CN105985293B - The preparation method of AMN107 intermediate - Google Patents

The preparation method of AMN107 intermediate Download PDF

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CN105985293B
CN105985293B CN201510095187.2A CN201510095187A CN105985293B CN 105985293 B CN105985293 B CN 105985293B CN 201510095187 A CN201510095187 A CN 201510095187A CN 105985293 B CN105985293 B CN 105985293B
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compound
iii
methyl
alcohol
trifluoromethyl
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CN105985293A (en
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赵立强
王昭
江宏
董金
徐晓飞
郑国荣
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Esteve Huayi Pharmaceutical Co Ltd
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Esteve Huayi Pharmaceutical Co Ltd
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Abstract

The present invention relates to (4 methyl 1 of AMN107 intermediate 3 (trifluoromethyl) 5HThe base of imidazoles 1) aniline (I) preparation method, including by 3 (trifluoromethyl) 5 (4 methyl 1HThe base of imidazoles 1) further reaction changes into 3 (trifluoromethyl) 5 (4 methyl 1 to by-product compounds (III) of the benzoic acid (VII) through Ku Ertisi rearrangement generationsHThe base of imidazoles 1) aniline (I).The inventive method has raw material availability height, is adapted to the advantages of industrial operation.

Description

The preparation method of AMN107 intermediate
Technical field
The present invention relates to medicine intermediate technical field, and in particular to AMN107 intermediate 3- (trifluoromethyl) -5- (4- Methyl isophthalic acidH- imidazoles -1- bases) aniline preparation method.
Background technology
AMN107 (Nilotinib), entitled 4- methyl-N- [3- (4- the methyl-1 H-imidazole-1-groups) -5- trifluoros of chemistry Aminomethyl phenyl] -3- [[4- (3- pyridine radicals) -2- pyrimidine radicals] amino] benzamide, researched and developed by Novartis of Switzerland The oral tyrosine kinase inhibitor of high selectivity, its mono-hydrochloric salts monohydrate obtain U.S. FDA approval listing in October, 2007, It is clinically used for treating the invalid chronic myelocytic leukemia of imatinib mesylate.AMN107 can pass through targeting selectivity Suppress the Philadelphia Chromosome Positive chronic myelocytic leukemia as caused by tyrosinase and its encoding gene mutation, patient tolerability Good, selectivity is strong, evident in efficacy.
3- (trifluoromethyl) -5- (4- methyl isophthalic acidsH- imidazoles -1- bases) aniline (I) be synthesize AMN107 key among Body, have following structural formula (I),
,
It can obtain AMN107 with the condensation of 4- methyl -3- [[4- (3- pyridine radicals) -2- pyrimidine radicals] amino] benzoic acid.
International patent application WO2004005281A1 discloses the preparation method of compound (I), the following institute of reaction scheme 1 Show, including 4 step synthesis steps, by the aromatics substitution reaction of compound (IV) and compound (V),。
Wherein compound (VII) resets (Curtius rearrangement) generation compound (II) via Ku Ertisi, Compound (II) obtains compound (I) through chromatogram purification, Deprotection.But the applicant has found through experiment, from compound (VII) during prepare compound (I) this two-step reaction, the utilization rate of compound (VII) is low, causes the yield of compound (I) low； And chromatogram purification is not suitable for industrial operation.It is therefore desirable to this method is improved further.
The content of the invention
In view of this, it is an object of the present invention to provide a kind of 3- (trifluoromethyl) -5- (4- methyl isophthalic acidsH- imidazoles- 1- yls) aniline (I) preparation method, to improve raw material availability, and be suitable to industrial operation.
The present invention includes on the preparation method of compound (I)：By 3- (trifluoromethyl) -5- (4- methyl isophthalic acidsH- imidazoles -1- Base) further reaction changes into compound (I) to by-product compounds (III) of the benzoic acid (VII) through Ku Ertisi rearrangement generations,
。
Preferably, the by-product compounds (III) need not with resetting the main product compounds (II) of generation through Ku Ertisi Separation, under same reaction condition, while changes into compound (I),
。
Preferably, the same reaction condition includes the organic solvent containing alkali.
Preferably, the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide and its mixing Thing.
Preferably, the organic solvent is selected from one or more of C3-6Alcohol.
Preferably, the organic solvent is one or more of C3-6The mixed solvent of alcohol and dimethylbenzene.
Preferably, the C3-6Alcohol is selected from normal propyl alcohol, isopropanol, n-butyl alcohol, 2- butanol, the tert-butyl alcohol or 2- methylpropanols.
Preferably, the dimethylbenzene is selected from paraxylene, meta-xylene, ortho-xylene and its mixture.
Another object of the present invention is to provide the compound (III) with following structural formula,
。
Another object of the present invention is to provide the method for prepare compound (III) a kind of, including：In toluene solvant and In the presence of triethylamine, 3- (trifluoromethyl) -5- (4- methyl isophthalic acidsH- imidazoles -1- bases) benzoic acid (VII) through Ku Ertisi reset give birth to Into compound (III).
Another object of the present invention is to provide the application by compound (III) in prepare compound (I).
Compared with prior art, the invention provides the method for prepare compound (I) a kind of, by compound (VII) through Ku Er Carrying the by-product compounds (III) that this resets generation, further reaction changes into compound (I), improves raw material availability；And This method process is adapted to industrial operation without chromatogram purification.
Embodiment
The Ku Ertisi rearrangement reactions of compound (VII) disclosed in the repeated WO2004005281A1 of the applicant, hair Compound (VII) successful conversion for now there was only about 50% is that estimated principal product is compound (II), and compound (II) is through chromatographically pure Change for reacting in next step, thus cause the utilization rate of compound (VII) low, compound (I) to prepare yield low.
In fact, testing discovery repeatedly through the applicant, about 50% compound (VII) is reset through Ku Ertisi is converted into pair Product is compound (III), and compound (III), which can further react, changes into compound (I), so as to improve the chemical combination as raw material The utilization rate of thing (VII) and compound (I) prepare yield.
The preparation method of compound (I) provided by the invention includes：Compound (VII) is reset into generation through Ku Ertisi Further reaction changes into compound (I) to by-product compounds (III).
The present invention simultaneously has no special requirements for the source of the primary raw material compound (VII) of use, can be it is general commercially available, It can also be prepared by prior art.
In the preparation method of compound provided by the invention (I), the compound (III) as byproduct of reaction can be single Solely isolate, target compound (I) is changed into through further reaction；Compound (III) need not can also be separately separated out, and with Compound (II) is together under same reaction condition, while change into compound (I).
But preferred compound (III) does not separate with compound (II), but under same reaction condition, while changing into Compound (I), shown in following reaction scheme 2,
。
Due to compound (III) with compound (II) without separating, so as to avoid cumbersome chromatographic purification step, it is adapted to Industrial operation, improve production efficiency.
In the preparation method of compound provided by the invention (I), described same reaction condition includes having containing alkali Solvent.
The organic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide and its mixture； But it is preferred that sodium hydroxide.
The organic solvent is selected from one or more of C3-6Alcohol, or selected from one or more of C3-6Alcohol and dimethylbenzene it is mixed Bonding solvent.The C3-6Alcohol is selected from normal propyl alcohol, isopropanol, n-butyl alcohol, 2- butanol, the tert-butyl alcohol or 2- methylpropanols.The dimethylbenzene Selected from paraxylene, meta-xylene, ortho-xylene and its mixture.
In addition, it can regard as invention further provides a kind of compound (III) with brand new, the compound For the dimer of compound (I), available for prepare compound (I).Compound (III) is individually converted into the reaction bar of compound (I) Part can apply above-mentioned " same reaction condition ", but be not limited to " the same reaction condition ", can be further to this reaction condition Optimize or develop new different reaction conditions.
Present invention also offers the preparation method of compound (III), including：In toluene solvant and in the presence of triethylamine, change Compound (VII) resets generation compound (III) through Ku Ertisi.In the method, compound (VII) being converted into specific manner Compound (III), rather than the mixture of compound (II) or compound (II) and compound (III).
The compound (I), (II) and (III) being prepared from embodiment is respectively through following nuclear magnetic resonance and mass spectrometric data Confirm its structure.
Compound (I):
1H-NMR (400 MHz, DMSO-d 6): δ = 8.07 (s, 1H), 7.37 (s, 1H), 6.97 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.88 (s, 2H), 2.15 (s, 3H);
13C-NMR (100 MHz, DMSO-d 6): δ = 150.9, 138.5, 134.8, 131.2 (q, J = 31.4 Hz), 124.0 (q, J = 271.4 Hz), 114.2, 107.8, 103.2 (q, J = 3.7 Hz), 13.6;
LC-MS: m/z [M+H]+ 242.2。
Compound (II):
1H-NMR (400 MHz, DMSO-d 6): δ = 9.91 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 2.16 (s, 3H), 1.49 (s, 9H);
13C-NMR (100 MHz, DMSO-d 6): δ = 152.6, 141.8, 138.8, 138.0, 134.9, 130.9 (q, J = 32.3 Hz), 123.6 (q, J = 271.4 Hz), 114.2, 112.8, 112.0, 110.2 (q, J = 3.0 Hz), 80.2, 28.0, 13.5;
LC-MS: m/z [M+H]+ 342.2。
Compound (III):
1H-NMR (400 MHz, DMSO-d 6): δ = 10.92 (s, 2H), 9.37 (s, 2H), 8.18 (s, 2H), 8.02 (s, 2H), 7.87 (s, 2H), 7.72 (s, 2H), 2.27 (s, 6H);
13C-NMR (100 MHz, DMSO-d 6): δ = 152.4, 141.6, 138.9, 138.1, 135.1, 131.0 (q, J = 32.0 Hz), 123.7 (q, J = 271.5 Hz), 114.3, 113.4, 112.7, 110.3 (q, J = 3.8 Hz), 13.6;
LC-MS: m/z [M+H]+ 509.2。
Embodiment
In order to further illustrate the present invention, with reference to embodiment to compound provided by the invention (III) and the system of (I) Preparation Method is described in detail.
Embodiment 1
Compound (VII) (10g), the tert-butyl alcohol (300mL), triethylamine (7.9g) and diphenyl are added into 500mL reaction bulbs Phosphoryl azides (11.2g).Stirring is opened, heats the mixture to backflow, and maintains the reflux for 16 hours, is subsequently cooled to Room temperature, solvent removed by evaporation at reduced pressure, residue is handled with water (150mL), is extracted with ethyl acetate (2 × 150mL).Merge extraction Liquid is taken, is washed, is dried with sodium sulphate, under reduced pressure evaporation of solvent with salt solution (150mL), obtains crude product (12.1g).
Embodiment 2
The crude product (12.1g) that embodiment 1 is obtained (silica gel, is washed through chromatogram purification with the ethyl acetate containing 2% ethanol It is de-), two kinds of compositions are obtained, are recrystallized respectively from ether-hexane, obtain solid chemical compound (II) (5.25g) and solid chemical combination Thing (III) (3.76g).
Embodiment 3
Compound (VII) (10g), the tert-butyl alcohol (300mL), triethylamine (7.9g) and diphenyl are added into 500mL reaction bulbs Phosphoryl azides (11.2g).Stirring is opened, heats the mixture to backflow, and maintains the reflux for 16 hours, is subsequently cooled to Room temperature, solvent removed by evaporation at reduced pressure, residue is handled with water (150mL), is extracted with ethyl acetate (2 × 150mL).Merge extraction Liquid is taken, is washed, is dried with sodium sulphate, under reduced pressure evaporation of solvent with salt solution (150mL), obtains crude product (12.5g).
Added into 500mL reaction bulbs above-mentioned crude product (12.5g), normal propyl alcohol (125mL), paraxylene (125mL) and Solid sodium hydroxide (7.3g).Stirring is opened, heats the mixture to backflow, and maintains the reflux for 30 hours, stops heating stirring, Water (162mL) is added, is evaporated under reduced pressure and removes azeotropic mixture.Residue is diluted with water (20mL), 0 DEG C is cooled to, it is small to be slowly stirred 1 When, filtering.Filter cake is washed with water (2 × 30mL), in 55 DEG C of vacuum drying, obtains 7.1g solid chemical compounds (I), HPLC purity is 98.7%, two-step reaction total recovery is 79.5%.
Embodiment 4
Compound (VII) (10g), the tert-butyl alcohol (300mL), triethylamine (7.9g) and diphenyl are added into 500mL reaction bulbs Phosphoryl azides (11.2g).Stirring is opened, heats the mixture to backflow, and maintains the reflux for 16 hours, is subsequently cooled to Room temperature, solvent removed by evaporation at reduced pressure, residue is handled with water (150mL), is extracted with ethyl acetate (2 × 150mL).Merge extraction Liquid is taken, is washed, is dried with sodium sulphate, under reduced pressure evaporation of solvent with salt solution (150mL), obtains crude product (12.2g).
Above-mentioned crude product (12.2g), 2- methylpropanols (250mL) and solid potassium hydroxide are added into 500mL reaction bulbs (10.2g).Stirring is opened, heats the mixture to backflow, and maintains the reflux for 35 hours, stops heating stirring, adds water (160mL), it is evaporated under reduced pressure and removes azeotropic mixture.Residue is diluted with water (20mL), 0 DEG C is cooled to, is slowly stirred 1 hour, mistake Filter.Filter cake is washed with water (2 × 30mL), in 55 DEG C of vacuum drying, obtains 6.9g solid chemical compounds (I), HPLC purity is 99.2%, two-step reaction total recovery is 77.3%.
Embodiment 5
The solid chemical compound (III) (3.76g) obtained from embodiment 2, isopropanol are added into 500mL reaction bulbs (40mL), meta-xylene (40mL) and solid sodium hydroxide (2.2g).Stirring is opened, heats the mixture to backflow, and keep Backflow 25 hours, stop heating stirring, add water (50mL), be evaporated under reduced pressure and remove azeotropic mixture.Residue is dilute with water (7mL) Release, be cooled to 0 DEG C, be slowly stirred 1 hour, filter.Filter cake is washed with water (2 × 10mL), in 55 DEG C of vacuum drying, is obtained 3.31g solid chemical compounds (I), HPLC purity are 99.5%, reaction yield 92.8%.
Embodiment 6
Compound (VII) (10g), toluene (300mL), triethylamine (10g) and diphenylphosphine are added into 500mL reaction bulbs Acyl azide (12g).Stirring is opened, heats the mixture to 100 DEG C, and is kept for 5 hours at this temperature, is then cooled down To room temperature, solvent removed by evaporation at reduced pressure, residue is handled with water (150mL), is extracted with ethyl acetate (2 × 150mL).Merge Extract, washed, dried with sodium sulphate, under reduced pressure evaporation of solvent, then by residue in second with salt solution (150mL) Recrystallized in ether-hexane, obtain solid chemical compound (III) (7.71g), HPLC purity is 99.2%, reaction yield 82.0%.
The explanation of above example is only intended to help the method and its core concept for understanding the present invention.It should be pointed out that pair For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.

Claims (10)

1. a kind of preparation method of 3- (trifluoromethyl) -5- (4- methyl-1 H-imidazole-1-groups) aniline (I), including：By 3- (three Methyl fluoride) by-product compounds (III) of -5- (4- methyl-1 H-imidazole-1-groups) benzoic acid (VII) through Ku Ertisi rearrangement generations Further reaction changes into 3- (trifluoromethyl) -5- (4- methyl-1 H-imidazole-1-groups) aniline (I),
2. according to the method for claim 1, it is characterised in that the by-product compounds (III) through Ku Ertisi with resetting The main product compounds (II) of generation under same reaction condition, while change into 3- (trifluoromethyl) -5- (4- without separation Methyl-1 H-imidazole-1-group) aniline (I),
3. according to the method for claim 2, it is characterised in that the same reaction condition includes organic molten containing alkali Agent.
4. according to the method for claim 3, it is characterised in that the alkali is selected from sodium hydroxide, potassium hydroxide, hydroxide Lithium, magnesium hydroxide, calcium hydroxide and its mixture.
5. according to the method for claim 3, it is characterised in that the organic solvent is selected from one or more of C3-6Alcohol.
6. according to the method for claim 3, it is characterised in that the organic solvent is one or more of C3-6Alcohol and two The mixed solvent of toluene.
7. the method according to claim 5 or 6, it is characterised in that the C3-6Alcohol is selected from normal propyl alcohol, isopropanol, 1- fourths Alcohol, 2- butanol, the tert-butyl alcohol or 2- methylpropanols.
8. according to the method for claim 6, it is characterised in that the dimethylbenzene is selected from paraxylene, meta-xylene, neighbour two Toluene and its mixture.
9. the compound (III) with following structural formula,
10. the preparation method of compound described in claim 9 (III), including：In toluene solvant and in the presence of triethylamine, 3- (trifluoromethyl) -5- (4- methyl-1 H-imidazole-1-groups) benzoic acid (VII) resets generation compound (III) through Ku Ertisi.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101045727A (en) * 2002-07-05 2007-10-03 诺瓦提斯公司 Inhibitors of tyrosine kinases
CN101189212A (en) * 2005-06-09 2008-05-28 诺瓦提斯公司 Process for the synthesis of organic compounds
CN103172543A (en) * 2011-12-21 2013-06-26 中国科学院上海药物研究所 Urea compound, preparation method and application thereof
WO2013120852A1 (en) * 2012-02-13 2013-08-22 Grindeks, A Joint Stock Company Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101045727A (en) * 2002-07-05 2007-10-03 诺瓦提斯公司 Inhibitors of tyrosine kinases
CN101189212A (en) * 2005-06-09 2008-05-28 诺瓦提斯公司 Process for the synthesis of organic compounds
CN103172543A (en) * 2011-12-21 2013-06-26 中国科学院上海药物研究所 Urea compound, preparation method and application thereof
WO2013120852A1 (en) * 2012-02-13 2013-08-22 Grindeks, A Joint Stock Company Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors

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