid Erlotinib, yield 92.5%.It is detected through HPLC, product purity is up to 99.0% or more.
Embodiment 5
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
After mixing 10.5Kg n,N-Dimethylformamide is added, reacting liquid temperature is 0~30 in control reaction kettle in 4 (3H) -one
DEG C, 29.6Kg oxalyl chloride is disposably rapidly joined, after dripping off, reaction solution maintains the temperature at 50 DEG C of reaction 2h in reaction kettle, obtains instead
Liquid I is answered, through detecting, in reaction solution I, the content of impurity A is 0.6%.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.490Kg ethyl alcohol is added into vinasse, solid dissolved clarification is warming up under stirring.1.2Kg active carbon is added, stirs
Filtrate II is obtained after mixing, filtering, and impurity A is not detected in filtrate II.
(3) 15.3Kg 3- amino phenylacetylene is added in filtrate II, heats up 80 DEG C and reacts 4h, obtain reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
55~65 DEG C of boiler temperature of control, vacuum degree≤- 0.09MPa, gained are centrifuged the dry 8h of wet product, and rewinding is packed,
Up to product hydrochloric acid Erlotinib, yield 87.5%.It is detected through HPLC, product purity is 99.0% or more.
Embodiment 6
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
After mixing 3.6Kg n,N-Dimethylformamide is added, reacting liquid temperature is 20~30 in control reaction kettle in 4 (3H) -one
DEG C, 60.1Kg phosphorus oxychloride is disposably rapidly joined, after dripping off, reaction solution is warming up to back flow reaction 8h in reaction kettle, must react
Liquid I, through detecting, in reaction solution I, the content of impurity A is 0.3%.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.471Kg methanol is added into vinasse, solid dissolved clarification is warming up under stirring, filtrate II is obtained after filtering, through examining
The content for surveying impurity A in filtrate II is 0.3%.
(3) 17.2Kg 3- amino phenylacetylene is added in filtrate II, is warming up to 80 DEG C of reaction 8h, obtains reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
55~65 DEG C of boiler temperature of control, vacuum degree≤- 0.09MPa, gained are centrifuged the dry 8h of wet product, and rewinding is packed,
Up to product hydrochloric acid Erlotinib, yield 85.9%.It is detected through HPLC, product purity is 99.0% or more, but Impurity A content reaches
To 0.5%.
Comparative example 1
(1) 400Kg methylene chloride and 30.0Kg 6,7- bis- (2- methoxy ethoxy)-quinazoline-are added into reaction kettle
4 (3H) -one control reacting liquid temperature in reaction kettle and 23.5Kg phosphorus oxychloride are slowly added dropwise at 0~30 DEG C, drip after mixing
After complete, reaction solution is warming up to back flow reaction 3h in reaction kettle, obtains reaction solution I, and through detecting, in reaction solution I, the content of impurity A is
2%.
(2) reaction solution I is added in 800Kg ice water, stirring is stood, layering.Organic phase is primary with 110Kg water washing
After removed under reduced pressure, control reacting kettle jacketing temperature be no more than 40 DEG C, vacuum degree≤- 0.06MPa, vacuum distillation organic layer extremely
No fraction outflow.471Kg methanol is added into vinasse, solid dissolved clarification is warming up under stirring.0.6Kg active carbon is added, stirs
Filtrate II is obtained after mixing, filtering, through detecting, Impurity A content is 0.1% or less in filtrate II.
(3) 11.9Kg 3- amino phenylacetylene is added in filtrate II, is warming up to back flow reaction 3h, obtains reaction solution III.
(4) reaction solution III is cooled to 10 DEG C, puts into a centrifuge centrifugation after stirring 1h, elutes filter cake with methanol.
(5) 55~65 DEG C of boiler temperature are controlled, vacuum degree≤- 0.09MPa, gained is centrifuged the dry 8h of wet product, rewinding, packet
Dress is to get product hydrochloric acid Erlotinib, yield 78.3%.It is detected through HPLC, product purity is 99.0% or more.
Claims (5)
1. a kind of method that one-step method prepares hydrochloric acid Erlotinib, which is characterized in that specifically includes the following steps:
(1) with 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one for starting material, chloro is carried out with chlorinating agent
Reaction solution I is obtained after reaction；
(2) reaction solution I is poured into ice water, is removed under reduced pressure after organic phase is separated, solvent is added into vinasse, stirring rises
Temperature is added active carbon, obtains filtrate II after stirring, filtering to solid dissolved clarification；
(3) 3- amino phenylacetylene is added in filtrate II, reaction solution III is obtained after condensation reaction；
(4) reaction solution III is after cooling, stirring, centrifugation, drying up to hydrochloric acid Erlotinib；
In step (1), after mixing with solvent by (2- methoxy ethoxy)-quinazoline -4 (3H) -one of 6,7- bis-, N is added,
Dinethylformamide, the temperature for controlling mixed solution in reaction kettle is 0~50 DEG C, and then property rapidly joins chloro examination again
Agent；
Wherein, the molar ratio of n,N-Dimethylformamide and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is
1.0~1.5:1；
The chlorinating agent is phosphorus oxychloride, and the temperature of the chlorination is 20~30 DEG C, and the time of the chlorination is 3
~5 hours；
In step (2), the dosage of the active carbon is 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one dosage
0.5~5%；
In step (3), the time of the condensation reaction is 3~4 hours.
2. the method that one-step method according to claim 1 prepares hydrochloric acid Erlotinib, which is characterized in that in step (1), institute
The molar ratio for stating chlorinating agent and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 0.8~4:1.
3. the method that one-step method according to claim 1 prepares hydrochloric acid Erlotinib, which is characterized in that in step (1), institute
The molar ratio for stating chlorinating agent and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 1.3~1.7:1.
4. the method that one-step method according to claim 1 prepares hydrochloric acid Erlotinib, which is characterized in that the 3- aminobenzene
The molar ratio of acetylene and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 0.8~1.5:1.
5. the method that one-step method according to claim 1 prepares hydrochloric acid Erlotinib, which is characterized in that the 3- aminobenzene
The molar ratio of acetylene and 6,7- bis- (2- methoxy ethoxy)-quinazoline -4 (3H) -one is 0.95~1.05:1.
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