CN102295638B - Novel method for preparing lapatinib - Google Patents
Novel method for preparing lapatinib Download PDFInfo
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- CN102295638B CN102295638B CN201010208544.9A CN201010208544A CN102295638B CN 102295638 B CN102295638 B CN 102295638B CN 201010208544 A CN201010208544 A CN 201010208544A CN 102295638 B CN102295638 B CN 102295638B
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- 0 *c1ccc(C=O)[o]1 Chemical compound *c1ccc(C=O)[o]1 0.000 description 1
- SDNXQWUJWNTDCC-UHFFFAOYSA-N CS(CCN)(=O)=O Chemical compound CS(CCN)(=O)=O SDNXQWUJWNTDCC-UHFFFAOYSA-N 0.000 description 1
- UHFPFDMMKYQMLC-UHFFFAOYSA-N Fc1cccc(COc(c(Cl)c2)ccc2Nc(c2c3)ncnc2ccc3I)c1 Chemical compound Fc1cccc(COc(c(Cl)c2)ccc2Nc(c2c3)ncnc2ccc3I)c1 UHFPFDMMKYQMLC-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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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- 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 provides a novel method for preparing lapatinib. Specifically, the method for preparing a compound shown in a formula I or medicinal salt thereof comprises the following steps of: (1) reacting a compound shown in a formula II or salt thereof and a compound shown in a formula III at the first temperature; (2) reacting a reaction product obtained in the step (1) and a compound shown in a formula IV in reaction liquid in the step (1) at the second temperature; (3) adding a reducing agent into reaction liquid in the step (2) to reduce the reaction product obtained in the step (2) to obtain the compound shown in the formula I; and optionally (4) reacting the compound shown in the formula I and obtained in the step (3) and acid to obtain medicinal salt of the compound shown in the formula I. The method is high in yield, and can overcome one or more disadvantages of the conventional method and the purity of a product is high.
Description
Technical field
The invention belongs to pharmaceutical chemistry field; be specifically related to a kind of synthesized micromolecule targeted drug lapatinibditosylate, i.e. N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-6-[5-({ [2-(methylsulfonyl) ethyl] amino } methyl)-2-furyl] preparation method of-4-quinolyl amine.
Background technology
Lapatinibditosylate (structural formula I); be N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-6-[5-({ [2-(methylsulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinolyl amine is a kind of small molecules targeted drug, at present for the treatment of mammary cancer.The structural formula of lapatinibditosylate is as follows:
A kind of lapatinibditosylate preparation method that WO9935146A1 has reported, the method is summarized in following reaction scheme 1:
Reaction scheme 1,
More than in reaction, use hypertoxic organotin reagent
there is very high risk for security, drug safety and the environmental protection of producing.
In addition, WO2008024439 has reported the synthetic method of another lapatinibditosylate, and the method is summarized in following reaction scheme 2:
Reaction scheme 2
The method comprises the reactions steps of nitrogen protection, needs carry out the Boc protection on N and slough Boc protection, and obviously this can increase operating time and production cost and may produce such as issues of purification of some other problem etc., is unfavorable for suitability for industrialized production.
CN1440403A discloses another lapatinibditosylate synthetic method, and the method is summarized in following reaction scheme 3:
Reaction scheme 3
The method that above-mentioned document is recorded is used commercial scale production, and yield is higher, but still has certain defect:
1) aldehyde radical in reaction intermediate is at high temperature unstable, and claimed measure is strict, increases the difficulty of suitability for industrialized production; 2) from initial starting material
need 3 steps to end product, reaction process is longer; 3) each reactions steps all needs to carry out purification process, aftertreatment complexity, and the production cycle is long; 4) because reactions steps is long, need aftertreatment at every turn, use a large amount of organic solvents, contaminate environment, and can greatly increase production cost.
In view of still there is at least one following defect in the synthetic method of existing lapatinibditosylate: need to use that the high and/or environmentally harmful solvent of toxicity and/or reagent, reaction scheme are long, the operating time is long, reactant and/or intermediate is unstable in reaction system, need numerous and diverse purge process or purge process is more complicated, organic solvent and/or using amount of reagent more, be not suitable for suitability for industrialized production etc., it is very urgent therefore finding better synthetic route.
Summary of the invention
Technical problem to be solved by this invention is to overcome the problem existing in the synthetic lapatinibditosylate method of prior art, and a kind of method of the synthetic lapatinibditosylate with at least one following advantage is provided: avoid using toxicity high and/or environmentally harmful solvent and/or reagent, reaction scheme is short, the operating time is short, reactant and intermediate is stable in reaction system, purge process that need not be numerous and diverse or purge process is simple, organic solvent and/or using amount of reagent is few, be applicable to suitability for industrialized production etc.
The inventor is surprisingly found out that, use 2-(methylsulfonyl) ethamine or its salt (in this article, can be called Compound I I or formula II compound, although for example may only draw hereinafter 2-(methylsulfonyl) ethamine in reaction process, but should understand can be the pharmacologically acceptable salt of 2-(methylsulfonyl) ethamine) in amino and 5-aldehyde radical-2-furans boric acid (in this article, can be called compound III or formula III compound) in aldehyde radical reaction and form imines, can protect unsettled aldehyde radical; Then directly carry out suzuki coupling; Restore imines and obtain lapatinibditosylate or its salt (in this article, can be called Compound I or formula I compound, although for example may only draw lapatinibditosylate in reaction process hereinafter, but should understand can be the salt that forms lapatinibditosylate after simple process), this simple one kettle way is prepared lapatinibditosylate can overcome one or more defects that prior art exists completely.
For this reason, first aspect present invention provides the method for preparation with following formula I compound or pharmaceutically acceptable salt thereof,
The method comprises the following steps:
(1) formula II compound or its salt reacts at the first temperature with formula III compound:
(2), in the reaction solution of step (1), make step (1) gained reaction product and react at the second temperature with following formula IV compound:
(3) in the reaction solution of step (2), add reductive agent, make the reduction of step (2) gained reaction product, obtain formula I compound; With optional
(4) make step (3) gained formula I compound and acid-respons, obtain the pharmaceutical salts of formula I compound.
According to the method for first aspect present invention, wherein step (1) is to react in solvent.In one embodiment, described solvent is selected from one or more in amides organic solvent, alcohol organic solvent, ether organic solvent, or is selected from water and the above-mentioned mixture that is selected from one or more organic solvents in acid amides, alcohol, ether.In one embodiment, described amides organic solvent is selected from DMF and N,N-dimethylacetamide.In one embodiment, described alcohol organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol and the trimethyl carbinol.In one embodiment, wherein said ether organic solvent is selected from ether and tetrahydrofuran (THF).In one embodiment, the solvent in step (1) is selected from one or more in alcohol organic solvent and ether organic solvent.In one embodiment, the solvent in step (1) is selected from DMF, ethanol, tetrahydrofuran (THF) or its mixture.
According to the method for first aspect present invention, wherein step (1) is to react under alkali exists.In one embodiment, described alkali is organic bases or mineral alkali.In one embodiment, described alkali is organic bases.In one embodiment, described organic bases is selected from triethylamine.
According to the method for first aspect present invention, wherein step (1) is to react under catalyzer exists.In one embodiment, described catalyzer is palladium catalyst.In one embodiment, described catalyzer is selected from 1,1 '-bis-(diphenylphosphine) ferrocene Palladous chloride ((dppf) PdCl
2), palladium charcoal, PdCl
2or its mixture.
According to the method for first aspect present invention, wherein the first temperature described in step (1) is 0 DEG C to 80 DEG C, or 0 DEG C to solvent refluxing temperature, or identical with the second temperature described in step (2).In one embodiment, described in step (1), the first temperature is selected from: 5 DEG C to solvent refluxing temperature, 10 DEG C to solvent refluxing temperature, 10 DEG C to 60 DEG C, 10 DEG C to 50 DEG C, 15 DEG C to 40 DEG C, 15 DEG C to 35 DEG C, 20 DEG C to 30 DEG C, about room temperature or identical with the second temperature described in step (2).
According to the method for first aspect present invention, wherein the second temperature described in step (2) is 40 DEG C to 130 DEG C, or 40 DEG C to solvent refluxing temperature, or identical with the first temperature described in step (1).In one embodiment, described in step (2), the first temperature is selected from: 45 DEG C to solvent refluxing temperature, 50 DEG C to solvent refluxing temperature, 50 DEG C to 120 DEG C, 50 DEG C to 100 DEG C, 50 DEG C to 90 DEG C, 50 DEG C to 80 DEG C, 55 DEG C to 80 DEG C, solvent refluxing temperature or identical with the first temperature described in step (1).
According to the method for first aspect present invention, wherein the salt of formula II compound described in step (1) is the salt of formula II compound and mineral acid or organic acid formation.In one embodiment, the salt of formula II compound described in step (1) is formula II compound and the salt that is selected from following mineral acid formation: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.In one embodiment, the salt of formula II compound described in step (1) is formula II compound and the salt that is selected from following organic acid formation: trifluoroacetic acid, toxilic acid, tosic acid, methylsulfonic acid.
According to the method for first aspect present invention, wherein step (1) gained reaction product is with transition intermediate shown in following formula 1:
According to the method for first aspect present invention, wherein step (2) gained reaction product is with transition intermediate shown in following formula 2:
According to the method for first aspect present invention, wherein the formula IV compound in step (2) is that formula II compound or its salt in step (1) joins in reaction solvent together with formula III compound.
According to the method for first aspect present invention, wherein the formula IV compound in step (2) is that formula II compound or its salt in step (1) reacts with formula III compound after complete and joins in reaction solution.
According to the method for first aspect present invention, wherein the reductive agent in step (3) is selected from sodium triacetoxy borohydride, sodium borohydride and POTASSIUM BOROHYDRIDE.In one embodiment, described reductive agent is sodium triacetoxy borohydride.
According to the method for first aspect present invention, wherein the temperature of step (3) reduction reaction is-20 DEG C to 40 DEG C.In one embodiment, the temperature of step (3) reduction reaction is-10 DEG C to 40 DEG C, 0 DEG C to 40 DEG C, 5 DEG C to 35 DEG C, 10 DEG C to 35 DEG C, 15 DEG C to 30 DEG C, 20 DEG C to 30 DEG C or about room temperature.
According to the method for first aspect present invention, the described acid that wherein step (4) is used to form pharmaceutical salts is selected from: tosic acid.
According to the method for first aspect present invention, wherein the reaction of step (2) is carried out in step (1) gained reaction solution.
According to the method for first aspect present invention, wherein the reaction of step (3) is carried out in step (2) gained reaction solution.
According to the method for first aspect present invention, wherein the reaction of step (4) is carried out in step (3) gained reaction solution.
According to the method for first aspect present invention, wherein said step (1) to (3) any one is carried out under nitrogen protection.
According to the method for first aspect present invention, the start material of wherein said step (1) and (2) is simultaneously or substantially adds in reaction solvent simultaneously.According to the method for first aspect present invention, the start material of wherein said step (1) and (2) is simultaneously or substantially adds in reaction solvent simultaneously, and then react.According to the method for first aspect present invention, the start material of wherein said step (1) and (2) is simultaneously or substantially adds in reaction solvent simultaneously, and then carries out the reaction of production 1 transition intermediate and production 2 transition intermediates.According to the method for first aspect present invention, the start material of wherein said step (1) and (2) is simultaneously or substantially adds in reaction solvent simultaneously, then at the first temperature, carry out the reaction of production 1 transition intermediate, then at the second temperature, carry out the reaction of production 2 transition intermediates.According to the method for first aspect present invention, the start material of wherein said step (1) and (2) is simultaneously or substantially adds in reaction solvent simultaneously, then at the first temperature and the second temperature, carries out respectively the reaction of production 1 transition intermediate and formula 2 transition intermediates.According to the method for first aspect present invention, the start material of wherein said step (1) and (2) is simultaneously or substantially adds in reaction solvent simultaneously, then at solvent refluxing temperature, carries out greatly the reaction of production 1 transition intermediate and formula 2 transition intermediates.
Second aspect present invention provides the method for preparation I compound or its pharmaceutical salts,
The method comprises the following steps:
(a) starting material compound II, compound III, compound IV, catalyzer are dissolved in organic solvent to reacting by heating;
(b) add reductive agent reaction to obtain Compound I;
Or
(a) starting material compound II, compound III are dissolved in organic solvent, then add compound IV, catalyzer, reacting by heating;
(b) add reductive agent reaction to obtain Compound I;
Its chemical equation is as follows:
According to method described in second aspect present invention, wherein each reaction conditions is independently of one another as described in first aspect present invention.
Third aspect present invention provides the method for preparation I compound or its pharmaceutical salts,
The method comprises the following steps:
(a) starting material compound II, compound III, compound IV, catalyzer are dissolved in solvent, reaction generates transition intermediate 1;
(b) heating, transition intermediate 1 reacts with starting material compound IV and generates transition intermediate 2;
(c) add reductive agent, transition intermediate 2 is reduced and obtains lapatinibditosylate;
Or
(a) starting material compound II, compound III are dissolved in solvent, reaction generates transition intermediate 1;
(b) add compound IV, catalyzer, heating, transition intermediate 1 reacts with initial compounds IV and generates transition intermediate 2;
(c) add reductive agent, transition intermediate 2 is reduced and obtains lapatinibditosylate;
Its chemical equation is as follows:
According to method described in third aspect present invention, wherein each reaction conditions is independently of one another as described in first aspect present invention.
Fourth aspect present invention provides with following formula I compound or pharmaceutically acceptable salt thereof:
It is prepared by method described in first aspect present invention, second aspect or the third aspect.
The feature that arbitrary specific embodiments of either side of the present invention or this either side has is equally applicable to other arbitrary specific embodiments of this aspect, is applicable to too arbitrary specific embodiments of other either side or other either side.
Detailed Description Of The Invention:
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
As described herein, term " the first temperature " and " the second temperature ", refer to temperature used under two reaction conditionss, should not be construed as the precedence relationship on any time between them.
As described herein, term " solvent refluxing temperature " should can be regarded as boiling temperature or the reflux temperature of reaction solvent, or can be understood as boiling temperature or the reflux temperature of reaction mixture, particularly, under mixture even comprises that reaction reagent is to the influential situation of boiling temperature, to be appreciated that boiling temperature or the reflux temperature of reaction mixture for this reason at reaction solvent.It will be appreciated by those skilled in the art that above-mentioned " solvent refluxing temperature " should not be limited to the boiling temperature of solvent, although sometimes really can be identical with boiling temperature or close.
As described herein, term " pharmaceutical salts " and representing certain compound " salt " that forms etc., should do the understanding of broad sense, be the industrial applicable salt that parent compound and any acid or alkali form, comprise salt applicable in chemosynthesis process (the salt type intermediate for example forming for purifying object) and pharmacy and/or the acceptable salt of physiology (for example, by being applied to the applicable salt of human body).
As described herein, term " transition intermediate " can be understood as the intermediate in chemosynthesis process, or the reaction product of a certain chemical reaction.The for example step of first aspect present invention method (1) gained formula 1 transition intermediate, this class transition intermediate can extract from reaction mixture, can also from reaction mixture, not extract and direct in-situ (is appreciated that for the process of next reactions steps, now can the formation of corresponding transition intermediate and/or the consumption of start material be detected by for example HPLC method of appropriate means, and the degree of their formation and/or consumption).In a preferred embodiment, the transition intermediate that the inventive method obtains from reaction mixture, do not extract and direct in-situ for the process of next reactions steps.
The method according to this invention, wherein said step (1) to (4) can be carried out in same solvent, and original position is reacted.It will be appreciated by those skilled in the art that the inventive method is that one is suitable for industrialized one kettle way production technique very much.
For convenience of description, in the present invention, can be by 2-(methylsulfonyl) ethamine or its salt referred to as Compound I I; By 5-aldehyde radical-2-furans boric acid referred to as compound III; By iodo-6-{ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-4-quinolyl amine referred to as compound IV; N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl-6-[5-({ [2-(methylsulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinolyl amine be lapatinibditosylate be called for short Compound I, also comprise its salt.
In one embodiment, Compound I of the present invention is that the preparation method of lapatinibditosylate is as follows:
(1) starting material compound II, compound III, compound IV, catalyzer are dissolved in organic solvent to reacting by heating;
(2) add reductive agent reaction to obtain Compound I;
Or
(1) starting material compound II, compound III are dissolved in organic solvent, then add compound IV, catalyzer, reacting by heating;
(2) add reductive agent reaction to obtain Compound I;
Its chemical equation is as follows:
Wherein Compound I I is 2-(methylsulfonyl) ethamine or its pharmacologically acceptable salt; wherein pharmacologically acceptable salt is inorganic acid salt or organic acid salt; wherein mineral acid is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acid is selected from trifluoroacetic acid, toxilic acid, tosic acid and methylsulfonic acid.
In a specific embodiment, the reaction process of Compound I of the present invention is as follows:
(1) starting material compound II, compound III, compound IV, catalyzer are dissolved in solvent, reaction generates transition intermediate 1;
(2) heating, transition intermediate 1 reacts with starting material compound IV and generates transition intermediate 2;
(3) add reductive agent, transition intermediate 2 is reduced and obtains lapatinibditosylate;
Or
(1) starting material compound II, compound III are dissolved in solvent, reaction generates transition intermediate 1;
(2) add compound IV, catalyzer, heating, transition intermediate 1 reacts with initial compounds IV and generates transition intermediate 2;
(3) add reductive agent, transition intermediate 2 is reduced and obtains lapatinibditosylate;
Its chemical equation is as follows:
Wherein Compound I I is 2-(methylsulfonyl) ethamine or its pharmacologically acceptable salt; wherein pharmacologically acceptable salt is inorganic acid salt or organic acid salt; wherein mineral acid is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acid is selected from trifluoroacetic acid, toxilic acid, tosic acid and methylsulfonic acid.
In lapatinibditosylate preparation method of the present invention, the selection of described solvent is very widely, be selected from amides organic solvent, alcohol organic solvent, one or more in ether organic solvent, or water and amides organic solvent, alcohol organic solvent, the mixture of ether organic solvent, wherein amides organic solvent is selected from N, dinethylformamide and N,N-dimethylacetamide; Alcohol organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol and the trimethyl carbinol; Ether organic solvent is selected from ether and tetrahydrofuran (THF); Wherein preferred alcohol organic solvent and ether organic solvent.
In lapatinibditosylate preparation method of the present invention, described catalyzer is selected from 1,1 '-bis-(diphenylphosphine) ferrocene Palladous chloride ((dppf) PdCl
2), palladium charcoal and PdCl
2.
In preparation method of the present invention, described reductive agent is selected from sodium triacetoxy borohydride, sodium borohydride and POTASSIUM BOROHYDRIDE, wherein preferred sodium triacetoxy borohydride.
In preparation method of the present invention, the temperature of reaction that reaction generation transition intermediate 1 adopts is 0～80 DEG C; The temperature of reaction that reaction generation transition intermediate 2 adopts is 40 DEG C～130 DEG C; The temperature of reaction that reduction imines obtains lapatinibditosylate employing is-20～40 DEG C.
Lapatinibditosylate preparation method of the present invention, each starting raw material all can make full use of each functional group in chemical structure in reaction process, and reaction obtains required the finished product.Specifically, the amino in Compound I I reacts with the aldehyde radical in compound III and forms imines, has avoided aldehyde radical to be at high temperature oxidized cause unstable; And aldehyde radical formation imines is very easy in compound III, selectivity is good.Simultaneously the aldehyde radical in compound III does not affect Suzuki reaction subsequently after forming imines, and the transition intermediate 1 that Compound I I reacts generation with compound III reacts with compound IV and obtains transition intermediate 2; Then under the effect of reductive agent, transition intermediate 2 is reduced and obtains the finished product lapatinibditosylate.
In prior art, taking industrialization preferably reaction scheme 3 as example, need compound
and compound
reaction obtains compound
in preparation process, need strict control temperature of reaction and acid-basicity, because compound
aldehyde radical is unsettled in high temperature and soda acid, oxidizing reaction easily occurs and generate carboxyl, so just inevitably increases impurity, reduces productive rate.
Simultaneously because compound III and compound IV are reacted the chloro-4-{[(3-fluorophenyl of the 5-{4-[(3-obtaining) methyl] oxygen base } phenyl) amino]-6-quinazolyl }-2 furan carboxyaldehyde need to enrichment from solution, prior art adopts the chloro-4-{[(3-fluorophenyl of 5-{4-[(3-) methyl] oxygen base } phenyl) amino]-6-quinazolyl }-2 furan carboxyaldehyde becomes the form enrichment of hydrochloride, for the refining chloro-4-{[(3-fluorophenyl of 5-{4-[(3-) methyl] oxygen base } phenyl) amino]-6-quinazolyl }-2 furan carboxyaldehyde hydrochloride, need be by chloro-5-{4-[(3-4-{[(3-fluorophenyl) methyl] oxygen base } phenyl) amino]-6-quinazolyl }-2 furan carboxyaldehyde hydrochloride converts the chloro-4-{[(3-fluorophenyl of 5-{4-[(3-to) methyl] oxygen base } phenyl) amino]-6-quinazolyl }-2 furan carboxyaldehyde tosilate processes, its last handling process is very loaded down with trivial details.And then the chloro-4-{[(3-fluorophenyl of dissolving 5-{4-[(3-) methyl] oxygen base } phenyl) amino]-6-quinazolyl }-2 furan carboxyaldehyde tosilate, I reacts with Compound I, obtains reduction after imines and obtains final product lapatinibditosylate.So complicated operation is very disadvantageous for suitability for industrialized production.
Preparation method of the present invention, is also suitable for the preparation of lapatinibditosylate derivative.
Preparation method of the present invention adopts one kettle way to prepare lapatinibditosylate, adopts the amino of Compound I I 2-(methylsulfonyl) ethamine and the aldehyde radical of compound III 5-aldehyde radical-2-furans boric acid to form imines---protect unsettled aldehyde radical; Then directly carry out suzuki coupling; Restore imines and obtain lapatinibditosylate free alkali.Processing step shortens, and the production cycle shortens, and pilot process does not need aftertreatment, easy and simple to handle, there is no harsh reaction conditions, and reaction is easy to control, and productive rate is high, reaches more than 79%, obtains product purity high, reaches more than 98%, is more applicable to scale suitability for industrialized production.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
embodiment 1
In 20L reactor, add 10L N, dinethylformamide, then adds starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, (dppf) PdCl successively
210g, stir, nitrogen protection, 25 DEG C of stirrings, after TLC analysis starting compound III reacts completely, be warming up to back flow reaction, after TLC analysis starting compound IV reacts completely, be cooled to room temperature, add sodium triacetoxy borohydride 630g (2.97mol), stirring at room temperature reaction, after TLC analysis transition intermediate 2 reacts completely, suction filtration, filtrate adds 20L methylene dichloride, with the sodium hydroxide solution washing of 10L 1N, the washing of 20L saturated nacl aqueous solution, anhydrous sodium sulfate drying, suction filtration, filtrate adds and under stirring, adds 750g (3.94mol) tosic acid, room temperature crystallization, suction filtration, dry, obtain lapatinibditosylate tosilate 731.4g, yield 79.9%, HPLC purity 98.69%.
embodiment 2
In 20L reactor, add 10L ethanol, then add successively starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, (dppf) PdCl
210g; stir; nitrogen protection, stirring at room temperature, after TLC analysis starting material III reacts completely; be warming up to back flow reaction; after TLC analysis starting material IV reacts completely, be cooled to room temperature, add sodium triacetoxy borohydride 630g (2.97mol); stirring at room temperature reaction; after TLC analysis transition intermediate 2 reacts completely, suction filtration, filtrate adds 750g (3.94mol) tosic acid under stirring; room temperature crystallization; suction filtration, dries, and obtains lapatinibditosylate tosilate 725g; yield 79.2%, HPLC purity 98.35%.
embodiment 3
In 20L reactor, add 10L tetrahydrofuran (THF), then add successively starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, (dppf) PdCl
210g; stir; nitrogen protection, stirring at room temperature, after TLC analysis starting material III reacts completely; be warming up to back flow reaction; after TLC analysis starting material IV reacts completely, be cooled to room temperature, add sodium triacetoxy borohydride 630g (2.97mol); stirring at room temperature reaction; after TLC analysis transition intermediate 2 reacts completely, suction filtration, filtrate adds 750g (3.94mol) tosic acid under stirring; room temperature crystallization; suction filtration, dries, and obtains lapatinibditosylate tosilate 737.8g; yield 80.6%, HPLC purity 98.51%.
embodiment 4
In 20L reactor, add 10L ethanol, then add successively starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, (dppf) PdCl
210g, stirs, nitrogen protection; be warming up to back flow reaction, after TLC analysis of compounds IV reacts completely, be cooled to room temperature; add sodium triacetoxy borohydride 630g (2.97mol), stirring at room temperature reaction, after TLC analysis transition intermediate 2 reacts completely; suction filtration, filtrate adds 750g (3.94mol) tosic acid, room temperature crystallization under stirring; suction filtration, dries, and obtains lapatinibditosylate tosilate 748.8g; yield 81.8%, HPLC purity 98.02%.
embodiment 5
In 20L reactor, add 10L tetrahydrofuran (THF), then add successively starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, PdCl
220g, stirs, nitrogen protection; be warming up to back flow reaction, after TLC analysis of compounds IV reacts completely, be cooled to room temperature; add sodium triacetoxy borohydride 630g (2.97mol), stirring at room temperature reaction, after TLC analysis transition intermediate 2 reacts completely; suction filtration, filtrate adds 750g (3.94mol) tosic acid, room temperature crystallization under stirring; suction filtration, dries, and obtains lapatinibditosylate tosilate 724.1g; yield 79.1%, HPLC purity 98.44%.
embodiment 6
In 20L reactor, add 10L tetrahydrofuran (THF), then add successively starting material compound II 352g (1.485mol), compound III 194g (1.386mol), compound IV 500g (0.990mol), triethylamine 1500g, 10% palladium charcoal 40g, stir, nitrogen protection, stirring at room temperature, after TLC analysis of compounds III reacts completely, be warming up to back flow reaction, after TLC analysis of compounds IV reacts completely, be cooled to room temperature, add sodium triacetoxy borohydride 630g (2.97mol), stirring at room temperature reaction, after TLC analysis transition intermediate 2 reacts completely, suction filtration, room temperature crystallization, suction filtration, dry, obtain lapatinibditosylate 459.8g, yield 80.0%, HPLC purity 98.87%.
Claims (5)
1. prepare the method with following formula I compound or pharmaceutically acceptable salt thereof,
The method comprises the following steps:
(1) formula II compound or its salt reacts at the first temperature with formula III compound:
(2), in the reaction solution of step (1), make step (1) gained reaction product and react at the second temperature with following formula IV compound:
(3) in the reaction solution of step (2), add reductive agent, make the reduction of step (2) gained reaction product, obtain formula I compound; With optional
(4) make step (3) gained formula I compound and acid-respons, obtain the pharmaceutical salts of formula I compound;
Wherein, the solvent in step (1) is selected from one or more in alcohol organic solvent, ether organic solvent; Described alcohol organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol and the trimethyl carbinol, and described ether organic solvent is selected from ether and tetrahydrofuran (THF);
The first temperature described in step (1) is 0 DEG C to 80 DEG C, or 0 DEG C to solvent refluxing temperature;
The second temperature described in step (2) is 40 DEG C to 130 DEG C, or 40 DEG C to solvent refluxing temperature.
2. the method for preparation I compound or its pharmaceutical salts,
The method comprises the following steps:
(1) starting material compound II, compound III, compound IV, catalyzer are dissolved in solvent;
(2) reacting by heating;
(3) add reductive agent reaction to obtain Compound I;
Or
(1) starting material compound II, compound III are dissolved in solvent, then add compound IV, catalyzer,
(2) reacting by heating;
(3) add reductive agent reaction to obtain Compound I;
Its chemical equation is as follows:
3. method according to claim 1 and 2, the reductive agent in step (3) is selected from sodium triacetoxy borohydride, sodium borohydride and POTASSIUM BOROHYDRIDE.
4. according to the method for claim 1 or 2, the temperature of step (3) reduction reaction is-20 DEG C to 40 DEG C.
5. method according to claim 1 and 2, is used palladium catalyst in step (1).
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| MX2013007257A (en) | 2010-12-23 | 2013-10-01 | Apotex Pharmachem Inc | A process for the preparation of lapatinib and its ditosylate salt. |
| CN102675297B (en) * | 2012-04-17 | 2014-10-15 | 人福医药集团股份公司 | Preparation method of Lapatinib |
| CN103483324B (en) * | 2012-06-12 | 2016-03-30 | 人福医药集团股份公司 | The new preparation process of lapatinibditosylate |
| WO2014170910A1 (en) | 2013-04-04 | 2014-10-23 | Natco Pharma Limited | Process for the preparation of lapatinib |
| CN104513231A (en) * | 2015-01-09 | 2015-04-15 | 安润医药科技（苏州）有限公司 | Synthetic method for lapatinib and lapatinib intermediates |
| CN105085496B (en) * | 2015-09-12 | 2018-02-23 | 重庆医科大学 | A kind of method and intermediate for preparing Lapatinib |
| CN105503839A (en) * | 2015-12-26 | 2016-04-20 | 神威药业集团有限公司 | Preparing method of lapatinib and preparing method of lapatinib ditosylate |
| CN106946861A (en) * | 2017-03-21 | 2017-07-14 | 上海普凯姆化学科技有限公司 | A kind of synthesis optimizing method of Lapatinib structure fragment |
| CN113321642A (en) * | 2021-08-02 | 2021-08-31 | 北京鑫开元医药科技有限公司 | Quinazoline imine compound and application and preparation method thereof |
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| WO2010061400A1 (en) * | 2008-11-03 | 2010-06-03 | Natco Pharma Limited | A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts |
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| US20100197915A1 (en) * | 2008-08-06 | 2010-08-05 | Leonid Metsger | Lapatinib intermediates |
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| WO2010061400A1 (en) * | 2008-11-03 | 2010-06-03 | Natco Pharma Limited | A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts |
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