CN105985293A - Preparation method of nilotinib intermediate - Google Patents
Preparation method of nilotinib intermediate Download PDFInfo
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- CN105985293A CN105985293A CN201510095187.2A CN201510095187A CN105985293A CN 105985293 A CN105985293 A CN 105985293A CN 201510095187 A CN201510095187 A CN 201510095187A CN 105985293 A CN105985293 A CN 105985293A
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Abstract
The invention relates to a preparation method of a nilotinib intermediate, namely, 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)aniline (I). The preparation method comprises the steps that 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)benzoic acid (VII) is subjected to Curtius rearrangement to generate a by-product compound (III) and then subjected to further reacting to be converted into 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)aniline (I). The preparation method has the advantages of being high in utilization rate of the raw materials and suitable for industrialized operation. Please see the formula in the description.
Description
Technical field
The present invention relates to medicine intermediate technical field, be specifically related to AMN107 intermediate 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) preparation method of aniline.
Background technology
AMN107 (Nilotinib), entitled 4-methyl-N-[3-(4-methyl-1 H-imidazole-1-group)-5-trifluoromethyl]-3-[[4-(3-the pyridine radicals)-2-pyrimidine radicals] amino] benzamide of chemistry, it is the high selectively oral tyrosine kinase inhibitor researched and developed by Novartis of Switzerland, its mono-hydrochloric salts monohydrate obtains U.S. FDA approval listing in October, 2007, is clinically used for treating the invalid chronic myelocytic leukemia of imatinib mesylate.The Philadelphia Chromosome Positive chronic myelocytic leukemia that AMN107 can be caused by tyrosinase and encoding gene sudden change thereof by targeting Selective depression, patient tolerability is good, selectively strong, evident in efficacy.
3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) aniline (I) be synthesis AMN107 key intermediate, there is (I) following structural formula,
,
It just can get 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), shown in following reaction scheme 1, including 4 step synthesis steps, by the aromatics substitution reaction of compound (IV) and compound (V),。
Wherein compound (VII) is reset (Curtius rearrangement) via Ku Ertisi and is generated compound (II), and compound (II) obtains compound (I) through chromatogram purification, Deprotection.But the applicant is through experiment discovery, during compound (VII) prepares compound (I) this two-step reaction, the utilization rate of compound (VII) is low, and the yield causing compound (I) is low；And chromatogram purification is not suitable for industrial operation.It is therefore desirable to the method is improved further.
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 acidH-imidazoles-1-base) preparation method of aniline (I), improving raw material availability, and be suitable to industrial operation.
The present invention includes with regard to the preparation method of compound (I): by 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) benzoic acid (VII) resets, through Ku Ertisi, the by-product compounds (III) generating and reacts further and change into compound (I),
。
Preferably, described by-product compounds (III) is with the principal product compound (II) resetting generation through Ku Ertisi without separating, and under same reaction condition, changes into compound (I) simultaneously,
。
Preferably, described same reaction condition includes the organic solvent containing alkali.
Preferably, described alkali is selected from NaOH, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide and mixture thereof.
Preferably, described organic solvent is selected from one or more of C3-6Alcohol.
Preferably, described organic solvent is one or more of C3-6Alcohol and the mixed solvent of dimethylbenzene.
Preferably, described C3-6Alcohol is selected from normal propyl alcohol, isopropanol, n-butyl alcohol, 2-butanol, the tert-butyl alcohol or 2-methylpropanol.
Preferably, described dimethylbenzene is selected from paraxylene, meta-xylene, ortho-xylene and mixture thereof.
Another object of the present invention is to provide the compound (III) with following structural formula,
。
The method that another object of the present invention is to provide one to prepare compound (III), comprising: in toluene solvant and in the presence of triethylamine, 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) benzoic acid (VII) through Ku Ertisi reset generate compound (III).
Another object of the present invention is to provide by application in preparing compound (I) for the compound (III).
Compared with prior art, the invention provides the method that one prepares compound (I), compound (VII) is reacted further through the by-product compounds (III) that Ku Ertisi rearrangement generates and changes into compound (I), improve raw material availability；It and the method process is not necessarily to chromatogram purification, is suitable for industrial operation.
Detailed description of the invention
The Ku Ertisi rearrangement reaction of compound (VII) disclosed in the repeated WO2004005281A1 of the applicant, compound (VII) successful conversion of discovery only about 50% is anticipated principal product i.e. compound (II), compound (II) reacts for next step through chromatogram purification, the utilization rate thus causing compound (VII) is low, compound (I) to prepare yield low.
In fact, repeatedly test discovery through the applicant, the compound (VII) of about 50% is reset through Ku Ertisi and is converted into accessory substance i.e. compound (III), compound (III) can react further and change into compound (I), thus improves and prepare yield as the utilization rate of compound (VII) of raw material and compound (I).
The preparation method of the compound (I) that the present invention provides includes: reacts compound (VII) through the by-product compounds (III) that Ku Ertisi rearrangement generates further and changes into compound (I).
The present invention is for the source of primary raw material compound (VII) using and has no special requirements, and can be typically commercially available, it is also possible to prepare by prior art.
In the preparation method of the compound (I) that the present invention provides, the compound (III) as byproduct of reaction can be separately separated out, changes into target compound (I) through reaction further；Compound (III) also can be not necessarily to be separately separated out, and together with compound (II) under same reaction condition, change into compound (I) simultaneously.
But preferred compound (III) does not separates with compound (II), but under same reaction condition, change into compound (I) simultaneously, shown in following reaction scheme 2,
。
Owing to compound (III) and compound (II) are not necessarily to separate, thus avoid loaded down with trivial details chromatographic purification step, be suitable for industrial operation, improve production efficiency.
In the preparation method of the compound (I) that the present invention provides, described same reaction condition includes the organic solvent containing alkali.
Described organic base is selected from NaOH, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide and mixture thereof；But preferred NaOH.
Described organic solvent is selected from one or more of C3-6Alcohol, or it is selected from one or more of C3-6Alcohol and the mixed solvent of dimethylbenzene.Described C3-6Alcohol is selected from normal propyl alcohol, isopropanol, n-butyl alcohol, 2-butanol, the tert-butyl alcohol or 2-methylpropanol.Described dimethylbenzene is selected from paraxylene, meta-xylene, ortho-xylene and mixture thereof.
Additionally, invention further provides a kind of compound (III) with brand new, this compound can see the dimer of compound (I) as, can be used for preparing compound (I).The reaction condition that compound (III) is individually converted into compound (I) can apply above-mentioned " same reaction condition ", but it is not limited to this " same reaction condition ", this reaction condition can be optimized further or develop the different reaction condition making new advances.
Present invention also offers the preparation method of compound (III), comprising: in toluene solvant and in the presence of triethylamine, compound (VII) is reset through Ku Ertisi and is generated compound (III).In the method, compound (VII) can be converted into compound (III), rather than the mixture of compound (II) or compound (II) and compound (III) in specific manner.
The compound (I), (II) and (III) preparing from embodiment confirms its structure through following nuclear magnetic resonance and mass spectrometric data respectively.
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, the compound (III) providing the present invention below in conjunction with embodiment and the preparation method of (I) are described in detail.
Embodiment 1
Compound (VII) (10g), the tert-butyl alcohol (300mL), triethylamine (7.9g) and diphenyl phosphoryl azide (11.2g) is added in 500mL reaction bulb.Open stirring, heat the mixture to backflow, and maintain the reflux for 16 hours, be then cooled to room temperature, solvent removed by evaporation at reduced pressure, residue is processed by water (150mL), is extracted with ethyl acetate (2 × 150mL).Combining extraction liquid, with salt solution (150mL) washing, is dried by sodium sulphate, under reduced pressure evaporation of solvent, obtains crude product (12.1g).
Embodiment 2
The crude product (12.1g) obtaining embodiment 1 is through chromatogram purification (silica gel, ethyl acetate wash-out with containing 2% ethanol), obtain two kinds of compositions, recrystallize from ether-hexane respectively, obtain solid chemical compound (II) (5.25g) and solid chemical compound (III) (3.76g).
Embodiment 3
Compound (VII) (10g), the tert-butyl alcohol (300mL), triethylamine (7.9g) and diphenyl phosphoryl azide (11.2g) is added in 500mL reaction bulb.Open stirring, heat the mixture to backflow, and maintain the reflux for 16 hours, be then cooled to room temperature, solvent removed by evaporation at reduced pressure, residue is processed by water (150mL), is extracted with ethyl acetate (2 × 150mL).Combining extraction liquid, with salt solution (150mL) washing, is dried by sodium sulphate, under reduced pressure evaporation of solvent, obtains crude product (12.5g).
Above-mentioned crude product (12.5g), normal propyl alcohol (125mL), paraxylene (125mL) and solid sodium hydroxide (7.3g) is added in 500mL reaction bulb.Opening stirring, heating the mixture to backflow, and maintain the reflux for 30 hours, stop heating stirring, add water (162mL), decompression is distilled off azeotropic mixture.Residue is diluted by water (20mL), is cooled to 0 DEG C, is slowly stirred 1 hour, filter.Filter cake water (2 × 30mL) washs, and in 55 DEG C of vacuum drying, obtains 7.1g solid chemical compound (I), and HPLC purity is 98.7%, and two-step reaction total recovery is 79.5%.
Embodiment 4
Compound (VII) (10g), the tert-butyl alcohol (300mL), triethylamine (7.9g) and diphenyl phosphoryl azide (11.2g) is added in 500mL reaction bulb.Open stirring, heat the mixture to backflow, and maintain the reflux for 16 hours, be then cooled to room temperature, solvent removed by evaporation at reduced pressure, residue is processed by water (150mL), is extracted with ethyl acetate (2 × 150mL).Combining extraction liquid, with salt solution (150mL) washing, is dried by sodium sulphate, under reduced pressure evaporation of solvent, obtains crude product (12.2g).
Above-mentioned crude product (12.2g), 2-methylpropanol (250mL) and solid potassium hydroxide (10.2g) is added in 500mL reaction bulb.Opening stirring, heating the mixture to backflow, and maintain the reflux for 35 hours, stop heating stirring, add water (160mL), decompression is distilled off azeotropic mixture.Residue is diluted by water (20mL), is cooled to 0 DEG C, is slowly stirred 1 hour, filter.Filter cake water (2 × 30mL) washs, and in 55 DEG C of vacuum drying, obtains 6.9g solid chemical compound (I), and HPLC purity is 99.2%, and two-step reaction total recovery is 77.3%.
Embodiment 5
The solid chemical compound (III) (3.76g) obtaining from embodiment 2, isopropanol (40mL), meta-xylene (40mL) and solid sodium hydroxide (2.2g) is added in 500mL reaction bulb.Opening stirring, heating the mixture to backflow, and maintain the reflux for 25 hours, stop heating stirring, add water (50mL), decompression is distilled off azeotropic mixture.Residue is diluted by water (7mL), is cooled to 0 DEG C, is slowly stirred 1 hour, filter.Filter cake water (2 × 10mL) washs, and in 55 DEG C of vacuum drying, obtains 3.31g solid chemical compound (I), and HPLC purity is 99.5%, and reaction yield is 92.8%.
Embodiment 6
Compound (VII) (10g), toluene (300mL), triethylamine (10g) and diphenyl phosphoryl azide (12g) is added in 500mL reaction bulb.Open stirring, heat the mixture to 100 DEG C, and keep 5 hours at this temperature, be then cooled to room temperature, solvent removed by evaporation at reduced pressure, residue is processed by water (150mL), is extracted with ethyl acetate (2 × 150mL).Combining extraction liquid, with salt solution (150mL) washing, it is dried with sodium sulphate, under reduced pressure evaporation of solvent, then residue is recrystallized in ether-hexane, obtaining solid chemical compound (III) (7.71g), HPLC purity is 99.2%, and reaction yield is 82.0%.
The explanation of above example is only intended to help to understand method and the core concept thereof of the present invention.It should be pointed out that, for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify in the protection domain also falling into the claims in the present invention.
Claims (10)
1. 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) preparation method of aniline (I), comprising:
By 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) benzoic acid (VII) resets, through Ku Ertisi, the by-product compounds (III) generating and reacts further and change into 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) aniline (I),
。
2. method according to claim 1, it is characterized in that, described by-product compounds (III) resets the principal product compound (II) generating without separating with through Ku Ertisi, under same reaction condition, change into 3-(trifluoromethyl)-5-(4-methyl isophthalic acid simultaneouslyH-imidazoles-1-base) aniline (I),
。
3. method according to claim 2, it is characterised in that described same reaction condition includes the organic solvent containing alkali.
4. method according to claim 3, it is characterised in that described alkali is selected from NaOH, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide and mixture thereof.
5. method according to claim 3, it is characterised in that described organic solvent is selected from one or more of C3-6Alcohol.
6. method according to claim 3, it is characterised in that described organic solvent is one or more of C3-6Alcohol and the mixed solvent of dimethylbenzene.
7. the method according to claim 5 or 6, it is characterised in that described C3-6Alcohol is selected from normal propyl alcohol, isopropanol, n-butyl alcohol, 2-butanol, the tert-butyl alcohol or 2-methylpropanol.
8. method according to claim 6, it is characterised in that described dimethylbenzene is selected from paraxylene, meta-xylene, ortho-xylene and mixture thereof.
9. there is the compound (III) of following structural formula,
。
10. the preparation method of a compound (III), comprising: in toluene solvant and in the presence of triethylamine, 3-(trifluoromethyl)-5-(4-methyl isophthalic acidH-imidazoles-1-base) benzoic acid (VII) through Ku Ertisi reset generate compound (III).
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Citations (4)
| 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 |
-
2015
- 2015-03-04 CN CN201510095187.2A patent/CN105985293B/en active Active
Patent Citations (4)
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 冯万祥，等: "《生化技术》", 30 November 1989, 湖南科学技术出版社 * |
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