CN104418845B - Prepare the method and intermediate of Lapatinib - Google Patents

Prepare the method and intermediate of Lapatinib Download PDF

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Publication number
CN104418845B
CN104418845B CN201310396006.0A CN201310396006A CN104418845B CN 104418845 B CN104418845 B CN 104418845B CN 201310396006 A CN201310396006 A CN 201310396006A CN 104418845 B CN104418845 B CN 104418845B
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compound
formula
lapatinib
salt
solvent
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CN104418845A (en
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陈勇发
朱莉安·亨施克
张孝恒
陈以静
许春芳
母勇
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Scianda Changshu Pharmaceuticals Ltd
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Scinopharm Changshu Pharmaceuticals Ltd
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention provides a kind of formula (X) compound：It can be used as the intermediate for preparing Lapatinib or its pharmaceutically acceptable salt.

Description

Prepare the method and intermediate of Lapatinib
Technical field
The present invention relates to a kind of method for preparing Lapatinib, its salt and novel intermediates.
Lapatinib has structure formula (I) and chemical name N- [the chloro- 4- of 3- [(3- fluorophenyls) methoxyl group] phenyl] -6- [5- [(2- methyl sulphonyls ethylamino) methyl] -2- furyls] quinazoline -4- amine.
Background technology
Lapatinib is a kind of oral small molecule epidermal growth factor (EGFR) tyrosine kinase inhibitor, with its diformazan Benzenesulfonate salt forms, which are used to treat, previously to be received to include anthracycline, taxol, the late period of Herceptin (Trastuzumab) treatment Or metastatic breast cancer and other entity tumors.Xylene monosulfonic acid Lapatinib was ratified in 2007 by FDA, public by GlaxoSmithKline PLC (GlaxoSmithKline, GSK) is taken charge of in the U.S. with trade nameSell, and ratified in 2008 by EMEA, in Europe With trade nameSell.
Need a kind of improved method for preparing Lapatinib and its pharmaceutically acceptable salt.
The content of the invention
According to an aspect of the present invention, it is a kind of to prepare Lapatinib or the method for its pharmaceutically acceptable salt is included Make formula (X) compound：
It is converted into Lapatinib or its pharmaceutically acceptable salt.
Another aspect of the present invention is formula (X) compound or its salt as indicated above, preferably HCl salt.Formula (X) chemical combination Thing is stable and suitable for industrial production.In addition, formula (X) compound can be provided for the method for preparing Lapatinib Compared with high selectivity and yield.
According to another aspect of the present invention, formula (X) compound is by making formula (IX) compound
With SOCl2React to synthesize in the presence of dimethylformamide (DMF).
The various novel features for characterizing the present invention will in the right for the part for being attached to the present invention and the formation present invention Ask in book and particularly point out.For a better understanding of the present invention, its operational advantage and obtained objectives are used by it, Answer refer to the attached drawing and illustrate and describe the descriptive content of the preferred embodiments of the present invention.
Brief description of the drawings
In the accompanying drawings：
Fig. 1 shows the IR spectrum of formula (X) compound.
Fig. 2 shows the DSC of formula (X) compound.
Fig. 3 shows the TGA of formula (X) compound.
Fig. 4 displaying formula (X) compounds1H H NMR spectroscopies.
Embodiment
In one embodiment, Lapatinib is through the following steps that manufacture：
I) formula (X) compound is made
With the chloro- 4- of 3- (3- fluorine benzyloxy) aniline (VII)
Reacted in the solvent with or without alkali, produce formula (IV) compound or its salt；
With
Ii) with 2- (methyl sulphonyl) ethamine (VIII) or its salt (such as (VIII) .HCI) make formula (IV) compound or its Salt reduction amination, obtains Lapatinib.
Solvent in step i) can be tetrahydrofuran (THF), acetonitrile (MeCN), N,N-dimethylformamide (DMF), N, N- Dimethyl acetamide (DMAC), 1,3- dimethyl -2- imidazolidinones (DMI), 1-METHYLPYRROLIDONE (NMP) or tetramethylurea (TMU), and preferably choosing is white respectively has moisture content no more than THF, DMF and MeCN of 100ppm Karl-Fischer (KF) value, optimal Elect the MeCN that KF values are no more than 100ppm as.
In another embodiment, formula (X) compound and formula (VII) compound in such as DMF, DMAC, DMI, NMP or Reacted in TMU polar solvents, obtain homogeneous reaction solution.After completion of the reaction, addition water is with Precipitation (IV) .HCl.With After (IV) .HCl is isolated by filtration.
High yield is provided using the novel intermediates and the method for preparing Lapatinib of formula (X) compound.
Example
Following instance is provided to illustrate (but not limiting) present invention.
Example 1：Synthesize 5- (4- oxo -3,4- dihydroquinazoline -6- bases) furans -2- formaldehyde (IX)
At ambient temperature, dimethyl sulfoxide (DMSO) and H are made using nitrogen2O 5: 2v/v admixture solvent (1400mL) Degassing 30 minutes.Under nitrogen protection, addition 5- formyl furans -2- ylboronic acids ((VIa)；26.8g, 193mmol) it is molten to mixing Agent, dissolving.Add [HP (t-Bu)3]BF4(840mg, 2.94mmol) and palladium Pd (OAc)2(680mg, 2.94mmol), and At ambient temperature, potassium acetate (AcOK, 18.8g, 192mmol) is added in reactor by stirring mixture after 20 minutes, after Continuous stirring 20 minutes, (3H) -one ((Va) of addition 6- iodine quinazoline -4；40g, 147mmol).Reactant mixture is heated to 80 ± 5 DEG C (internal temperature).After the completion of HPLC monitoring reactions, reactant mixture is filtered while hot, then by hot water (400mL, 80 ± 5 DEG C) It is added in filtrate.Progressively cooled to 0-15 DEG C (starting precipitation when warm 70 DEG C including solid), then filtering, in succession use H2O (80mL), MeCN (60mL) wash filter cake.Filter cake is dried in vacuo 6 hours at 60 ± 5 DEG C, obtains 5- (4- oxos -3,4- Dihydroquinazoline -6- bases)-furans -2- formaldehyde ((IX)；34.6g, 144mmol), HPLC purity assays are 99.7%, and yield is 97.6%.1H NMR (300MHz, d6- DMSO): δ 7.47 (d, J=3.8Hz, 1H), 7.69 (d, J=3.8Hz, 1H), 7.77 (d, J= 8.6Hz, 1H), 8.17 (s, 1H), 8.27 (dd, J=8.6,2.1Hz, 1H), 8.52 (d, J=2.1Hz, 1H), 9.66 (s, 1H)；13C NMR (75MHz, CDCl3): δ 110.5,122.6,123.9,126.0,127.5,129.0,131.4,147.1,150.1, 152.7,157.6,161.2,178.8；ESI-MS, cation: [M+H]+M/z241；IR(cm-1): 1713,1671,1604, 1462；Fusing point: 267 DEG C.
Example 2：Synthesize formula (X) compound
By DMF (8.7mL, 116mmol, 0.16eq.) be added to containing formula (IX) compound (174.0g, 725mmol, In thionyl chloride (1740mL) 1.0eq.), mixture is stirred, and is heated to 55-60 DEG C, is kept for 1 hour, then increases temperature Stir to 80 DEG C and at this temperature and be no less than 2 hours.Excessive thionyl chloride is removed by vacuum distillation, and makes residue With toluene (1740mL) azeotropic distillation twice (control temperature is at 80-90 DEG C), to residue400mL.By toluene (350mL) It is added to normal heptane (1400mL) in residue and stirring is no less than 2 hours at ambient temperature.Filtering, uses normal heptane (500mL) wash wet cake, at 40 ± 5 DEG C be dried in vacuo 10 hours, obtain bright yellow solid formula (X) compound (212g, 83.5% yield, 91.8% purity).1H NMR (400MHz, CDCl3)δ：9.07 (s, 1H), 8.55 (d, J=1.8Hz, 1H), 8.30 (dd, J=8.8,1.8Hz, 1H), 8.18 (d, J=8.8Hz, 1H), 6.92 (d, J=3.5Hz, 1H), 6.81 (s, 1H), 6.76 (d, J=3.5Hz, 1H).
The IR spectrum of formula (X) compound, DSC, TGA and1H NMR are shown in Fig. 1-4.DSA, TGA, IR and NMR are surveyed Examination condition used provides as follows respectively：
DSC：DSC-TA Q2000；Condition：40 DEG C to 200 DEG C (10 DEG C/min)
TGA：TGA-TA Q500；Condition：Room temperature is to 300 DEG C (10 DEG C/min)
IR：Nicolai (Nicolet) FT-IR A Fanda (Avatar) 360；Condition：KBr tablettings
NMR：Brooker (Bruker) AVANCE III400MHz；Condition：In CDCl3In, 298K.
Example 3：Synthesize formula (IV) compound
3.0g formulas (X) compound and THF (24mL) are added in flask, backflow is subsequently heated to.3- is added dropwise chloro- THF (12mL) solution of 4- (3- fluorine benzyloxy) aniline ((VII), 2.4g).Reactant mixture is kept stirring for and flowed back 1 hour. Then add H2O (3mL) and maintain the reflux for 0.5 hour.Cooling mixture is to 25 DEG C in a water bath.Use 30%K3PO4The aqueous solution makes Mixture is basified to pH=8-9.Organic phase is separated, backflow is heated to, normal heptane (12mL) is added dropwise.Finish, cool down mixture To environment temperature, continue to stir 2 hours.Mixture is filtered, and washs filter cake with THF/ heptane (1: Isosorbide-5-Nitrae .5mL) and then exists It is dried in vacuo 4 hours at 80 ± 5 DEG C, obtains 3.6g (IV), 96.4%HPLC purity.
Example 5：Synthesize xylene monosulfonic acid N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- (5- ((2- (methyl sulphonyl) Ethylamino) methyl) furans -2- bases) quinazoline -4- amine (xylene monosulfonic acid Lapatinib)
To 2- (methyl sulphonyl) ethylamine hydrochloride (1.3g, 8.1mmol) and formula (IV) compound (3.0g, 6.3mmol) THF (60mL) suspension in addition DIPEA (4.7mL).After stirring 0.5 hour at ambient temperature, triacetoxyl group is added Sodium borohydride (4.0g, 24.3mmol) and mixture is stirred under 20 ± 5 DEG C (external temperature), until HPLC displays have been reacted Into.H is used in ice-water bath2Reactant mixture is quenched in O (9mL, 3P), keeps TIt is internal<25℃.Use 10%NH4The C1 aqueous solution (6mL) Organic phase is washed, p-TsOH (4.8g, 25.2mmol) is added in the organic phase after filtering, mixture is heated to back by filtering Flow and kept for 2 hours.Mixture is cooled down to environment temperature, continues to stir 15 hours.Mixture is filtered, with 1: 1 (v/v) THF/ H2O (4.5mL) wash filter cake, at 80 ± 5 DEG C be dried in vacuo 6 hours, obtain xylene monosulfonic acid Lapatinib crude product (3.4g, HPLC purity：95.2%).Xylene monosulfonic acid Lapatinib1HNMR (300MHz, d6- DMSO): δ 11.41 (s, 2H), 9.33 (s, 3H), 9.04 (d, J=1.3Hz, 2H), 8.93 (s, 2H), 8.41 (dd, J=8.8,1.6Hz, 2H), 7.91 (d, J=2.6Hz, 2H), 7.54-7.41 (m, 9H), 7.37-7.27 (m, 6H), 7.25 (d, J=3.4Hz, 2H), 7.22-7.13 (m, 2H), 7.08 (dd, J= 8.4,0.6Hz, 8H), 6.87 (d, J=3.5Hz, 2H), 5.29 (s, 4H), 4.46 (s, 4H), 3.65-3.51 (m, 4H), 3.51- 3.38 (m, 4H), 2.26 (s, 12H).
The tetrahydrofuran solution of xylene monosulfonic acid Lapatinib is washed with the NaOH aqueous solution, is then concentrated and is converted into its trip From alkali form Lapatinib solution, solid Lapatinib is obtained：1H NMR (300MHz, d6-DMSO)：δ 2.98 (t, J=6.75Hz, 1H), 3.04 (s, 1H), 3.29 (t, J=6.6Hz, 1H), 3.83 (s, 1H), 5.28 (s, 1H), 6.50 (d, J=3.0Hz, 1H), 7.08 (d, J=3.3Hz, 1H), 7.20 (m, 1H), 7.33 (m, 4H), 7.48 (m, 1H), 7.76 (m, 1H), 7.80 (d, J=9Hz, 1H), 8.04 (d, J=2.75Hz, 1H), 8.17 (dd, J=8.7Hz, J=1.8Hz, 1H), 8.56 (s, 1H), 8.75 (d, J= 1.8Hz, 1H).
Example 6a：Purify xylene monosulfonic acid Lapatinib
Under 70 DEG C (internal temperature) by xylene monosulfonic acid Lapatinib (5.0g, 5.4mmol, 96.5%HPLC purity, most 0.8%) big individual impurities are accounted for is dissolved in DMSO (10mL).MeCN (10mL) is added dropwise under 70-80 DEG C (internal temperature) It is added in mixture and stirs 1 hour at this temperature.Through 4 hours, mixture is cooled to room temperature.MeCN is added dropwise (30mL), is finished, and continues to stir mixture 1 hour, is then filtered and is washed with MeCN (10mL).Filter is dried in vacuo at 60 DEG C Cake 16 hours, obtains the xylene monosulfonic acid Lapatinib that 4.0g is in crystal form 1 (such as US7, disclosed in 157,466B2), HPLC purity is that 99.6%, HPLC yields are 78%.
Example 6b. purifies xylene monosulfonic acid Lapatinib
Xylene monosulfonic acid Lapatinib (3g, 3.25mmol, 99.3%HPLC purity) is dissolved in DMF at 80 DEG C In (18mL) and stirring 1 hour.Heat filtering mixture.MeCN (18mL) is added in filtrate at 80 DEG C.Temperature is cooled down To 70 DEG C and make crystal settling.Hold the mixture at 70 DEG C 1 hour and be then maintained at 60 DEG C 1 hour.It is further cold But mixture is to 0 DEG C and stirs 2 hours.The crystal of xylene monosulfonic acid Lapatinib is isolated by filtration and vacuum is done at 40 DEG C It is dry to stay overnight.Obtain the xylene monosulfonic acid Lapatinib (2.5g, 2.70mmol, 83% yield) that HPLC purity is 99.9%.XRPD Analysis indicates that it is the form 2 as disclosed in WO2009/079541A1.
The present invention is not limited by embodiment described above, and these embodiments are only to be presented as example, but can be appended Changed in a variety of ways in the protection domain that patent claims are limited.

Claims (8)

1. one kind prepares Lapatinib (lapatinib) or the method for its pharmaceutically acceptable salt, it, which is included, changes formula (X) Compound：
It is converted into Lapatinib：
Or the pharmaceutically acceptable salt, wherein described include the step of convert the formula (X) compound：
I) formula (X) compound is made：
Reacted in a solvent with formula (VII) compound：
Produce formula (IV) compound or its salt
With
Ii) formula (IV) compound or its salt reduction amination is made with formula (VIII) compound or its salt：
Lapatinib or the pharmaceutically acceptable salt are provided.
2. according to the method described in claim 1, wherein the solvent is selected from by tetrahydrofuran (THF), acetonitrile (MeCN), N, Dinethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAC), 1,3- dimethyl -2- imidazolidinones (DMI), N- methyl The group of pyrrolidones (NMP), tetramethylurea (TMU) and its combination composition.
3. according to the method described in claim 1, wherein the solvent is selected from the Karl- that respectively there is moisture content to be no more than 100ppm THF, DMF, MeCN of Fischer values and its combination.
4. according to the method described in claim 1, wherein the solvent, which is moisture content Karl-Fische values, is no more than 100ppm MeCN。
Lapatinib is set to react generation diformazan with p-methyl benzenesulfonic acid 5. according to the method described in claim 1, it is further included The step of benzene sulfonic acid Lapatinib.
6. a kind of formula (X) compound,
Or its salt.
7. compound according to claim 6, wherein the salt is the hydrochloride of the formula (X) compound.
8. a kind of method for preparing formula (X) compound,
It, which is included, makes formula (IX) compound
With SOCl2The step of being reacted in the presence of toluene.
CN201310396006.0A 2013-09-04 2013-09-04 Prepare the method and intermediate of Lapatinib Active CN104418845B (en)

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