CN108373452A - A kind of preparation method of lapatinib key intermediate - Google Patents
A kind of preparation method of lapatinib key intermediate Download PDFInfo
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- CN108373452A CN108373452A CN201810139151.3A CN201810139151A CN108373452A CN 108373452 A CN108373452 A CN 108373452A CN 201810139151 A CN201810139151 A CN 201810139151A CN 108373452 A CN108373452 A CN 108373452A
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- compound
- lapatinib
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- key intermediate
- reaction
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- MOBNCKURXDGQCB-UHFFFAOYSA-N [O-][N+](c(cc12)ccc1NC=NC2=O)=O Chemical compound [O-][N+](c(cc12)ccc1NC=NC2=O)=O MOBNCKURXDGQCB-UHFFFAOYSA-N 0.000 description 1
- LZOSFEDULGODDH-UHFFFAOYSA-N [O-][N+](c(ccc1ncn2)cc1c2Cl)=O Chemical compound [O-][N+](c(ccc1ncn2)cc1c2Cl)=O LZOSFEDULGODDH-UHFFFAOYSA-N 0.000 description 1
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of lapatinib key intermediate, include the following steps：(1) compound 2 or its salt is prepared with N chlorosuccinimides generation chlorination in carbonamidine or its salt；(2) compound 2 or its salt are reacted with compound 3, obtain compound 5；(3) compound 6, i.e. lapatinib key intermediate is obtained by the reaction with thionyl chloride in the compound 5 described in.The method of the present invention has many advantages, such as that starting material is cheap and easily-available, step is simplified, atom utilization is high, reaction condition is mild, yield is high and suitable industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of lapatinib key intermediate.
Background technology
As a kind of anti-tumor drug, Lapatinib (lapatinib) chemical name is N- (3- chloro- 4- ((3- fluorobenzene
Base) methoxyl group) phenyl) -6- (5- (((2- (mesyl) ethyl) amino) methyl) -2- furyls) -4- quinazolines amine two is right
Toluene fulfonate is ratified to list, is a kind of 4- anilinoquinazolines receptoroid tyrosine kinase in March, 2007 by U.S. FDA
Inhibitor, for treating late period or metastatic breast cancer.
Key intermediate of the chloro- 6- nitro-quinazolines of 4- as Lapatinib, patent WO05046678, WO020255 report
Lapatinib and related intermediate preparation method.Directly used in known synthetic route 6- it is halogenated-quinazoline-4-one for original
Material, with intermediate 6- made from the chlorinating agents such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride it is halogenated-chloroquine
Oxazoline, this method directly use expensive 6- it is halogenated-quinazoline-4-one for raw material, cause industrial production high expensive
The problem of, it is not suitable for large industrialized production, it is difficult to control that production process pollutes environment, security risk.
It is also deposited about the preparation method of Lapatinib although there are many methods for side chain link and quinazoline cyclization at present
Process is lengthy and jumbled, reaction condition and operation require that high, starting material is expensive and atom utilization is low, heavy metal pollution and low yield
The problems such as.
Invention content
Goal of the invention：In order to solve the above-mentioned problems in the prior art, the present invention provides a kind of novel structures
The method of lapatinib intermediate quinazoline ring, this method is simple for process, and raw material is easy to get, environmental-friendly, and operation is controllable, yield and
Purity is higher, is suitble to industrialized production.
Technical solution：The preparation method of lapatinib key intermediate of the present invention, includes the following steps：
(1) compound 2 or its salt is prepared with N- chlorosuccinimides generation chlorination in carbonamidine or its salt；
(2) compound 2 or its salt are reacted with compound 3, obtain compound 5；
(3) compound 6, i.e. lapatinib key intermediate is obtained by the reaction with thionyl chloride in the compound 5 described in,
In step (1), the formamidine salt is formamidine hydrochloride or formamidine acetate, preferably formamidine acetate.Carbonamidine or its salt with
The molar ratio of N- chlorosuccinimides is 1: (1-1.2), preferably 1: 1.
In step (1), the reaction dissolvent of chlorination is acetonitrile, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), dioxy six
One or more of ring, preferably acetonitrile.The reaction temperature of chlorination is 60-120 DEG C, preferably 80-100 DEG C.Chloro is anti-
The reaction time answered is 5-7h.
Step (2) reaction carries out in the system comprising catalyst, oxidant, alkali and reaction dissolvent.
The catalyst is one or more of copper acetate, copper chloride, copper oxide, iron chloride, preferably copper acetate.
The oxidant is in tert-butyl hydroperoxide, peroxidized t-butyl perbenzoate, di-tert-butyl peroxide, hydrogen peroxide
One or more, preferably tert-butyl hydroperoxide.The alkali is one kind in potassium carbonate, sodium carbonate, sodium acetate, cesium carbonate
Or several, preferably potassium carbonate.The reaction dissolvent is acetonitrile, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), dioxane
One or more of, preferably acetonitrile.
Compound 3, compound 2 or its salt, catalyst, oxidant and alkali molar ratio be 1: (1-1.5): (0.1-0.5)：
(2-4): (1-1.5), preferably 1: 1.25: 0.1: 3: 1.
In step (2), the salt of the compound 2 is the hydrochloride or acetate of compound 2, preferably acetate.Instead
It is 60-120 DEG C, preferably 80-100 DEG C to answer temperature.Reaction time is 22-26h.
In step (3), the mass volume ratio of compound 5 and thionyl chloride is 1: (7-12) g/ml, preferably 1: (7.9-
10.5)g/ml.The dosage of thionyl chloride is excessive.
The reaction temperature of step (3) is 80-120 DEG C, preferably 90-100 DEG C.Reaction dissolvent is n,N-Dimethylformamide.
Reaction time is 2.5-3.5h.
In more detail, the preparation method of lapatinib key intermediate of the present invention, includes the following steps：
A, carbonamidine (compound 1) or its salt, which are heated with N- chlorosuccinimides (NCS) under the conditions of reaction dissolvent, reacts；
B, gained in step (a) is added with alkali in the iodo- 5- nitrotoleunes (compound 3) of starting material 2-, catalyst, oxidant
In reaction solution, 4- hydroxyl -6- nitro-quinazolines (compound 5) are made in heating reaction；
C, 4- hydroxyls -6- nitro-quinazolines (compound 5) heat reaction under conditions of thionyl chloride and generate the chloro- 6- nitre of 4-
Base quinazoline (compound 6), as lapatinib key intermediate.
The preparation method of Lapatinib of the present invention is using compound 1 as starting material, by a series of anti-
It answers made：
Advantageous effect：The iodo- 5- nitrotoleunes of starting material 2- used in the present invention build quinazoline ring with formamidine acetate
Method it is novel and atom utilization is high；Raw material of the present invention are cheap and easy to get, and reaction condition is mild, easy to operate, and yield is high, has
Good industrial prospect.
Specific embodiment
The preparation of embodiment 1, N '-chloroform imines amide (acetate of compound 2)
Formamidine acetate (5.2g, 0.05mol) is dissolved in 30mL acetonitriles, add N- chlorosuccinimides (6.68g,
0.05mol), reaction system is heated to 80 DEG C, is stirred to react 6h, gained reaction solution stays for the next step.
The preparation of embodiment 2,4- hydroxyl -6- nitro-quinazolines (compound 5)
By the iodo- 5- nitrotoleunes (10.5g, 0.04mol) of 2-, copper acetate (0.72g, 0.004mol), tert-butyl hydroperoxide
Hydrogen (15.4g, 0.12mol) and potassium carbonate (5.5g, 0.04mol) are added into 1 gained reaction solution of embodiment, by reaction system plus
Heat is stirred to react for 24 hours, is cooled to room temperature, pour into ice water to 80 DEG C, and filtering, water washing obtains 4- hydroxyl -6- nitro quinoline azoles
The acicular crystal 7.13g of quinoline (compound 5), yield 93.3%, HPLC purity 99.80%.
The preparation of embodiment 3,4- hydroxyl -6- nitro-quinazolines (compound 5)
By the iodo- 5- nitrotoleunes (10.5g, 0.04mol) of 2-, copper chloride (0.72g, 0.004mol), tert-butyl hydroperoxide
Hydrogen (15.4g, 0.12mol) and potassium carbonate (5.5g, 0.04mol) are added into 1 gained reaction solution of embodiment, by reaction system plus
Heat is stirred to react for 24 hours, is cooled to room temperature, pour into ice water to 90 DEG C, and filtering, water washing obtains 4- hydroxyl -6- nitro quinoline azoles
The acicular crystal 6.97g of quinoline (compound 5), yield 91.2%, HPLC purity 99.72%.
The preparation of embodiment 4,4- hydroxyl -6- nitro-quinazolines (compound 5)
By the iodo- 5- nitrotoleunes (10.5g, 0.04mol) of 2-, copper acetate (0.72g, 0.004mol), tert-butyl hydroperoxide
Hydrogen (20.6,0.16mol) and potassium carbonate (5.5g, 0.04mol) are added into 1 gained reaction solution of embodiment, by reaction system plus
Heat is stirred to react for 24 hours, is cooled to room temperature, pour into ice water to 80 DEG C, and filtering, water washing obtains 4- hydroxyl -6- nitro quinoline azoles
The acicular crystal 6.90g of quinoline (compound 5), yield 90.3%, HPLC purity 99.74%.
The preparation of embodiment 5,4- hydroxyl -6- nitro-quinazolines (compound 5)
By the iodo- 5- nitrotoleunes (10.5g, 0.04mol) of 2-, copper acetate (0.72g, 0.004mol), tert-butyl hydroperoxide
Hydrogen (15.4g, 0.12mol) and potassium carbonate (5.5g, 0.04mol) are added into 1 gained reaction solution of embodiment, by reaction system plus
Heat is stirred to react for 24 hours, is cooled to room temperature, pour into ice water to 100 DEG C, and filtering, water washing obtains 4- hydroxyl -6- nitro quinoline azoles
The acicular crystal 7.08g of quinoline (compound 5), yield 92.6%, HPLC purity 99.62%.
The preparation of the chloro- 6- nitro-quinazolines (compound 6) of embodiment 6,4-
4- hydroxyl -6- nitro-quinazolines (compound 5) (3.8g, 0.02mol) are placed in 100ml flasks, are slowly added to
Thionyl chloride 40ml and n,N-Dimethylformamide 1ml, reaction system are heated to 90 DEG C, and solid is completely dissolved, reaction 3h (detections
It was found that the reaction was complete at this time), it steams thionyl chloride decompression to obtain the chloro- 6- nitro-quinazolines (compound 6) of brown solid 4-
3.92g, yield 93.5%, HPLC purity 99.67%.1HNMR (300MHz, CDCl3) 89.56 (s, 1H), 8.39 (d, J=
1.5Hz 1H), 8.76 (d, J=1.5Hz, J=6.0Hz, 1H), 8.77 (d, J=6.0Hz, 1H).
The preparation of the chloro- 6- nitro-quinazolines (compound 6) of embodiment 7,4-
4- hydroxyl -6- nitro-quinazolines (compound 5) (3.8g, 0.02mol) are placed in 100ml flasks, are slowly added to
Thionyl chloride 40ml and n,N-Dimethylformamide 0.8ml, reaction system are heated to 100 DEG C, and solid is completely dissolved, and react 3h
(detection finds that the reaction was complete at this time) steams thionyl chloride decompression to obtain the chloro- 6- nitro-quinazolines (chemical combination of brown solid 4-
Object 6) 3.84g, yield 91.6%, HPLC purity 99.58%.
The preparation of the chloro- 6- nitro-quinazolines (compound 6) of embodiment 8,4-
4- hydroxyl -6- nitro-quinazolines (compound 5) (3.8g, 0.02mol) are placed in 100ml flasks, are slowly added to
Thionyl chloride 30ml and n,N-Dimethylformamide 1ml, reaction system are heated to 90 DEG C, and solid is completely dissolved, reaction 3h (detections
It was found that the reaction was complete at this time), it steams thionyl chloride decompression to obtain the chloro- 6- nitro-quinazolines (compound 6) of brown solid 4-
3.81g, yield 91.0%, HPLC purity 99.53%.
The preparation of embodiment 9, N '-chloroform imines amide (hydrochloride of compound 2)
It is same as Example 1, it differs only in：Formamidine salt is formamidine hydrochloride, and the molar ratio of formamidine hydrochloride and NCS are 1:
1.2.Reaction dissolvent is n,N-Dimethylformamide, and reaction temperature is 60 DEG C.
The preparation of embodiment 10, N '-chloroform imines amide (acetate of compound 2)
It is same as Example 1, it differs only in：Reaction dissolvent is dioxane, and reaction temperature is 120 DEG C.
The preparation of embodiment 11,4- hydroxyl -6- nitro-quinazolines (compound 5)
It is same as Example 3, it differs only in：Catalyst is copper chloride.Oxidant is peroxidized t-butyl perbenzoate.Alkali
For sodium acetate.Compound 3, the acetate of compound 2, catalyst, oxidant and alkali molar ratio be 1: 1: 0.1: 2: 1.Reaction
Temperature is 60 DEG C.
The preparation of embodiment 12,4- hydroxyl -6- nitro-quinazolines (compound 5)
It is same as Example 3, it differs only in：Catalyst is copper oxide.Oxidant is hydrogen peroxide.Alkali is cesium carbonate.
Compound 3, the acetate of compound 2, catalyst, oxidant and alkali molar ratio be 1: 1.5: 0.5: 4: 1.5.Reaction temperature is
120℃。
The preparation of the chloro- 6- nitro-quinazolines (compound 6) of embodiment 13,4-
It is same as Example 6, it differs only in：The mass volume ratio of compound 5 and thionyl chloride is 1: 7g/ml.Reaction
Temperature is 80 DEG C.
The preparation of the chloro- 6- nitro-quinazolines (compound 6) of embodiment 14,4-
It is same as Example 6, it differs only in：The mass volume ratio of compound 5 and thionyl chloride is 1: 7g/ml.Reaction
Temperature is 120 DEG C.
Claims (9)
1. a kind of preparation method of lapatinib key intermediate, which is characterized in that include the following steps：
(1) compound 2 or its salt is prepared with N- chlorosuccinimides generation chlorination in carbonamidine or its salt；
(2) compound 2 or its salt are reacted with compound 3, obtain compound 5；
(3) compound 6, i.e. lapatinib key intermediate is obtained by the reaction with thionyl chloride in the compound 5 described in,
2. the preparation method of lapatinib key intermediate according to claim 1, which is characterized in that in step (1), institute
It is formamidine hydrochloride or formamidine acetate to state formamidine salt, and carbonamidine or the molar ratio of its salt and N- chlorosuccinimides are 1: (1-1.2).
3. the preparation method of lapatinib key intermediate according to claim 1, which is characterized in that in step (1), chlorine
The reaction dissolvent of generation reaction is one or more of acetonitrile, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), dioxane, chlorine
The reaction temperature of generation reaction is 60-120 DEG C.
4. the preparation method of lapatinib key intermediate according to claim 1, which is characterized in that step (2) is reacted
It is carried out in the system comprising catalyst, oxidant, alkali and reaction dissolvent.
5. the preparation method of lapatinib key intermediate according to claim 4, which is characterized in that the catalyst
For one or more of copper acetate, copper chloride, copper oxide, iron chloride, the oxidant is tert-butyl hydroperoxide, peroxide
Change one or more of t-butyl perbenzoate, di-tert-butyl peroxide, hydrogen peroxide, the alkali is potassium carbonate, carbonic acid
One or more of sodium, sodium acetate, cesium carbonate, the reaction dissolvent are acetonitrile, n,N-Dimethylformamide, dimethyl Asia
One or more of sulfone, dioxane.
6. the preparation method of lapatinib key intermediate according to claim 4, which is characterized in that compound 3, chemical combination
Object 2 or its salt, catalyst, oxidant and alkali molar ratio be 1: (1-1.5): (0.1-0.5): (2-4): (1-1.5).
7. the preparation method of lapatinib key intermediate according to claim 1, which is characterized in that in step (2), instead
It is 60-120 DEG C to answer temperature.
8. the preparation method of lapatinib key intermediate according to claim 1, which is characterized in that in step (3), change
The mass volume ratio for closing object 5 and thionyl chloride is 1: (7-12) g/ml.
9. the preparation method of lapatinib key intermediate according to claim 1, which is characterized in that step (3) it is anti-
It is 80-120 DEG C to answer temperature, and reaction dissolvent is one kind in n,N-Dimethylformamide, acetonitrile, dimethyl sulfoxide (DMSO), dioxane
Or it is several.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996009294A1 (en) * | 1994-09-19 | 1996-03-28 | The Wellcome Foundation Limited | Substituted heteroaromatic compounds and their use in medicine |
| CN105111193A (en) * | 2015-09-12 | 2015-12-02 | 山东罗欣药业集团股份有限公司 | Lapatinib preparation method |
| CN106432205A (en) * | 2016-08-30 | 2017-02-22 | 成都美睿科生物科技有限公司 | Method for synthesizing lapatinib or intermediate thereof |
| WO2019128995A1 (en) * | 2017-12-26 | 2019-07-04 | 北京理工大学 | Ammonium salt, perovskite material, and application |
-
2018
- 2018-02-09 CN CN201810139151.3A patent/CN108373452B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996009294A1 (en) * | 1994-09-19 | 1996-03-28 | The Wellcome Foundation Limited | Substituted heteroaromatic compounds and their use in medicine |
| CN105111193A (en) * | 2015-09-12 | 2015-12-02 | 山东罗欣药业集团股份有限公司 | Lapatinib preparation method |
| CN106432205A (en) * | 2016-08-30 | 2017-02-22 | 成都美睿科生物科技有限公司 | Method for synthesizing lapatinib or intermediate thereof |
| WO2019128995A1 (en) * | 2017-12-26 | 2019-07-04 | 北京理工大学 | Ammonium salt, perovskite material, and application |
Non-Patent Citations (2)
| Title |
|---|
| GOERDELER JOACHIM等: "1,2,4-Thiadiazoles. I. Preparation and properties of 5-amino-1,2,4-thiadiazoles", 《CHEMISCHE BERICHTE》 * |
| YE SONG等: "Theoretical Study of the Isomerization Reaction of 1-3H Transfer on Formamidine Substituted by Halogen", 《CHINESE J. STRUCT. CHEM.》 * |
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