CN108373452B - Preparation method of lapatinib key intermediate - Google Patents
Preparation method of lapatinib key intermediate Download PDFInfo
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- CN108373452B CN108373452B CN201810139151.3A CN201810139151A CN108373452B CN 108373452 B CN108373452 B CN 108373452B CN 201810139151 A CN201810139151 A CN 201810139151A CN 108373452 B CN108373452 B CN 108373452B
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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
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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- C07—ORGANIC CHEMISTRY
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- 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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Abstract
The invention discloses a preparation method of a lapatinib key intermediate, which comprises the following steps: (1) chlorination of formamidine or its salt with N-chlorosuccinimideCarrying out substitution reaction to obtain a compound 2 or a salt thereof; (2) reacting compound 2 or a salt thereof with compound 3 to give compound 5; (3) and reacting the compound 5 with thionyl chloride to obtain a compound 6, namely a lapatinib key intermediate. The method has the advantages of cheap and easily obtained starting materials, simplified steps, high atom utilization rate, mild reaction conditions, high yield, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a lapatinib key intermediate.
Background
As an anti-tumor drug, lapatinib (lapatinib) has the chemical name of N- (3-chloro-4- ((3-fluorophenyl) methoxy) phenyl) -6- (5- (((2- (methylsulfonyl) ethyl) amino) methyl) -2-furyl) -4-quinazolinamine di-p-toluenesulfonate, is approved by the FDA in the United states and is marketed in 3 months 2007, is a 4-anilinoquinazoline receptor tyrosine kinase inhibitor and is used for treating advanced or metastatic breast cancer.
4-chloro-6-nitro quinazoline is used as a key intermediate of lapatinib, and patents WO05046678 and WO020255 report preparation methods of lapatinib and related intermediates. In the known synthetic route, 6-halogenated-quinazoline-4-ketone is directly used as a raw material and is prepared into an intermediate 6-halogenated-chloroquinazoline with chlorinating agents such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride and the like, and the method directly uses expensive 6-halogenated-quinazoline-4-ketone as a raw material, so that the problem of high industrial production cost is caused, the method is not suitable for large-scale industrial production, the environment is polluted in the production process, and the safety risk is difficult to control.
At present, regarding the preparation method of lapatinib, although a plurality of methods exist for side chain linkage and quinazoline cyclization, the problems of complex process, high requirements on reaction conditions and operation, expensive starting materials, low atom utilization rate, heavy metal pollution, low yield and the like exist.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a novel method for constructing a lapatinib intermediate quinazoline ring, which has the advantages of simple process, easily obtained raw materials, environmental friendliness, controllable operation, high yield and purity and suitability for industrial production.
The technical scheme is as follows: the preparation method of the lapatinib key intermediate comprises the following steps:
(1) performing chlorination reaction on formamidine or salts thereof and N-chlorosuccinimide to prepare a compound 2 or salts thereof;
(2) reacting compound 2 or a salt thereof with compound 3 to give compound 5;
(3) the compound 5 reacts with thionyl chloride to obtain a compound 6, namely a lapatinib key intermediate,
in the step (1), the formamidine salt is formamidine hydrochloride or formamidine acetate, and formamidine acetate is preferred. The molar ratio of formamidine or a salt thereof to N-chlorosuccinimide is 1: (1-1.2), preferably 1:1.
In the step (1), the reaction solvent of the chlorination reaction is one or more of acetonitrile, N-dimethylformamide, dimethyl sulfoxide and dioxane, preferably acetonitrile. The reaction temperature for the chlorination reaction is 60 to 120 deg.C, preferably 80 to 100 deg.C. The reaction time of the chlorination reaction is 5-7 h.
The reaction of step (2) is carried out in a system comprising a catalyst, an oxidant, a base and a reaction solvent.
The catalyst is one or more of copper acetate, copper chloride, copper oxide and ferric chloride, and is preferably copper acetate. The oxidant is one or more of tert-butyl hydroperoxide, tert-butyl peroxybenzoate, di-tert-butyl peroxide and hydrogen peroxide, and is preferably tert-butyl hydroperoxide. The alkali is one or more of potassium carbonate, sodium acetate and cesium carbonate, and preferably potassium carbonate. The reaction solvent is one or more of acetonitrile, N-dimethylformamide, dimethyl sulfoxide and dioxane, and is preferably acetonitrile.
The molar ratio of the compound 3, the compound 2 or the salt thereof, the catalyst, the oxidant and the base is 1: (1-1.5): (0.1-0.5): (2-4): (1-1.5), preferably 1:1.25:0.1:3: 1.
In the step (2), the salt of the compound 2 is hydrochloride or acetate of the compound 2, and preferably acetate. The reaction temperature is 60 to 120 ℃ and preferably 80 to 100 ℃. The reaction time is 22-26 h.
In the step (3), the mass-to-volume ratio of the compound 5 to the thionyl chloride is 1: (7-12) g/ml, preferably 1: (7.9-10.5) g/ml. The thionyl chloride is used in excess.
The reaction temperature in step (3) is 80 to 120 ℃, preferably 90 to 100 ℃. The reaction solvent is N, N-dimethylformamide. The reaction time is 2.5-3.5 h.
In more detail, the preparation method of the lapatinib key intermediate comprises the following steps:
a. heating formamidine (compound 1) or a salt thereof and N-chlorosuccinimide (NCS) to react under the condition of a reaction solvent;
b. adding a starting material 2-iodine-5-nitrotoluene (compound 3), a catalyst, an oxidant and alkali into the reaction liquid obtained in the step (a), and heating to react to obtain 4-hydroxy-6-nitroquinazoline (compound 5);
c. the 4-hydroxy-6-nitro quinazoline (compound 5) is heated to react under the condition of thionyl chloride to generate 4-chloro-6-nitro quinazoline (compound 6), namely the lapatinib key intermediate.
The preparation method of the lapatinib is prepared by taking the compound 1 as an initial raw material through a series of reactions as follows:
has the advantages that: the method for constructing the quinazoline ring by using the starting raw materials of 2-iodine-5-nitrotoluene and formamidine acetate is novel and has high atom utilization rate; the invention has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple and convenient operation, high yield and good industrialization prospect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
EXAMPLE 1 preparation of N' -Chloroimidamide (acetate salt of Compound 2)
Formamidine acetate (5.2g, 0.05mol) was dissolved in 30mL of acetonitrile, N-chlorosuccinimide (6.68g, 0.05mol) was added, the reaction was heated to 80 ℃ and stirred for reaction for 6h, and the resulting reaction solution was left for the next step.
EXAMPLE 2 preparation of 4-hydroxy-6-nitroquinazoline (Compound 5)
2-iodo-5-nitrotoluene (10.5g, 0.04mol), copper acetate (0.72g, 0.004mol), tert-butyl hydroperoxide (15.4g, 0.12mol) and potassium carbonate (5.5g, 0.04mol) were added to the reaction solution obtained in example 1, the reaction system was heated to 80 ℃, stirred for reaction for 24h, cooled to room temperature, poured into ice water, filtered, and washed with water to obtain 7.13g of needle crystals of 4-hydroxy-6-nitroquinazoline (compound 5), yield 93.3%, and HPLC purity 99.80%.
EXAMPLE 3 preparation of 4-hydroxy-6-nitroquinazoline (Compound 5)
2-iodo-5-nitrotoluene (10.5g, 0.04mol), copper chloride (0.72g, 0.004mol), tert-butylhydroperoxide (15.4g, 0.12mol) and potassium carbonate (5.5g, 0.04mol) were added to the reaction solution obtained in example 1, the reaction system was heated to 90 ℃, stirred for reaction for 24h, cooled to room temperature, poured into ice water, filtered, and washed with water to obtain 6.97g of needle-like crystals of 4-hydroxy-6-nitroquinazoline (compound 5), yield 91.2%, and HPLC purity 99.72%.
EXAMPLE 4 preparation of 4-hydroxy-6-nitroquinazoline (Compound 5)
2-iodo-5-nitrotoluene (10.5g, 0.04mol), copper acetate (0.72g, 0.004mol), tert-butyl hydroperoxide (20.6, 0.16mol) and potassium carbonate (5.5g, 0.04mol) were added to the reaction solution obtained in example 1, the reaction system was heated to 80 ℃, stirred for reaction for 24h, cooled to room temperature, poured into ice water, filtered, and washed with water to obtain 6.90g of needle crystals of 4-hydroxy-6-nitroquinazoline (compound 5), yield 90.3%, and HPLC purity 99.74%.
EXAMPLE 5 preparation of 4-hydroxy-6-nitroquinazoline (Compound 5)
2-iodo-5-nitrotoluene (10.5g, 0.04mol), copper acetate (0.72g, 0.004mol), tert-butyl hydroperoxide (15.4g, 0.12mol) and potassium carbonate (5.5g, 0.04mol) were added to the reaction solution obtained in example 1, the reaction system was heated to 100 ℃, stirred for reaction for 24h, cooled to room temperature, poured into ice water, filtered, and washed with water to obtain 7.08g of needle crystals of 4-hydroxy-6-nitroquinazoline (compound 5), yield 92.6%, and HPLC purity 99.62%.
EXAMPLE 6 preparation of 4-chloro-6-nitroquinazoline (Compound 6)
4-hydroxy-6-nitroquinazoline (compound 5) (3.8g, 0.02mol) was placed in a 100ml flask, thionyl chloride 40ml and N, N-dimethylformamide 1ml were slowly added, the reaction system was heated to 90 ℃, the solid was completely dissolved, the reaction was carried out for 3 hours (completion of the reaction was detected), thionyl chloride was evaporated under reduced pressure to give 4-chloro-6-nitroquinazoline (compound 6) as a brown solid (3.92 g, yield 93.5%, HPLC purity 99.67%).1HNMR(300MHz，CDCl3)9.56(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)。
EXAMPLE 7 preparation of 4-chloro-6-nitroquinazoline (Compound 6)
4-hydroxy-6-nitro quinazoline (compound 5) (3.8g, 0.02mol) was placed in a 100ml flask, thionyl chloride 40ml and N, N-dimethylformamide 0.8ml were slowly added, the reaction system was heated to 100 ℃, the solid was completely dissolved, the reaction was carried out for 3 hours (detection showed that the reaction was complete), thionyl chloride was evaporated under reduced pressure to give 3.84g of brown solid 4-chloro-6-nitro quinazoline (compound 6), yield was 91.6%, and HPLC purity was 99.58%.
EXAMPLE 8 preparation of 4-chloro-6-nitroquinazoline (Compound 6)
4-hydroxy-6-nitro quinazoline (compound 5) (3.8g, 0.02mol) was placed in a 100ml flask, 30ml of thionyl chloride and 1ml of N, N-dimethylformamide were slowly added, the reaction system was heated to 90 ℃, the solid was completely dissolved, the reaction was carried out for 3 hours (completion of the reaction was detected), and thionyl chloride was evaporated under reduced pressure to give 3.81g of brown solid 4-chloro-6-nitro quinazoline (compound 6), yield 91.0%, and HPLC purity 99.53%.
EXAMPLE 9 preparation of N' -Chloroimidamide (hydrochloride salt of Compound 2)
As in example 1, the only difference is: the formamidine salt is formamidine hydrochloride, and the molar ratio of the formamidine hydrochloride to NCS is 1: 1.2. the reaction solvent is N, N-dimethylformamide, and the reaction temperature is 60 ℃.
EXAMPLE 10 preparation of N' -Chloroimidamide (acetate salt of Compound 2)
As in example 1, the only difference is: the reaction solvent is dioxane, and the reaction temperature is 120 ℃.
EXAMPLE 11 preparation of 4-hydroxy-6-nitroquinazoline (Compound 5)
As in example 3, the only difference is: the catalyst is cupric chloride. The oxidant is tert-butyl peroxybenzoate. The base is sodium acetate. The mol ratio of the compound 3 to the acetate of the compound 2 to the catalyst to the oxidant to the base is 1: 1: 0.1: 2: 1. the reaction temperature was 60 ℃.
EXAMPLE 12 preparation of 4-hydroxy-6-nitroquinazoline (Compound 5)
As in example 3, the only difference is: the catalyst is copper oxide. The oxidizing agent is hydrogen peroxide. The base is cesium carbonate. The mol ratio of the compound 3 to the acetate of the compound 2 to the catalyst to the oxidant to the base is 1: 1.5: 0.5: 4: 1.5. the reaction temperature was 120 ℃.
EXAMPLE 13 preparation of 4-chloro-6-nitroquinazoline (Compound 6)
As in example 6, the only difference is: the mass-to-volume ratio of the compound 5 to the thionyl chloride is 1: 7 g/ml. The reaction temperature was 80 ℃.
EXAMPLE 14 preparation of 4-chloro-6-nitroquinazoline (Compound 6)
As in example 6, the only difference is: the mass-to-volume ratio of the compound 5 to the thionyl chloride is 1: 7 g/ml. The reaction temperature was 120 ℃.
Claims (5)
1. A preparation method of a lapatinib key intermediate is characterized by comprising the following steps:
(1) performing chlorination reaction on formamidine or salts thereof and N-chlorosuccinimide to prepare a compound 2 or salts thereof;
(2) reacting compound 2 or a salt thereof with compound 3 to give compound 5;
(3) the compound 5 reacts with thionyl chloride to obtain a compound 6, namely a lapatinib key intermediate,
the reaction of step (2) is carried out in a system comprising a catalyst, an oxidant, a base and a reaction solvent;
the catalyst is one or more of copper acetate, copper chloride, copper oxide and ferric chloride, the oxidant is one or more of tert-butyl hydroperoxide, tert-butyl peroxybenzoate, di-tert-butyl peroxide and hydrogen peroxide, the alkali is one or more of potassium carbonate, sodium acetate and cesium carbonate, and the reaction solvent is one or more of acetonitrile, N-dimethylformamide, dimethyl sulfoxide and dioxane;
the molar ratio of the compound 3, the compound 2 or the salt thereof, the catalyst, the oxidant and the base is 1: (1-1.5): (0.1-0.5): (2-4): (1-1.5);
in the step (2), the reaction temperature is 60-120 ℃.
2. The method for preparing lapatinib key intermediate according to claim 1, wherein in step (1), the formamidine salt is formamidine hydrochloride or formamidine acetate, and the molar ratio of formamidine or its salt to N-chlorosuccinimide is 1: (1-1.2).
3. The method for preparing the lapatinib key intermediate according to claim 1, wherein in step (1), the reaction solvent for the chlorination reaction is one or more of acetonitrile, N-dimethylformamide, dimethyl sulfoxide and dioxane, and the reaction temperature for the chlorination reaction is 60-120 ℃.
4. The method for preparing lapatinib key intermediate according to claim 1, wherein in step (3), the mass-to-volume ratio of compound 5 to thionyl chloride is 1: (7-12) g/ml.
5. The preparation method of lapatinib key intermediate according to claim 1, wherein the reaction temperature in step (3) is 80-120 ℃, and the reaction solvent is one or more of N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide and dioxane.
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| 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 |
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