CN104109152A - Method for preparing lapatinib - Google Patents

Method for preparing lapatinib Download PDF

Info

Publication number
CN104109152A
CN104109152A CN201310139358.8A CN201310139358A CN104109152A CN 104109152 A CN104109152 A CN 104109152A CN 201310139358 A CN201310139358 A CN 201310139358A CN 104109152 A CN104109152 A CN 104109152A
Authority
CN
China
Prior art keywords
lapatinibditosylate
reaction
compound
methylsulfonyl
sodium cyanoborohydride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201310139358.8A
Other languages
Chinese (zh)
Inventor
周艳红
袁哲东
王胡博
江华
俞雄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
China State Institute of Pharmaceutical Industry
Original Assignee
Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry filed Critical Shanghai Institute of Pharmaceutical Industry
Priority to CN201310139358.8A priority Critical patent/CN104109152A/en
Publication of CN104109152A publication Critical patent/CN104109152A/en
Pending legal-status Critical Current

Links

Classifications

    • 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

Abstract

The invention discloses a method for preparing lapatinib. The method comprises that in the presence of an organic solvent, 5-[4-{3-chloro-4-(3-fluorophenylmethoxy)anilino}quinazolinyl-6-yl]furyl-2-formaldehyde and 2-methylsulfonylethylamine or its salt undergo a reaction under the action of sodium cyanoborohydride as a reducing agent. The method greatly reduces reaction time, has mild reaction conditions and simple processes, produces high-purity products and does not need column chromatography isolation purification before the next reaction.

Description

A kind of method of preparing lapatinibditosylate
Technical field
The present invention relates to the field of chemical synthesis, relate in particular to a kind of method of preparing lapatinibditosylate.
Background technology
Lapatinibditosylate (Lapatinib) is the novel receptor tyrosine kinase inhibitors of GlaxoSmithKline PLC company development, belongs to quinazoline ditosylate salt micromolecular compound, the clinical advanced breast cancer that is used for the treatment of.In March, 2007 is by U.S. FDA approval listing.Its mechanism of action, for suppressing the ATP site of intracellular EGFR (ErbB-1) and HER2 (ErbB-2), stops tumour cell phosphorylation and activation, and the mammary cancer of HER2 overexpression is worked.
The chemistry of lapatinibditosylate is by name: N-{3-chloro-4-[(3-fluoro benzyl) oxygen base] phenyl }-6-[5-({ [2-(methylsulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine; English by name: N-{3-Chloro-4-[(3-fluorobenzyl) oxy] phenyl}-6-[5-([2-(methylsulfonyl) et hy1] amino}methyl) and-2-furyl]-4-quinazolinamine.
Its CAS registration number: 231277-92-2,388082-78-8 (two tosilate monohydrates);
Molecular formula: C 29h 26clFN 4o 4s;
Molecular weight: 581.06;
Its chemical structure is suc as formula shown in I:
Clinically, use with the form of lapatinibditosylate two tosilate monohydrates (Tykerb).
Because lapatinibditosylate has active high, long action time, synthesis technique has higher technology content.There are the potentiality that form high value added product.
The method of preparing lapatinibditosylate is first open in International Application No. WO 9935146, taking the chloro-4-nitrophenols of 2-as starting raw material, be substituted, reduce using stannane base furan compound as reductive agent, the polystep reaction such as replacement, Suzuki coupling, reduction amination finally obtains lapatinibditosylate, its synthetic route is as follows:
In International Application No. WO 0202552, disclose another kind of preparation method, it substitutes hypertoxic stannane base furan compound with 5-formylfuran-2-boric acid and prepares lapatinibditosylate, and its synthetic route is as follows:
In the lapatinibditosylate that International Application No. WO 0104111, WO05046678, WO08067144 etc. report and the preparation method of two tosilate monohydrates thereof, reductive amination process is committed step wherein, and the reductive agent that the reduction amination of its report uses is respectively sodium triacetoxy borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE.
But through experiment showed, that the sodium triacetoxy borohydride reduction reaction time is long, efficiency is low, product need to be crossed column separating purification; Sodium borohydride must separate imines with potassium borohydride reduction, could further react, otherwise aldehyde radical in raw material also can be reduced, and introduces the hydroxyl impurity that is difficult to remove in finished product.Such two-step reaction operation also extends, and cost also can increase, and the reaction of sodium borohydride and POTASSIUM BOROHYDRIDE is comparatively violent, need to strictly control.
Therefore need to develop the new method of preparing lapatinibditosylate.
Summary of the invention
Contriver surprisingly finds, adopt sodium cyanoborohydride as the reductive agent of reductive amination process of preparing lapatinibditosylate, can treat different things alike and obtain lapatinibditosylate, and the time of described method reaction shortens greatly, reaction conditions gentleness, easy and simple to handle, and the purity of product is higher, and do not need column chromatographic isolation and purification can drop into next step reaction.
Therefore; the object of this invention is to provide a kind of new method of preparing lapatinibditosylate; described method is included under organic solvent existence; make the chloro-4-of 5-[4-{3-(3-fluorobenzene methoxyl group) aniline } quinazoline-6-yl] furans-2-formaldehyde (compound 10) and 2-methylsulfonyl ethamine or its salt (compound 11) step of reacting under the effect of reductive agent sodium cyanoborohydride
The reaction formula of described method is as follows:
According to of the present invention one preferred embodiment, described organic solvent is preferably tetrahydrofuran (THF) and alcoholic solvent, wherein alcoholic solvent particular methanol.
According to of the present invention another preferred embodiment, the temperature of described reaction is preferably 0-50 DEG C.
According to of the present invention another preferred embodiment, the time of described reaction is preferably 2-8 hour, preferably 3-6 hour.
According to of the present invention one preferred embodiment, the salt of 2-methylsulfonyl ethamine is 2-methylsulfonyl ethylamine hydrochloride.
According to of the present invention another preferred embodiment, compound 10 is preferably 1 with the mol ratio of sodium cyanoborohydride: 0.5-1: 10, more preferably 1: 0.5-1: 2.After described reaction finishes, can also carry out aftertreatment, be further purified Compound I.The mode of described aftertreatment can be the post processing mode of this area routine, preferably includes following steps: extraction, and organic phase saturated sodium bicarbonate, saturated common salt water washing, filters, and filtrate decompression is concentrated.Wherein, described extraction is preferably with ethyl acetate or dichloromethane extraction.
Meeting on the basis of this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and all commercially available obtaining of compound 10,11.Positive progressive effect of the present invention is: preparation method of the present invention Reaction time shorten greatly, and reaction conditions gentleness, and simple to operate, yield is higher, and by product is less, does not need separation and purification can drop into the next step salify.
Embodiment
In following examples, the chloro-4-of 2-methylsulfonyl ethylamine hydrochloride and 5-[4-{3-(3-fluorobenzene methoxyl group) aniline } quinazoline-6-yl] furans-2-formaldehyde very can medication chemistry company limited purchased from Nanjing; Anhydrous methanol, Glacial acetic acid, tetrahydrofuran (THF), ethyl acetate, sodium bicarbonate, methylene dichloride, triethylamine, sodium cyanoborohydride, all purchased from Chemical Reagent Co., Ltd., Sinopharm Group.
Embodiment 1: the preparation of lapatinibditosylate (I)
Under room temperature, take 5g2-methylsulfonyl ethylamine hydrochloride (compound 11), be dissolved in 100ml absolute methanol solution, drip triethylamine until solid all dissolves, drip acetic acid, adjust pH5-7, add 10g (21.1mmol, leq) compound 10, stir 3h, add again the dilution of 100ml tetrahydrofuran (THF), add 2g (31.8mmol, 1.5eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, ethyl acetate extraction, water layer is stripped by ethyl acetate, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate (I) 8.59g, yield 70.1%.ESI-MS?m/z：581[M+H] +； 1HNMR(DMSO-d6，400Hz)：9.864(s，1H)，8.726-8.730(d，J＝1.6Hz，1H)，8.552(s，1H)，8.142-8.168(m，1H)，8.012-8.019(d，J＝2.8Hz，1H)，7.740-7.813(m，2H)，7.471-7.485(d，J＝5.6Hz，1H)，7.279-7.354(m，3H)，7.182(m，1H)，7.041-7.050(d，J＝3.6Hz，1H)，6.489-6.497(d，J＝3.2Hz，1H)，5.735(s，1H)，5.270(s，2H)，3.849(s，2H)，3.264-3.306(m，2H)，2.997-3.023(m，5H).
Embodiment 2:
The preparation of lapatinibditosylate (I)
Take 3.9gg2-methylsulfonyl ethamine (compound 11), be dissolved in 150ml tetrahydrofuran solution, at 0 DEG C, stir, drip acetic acid, adjust pH5-7, add 3.0g (6.33mmol, leq) compound 10, stir 8h, add 3.98g (63.3mmol, 10eq) sodium cyanoborohydride, at keeping 0 DEG C, being stirred to reaction finishes, cancellation adds water, ethyl acetate extraction, water layer is stripped by ethyl acetate, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate (I) 2.62g, yield 71.3%.
Embodiment 3:
The preparation of lapatinibditosylate (I)
Take 5g2-methylsulfonyl ethylamine hydrochloride (compound 11), be dissolved in 100ml absolute methanol solution, at 50 DEG C, stir, drip triethylamine until solid all dissolves, add 10g (21.1mmol, leq) compound 10, stir 2h, add 0.66g (10.55mmol, 0.5eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, ethyl acetate extraction, water layer is stripped by ethyl acetate, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate (I) 8.2g, yield 67%.
Embodiment 4:
The preparation of lapatinibditosylate (I)
Get 5g2-methylsulfonyl ethylamine hydrochloride (compound 11), be dissolved in 100ml absolute methanol solution, at 50 DEG C, stir, drip triethylamine until solid all dissolves, the appropriate acetic acid that drips makes pH5-7, add 10g (21.1mmol, leq) compound 10, stir 3h, add 0.66g (10.55mmol, 0.5eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, ethyl acetate extraction, water layer is stripped by ethyl acetate, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate (I) 8.28g, yield 67.5%.
Embodiment 5:
The preparation of lapatinibditosylate (I)
Under room temperature, (compound n) to take 5g2-methylsulfonyl ethylamine hydrochloride, be dissolved in 100ml absolute methanol solution, drip triethylamine until solid all dissolves, drip acetic acid, adjust pH5-7, add 10g (21.1mmol, leq) compound 10, stir 3h, add again the dilution of 100ml tetrahydrofuran (THF), add 1g (15.9mmol, 0.75eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, dichloromethane extraction, water layer dichloromethane extraction, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate 8.49g, yield 69.3%.
Embodiment 6:
The preparation of lapatinibditosylate (I)
Under room temperature, take 5g2-methylsulfonyl ethylamine hydrochloride (compound 11), be dissolved in 100ml absolute methanol solution, drip triethylamine until solid all dissolves, drip acetic acid, adjust pH5-7, add 10g (21.1mmol, leq) compound 10, stir 3h, add again the dilution of 100ml tetrahydrofuran (THF), add 2.65g (42.2mmol, 2eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, dichloromethane extraction, water layer dichloromethane extraction, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate 8.79g, yield 71.7%.
Embodiment 7:
The preparation of lapatinibditosylate (I)
Under room temperature, take 5g2-methylsulfonyl ethylamine hydrochloride (compound 11), be dissolved in 100ml absolute methanol solution, drip triethylamine until solid all dissolves, drip acetic acid, adjust pH5-7, add 10g (21.1mmol, leq) compound 10, stir 3h, add again the dilution of 100ml tetrahydrofuran (THF), add 6.6g (105mmol, 5eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, ethyl acetate extraction, water layer is stripped by ethyl acetate, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate (I) 8.66g, yield 70.6%.
Embodiment 8:
The preparation of lapatinibditosylate (I)
Under room temperature, take 5g2-methylsulfonyl ethylamine hydrochloride (compound 11), be dissolved in 100ml absolute methanol solution, drip triethylamine until solid all dissolves, drip acetic acid, adjust pH5-7, add 10g (21.1mmol, leq) compound 10, stir 3h, add again the dilution of 100ml tetrahydrofuran (THF), add 1.72g (27.4mmol, 1.3eq) sodium cyanoborohydride, being stirred to reaction finishes, cancellation adds water, ethyl acetate extraction, water layer is stripped by ethyl acetate, merge organic layer, wash with saturated sodium bicarbonate, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain faint yellow compound lapatinibditosylate (I) 8.6g, yield 70%.

Claims (10)

1. prepare the method for lapatinibditosylate for one kind; described method is included under organic solvent exists, and makes the chloro-4-of 5-[4-{3-(3-fluorobenzene methoxyl group) aniline } quinazoline-6-yl] furans-2-formaldehyde and 2-methylsulfonyl ethamine or its salt step of reacting under the effect of reductive agent sodium cyanoborohydride.
2. method according to claim 1, wherein said organic solvent is tetrahydrofuran (THF) and alcoholic solvent.
3. method according to claim 2, wherein said alcoholic solvent is methyl alcohol.
4. method according to claim 1, the temperature of wherein said reaction is 0-50 DEG C.
5. method according to claim 1, the time of wherein said reaction is 2-8 hour, preferably 3-6 hour.
6. method according to claim 1, the salt of wherein said 2-methylsulfonyl ethamine is 2-methylsulfonyl ethylamine hydrochloride.
7. method according to claim 1, the chloro-4-of wherein said 5-[4-{3-(3-fluorobenzene methoxyl group) aniline } quinazoline-6-yl] mol ratio of furans-2-formaldehyde and sodium cyanoborohydride is 1: 0.5-1: 10, preferably 1: 0.5-1: 2.
8. method according to claim 1, wherein said reaction further comprises post-processing step.
9. method according to claim 8, wherein said post-processing step comprises the steps: that extraction, washing, filtration and filtrate decompression are concentrated.
10. method according to claim 9, wherein said extraction step adopts ethyl acetate or dichloromethane extraction.
CN201310139358.8A 2013-04-19 2013-04-19 Method for preparing lapatinib Pending CN104109152A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310139358.8A CN104109152A (en) 2013-04-19 2013-04-19 Method for preparing lapatinib

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310139358.8A CN104109152A (en) 2013-04-19 2013-04-19 Method for preparing lapatinib

Publications (1)

Publication Number Publication Date
CN104109152A true CN104109152A (en) 2014-10-22

Family

ID=51706160

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310139358.8A Pending CN104109152A (en) 2013-04-19 2013-04-19 Method for preparing lapatinib

Country Status (1)

Country Link
CN (1) CN104109152A (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004111A1 (en) * 1999-07-09 2001-01-18 Glaxo Group Limited Anilinoquinazolines as protein tyrosine kinase inhibitors
WO2005046678A1 (en) * 2003-11-07 2005-05-26 Smithkline Beecham (Cork) Limited Cancer treatment method
WO2010061400A1 (en) * 2008-11-03 2010-06-03 Natco Pharma Limited A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts
US20110053964A1 (en) * 2006-08-22 2011-03-03 Roger Tung 4-aminoquinazoline derivatives and methods of use thereof
CN102079759A (en) * 2009-12-01 2011-06-01 天津药物研究院 6-substituted quinazoline derivative, preparation method and application thereof
CN102249946A (en) * 2011-05-13 2011-11-23 上海海嘉诺医药发展股份有限公司 Preparation method of N-alkyloxy oxalyl alanine alkyl ester
CN102321076A (en) * 2011-07-07 2012-01-18 中国科学技术大学 The preparation method of lapatinibditosylate midbody and analogue thereof
WO2012083440A1 (en) * 2010-12-23 2012-06-28 Apotex Pharmachem Inc A process for the preparation of lapatinib and its ditosylate salt
CN102531935A (en) * 2011-12-20 2012-07-04 安徽华恒生物工程有限公司 Method for synthesizing N-methyl-D-aspartate

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004111A1 (en) * 1999-07-09 2001-01-18 Glaxo Group Limited Anilinoquinazolines as protein tyrosine kinase inhibitors
WO2005046678A1 (en) * 2003-11-07 2005-05-26 Smithkline Beecham (Cork) Limited Cancer treatment method
US20110053964A1 (en) * 2006-08-22 2011-03-03 Roger Tung 4-aminoquinazoline derivatives and methods of use thereof
WO2010061400A1 (en) * 2008-11-03 2010-06-03 Natco Pharma Limited A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts
CN102079759A (en) * 2009-12-01 2011-06-01 天津药物研究院 6-substituted quinazoline derivative, preparation method and application thereof
WO2012083440A1 (en) * 2010-12-23 2012-06-28 Apotex Pharmachem Inc A process for the preparation of lapatinib and its ditosylate salt
CN102249946A (en) * 2011-05-13 2011-11-23 上海海嘉诺医药发展股份有限公司 Preparation method of N-alkyloxy oxalyl alanine alkyl ester
CN102321076A (en) * 2011-07-07 2012-01-18 中国科学技术大学 The preparation method of lapatinibditosylate midbody and analogue thereof
CN102531935A (en) * 2011-12-20 2012-07-04 安徽华恒生物工程有限公司 Method for synthesizing N-methyl-D-aspartate

Similar Documents

Publication Publication Date Title
CN103664912B (en) A kind of synthesis technique of prucalopride
CN105712984A (en) Preparation method of Azilsartan
WO2011160594A1 (en) New preparation method of lapatinib
JP2007099680A (en) Method for producing epalrestat
WO2019019795A1 (en) Method for preparing sacubitril intermediate
CN1915976B (en) Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate
CN106928191B (en) A kind of preparation process of Lansoprazole
CN107298678B (en) Preparation method of bulk drug suvorexant
CN103601777A (en) Preparation method of capecitabine
CN109748902B (en) Preparation method of erlotinib hydrochloride
CN104829590B (en) Method for purifying trelagliptin
CN104086545A (en) Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride
CN108456198B (en) Preparation method of vilazodone or hydrochloride thereof
CN111943937A (en) Synthesis method of triphenyl candesartan
CN104109152A (en) Method for preparing lapatinib
CN106083689B (en) Preparation method of silodosin compound
CN105085531B (en) A kind of Xi Gelieting impurity synthetic method
CN104277005A (en) Preparation method of crystal form of gefitinib Form 1
CN103396323A (en) Production method of bromhexine hydrochloride
WO2013020461A1 (en) Preparation method for gefitinib intermediate
CN103739502B (en) A kind of separation and purification technique of ambroxol alkali
CN107011322A (en) A kind of high-purity dehydrophenylahistin class compound prepares purification process
CN107382898B (en) Energetic material based on ANPZ energetic parent structure and synthetic method thereof
CN107652269A (en) Methanesulfonic acid fluorine imatinib purification of intermediate method
CN105294620A (en) Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C41 Transfer of patent application or patent right or utility model
CB03 Change of inventor or designer information

Inventor after: Zhou Yanhong

Inventor after: Yuan Zhedong

Inventor after: Wang Hubo

Inventor after: Jiang Hua

Inventor after: Yu Xiong

Inventor after: Zhang Xiquan

Inventor after: Wang Shanchun

Inventor before: Zhou Yanhong

Inventor before: Yuan Zhedong

Inventor before: Wang Hubo

Inventor before: Jiang Hua

Inventor before: Yu Xiong

COR Change of bibliographic data
TA01 Transfer of patent application right

Effective date of registration: 20160427

Address after: 200040 Beijing West Road, Shanghai, No. 1320, No.

Applicant after: Shanghai Institute of pharmaceutical industry

Applicant after: China State Institute of Pharmaceutical Industry

Applicant after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

Address before: 200040 Beijing West Road, Shanghai, No. 1320, No.

Applicant before: Shanghai Institute of pharmaceutical industry

Applicant before: China State Institute of Pharmaceutical Industry

RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20141022