CN104193689B - Method for synthesizing erlotinib hydrochloride - Google Patents
Method for synthesizing erlotinib hydrochloride Download PDFInfo
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- CN104193689B CN104193689B CN201410353572.8A CN201410353572A CN104193689B CN 104193689 B CN104193689 B CN 104193689B CN 201410353572 A CN201410353572 A CN 201410353572A CN 104193689 B CN104193689 B CN 104193689B
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- SUIHZAHOPBDEKX-UHFFFAOYSA-N CC(c1cc(Nc2c(cc(c(OCCOC)c3)OCCOC)c3ncn2)ccc1)=C Chemical compound CC(c1cc(Nc2c(cc(c(OCCOC)c3)OCCOC)c3ncn2)ccc1)=C SUIHZAHOPBDEKX-UHFFFAOYSA-N 0.000 description 1
Classifications
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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 invention relates to the technical field of medicines, and particularly relates to a novel method for synthesizing erlotinib hydrochloride. The method comprises the following steps: (1) carrying out a nitration reaction in mixed acid on acetophenone serving as an initial raw material to obtain 3-nitroacetophenone; (2) carrying out a chlorination reaction on 3-nitroacetophenone and a chloride agent in an organic solvent to obtain 1-chloro-1-(3-nitrophenyl) ethylene; (3) removing hydrogen chloride from 1-chloro-1-(3-nitrophenyl) ethylene in existence of the organic solvent and strong alkali to obtain m-nitrophenylacetylene; (4) carrying out selective reduction on m-nitrophenylacetylene by means of nitryl to obtain 3-aminophenylacetylene, wherein the reduction method performs reduction by a reducing agent or catalytic hydrogenation; (5) reacting 3-aminophenylacetylene and 4-chloro-6,7-bis-(2-methoxyethoxy) quinazoline in the organic solvent to obtain erlotinib hydrochloride. The method has the advantages of low production cost, mild reaction conditions and the like, is simple and convenient to operate, and is suitable for industrial production; and the raw materials are low in cost and easily available.
Description
Technical field
The present invention relates to technical field of medicine synthesis, it is related to a kind of synthetic method of erlotinib Hydrochloride.
Background technology
Erlotinib Hydrochloride (Erlotinib Hydrochloride), trade name Erlotinib, is biological by Roche, west difficult to understand
Drugmaker and a kind of EGF tyrosine kinase inhibitor of Genentech drugmaker joint development, clinical at present
On be mainly used in the treatment of Locally Advanced and Metastatic Nsclc.Its chemical constitution is shown below：
The chloro- 6,7- of 4- bis--(2- methoxy ethoxy) quinazoline and an ammonia are mainly passed through in the synthesis of erlotinib Hydrochloride
The reaction of base phenylacetylene obtains.Patent US5747498, WO20070606091, CN101463013A etc. have been directed to 4- chloro- 6,
The synthetic method of 7- bis--(2- methoxy ethoxy) quinazoline, but another key intermediate as erlotinib Hydrochloride,
The synthetic method report of amino phenylacetylene is relatively fewer, and method that it is mainly coupled by palladium chtalyst at present is preparing：
Patent EP2433931, US5902902, CN98808385 etc. all report halogenated nitrobenzene or a halo ammonia between using
Base benzene occurs coupling reaction to generate corresponding benzyne alcohol intermediate with the alkynes with protection under palladium chtalyst, by deprotection and reduction
The method of prepared 3-aminophenylacetylene.But they are required to using expensive palladium catalyst and protection reagent so that the method
Production cost higher, be not suitable for industrialized production.
Content of the invention
For overcoming the shortcomings of background technology, it is an object of the invention to provide a kind of synthesis of erlotinib Hydrochloride newly side
Method.Compared with existing synthetic method, this route has the advantages that low production cost, easy and simple to handle, suitable industrialized production.
A kind of synthetic method of erlotinib Hydrochloride, this synthetic method comprises the steps：
1) with acetophenone as initiation material, nitration reaction is occurred to obtain m-nitroacetophenone in nitration mixture；Acetophenone and nitre
The mol ratio changing reagent is 1:1～7；Reaction temperature is -40～50 DEG C；Described nitration mixture is selected from red fuming nitric acid (RFNA) and the concentrated sulfuric acid, nitre of being fuming
In acid and the concentrated sulfuric acid, red fuming nitric acid (RFNA) and acetic acid, fuming nitric aicd and acetic acid one group；Nitrating agent is red fuming nitric acid (RFNA) or nitre of being fuming in nitration mixture
Acid；
2) m-nitroacetophenone and chlorination reagent occur chlorination reaction to obtain 1- chloro- 1- (3- nitrobenzene in organic solvent
Base) ethene, reaction temperature be 25～150 DEG C；M-nitroacetophenone is 1 with the mol ratio of chlorination reagent:0.5～10；
3) the chloro- 1- of 1- (3- nitrobenzophenone) ethene dehydrochlorination in the presence of organic solvent and highly basic obtains m-nitro second
Alkynes, reaction temperature is 20～180 DEG C；The chloro- 1- of 1- (3- nitrobenzophenone) ethene is 1 with the mol ratio of highly basic:1～10；
4) m-nitrobenzene acetylene obtains 3-aminophenylacetylene by nitro selective reduction；Method of reducing reduces for reducing agent
Or catalytic hydrogenating reduction；When method of reducing reduces for reducing agent, m-nitrobenzene acetylene is 1 with the mol ratio of reducing agent:1～10；
Method of reducing be catalytic hydrogenating reduction when, Hydrogen Vapor Pressure be 0.1-5MPa, catalyst amount be m-nitrobenzene acetylene 0.1%～
50%；
5) 3-aminophenylacetylene and the chloro- 6,7- of 4- bis--(2- methoxy ethoxy) quinazoline react in organic solvent
To erlotinib Hydrochloride, reaction temperature is 20～100 DEG C；
The synthetic route formula of erlotinib Hydrochloride is as follows：
Described chlorination reagent be selected from one of POCl3, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, oxalyl chloride or
Two or more mixing.
Step 2) in, organic solvent is selected from toluene, dimethylbenzene, normal heptane, n-hexane, dimethyl sulfoxide, acetonitrile, 1,2- dichloro
One of ethane, chloroform, dichloromethane or two or more mixing；Course of reaction adds acid binding agent, selected from triethylamine, front three
Amine, pyridine, piperidines, to one of dimethylamino naphthyridine, potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate or two or more
Mixing.
Step 3) in, described highly basic is selected from potassium hydroxide, NaOH, potassium tert-butoxide, sodium methoxide, caustic alcohol, hydrogenation
One of sodium, hydrofining or two or more mixing；Organic solvent be selected from isoamyl alcohol, tert-pentyl alcohol, the tert-butyl alcohol, isopropanol, ethanol,
In methyl alcohol, dichloromethane, toluene, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide one
Plant or two or more mixing.
Step 4) in, described reducing agent be one of iron powder, zinc powder, hydrazine hydrate, vulcanized sodium, sodium dithionite or
Two or more mixing；The catalyst of catalytic hydrogenation is one of Rany-Ni, Pd/C, Pt/C, Ru/C or two or more mixing.
Step 5) in, organic solvent is selected from methyl alcohol, ethanol, isopropanol, DMF, N, N- dimethyl second
One of acid amides or two or more mixing.
The invention has the beneficial effects as follows：The synthetic method of the present invention has that raw material is cheap and easy to get, low production cost, operation letter
Just the advantages of, reaction condition is gentle, is suitable to industrialized production.
Brief description
Accompanying drawing is the hydrogen nuclear magnetic resonance spectrogram (1H NMR) of erlotinib Hydrochloride.
Specific embodiment
Below by specific embodiment, the present invention is further elaborated, makes man skilled in the art will appreciate that the present invention
Content and implement according to this, can not be limited the scope of the invention with this.
The synthesis of embodiment 1 m-nitroacetophenone
The 400ml concentrated sulfuric acid is added 1000ml reaction bulb, drips 180.0g (1.5mol) acetophenone, by the 200ml concentrated sulfuric acid
It is added dropwise to after mixing with 150ml red fuming nitric acid (RFNA) in system, whole process control system temperature is less than -5 DEG C, continue after completion of dropping
Reaction 20min, TLC detection reaction terminates.Under stirring, system is poured slowly in a large amount of frozen water, suction filtration, filter cake saturation
Sodium carbonate obtains product crude product after washing away residual acid.Crude product ethyl alcohol recrystallization is obtained faint yellow acicular crystal 220.1g, yield
88.9%, content >=99%.
Nuclear magnetic data：1H NMR(400MHz,CDCl3) δ 8.78 (s, 1H), 8.47 8.40 (m, 1H), 8.30 (d, J=
7.8Hz, 1H), 7.69 (t, J=8.0Hz, 1H), 2.70 (s, 3H)
The synthesis of embodiment 2 m-nitroacetophenone
The 400ml concentrated sulfuric acid is added 1000ml reaction bulb, drips 180.0g (1.5mol) acetophenone, by the 120ml concentrated sulfuric acid
It is added dropwise to after mixing with 80ml fuming nitric aicd in system, whole process control system temperature is less than -10 DEG C, and completion of dropping is follow-up
Continuous reaction 10min, TLC detection reaction terminates.Under stirring, system is poured slowly in a large amount of frozen water, suction filtration, filter cake is with satisfying
Wash away with sodium carbonate and after residual acid, obtain product crude product.Crude product ethyl alcohol recrystallization is obtained faint yellow acicular crystal 223.5g, receives
Rate 90.3%, content >=99%.
The synthesis of the chloro- 1- of embodiment 3 1- (3- nitrobenzophenone) ethene
132.0g (0.8mol) m-nitroacetophenone, 450ml toluene, 31.6g (0.4mol) pyridine are added 1000ml anti-
Answer in bottle, stirring makes to be slowly added dropwise 146.9g (0.96mol) POCl3 under dissolution of raw material, room temperature, is warming up to after completion of dropping
115 DEG C of reactions, TLC detects reaction process.After reaction terminates, cooling, add 100ml water in system.Organic layer saturated carbon
Sour sodium is washed, and saturated common salt is washed, and drying is concentrated to give crude product, and vacuum distillation obtains light yellow product 133.2g, yield 91.0%, contains
Amount >=97%.
Nuclear magnetic data：1H NMR(400MHz,CDCl3) δ 8.48 (s, 1H), 8.21 (d, J=8.4Hz, 1H), 7.95 (d, J
=7.8Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 5.93 (d, J=2.1Hz, 1H), 5.70 (d, J=2.0Hz, 1H)
The synthesis of the chloro- 1- of embodiment 4 1- (3- nitrobenzophenone) ethene
132.0g (0.8mol) m-nitroacetophenone, 450ml toluene, 40.4g (0.4mol) triethylamine are added 1000ml
In reaction bulb, stirring makes to be slowly added dropwise 244.8g (1.6mol) POCl3 under dissolution of raw material, room temperature, is warming up to after completion of dropping
95 DEG C of reactions, TLC detects reaction process.After reaction terminates, cooling, add 100ml water in system.Organic layer unsaturated carbonate
Sodium is washed, and saturated common salt is washed, and drying is concentrated to give crude product, and vacuum distillation obtains light yellow product 126.7g, yield 86.5%, content
>=97%.
The synthesis of embodiment 5 m-nitrobenzene acetylene
Chloro- for 54.9g (0.3mol) 1- 1- (3- nitrobenzophenone) ethene, 300ml ethanol are added in 500ml reaction bulb, plus
Enter 30.2g (0.54mol) potassium hydroxide, heating reflux reaction 4h.After reaction terminates, system is poured in aqueous ammonium chloride solution,
With dichloromethane extraction, organic layer washing, saturated common salt is washed, and drying is concentrated to give product crude product, and vacuum distillation obtains faint yellow product
Product 30.6g, yield 69.4%, content >=99%.
Nuclear magnetic data：1H NMR(400MHz,CDCl3)δ8.38–8.30(m,1H),8.24–8.19(m,1H),7.83–
7.76 (m, 1H), 7.53 (t, J=8.0Hz, 1H), 3.23 (s, 1H)
The synthesis of embodiment 6 m-nitrobenzene acetylene
Chloro- for 54.9g (0.3mol) 1- 1- (3- nitrobenzophenone) ethene, the 300ml tert-butyl alcohol are added in 500ml reaction bulb,
Add 50.4g (0.45mol) potassium tert-butoxide, 45 DEG C of heating responses 5h.After reaction terminates, system is poured into aqueous ammonium chloride solution
In, with dichloromethane extraction, organic layer washing, saturated common salt is washed, and drying is concentrated to give product crude product, and vacuum distillation obtains faint yellow
Product 32.3g, yield 73.2%, content >=99%.
The synthesis of embodiment 7 m-nitrobenzene acetylene
Chloro- for 54.9g (0.3mol) 1- 1- (3- nitrobenzophenone) ethene, the 300ml tert-butyl alcohol are added in 500ml reaction bulb,
Add 60.0g (1.5mol) NaOH, heating reflux reaction 10h.After reaction terminates, system is poured into aqueous ammonium chloride solution
In, with dichloromethane extraction, organic layer washing, saturated common salt is washed, and drying is concentrated to give product crude product, and vacuum distillation obtains faint yellow
Product 31.1g, yield 70.5%, content >=99%.
The synthesis of embodiment 8 m-nitrobenzene acetylene
Chloro- for 54.9g (0.3mol) 1- 1- (3- nitrobenzophenone) ethene, 270ml DMF are added in 500ml reaction bulb, plus
Enter 8.6g (0.36mol) sodium hydride, 55 DEG C of heating responses 5h.After reaction terminates, system is poured in aqueous ammonium chloride solution, uses two
Chloromethanes extracts, and organic layer is washed, and saturated common salt is washed, and drying is concentrated to give product crude product, and vacuum distillation obtains light yellow product
34.5g, yield 78.3%, content >=99%.
The synthesis of embodiment 9 3-aminophenylacetylene
By 21.8g (0.39mol) reduced iron powder, 2.8g (0.052mol) NH4Cl, 75ml water adds 250ml reaction bulb
In, it is warming up to 85 DEG C, 19.1g (0.13mol) m-nitrobenzene acetylene is dissolved in 50ml ethanol, is slowly dropped in system, 85
DEG C reaction 3h.After reaction terminates, suction filtration while hot, filter cake ethanol washs to the attachment of no product, filtrate reduced in volume, and residue is used
Dichloromethane extracts, and organic layer is washed, and saturated common salt is washed, and drying is concentrated to give yellow crude product, and vacuum distillation obtains water white transparency
Product 16.1g, yield 92.8%, content >=99%.
Nuclear magnetic data：1H NMR(400MHz,CDCl3) δ 7.10 (t, J=7.8Hz, 1H), 6.90 (d, J=7.6Hz, 1H),
6.84–6.77(m,1H),6.70–6.63(m,1H),3.67(brs,2H),3.01(s,1H)
The synthesis of embodiment 10 3-aminophenylacetylene
93.6g (0.39mol) nine hydrated sodium sulfide, 150ml water are added in 500ml reaction bulb, is warming up to 85 DEG C, will
19.1g (0.13mol) m-nitrobenzene acetylene is dissolved in 50ml methyl alcohol, is slowly dropped in system, 85 DEG C of reaction 5h.Reaction terminates
Afterwards, cool down, dichloromethane extracts, organic layer is washed, saturated common salt is washed, drying is concentrated to give yellow crude product, and vacuum distillation obtains
Water white transparency product 11.1g, yield 73.0%, content >=99%.
The synthesis of embodiment 11 erlotinib Hydrochloride
Chloro- for 12.5g (0.040mol) 4- 6,7- bis--(2- methoxy ethoxy) quinazoline is dissolved in 80ml ethanol, then
The aqueous isopropanol 20ml of dropping 5.7g (0.049mol) 3-aminophenylacetylene, heating reflux reaction 5h, TLC detection reaction knot
Bundle, cooling, suction filtration, filter cake ethyl acetate wash 3 times, drying, obtains Tarceva 12.8g, yield 81.3%, content >=
99%.
Nuclear magnetic data：1H NMR(400MHz,MeOD)δ8.62(s,1H),7.95(s,1H),7.87(s,1H),7.73(d,
J=8.0Hz, 1H), 7.48 7.33 (m, 2H), 7.24 (s, 1H), 4.40 4.32 (m, 4H), 3.89 3.83 (m, 4H), 3.56
(s, 1H), 3.46 (d, J=4.4Hz, 6H).
Claims (3)
1. a kind of synthetic method of erlotinib Hydrochloride is it is characterised in that following steps：
1) with acetophenone as initiation material, nitration reaction is occurred to obtain m-nitroacetophenone in nitration mixture；Acetophenone and nitrification examination
The mol ratio of agent is 1:1～7；Reaction temperature is -40～50 DEG C；Described nitration mixture be selected from red fuming nitric acid (RFNA) and the concentrated sulfuric acid, fuming nitric aicd with
In the concentrated sulfuric acid, red fuming nitric acid (RFNA) and acetic acid, fuming nitric aicd and acetic acid one group；Nitrating agent is red fuming nitric acid (RFNA) or fuming nitric aicd in nitration mixture；
2) m-nitroacetophenone and chlorination reagent occur chlorination reaction to obtain the chloro- 1- of 1- (3- nitrobenzophenone) second in organic solvent
Alkene, reaction temperature is 25～150 DEG C；M-nitroacetophenone is 1 with the mol ratio of chlorination reagent:0.5～10；
Described chlorination reagent is selected from one of POCl3, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, oxalyl chloride or two kinds
Mixed above；Described machine solvent is selected from toluene, dimethylbenzene, normal heptane, n-hexane, dimethyl sulfoxide, acetonitrile, 1,2- bis- chloroethene
One of alkane, chloroform, dichloromethane or two or more mixing；Course of reaction add acid binding agent, selected from triethylamine, trimethylamine,
Pyridine, piperidines, to one of dimethylamino naphthyridine, potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate or two or more mixed
Close；
3) the chloro- 1- of 1- (3- nitrobenzophenone) ethene dehydrochlorination in the presence of organic solvent and highly basic obtains m-nitrobenzene acetylene,
Reaction temperature is 20～180 DEG C；The chloro- 1- of 1- (3- nitrobenzophenone) ethene is 1 with the mol ratio of highly basic:1～10；
4) m-nitrobenzene acetylene obtains 3-aminophenylacetylene by nitro selective reduction；Method of reducing reduces for reducing agent,
Nitrobenzene acetylene is 1 with the mol ratio of reducing agent:1～10；Described reducing agent is iron powder, zinc powder, hydrazine hydrate, vulcanized sodium, company
One of sodium sulfite or two or more mixing；
5) 3-aminophenylacetylene and the chloro- 6,7- of 4- bis--(2- methoxy ethoxy) quinazoline react in organic solvent and obtain salt
Sour Tarceva, reaction temperature is 20～100 DEG C；
The synthetic route of erlotinib Hydrochloride is as follows：
2. synthetic method according to claim 1 is it is characterised in that step 3) in, described highly basic be selected from potassium hydroxide,
One of NaOH, potassium tert-butoxide, sodium methoxide, caustic alcohol, sodium hydride, hydrofining or two or more mixing；Organic solvent
Selected from isoamyl alcohol, tert-pentyl alcohol, the tert-butyl alcohol, isopropanol, ethanol, methyl alcohol, dichloromethane, toluene, dioxane, dimethyl sulfoxide, N,
One of dinethylformamide, DMAC N,N' dimethyl acetamide or two or more mixing.
3. synthetic method according to claim 1 and 2 is it is characterised in that step 5) in, organic solvent is selected from methyl alcohol, second
One of alcohol, isopropanol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or two or more mixing.
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| CN104910080B (en) * | 2015-05-26 | 2017-10-13 | 大连理工大学 | A kind of Tarceva related substances and preparation method thereof |
| CN106242957A (en) * | 2016-07-29 | 2016-12-21 | 湖北欣瑞特医药科技有限公司 | A kind of preparation method of 2 bromine 3 ' methoxyacetophenones |
| CN110776616B (en) * | 2019-10-26 | 2021-06-22 | 福建华夏蓝新材料科技有限公司 | Efficient wetting water-based isocyanate curing agent |
| CN112851527B (en) * | 2020-12-31 | 2022-11-01 | 湖北英纳氏生物科技有限公司 | Preparation method of m-aminophenylacetylene |
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