CN109651268A - A kind of preparation method of erlotinib Hydrochloride intermediate - Google Patents
A kind of preparation method of erlotinib Hydrochloride intermediate Download PDFInfo
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- CN109651268A CN109651268A CN201811645535.9A CN201811645535A CN109651268A CN 109651268 A CN109651268 A CN 109651268A CN 201811645535 A CN201811645535 A CN 201811645535A CN 109651268 A CN109651268 A CN 109651268A
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- preparation
- reaction
- erlotinib hydrochloride
- hydrochloride intermediate
- methanol
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- C—CHEMISTRY; METALLURGY
- 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
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The present invention provides a kind of preparation method of erlotinib Hydrochloride intermediate.This method are as follows: vanillic aldehyde becomes itrile group, nitrification through demethylation, etherificate, aldehyde radical, and reduction hydrolyzes, cyclization, and reaction route is as follows:
Description
Technical field:
The present invention relates to a kind of preparation methods of erlotinib Hydrochloride intermediate, belong to pharmaceutical technology field.
Background technique:
Small molecule compound Tarceva is a kind of receptor tyrosine kinase mortifier, by the cell with Adenosine triphosphate
The intracellular region catalytic site of glycosides competitive binding receptor tyrosine kinase inhibits phosphorylation reaction, so that blocking has downwards proliferation
Signal transduction inhibits the activity of the HER-1/EGFR of tumour cell ligand-dependent, has the function that inhibit tumor cell proliferation.
Tarceva is also the tyrosine kinase inhibitor that another is used for NSCLC treatment.Erlotinib Hydrochloride is mainly used for local evening
The treatment of phase or Metastatic Nsclc two wires or three lines treatment and cancer of pancreas.The pharmaceutical intermediate (structure I) at present
There are two types of principal synthetic routes:
Method one: it is etherified using 3,4-Dihydroxybenzoic acid ethyl ester as starting material, it nitrifies, reduction, 4 step of cyclization obtains
Product, synthetic route are shown below:
The route disadvantage is that starting material used and reduction palladium carbon used are expensive, at high cost.
Method two: etherified with 3,4- 4-dihydroxy benzaldehyde for starting material, aldehyde radical becomes itrile group, nitrification, and amidation is gone back
Original, 6 step of cyclization obtain product, and synthetic route is shown below:
The route disadvantage is to restore palladium carbon valuableness used, and cyclization temperature is high, and condition is violent, and total yield of products is low, cost
It is high.
Summary of the invention:
The purpose of the present invention is a kind of preparation method of erlotinib Hydrochloride intermediate in view of the above problems, the party
Method rational technology, easy to operate, at low cost, reaction yield is higher.
Above-mentioned purpose is realized by following technical scheme:
A kind of preparation method of erlotinib Hydrochloride intermediate, this method are as follows:
Vanillic aldehyde becomes itrile group, nitrification through demethylation, etherificate, aldehyde radical, and reduction hydrolyzes, cyclization, and reaction route is as follows:
The preparation method of the erlotinib Hydrochloride intermediate, in the demethylating reaction, reagent be alchlor or
Person's alchlor or aluminium triiodide, preferably alchlor；Catalysts are pyridine or triethylamine, preferably pyridine.
The preparation method of the erlotinib Hydrochloride intermediate, in the etherification reaction, reaction dissolvent is DMF or second
Nitrile or acetone, preferably DMF；Reacting agents useful for same is 2- chloroethyl methyl ether or 2- bromo-ethyl-methyl ether, preferably 2- chloroethene
Ylmethyl ether；Reacting acid binding agent used is potassium carbonate or sodium carbonate or sodium hydroxide or potassium hydroxide, preferably carbonic acid
Potassium.
The preparation method of the erlotinib Hydrochloride intermediate, the aldehyde radical become in itrile group reaction, and solvent for use is first
Acid or acetic acid, preferably formic acid；Agents useful for same is hydroxylamine hydrochloride or sodium formate.
The preparation method of the erlotinib Hydrochloride intermediate, in the nitration reaction, agents useful for same is fuming nitric aicd
Or concentrated nitric acid, preferred fuming nitric aicd.
The preparation method of the erlotinib Hydrochloride intermediate, described to restore, in hydrolysis, solvent for use is methanol
Or ethyl alcohol, preferred methanol；Reducing agent used is hydrazine hydrate；Alkali used is potassium hydroxide or sodium hydroxide or potassium carbonate,
It is preferred that potassium hydroxide.
The preparation method of the erlotinib Hydrochloride intermediate, solvent for use is methanol or second in the annulation
Alcohol, preferably methanol；Cyclization reagent used is formamidine acetate.
The utility model has the advantages that
The present invention is with vanillic aldehyde through demethylation, etherificate, aldehyde radical change itrile group, nitrification, reduction, hydrolysis, cyclization, with novelty
Completely new route.Agents useful for same is cheap and easily-available, easy to operate, and productivity ratio other methods are high, and easy to industrialized production.
Specific embodiment:
A kind of preparation method of erlotinib Hydrochloride intermediate, this method are as follows:
Vanillic aldehyde becomes itrile group, nitrification through demethylation, etherificate, aldehyde radical, and reduction hydrolyzes, cyclization, and reaction route is as follows:
The preparation method of the erlotinib Hydrochloride intermediate, in the demethylating reaction, reagent be alchlor or
Person's alchlor or aluminium triiodide, preferably alchlor；Catalysts are pyridine or triethylamine, preferably pyridine.
The preparation method of the erlotinib Hydrochloride intermediate, in the etherification reaction, reaction dissolvent is DMF or second
Nitrile or acetone, preferably DMF；Reacting agents useful for same is 2- chloroethyl methyl ether or 2- bromo-ethyl-methyl ether, preferably 2- chloroethene
Ylmethyl ether；Reacting acid binding agent used is potassium carbonate or sodium carbonate or sodium hydroxide or potassium hydroxide, preferably carbonic acid
Potassium.
The preparation method of the erlotinib Hydrochloride intermediate, the aldehyde radical become in itrile group reaction, and solvent for use is first
Acid or acetic acid, preferably formic acid；Agents useful for same is hydroxylamine hydrochloride or sodium formate.
The preparation method of the erlotinib Hydrochloride intermediate, in the nitration reaction, agents useful for same is fuming nitric aicd
Or concentrated nitric acid, preferred fuming nitric aicd.
The preparation method of the erlotinib Hydrochloride intermediate, described to restore, in hydrolysis, solvent for use is methanol
Or ethyl alcohol, preferred methanol；Reducing agent used is hydrazine hydrate；Alkali used is potassium hydroxide or sodium hydroxide or potassium carbonate,
It is preferred that potassium hydroxide.
The preparation method of the erlotinib Hydrochloride intermediate, solvent for use is methanol or second in the annulation
Alcohol, preferably methanol；Cyclization reagent used is formamidine acetate.
Step 1: the synthesis of intermediate 1:
80g vanillic aldehyde is put into the DMF of 320ml, and 80g aluminum trichloride (anhydrous) is added in batches at room temperature, and 80g pyrrole is added dropwise
Pyridine is warming up to 70-80 DEG C of reaction 16-20 hours, is cooled to room temperature and 3200ml water, the EA extraction 6 of feed liquid 480ml × 6 is added
It is secondary, merge organic layer, with saturated common salt water washing 2 times of 500ml × 2, is concentrated under reduced pressure into after organic layer anhydrous sodium sulfate is dry
Do to obtain 67.4g intermediate 1 (yield 92.8%).
Step 2: the synthesis of intermediate 2:
67.4g intermediate 1 is put into the DMF of 337ml, the 2- chloroethyl methyl ether and 3.5g sodium iodide of 115g is added,
It is warming up to back flow reaction 6-8 hours, reaction solution is concentrated to dryness, and 337ml water is added, it is extracted 4 times with the EA of 270ml × 4,
Merge saturated common salt water washing for 2 times of organic layer 300ml × 2, be concentrated to dryness after anhydrous sodium sulfate is dry in 120g
Mesosome 2 (yield 96.8%).
Step 3: the synthesis of intermediate 3:
120g intermediate 3 is put into the formic acid of 240ml, 42.4g hydroxylamine hydrochloride and 67.5g sodium formate is added, is warming up to
90-100 DEG C is reacted 8 hours, and room temperature is cooled to, and 960ml water is added, and is extracted 4 times with the EA of 360ml × 4, is merged organic layer and is used
The saturated common salt water washing of 400ml × 22 times is concentrated to dryness to obtain 3 (yield of 104.3g intermediate after anhydrous sodium sulfate is dry
87.9%).
Step 4: the synthesis of intermediate 4:
104.3g intermediate 4 is put into 208ml methylene chloride, 41.3g fuming nitric aicd is added dropwise at room temperature, it is anti-to drip complete room temperature
It answers 12 hours, 208ml water, filtering, washing, dry 115g intermediate 4 (yield 93.5%) is added.
Step 5: the synthesis of intermediate 5:
115g intermediate 4 is put into 690ml methanol, 11.5g active carbon, 5.8g ferric trichloride and 47.6g is added
80% hydrazine hydrate is warming up to back flow reaction 4 hours, and heat filter concentrates filtrate to dry, addition 690ml water and 230g hydrogen-oxygen
Change potassium, be warming up to back flow reaction 12 hours, be cooled to room temperature, be added dropwise hydrochloric acid tune PH to 3-4, among filtering, dry 102g
Body 5 (yield 92.1%).
Step 6: I synthesis:
102g intermediate 5 is put into 1020ml methanol, 55.3g formamidine acetate is added, is warming up to back flow reaction 8 hours,
Be cooled to room temperature, filtering, dry 95.7g product I (yield 90.9%, purity 99.6%).
The above is only highly preferred embodiment of the present invention, the method for the present invention includes but be not limited to the above embodiments, the present invention
Unaccomplished matter, belong to the common knowledge of those skilled in the art.
Claims (7)
1. a kind of preparation method of erlotinib Hydrochloride intermediate, it is characterized in that: this method are as follows:
Vanillic aldehyde becomes itrile group, nitrification through demethylation, etherificate, aldehyde radical, and reduction hydrolyzes, cyclization, and reaction route is as follows:
2. the preparation method of erlotinib Hydrochloride intermediate according to claim 1, it is characterized in that: the demethylating reaction
In, reagent is alchlor or alchlor or aluminium triiodide, preferably alchlor；Catalysts are pyridine or three
Ethamine, preferably pyridine.
3. the preparation method of erlotinib Hydrochloride intermediate according to claim 1, it is characterized in that: the etherification reaction
In, reaction dissolvent is DMF or acetonitrile or acetone, preferably DMF；Reacting agents useful for same is 2- chloroethyl methyl ether or 2- bromine
Ethyl-methyl ether, preferably 2- chloroethyl methyl ether；React acid binding agent used be potassium carbonate or sodium carbonate or sodium hydroxide or
Person's potassium hydroxide, preferably potassium carbonate.
4. the preparation method of erlotinib Hydrochloride intermediate according to claim 1, it is characterized in that: the aldehyde radical becomes itrile group
In reaction, solvent for use is formic acid or acetic acid, preferably formic acid；Agents useful for same is hydroxylamine hydrochloride or sodium formate.
5. the preparation method of erlotinib Hydrochloride intermediate according to claim 1, it is characterized in that: the nitration reaction
In, agents useful for same is fuming nitric aicd or concentrated nitric acid, preferably fuming nitric aicd.
6. the preparation method of erlotinib Hydrochloride intermediate according to claim 1, it is characterized in that: the reduction, hydrolysis
In reaction, solvent for use is methanol or ethyl alcohol, preferably methanol；Reducing agent used is hydrazine hydrate；Alkali used be potassium hydroxide or
Person's sodium hydroxide or potassium carbonate, preferably potassium hydroxide.
7. the preparation method of erlotinib Hydrochloride intermediate according to claim 1, it is characterized in that: in the annulation
Solvent for use is methanol or ethyl alcohol, preferably methanol；Cyclization reagent used is formamidine acetate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115108999A (en) * | 2019-07-26 | 2022-09-27 | 暨南大学 | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application |
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2018
- 2018-12-30 CN CN201811645535.9A patent/CN109651268A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115108999A (en) * | 2019-07-26 | 2022-09-27 | 暨南大学 | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application |
| CN115108999B (en) * | 2019-07-26 | 2023-11-03 | 暨南大学 | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application |
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Application publication date: 20190419 |
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