WO2013120852A1 - Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors - Google Patents

Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors Download PDF

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WO2013120852A1
WO2013120852A1 PCT/EP2013/052790 EP2013052790W WO2013120852A1 WO 2013120852 A1 WO2013120852 A1 WO 2013120852A1 EP 2013052790 W EP2013052790 W EP 2013052790W WO 2013120852 A1 WO2013120852 A1 WO 2013120852A1
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methyl
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WO2013120852A4 (en
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Viesturs Lusis
Svetlana STUPNIKOVA
Dzintra Muceniece
Armands Zandersons
Deniss LAIPNIEKS
Edvards LAVRINOVICS
Indra JONANE-OSA
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Grindeks, A Joint Stock Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • the present invention relates to intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors. More specifically present invention relates to intermediates for a novel process of preparing imatinib, nilotinib, WBZ-4, WBZ-7 and related tyrosine kinase inhibitors. Still more specifically the present invention relates to key intermediates of general formula (I), useful for preparing said tyrosine kinase inhibitors:
  • R is H or CH 3 ,
  • R is H or CH 3 ,
  • R 1 is H or CH 3 ,
  • X is a substituent (II), (III), an ester group- metoxycarbonyl or alkoxycarbonyl group or benzamido group,
  • the drawback of this method is the use of highly toxic POC for synthesis of 2-chloro-4-(3-pyridyl)pyrimidine.
  • isolation/purification procedure to remove the copper-containing catalyst used in the final step.
  • nilotinib either reacting 3-[4-(3- pyridyl)pyrimidin-2-ylamino)-4-methylbenzoic acid derivative with the appropriately substituted aniline (Ueda, Satoshi; Su, Mingjuan; Buchwald, Stephen L; Journal of the American Chemical Society; vol. 134; nb. 1 ; (2012); p. 700 - 706.
  • WO 2006/135641 A (NOVARTIS AG) 21.12.2006, WO2007/15870, US2010/16590) or arylating 2-amino-4-(pyrid-4- yl)pyrimidine (Huang, Wei-Sheng; Shakespeare, William C; Synthesis; nb. 14; (2007); p. 2121 - 2124).
  • the key intermediate is a 4- (pyrid-3-yl)pyrimidine derivative that is prepared in the same way as in imatinib processes. Disclosure of the invention
  • An object of the present invention is to provide intermediates for a convenient synthesis of phenylaminopyrimidine derivatives, based on common approach, using commercially available starting materials and intermediates, excluding hazardous chemicals and complex technologies.
  • N-(5-amino-2-methylphenyl)-4-(3- pyridyl)pyrimidineamine one of the two genotoxic impurities in the imatinib preparation, requiring special improvements in the manufacturing process for limiting its presence to acceptable levels:
  • 2-Phenylamino-4-oxopyrimidines are obtained in solvent free manner by melting 2-methylthio-4-oxopyrimidines with substituted anilines in presence of hydrochloric acid or in pivalic acid media as an option. After 1 -2 hours at 120-130 °C the melt is cooled and the solid treated with appropriate solvent. The undissolved 2-phenylamino-4-oxopyrimidines can be used in the next step without purification.
  • 2-Phenylamino-4-oxopyrimidines are suspended in anhydrous dioxane, PyBrOP and triethylamine added under argon. After stirring at ambient temperature for 2-2.5 hours a Suzuki coupling catalyst is introduced and the pyridyl or pyrimidinyl boronic acid is added, followed by Na2CO3 solution. The mixture is kept at 100 °C for 24 hours under argon. The mixture is evaporated till dryness, ethyl acetate and water is added.
  • the present invention provides intermediates for an improved process to prepare 2-arylaminopyrimidine derivatives, substituted at position 4 of the pyrimidine ring by pyridine ring.
  • 2-arylamino-4- oxopyrimidines react with pyridylboronic acids under Suzuki coupling conditions to yield 4-pyridyl-2-phenylaminopyrimidines.
  • This process allows to produce wide variety of compounds by similar steps.
  • Many 2- methylthio-4-oxopyrimidines are commercially available or easily synthesized by well-established methods.
  • 2-Methylthio-4-oxopyrimidines are reacted with anilines in melt without solvent, in presence of hydrochloric acid or pivalic acid media as option.
  • the hydrochloride of the corresponding aniline if available, can be used instead.
  • the reaction is conducted in a sealed system with a vent line to exhaust the methanethiol liberated in the reaction.
  • the methanethiol is absorbed in two caustic scrubbers in series connected to vent line, with an empty trap between the reaction vessel and scrubbers to avoid reverse flow of caustic solution into the reaction vessel.
  • reaction mixture is treated, for example by hot acetone, and the insoluble reaction product can be used in the next step without additional purification.
  • the synthesis is illustrated by the scheme below.
  • the reaction of 2-arylamino-4-oxopyrimidines with boronic acids is conducted in aqueous dioxane or tetrahydrofuran in presence of Suzuki coupling catalysts, for example, PyBrOP and bis(tri-phenylphosphine)- palladium(ll) chloride, or PyBrOP and palladium catalyst prepared in situ from palladium(ll) acetate and triphenylphosphine.
  • Suzuki coupling catalysts for example, PyBrOP and bis(tri-phenylphosphine)- palladium(ll) chloride, or PyBrOP and palladium catalyst prepared in situ from palladium(ll) acetate and triphenylphosphine.
  • the coupling reaction is carried out at about 100 °C for 24 hours, the product isolated after evaporation of solvents.
  • the synthesis is illustrated by the scheme below.
  • R, R 1 and X are as mentioned above. Applicability of diverse hetaryl boronic acids is shown by reaction of 4-oxopyrimidine derivative with 5-pyrimidinyl- and 2-thienyl boronic acid.
  • the proposed synthesis strategy of imatinib and analogues permits to avoid using most of the toxic chemicals employed in the known methods - cyanamide, phosphorus oxychloride and the known genotoxic intermediate N-(5-amino-2-methylphenyl)-4-(3-pyridyl)pyrimidineamine.
  • Imatinib monohydrate treated with hot acetone upon cooling yielded anhydrous imatinib base that was conveniently transformed to imatinib mesylate by known method.
  • 6-Methyl-2-methylthiopyrimidin-4-one (5.0 g, 0.032 mol) and 2-methyl-5- nitrophenylamine (7.3g. 0.048 mol) were heated to 120 °C.
  • Hydrochloric acid (0.28 ml, 35%, 0.003 mol) was added to homogenous melt and heating was continued at 160 °C for 1.5 h while the melt solidified.
  • the methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system.
  • Hot acetone 60 ml was added to the mixture when cooled down till 50 °C, the mixture was stirred for 0.5h and cooled to room temperature.
  • the catalyst - bis(tri-phenylphosphine)-palladium(ll) chloride 29 mg, 5 mol-%) and 6-methyl-3-pyridyl boronic acid (0.13 g, 0.95 mmol) were added.
  • Na2CO3 water solution (1 mol/L, 4.0 ml) was added dropwise and the mixture was refluxed for 24 h under argon. The mixture was evaporated till dryness, dissolved in ethyl acetate and washed with brine. Organic phase was dried and evaporated under reduced pressure.
  • the catalyst - bis(tri-phenylphosphine)-palladium(ll) chloride 29 mg, 5 mol-%) and 6-methyl-3-pyridyl boronic acid (0.13 g, 0.95 mmol) were added.
  • Na2CO3 water solution (1 mol/L, 4.0 ml) was added dropwise and the mixture was refluxed for 24 h under argon.
  • the mixture was evaporated till dryness, dissolved in ethyl acetate and washed with brine.
  • Organic phase was dried and evaporated under reduced pressure.
  • the product was subjected to flash chromatography on silica gel (dichloro methane: aceonitril 2: 1 ) to obtain 0.12 g (46%) of title compound, m.p. 172-173°C.
  • the catalyst - bis(tri-phenylphosphine)-palladium(ll) chloride (29 mg, 5 mol-%) and 5-pyrimidyl boronic acid (0.12 g, 0.97 mmol) were added.
  • Na2CO3 water solution (1 mol/L, 4.0 ml) was added dropwise and the mixture was refluxed for 24 h under argon.
  • the mixture evaporated till dryness was dissolved in ethyl acetate and washed with brine.
  • Organic phase was dried and evaporated under reduced pressure till dryness.
  • the residue was triturated with ethanol to obtain 0.14 g (56%) of title compound, m.p. 208-21 1 °C.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

4-Oxo-2-phenylaminopyrimidine derivatives as intermediates for synth of tyrosine kinase inhibitors, in particular imatinib and nilotinib.

Description

INTERMEDIATES FOR A NOVEL PROCESS OF PREPARING IMATINIB AND RELATED TYROSINE KINASE INHIBITORS
Technical Field
The present invention relates to intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors. More specifically present invention relates to intermediates for a novel process of preparing imatinib, nilotinib, WBZ-4, WBZ-7 and related tyrosine kinase inhibitors. Still more specifically the present invention relates to key intermediates of general formula (I), useful for preparing said tyrosine kinase inhibitors:
Figure imgf000002_0001
(I)
wherein:
R is H or CH3,
X is
Figure imgf000002_0002
an ester group- ill) (III)
metoxycarbonyl or alkoxycarbonyl group or benzamido group
and intermediates for preparing thereof.
A number of phenylaminopyrimidines having the common structural fragment of formula (IV)
Figure imgf000002_0003
(IV)
wherein:
R is H or CH3,
R1 is H or CH3,
X is a substituent (II), (III), an ester group- metoxycarbonyl or alkoxycarbonyl group or benzamido group,
are known as agents with tyrosine kinase inhibitor activity, displaying various biological effects and useful in treating various conditions. Some important of these derivatives are the following:
A. Imatinib (V)
Figure imgf000003_0001
(V)
B. WBZ-4 (VI)
Figure imgf000003_0002
(VI)
C. WBZ-7 (VII)
Figure imgf000003_0003
(VII) D. Nilotinib (VIII)
Figure imgf000004_0001
(VIII)
E. CPG 53716
Figure imgf000004_0002
Background Art
Various synthetic approaches are known for synthesizing the 4-heteroaryl- 2-arylaminopyrimidine fragment. The synthesis disclosed in EP 564409 (US 5,521 ,184), was based or reaction of 2-methyl-5-nitrophenyl-guanidine (X) with 3-dimethylamino-1 -(3-pyridyl)-2-propen-1 -one (XI) to yield N-(2- methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine (XII), further reduced to N-(5-amino-2-methylphenyl)-4-(3-pyridyl)pyrimidineamine (XIII) that could be acylated to (V), (VI) or (IX).
Figure imgf000004_0003
The drawbacks of this method are: use of highly toxic, hazardous and corrosive cyanamide for preparing the guanidine; complicated syntheses of methyl-substituted 3-acetylpyridines for preparing 3-dimethylamino-1 -(3- pyridyl)-2-propen-1 -ones methyl-substituted in pyridine ring (as disclosed in WO 2008/070350 A (UNIV TEXAS; RICE UNIVERSITY ) 12.06.2008). To avoid using cyanamide, an approach was developed (US 7507821 B (CHEMAGIS LTD) 24.03.2009), based on reacting the same intermediate -
3- dimethylamino-1 -(3-pyridyl)-2-propen-1 -one (XI) with urea to yield 2-oxo-
4- (3-pyridyl)-pyrimidine (XIV) that was chlorinated to yield 2-chloro-4-(3- pyridyl)-pyrimidine (XV), followed by reaction with 2-methyl-5-nitroaniline to yield the required N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2- pyrimidineamine (XII) and further reduced to N-(5-amino-2-methylphenyl)- 4-(3-pyrid l)pyrimidineamine (XIII)
Figure imgf000005_0001
The drawbacks of this method are: use of highly toxic POC for synthesis of 2-chloro-4-(3-pyridyl)-pyrimidine; the already mentioned limitations in introducing methyl group into the pyridine ring.
A further development of abovementioned approach was desribed in CN 100451015 C (HANGZHOU SHENGMEI MEDICINE TEC) 14.01.2009, where 2-chloro-4-(3-pyridyl)-pyrimidine (XV) was converted directly to imatinib by treating with N-(3-amino-4-methylphenyl)-4-(4-methylpiperazin- 1-ylmethyl)benzamide (XVI) to yield imatinib (V).
Figure imgf000006_0001
The drawback of this method is the use of highly toxic POC for synthesis of 2-chloro-4-(3-pyridyl)pyrimidine.
Still further improvement of this approach was described in CN 101497601 , where the reaction of 2-oxo-4-(3-pyridyl)-pyrimidine (XIV) with N-(3-amino- 4-methylphenyl)-4-(4-methylpiperazin-1 -ylmethyl)benzamide (XVI) was promoted by peptide coupling catalysts in presence of DBU.
The drawback of this method is the use of complex catalyst systems.
[0008] Another process for creating the 2-phenylaminopyrimidine system without using cyanamide was described in WO 2008/103068 A (KOPYRIN YURY IOSIFOVICH) 28.08.2008. It was also based on 2-oxo-4-(3-pyridyl)- pyrimidine (XIV) that was activated by tosylation or mesylation and then treated by 2-methyl-5-nitroaniline or 4-methyl-1 ,3-diaminobenzene to yield the important intermediates:
Figure imgf000006_0002
Although this pathway eliminates cyanamide, it introduces extra steps in the process from 3-acetylpyridine to intermediates (XII) or (XIII).
Another approach (WO 03/066613 A (NOVARTIS AG) 14.08.2003) for synthesizing 2-phenylamino-4-(3-pyridyl)pyrimidine fragment was based on reacting 2-amino-4-(3-pyridyl)pyrimidine (XVII) with arylbromide (XVIII)
Figure imgf000006_0003
The drawback of this process is the low reactivity of components, requiring use of rac-BINAP [2,2'-bis-(diphenylphosphino)-1 ,1 '-binaphtalin] and
[tris(dibenzylideneacetone)-dipalladium chloroform complex) catalyst plus sonification in the final step. The product contains about 10% of isomers, requiring purification by reverse phase chromatography.
A modification of the EP 0564409 B (NOVARTIS AG) 19.01.2000 method for synthesizing the 2-anilinopyrimidine intermediate was described in WO 2008/103068 A (KOPYRIN YURY IOSIFOVICH) 28.08.2008., where 3- acetylpyridine was converted into sodium salt of 3-oxo-(3- pyridine)propanal (XIX) that was treated either by 2-methyl-5- nitrophenylguanidine (X) or 2-methyl-5-aminophenylguanidine (XX) to yield the important intermediates (XII) or (XIII):
Figure imgf000007_0001
(XIX)
The drawback of this process is the use of cyanamide in preparing the guanidine intermediates (X) and (XX).
Yet another process that was based on the use of guanidine for creating the pyrimidine ring was described in WO 2010/014022 A (TEMAPHARM SP Z O O) 04.02.2010. The process differs from the above described in that the carbonylamino group is attached to 2-anilinopyrimidine system by arylation of amide function:
Figure imgf000007_0002
2-Methyl-5-bromoaniline is converted by cyanamide into 2-methyl-5- bromophenylguanidine (XXI) that is condensed with the 3-dimethylamino- 1-(pyridin-3-yl)prop-2-enone (XI) to yield N-(2-methyl-5-bromophenyl)-4- (pyridin-3-yl)pyrimidin-2-ylamine (XXII). In the final step (XXII) is reacted with 4-(4-methylpiperazin-1 -ylmethyl)benzamide (XXIII) to yield imatinib (V).
This process also suffers from the use of cyanamide in the synthesis of 2- methyl-5-bromophenylguanidine (XXI) and complicated
isolation/purification procedure to remove the copper-containing catalyst used in the final step.
An alternative approach, described in US 8168787 B (ITALIANA SINT SPA) 01.05.2012, used nicotinoylacetic ester for condensation with an appropriately substituted phenylguanidine. The 6-hydroxypyrimidine derivative was chlorinated and the nitro group reduced and chlorine eliminated by catalytic hydrogenation in the next step, thus providing the important imatinib intermediate.
Figure imgf000008_0001
Figure imgf000008_0002
This approach has no objective advantages over the traditional synthesis, based on 3-acetylpyridine.
An appropriately modified original imatinib synthesis was applied for WBZ- 4 and WBZ-7 (WO 2008/070350 A (UNIV TEXAS; RICE UNIVERSITY ) 12.06.2008) and CPG 53716 (Major TC, Keiser JA, JPET 283,1 ,402-410 (1997)).
The same strategy was used for preparing nilotinib: either reacting 3-[4-(3- pyridyl)pyrimidin-2-ylamino)-4-methylbenzoic acid derivative with the appropriately substituted aniline (Ueda, Satoshi; Su, Mingjuan; Buchwald, Stephen L; Journal of the American Chemical Society; vol. 134; nb. 1 ; (2012); p. 700 - 706. WO 2006/135641 A (NOVARTIS AG) 21.12.2006, WO2007/15870, US2010/16590) or arylating 2-amino-4-(pyrid-4- yl)pyrimidine (Huang, Wei-Sheng; Shakespeare, William C; Synthesis; nb. 14; (2007); p. 2121 - 2124). In both strategies the key intermediate is a 4- (pyrid-3-yl)pyrimidine derivative that is prepared in the same way as in imatinib processes. Disclosure of the invention
Problems that the invention is to solve
An object of the present invention is to provide intermediates for a convenient synthesis of phenylaminopyrimidine derivatives, based on common approach, using commercially available starting materials and intermediates, excluding hazardous chemicals and complex technologies.
One of the important intermediates that present invention allows to exclude from the manufacturing process is N-(5-amino-2-methylphenyl)-4-(3- pyridyl)pyrimidineamine, one of the two genotoxic impurities in the imatinib preparation, requiring special improvements in the manufacturing process for limiting its presence to acceptable levels:
(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_lnformation/human/000406/WC500022207.pdf. WO
2012/13171 1 A (IND SWIFT LAB LTD) 04.10.2012. Yadav RR et al, Determination of Potential Genotoxic Impurities in Imatinib Mesylate by RP-HPLC Method, Biological Forum - An International Journal 4(2), 15- 18(2012)).
In addition these intermediates allow to introduce into the position 4 of the pyrimidine ring substituents that would require very complicated synthetic procedures in the known strategies, and thus prepare a large set of new imatinib analogues.
Short description of the invention
We have found that 2-phenylamino-4-oxopyrimidine derivatives react with pyridylboronic acids in presence of Suzuki coupling catalysts as
demonstrated for some tautomerizable heterocycles in (Fu-An Kang, Zhihua Sui, and William V. Murray, Pd-Catalyzed Direct Arylation of Tautomerizable Heterocycles with Aryl Boronic Acids via C-OH Bond Activation Using Phosphonium Salts, JACS, 2008, 130, 1 1300-1 1302) to yield 2-phenylamino-4-pyridylpyrimidines. Since 2-phenylamino-4- oxopyrimidines are readily obtainable from various 2-methylthio-4- oxopyrimidines and various anilines, this method provides access to wide variety of 2-phenylamino-4-oxopyrimidines and further to wide variety of 2- phenylamino-4-pyridylpyrimidines with various substituents in benzene, pyridine and pyrimidine rings, in particular derivatives that are important intermediates for synthesis of known compounds with tyrosine kinase inhibitor activity, like imatinib, nilotinib, WBZ-4, WBZ-7 and CPG 53716 inter alia.
2-Phenylamino-4-oxopyrimidines are obtained in solvent free manner by melting 2-methylthio-4-oxopyrimidines with substituted anilines in presence of hydrochloric acid or in pivalic acid media as an option. After 1 -2 hours at 120-130 °C the melt is cooled and the solid treated with appropriate solvent. The undissolved 2-phenylamino-4-oxopyrimidines can be used in the next step without purification.
2-Phenylamino-4-oxopyrimidines are suspended in anhydrous dioxane, PyBrOP and triethylamine added under argon. After stirring at ambient temperature for 2-2.5 hours a Suzuki coupling catalyst is introduced and the pyridyl or pyrimidinyl boronic acid is added, followed by Na2CO3 solution. The mixture is kept at 100 °C for 24 hours under argon. The mixture is evaporated till dryness, ethyl acetate and water is added.
Organic phase is separated, washed with brine, dried, and evaporated under reduced pressure to small volume and subjected to flash
chromatography on silica gel to obtain the 4-pyridylpyrimidine derivative.
Detailed description of the invention
The present invention provides intermediates for an improved process to prepare 2-arylaminopyrimidine derivatives, substituted at position 4 of the pyrimidine ring by pyridine ring. We have found that 2-arylamino-4- oxopyrimidines react with pyridylboronic acids under Suzuki coupling conditions to yield 4-pyridyl-2-phenylaminopyrimidines. This process allows to produce wide variety of compounds by similar steps. Many 2- methylthio-4-oxopyrimidines are commercially available or easily synthesized by well-established methods. The ever-increasing number of commercially available aryl and heteroaryl boronic acids provides approach to wide variety of 4-substituted-2-phenylaminopyrimidines, including the objects, demonstrated in the present invention. The approach described in this invention allows to create the backbone of a number of important 2-phenylaminopyrimidine series tyrosine kinase inhibitors from commercially available starting materials.
2-Methylthio-4-oxopyrimidines are reacted with anilines in melt without solvent, in presence of hydrochloric acid or pivalic acid media as option. The hydrochloride of the corresponding aniline, if available, can be used instead. The reaction is conducted in a sealed system with a vent line to exhaust the methanethiol liberated in the reaction. The methanethiol is absorbed in two caustic scrubbers in series connected to vent line, with an empty trap between the reaction vessel and scrubbers to avoid reverse flow of caustic solution into the reaction vessel. There are established methods for work with methanethiol exhaust in industry without any environmental hazards.
Since the reaction products are sparingly soluble in usual organic solvents, the reaction mixture is treated, for example by hot acetone, and the insoluble reaction product can be used in the next step without additional purification. The synthesis is illustrated by the scheme below.
Figure imgf000011_0001
wherein R and X are as mentioned above.
The reaction of 2-arylamino-4-oxopyrimidines with boronic acids is conducted in aqueous dioxane or tetrahydrofuran in presence of Suzuki coupling catalysts, for example, PyBrOP and bis(tri-phenylphosphine)- palladium(ll) chloride, or PyBrOP and palladium catalyst prepared in situ from palladium(ll) acetate and triphenylphosphine. The coupling reaction is carried out at about 100 °C for 24 hours, the product isolated after evaporation of solvents. The synthesis is illustrated by the scheme below.
Figure imgf000012_0001
wherein R, R1 and X are as mentioned above. Applicability of diverse hetaryl boronic acids is shown by reaction of 4-oxopyrimidine derivative with 5-pyrimidinyl- and 2-thienyl boronic acid.
The proposed synthesis strategy of imatinib and analogues permits to avoid using most of the toxic chemicals employed in the known methods - cyanamide, phosphorus oxychloride and the known genotoxic intermediate N-(5-amino-2-methylphenyl)-4-(3-pyridyl)pyrimidineamine.
The following examples are provided to illustrate the invention without limiting the scope of the invention as defined in the claims.
Example 1
itrophenylamino)pyrimidin-4-one
Figure imgf000012_0002
2-Methythiopyrimidin-4-one (18.6 g, 0.13 mol) and 2-methyl-5- nitrophenylamine (29.7 g, 0.195 mol) were heated to melt at approximately 130 °C. The reaction is conducted in a sealed system with a vent line to exhaust the methanethiol liberated in the reaction. The methanethiol is absorbed in two caustic scrubbers in series connected to vent line, with an empty trap between the reaction vessel and scrubbers to avoid reverse flow of caustic solution into the reaction vessel. Hydrochloric acid (1 ml, 35%, 0.01 1 mol) was added and the melt heated at 160 °C for 1.5 h forming a solid. Hot acetone (200 ml) was added at 45-50 °C and the mixture was stirred for 0.5 h. Solid was filtered off and washed with acetone (130 ml) and water (60 ml) yielding 24.5 g (76%) of 2-(2-methyl-5- nitrophenylamino)pyrimidin-4-one. M.p. 271 -273 °C. 1H NMR (DMSO-Ok): 2.12 (s, 3H), 2.36 (s, 3H), 5.74 (s, 1 H), 7.49 (d J=8.4 Hz, 1 H), 7.86 (dd J=8.4;2.5 Hz, 1 H), 8.34 (br.s, 1 H), 9.04 (d J=2.5 Hz, 1 H), 1 1.13 (br.s, 1 H).
Example 2
methylphenylamino)pyrimidin-4-one
Figure imgf000013_0001
A 250 ml flask equipped with a PTFE stirrer and reflux condenser was charged with ethanol (50 ml) and iron powder (5.7 g, 0.1 mol).
Concentrated HCI (3 ml, 0.034 mol) was added in portions under constant stirring. The suspension was stirred at 65 °C for 2 h, cooled to 55-60 °C over a period of 10 min. 25% NH4CI aqueous solution (20 ml) was added. 2-(2-Methyl-5-nitrophenylamino)pyrimidin-4-one (5 g, 0.02 mol) was added in portions over a period of 30 min. The reaction mixture was stirred at 55- 65 °C for additional 3 h, cooled to 40 °C. Ethanol was added (100 ml), the mixture was warmed up to 55 °C and filtered hot through a celite pad. The celite pad was washed with hot ethanol (4 x 100 ml) by suction. Combined solution was evaporated. To the residue a 4% NaHCO3 aqueous solution (85 ml) was added, the suspension stirred for 10 min and filtered. The obtained tan solid was washed with water and refluxed for 10 min with ethanol (500 ml) with stirring and filtered. The filtrate was reduced in volume to -20 ml and left in refrigerator overnight. The solid was filtered off and dried to obtain 3.73 g (84%) of title compound. M.p. 252-255 °C.
1H NMR (DMSO-ok): 2.04 (s, 6H), 5.31 (br.s, 2H), 5.57 (s, 1 H), 6.30 (dd J= 8.1 ; 1.8 Hz, 1 H), 6.84 (d J=8.1 Hz, 1 H), 7.04 (d J= 1.8 Hz, 1 H), 7.92 (br.s, 1 H), 10.72 (br.s, 1 H).
Example 3
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-2- pyrimidinyl)amino]-phenyl]benzamide
Figure imgf000014_0001
2-(5-Amino-2-methylphenylamino)pyrinniclin-4-one (5.0 g, 0.023 mol) and 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride 2HCI (7.9 g, 0.024 mol) in dry tetrahydrofuran (100 ml) was stirred by magnetic stirrer at ambient temperature for 24 h in a closed flask. The solvent was evaporated, the residue dissolved in 140 ml water and slowly under stirring treated by 45 ml of 10% aqueous NaOH. The suspension thus obtained was stirred for 10 min and filtered to obtain 10.2g (94%) of N-[3-(4-oxopyrimidin-2- ylamino)-4-methylphenyl]-4-(4-methylpiperazin-1 -ylmethyl)-benzamide dihydrate; drying under vacuum affords anhydrous form with m.p. 273- 275 °C.
1H NMR (CDsOD): 2.28 (s, 3H), 2.30 (s, 3H), 3.32 (m, 8H), 3.63 (s, 2H), 5,83 (d J=6.3 Hz, 1 H), 7.20 (d J=8.4 Hz, 1 H), 7.50 (d J=8.3 Hz, 2H), 7.54 (dd J=8.4; 2.2 Hz, 1 H), 7.64 (d J=6.3 Hz, 1 H), 7.92 (d J=8.3 Hz, 2H), 8.08 (d J=2.2 Hz, 1 H).
3C NMR (CD3OD): 17.8, 46.1 , 53.7, 55.9, 63.4, 104.8, 1 17.8, 1 18.1 , 128.2, 128.8, 130.7, 131.6, 135.5, 138.3, 139.3, 143.0, 155.0, 160.6, 168.5, 174.9.
Example 4
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide monohydrate (imatinib monohydrate) and 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide (imatinib base)
Figure imgf000014_0002
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-2-pyrimidinyl)- amino]phenyl]benzamide dihydrate (3.0 g, 6.4 mmol) was suspended in deaerated dioxane (100 ml), PyBrOP (3.3 g, 7.1 mmol) and 4 ml of triethylamine added and stirred at ambient temperature under argon for 2 hours. The catalyst PdCI2(PPh3)2 (0.22 g, 5 mol%) was added and treated by 3-pyridylboronic acid (0.9 g, 7.3 mmol). After stirring for 0.5 h deaerated aqueous solution of 1 M Na2CO3 (30 ml) was added and stirring continued for 24 h at 100 °C under argon. Evaporated to dryness. The product was isolated on silica gel column, eluent methylene chloride:methanol 3: 1. The yield of imatinib monohydrate was 2.1 g (64%). M.p. 99-101 °C.
C29H31 N7O H2O Found: C 67.93 H 6.17 N 19.09
Calculated: C 68.08 H 6.50 N 19.16
Imatinib monohydrate treated with hot acetone upon cooling yielded anhydrous imatinib base that was conveniently transformed to imatinib mesylate by known method.
Example 5
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide monohydrate (imatinib monohydrate)
Figure imgf000015_0001
and 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]benzamide (imatinib base)
To a suspension of 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4- oxo-2-pyrimidinyl)amino]phenyl]benzamide dihydrate (0.30 g, 0.64 mmol) in purified dioxane (10 ml) bromo-tris-pyrrolidinophosphonium
hexafluorophosphate (0.35 g, 0.77 mmol) and triethylamine (0.40 ml, 2.9 mmol) were added under argon. The mixture was stirred at room temperature for 2 h. The catalyst prepared by stirring palladium(ll) acetate (7.0 mg, 5 mol-%) and triphenylphosphine (17 mg, 10 mol-%) in dioxane (5 ml) for 1 h under argon was transferred into the reaction mixture using cannula technique, followed by addition of 3-pyridylboronic acid (0.09 g, 0.77 mmol). The reaction mixture was stirred for 0.5 h at room
temperature. Then Na2CO3 solution (1 mol/L, 1.9 ml) was added dropwise and the mixture was held for 24 h at 100 °C under argon. Mixture was evaporated to dryness, DCM (250 ml) and water (50 ml) was added.
Organic phase was separated, washed with brine, dried, and evaporated under reduced pressure till 10 ml volume. The product was subjected to flash chromatography on silica gel (eluent methylene chloride: methanol 3: 1 ) to obtain 0.2 g (62%) of title compound as described in Example 4. Imatinib monohydrate treated with hot acetone upon cooling yielded anhydrous imatinib that was conveniently transformed to imatinib mesylate by known method.
Example 6
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(6-methylpyrid
2-pyrimidinyl]amino]-phenyl]benzamide (WBZ-4)
Figure imgf000016_0001
To a suspension of 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4- oxo-2-pyrimidinyl)amino]phenyl]benzamide (0.30 g, 0.69 mmol) in purified dioxane (15 ml) PyBrOP (0.34 g, 0.73 mmol) and triethylamine (0.29 ml, 2.1 mmol) were added under argon. The mixture was stirred at 45 °C for 1.5 h. Then 6-methyl-3-pyridylboronic acid (0.10 g, 0.73 mmol) and Pd(PPh3)2Cl2 (24.3 mg, 5 mol-%) there were added and the reaction was stirred at ambient temperature for 1 h. After aqueous Na2CO3 solution (2.1 ml, 1 mol/L; 2.1 mmol) was transferred into mixture by syringe the reaction was refluxed for 24 h under argon. Reaction mixture diluted with ethyl acetate (30 ml) and brine (5 % solution) was filtered through celite. Organic phase was separated and dried. After evaporation of solvent under reduced pressure the residue was treated with methanol to obtain 0.18 g (51 %) of title compound. Analytical sample could be obtained by flash chromatography (EtOAc:MeOH 10: 1 followed by the eluent with addition of NH4OH). M.p. 202- 205°C
1 H NMR (DMSO-ofe): 2.15 (s,3H), 2.21 (s,3H), 2.25- 2.45 (m, 8H), 2.52 (s,3H), 3.52 (s, 2H), 7.19 (d J= 8.5 Hz, 1 H) 7.37 (d J= 8.5 Hz, 1 H), 7.38 (d J= 5.2 Hz, 1 H), 7.43 (d J= 8.3 Hz, 2H), 7.48 (dd J= 8.2; 2.2 Hz, 1 H), 7.90 (d J= 8.3 Hz, 2H). 8.05 (d J= 2.0 Hz, 1 H), 8.36 (dd J= 8.2; 2.3 Hz, 1 H), 8.47 (d J=5.2 Hz, 1 H), 8.93 (s, 1 H), 9.14 (d J=2.3 Hz), 10.15 (s, 1 H).
Example 7
ethyl-5-nitrophenylamino)-pyrimidin-4-one
Figure imgf000017_0001
6-Methyl-2-methylthiopyrimidin-4-one (5.0 g, 0.032 mol) and 2-methyl-5- nitrophenylamine (7.3g. 0.048 mol) were heated to 120 °C. Hydrochloric acid (0.28 ml, 35%, 0.003 mol) was added to homogenous melt and heating was continued at 160 °C for 1.5 h while the melt solidified. The methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system. Hot acetone (60 ml) was added to the mixture when cooled down till 50 °C, the mixture was stirred for 0.5h and cooled to room temperature. Solid was filtered off, washed with acetone (25 ml) and water (15 ml) to obtain 7.0 g (84%) of 6-methyl-2-(2-methyl-5- nitrophenylamino)pyrimidin-4-one, m.p. 248-250 °C.
1H NMR (DMSO-Ok): 2.12 (s, 3H), 2.36 (s, 3H), 5.74 (s, 1 H), 7.49 (d J=8.4 Hz, 1 H), 7.86 (dd J=8.4;2.5 Hz, 1 H), 8.34 (br.s, 1 H), 9.04 (d J=2.5 Hz, 1 H), 1 1.13 (br.s, 1 H)
Example 8
ethylphenylamino)-6-methylpyrimidin-4-one
Figure imgf000017_0002
Cone, hydrochloric acid (4.2 ml) was added to suspension of Fe dust (5.7 g, 0.1 mol) in ethanol (50 ml). The suspension was warmed up to 65 °C and stirred for 2h, then NH4CI solution (25%, 27 ml) was added followed by portionwise addition of 6-methyl-2-(methyl-5- nitrophenylamino)pyrimidin-4-one (7.2 g, 0.027 mol). Reaction mixture was stirred at 65 °C for additional 3 h, diluted with ethanol (150 ml) and filtered through celite pad (1x4.5 cm). The celite pad was washed with hot ethanol (4 x 150 ml) by suction. Combined solution was evaporated. To the residue a saturated NaHCO3 aqueous solution (55 ml) was added, the suspension stirred for 10 min and filtered. The obtained tan solid was washed with water and refluxed for 10 min with ethanol (800 ml) with stirring and filtered. The filtrate was reduced in volume to -50 ml and left in refrigerator overnight. The solid was filtered off and dried to obtain 3.75 g (59%) of title compound. M.p. 245-247°C.
1 H NMR (DMSO-ofe): 2.06 (s,3H), 2.09 (s,3H), 3.34 (br.s, 2H), 5.59 (s, 1 H), 6.44 (dd J= 8.2; 1.9 Hz, 1 H), 6.96 (d J= 8.2 Hz, 1 H), 7.23 (d J= 1.9 Hz, 1 H), 7.90 (br.s, 2H).
Example 9
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-6-methyl-2- pyrimidinyl)amino]-phenyl]benzamide
Figure imgf000018_0001
2-(5-Amino-2-methylphenylamino)-6-methylpyrimidin-4-one (1.5 g,
0.006 mol) and 4-(4-methylpiperazin-1 -ylmethyl)benzoyl chloride 2HCI (2.55 g, 0.0078 mol) in dry tetrahydrofuran (40 ml) was stirred at ambient temperature for 24 h in a closed flask. The solvent was evaporated, the residue dissolved in 35 ml water and slowly under stirring treated by 14 ml of 10% aqueous NaOH. The suspension was stirred for 10 min and filtered to obtain 1.84g (54%) of 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3- [(4-oxo-6-methyl-2-pyrimidinyl)-amino]-phenyl]benzamide. M.p.221 -223 °C 1H NMR (DMSO-ok): 2.05 (s,3H), 2.15 (s,3H), 2.19 (s,3H), 2.36 (m, 6H), 3.35 (m, 2H),), 3.52 (s, 2H), 5.60 (s, 1 H), 7.17 (d J=8.3 Hz, 1 H), 7.43 (d J= 8.1 Hz, 2H), 7.48 (dd J= 8.3; 1.2, 1 H), 7.89 (d J= 8.1 , 2H), 8.14 (d J= 1.2 Hz, 1 H), 8.24 (br.s, 1 H), 10.15 (s, 1 H), 10.93 (br.s, 1 H).
Example 10 4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-methyl-6-(3-pyridinyl)- 2-pyrimidinyl]amino]-phenyl]benzamide (WBZ-7)
Figure imgf000019_0001
Mixture of 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-6- methyl-2-pyrimidinyl)annino]-phenyl]benzannide (0.35 g, 0.78 mmol) and PyBrOP (0.38 g, 0.82 mmol), and triethylamine (0.33 ml, 2.35 mmol) in anhydrous dioxane (15 ml) was stirred at 45°C for 2 h under argon. Then 3-pyridylboronic acid (0.10 g, 0.82 mmol) and Pd(PPh3)2CI2 (27.5 mg, 5 mol-%) there were added and the reaction was stirred at ambient temperature for 0.5 h under argon. After aqueous Na2CO3 solution (2.35 ml, 1 mol/L; 2.35 mmol) was transferred into mixture by syringe the reaction was refluxed for 22 h under argon. Reaction mixture diluted with ethyl acetate (30 ml) and brine (5 % solution) was filtered through celite. Organic phase was separated and dried. After evaporation of solvent under reduced pressure a residue was treated with diethyl ether to obtain 0.25 g (63%) of title compound. Analytical sample could be obtained by flash chromatography (EtOAc/MeOH 10:1 followed by the eluent with addition of NH4OH). M.p.199-201 °C
1H NMR (DMSO-Ok): 2.15 (s,3H), 2.22 (s,3H), 2.25- 2.45 (m, 8H), 2.40 (s,3H), 3.52 (s, 2H), 7.19 (d J= 8.3 Hz, 1 H), 7.36 (s, 1 H), 7.44 (m, 3H), 7.49 (dd J= 8.1 ; 4.8 Hz, 1 H), 7.90 (d J= 8.3 Hz, 2H), 8.14 (d J= 2.0 Hz, 1 H), 8.46 (dt J=8.1 ; 2.1 Hz, 1 H), 8.66 (dd J=4.8; 1.6 Hz, 1 H), 8.84 (s, 1 H), 9.25 (d J=2.2 Hz, 1 H), 10.14 (s, 1 H).
Example 1 1
Methyl 3-(4-oxopyrimidin-2-ylamino)-4-methylbenzoate
Figure imgf000019_0002
2-Methylthiopyrimidin-4-one (5.0 g, 0.035 mol) and methyl 3-amino-4- methylbenzoate (7.1 g. 0.043 mol) were heated to 130 °C. Hydrochloric acid (0.20 ml, 35%, 0.002 mol) was added to homogenous melt and the heating was continued at 160 °C for 1.5 h while the melt solidified. The methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system. Hot acetone (60 ml) was added to the mixture cooled down to 50 °C, the mixture was stirred for 0.5h and cooled to room temperature. Solid was filtered off and washed with water (15 ml) afforded 7.64 g (84%) of methyl 4-methyl-3-(4-oxopyrimidin-2-ylamino)benzoate. M.p. 231 -233°C.
The mixture of 2-methylthiopyrimidin-4-one (39.0 g, 0.274 mol), methyl 3- amino-4-methylbenzoate (51.9 g. 0.314 mol) and pivalic acid (270 ml) was heated under stirring at 130 °C for 15 h. The methanethiol liberated in reaction was vented by argon stream into a caustic scrubber system. Reaction mixture was cooled to 50- 60 °C, petrol ether (700 ml) was added and the mixture was stirred for 0.5 h. The precipitate filtered off was washed with petrol ether and crystallized from methanol (1.4 L) to afford title compound in 50.0 g (74%) amount.
1H NMR (CDCIs): 2.39 (s, 3H), 3.86 (s, 3H), 5.82 (d J=6.7 Hz, 1 H), 7.31 (d J=7.9Hz, 1 H), 7.61 (broad, 1 H), 7.80 (dd J=7.9; 2.1 Hz, 1 H), 8.17 (d J=2.1 Hz, 1 H).
Example 12
4-Methyl-N-(3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl)-3-(6- oxo-1 , 6-dihydropyrimidin-2-ylamino)benzamide
Figure imgf000020_0001
To a suspension of 5.95 g (0.023 mol) methyl 3-(4-oxopyrimidin-2- ylamino)-4-methylbenzoate and 5.60 g (0.023 mol) 3-(4-methyl-1 H- imidazol-1 -yl)-5-trifluoromethylaniline in 320 ml tetrahydrofuran under argon at -3 - -5 °C was slowly added a solution of t-BuOK (14.6 g, 5.5 eq) in tetrahydrofuran (80 ml). When 1/2 of butoxide solution is added, the suspension dissolves and a yellow solution is obtained. When all solution of butoxide has been added, the temperature was allowed to increase to room temperature and the reaction mixture stirred at room temperature for 16 hours. Reaction mixture was diluted with water (400 ml), some solid was filtered off and a calculated amount of 85% HsPO4 added to pH -7.0. The volume was reduced to 2/3 of the original one at 40-45 °C under reduced pressure. Organic layer was separated, warm aqueous layer was extracted by warm (about 40-45 °C) ethylacetate (3x200+150 ml). The organic extracts were pooled, cooled and the precipitate filtered to obtain 7.8 g of title compound. The filtrate was reduced to -150 ml and additional crop (1.2 g) of the product was isolated. The total yield was 9.0 g (83%). M.p. 229-232 °C
1 H NMR (DMSO-Ok): 2.17 (s,3H), 2,34 (s, 3H), 5.60 (d J=6.2 Hz, 1 H), 7.36 (d J= 7.9 Hz, 1 H), 7.48 (m, 1 H), 7.55 (d J= 6.2 Hz, 1 H), 7.65 (dd J= 7.9; 1.7 Hz), 7.70 (m, 1 H), 8.17 (m, 1 H), 8.20 (m, 1 H), 8.29 (m, 1 H), 10.17 (br.s, 1 H 10.68 (s, 1 H).
3C NMR (DMSO-Ok): 13.5, 18.1 , 104.1 , 1 1 1.4, 1 14.1 , 1 14.8, 123.2, 124.3, 123.6 (q J= 272.0 Hz), 130.2, 130.7 (q J= 32.3 Hz), 131.7, 134.9, 136.2, 137.8, 138.0, 138.8, 141.3, 155.3, 156.4, 165.7, 167.4.
Example 13
4-Methyl-N-(3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl)-3-(4- (pyridin-3-yl)pyrimidin-2-ylamino)benzamide (Nilotinib)
Figure imgf000021_0001
To a suspension of 1.20 g (2.56 mmol) 4-methyl-N-(3-(4-methyl-1 H- imidazol-1 -yl)-5-(trifluoromethyl)phenyl)-3-(6-oxo-1 ,6-dihydropyrimidin-2- ylamino)benzamide in anhydrous tetrahydrofuran (90 ml) bromo-tris- pyrrolidinophosphonium hexafluorophosphate (1.25 g, 2.69 mmol) and triethylamine (1.1 ml, 7.7 mmol) were added under argon. The mixture was stirred at 50 °C for 3.5 h under argon. Addition of 3-pyridylboronic acid (0.33 g, 2.69 mmol) was followed by transferring of catalyst (7.19 ml, 5 mol-%) into the reaction mixture by syringe. [The catalyst was prepared by stirring palladium(ll) acetate (28.8 mg, 1.128 mmol) and triphenylphosphine (67.2 mg, 0.256 mmol) in anhydrous THF (10 ml) for 1.5 h under argon]. After addition of catalyst the reaction mixture was stirred for 0.5 h at ambient temperature, then Na2CO3 aqueous solution (12.8 ml, 1 mol/L, 12.8 mmol) was introduced drop wise via syringe and reaction was refluxed for 22 h under argon. Mixture was filtered through celite pad. The celite pad was washed with hot (-50 °C) ethyl acetate by suction. Filtrate washed with water (2x30 ml) and reduced in volume by evaporation was left for crystallization at -18°C overnight. Solid was filtered off to obtain 0.882 g (65%) of nilotinib. M.p.232-234 °C. [Synthesis 2007, 2121 ; m.p. 231 - 233 °C]
1H NMR (DMSO-ofe): 2.18 (s, 3H), 2.36 (s, 3H), 7.40- 7.56 (m, 4H), 7.72 (s, 1 H), 7.76 (dd J= 7.9; 1.9, 1 H), 8.16 (s, 1 H), 8.20 (d J= 1.4 Hz, 1 H), 8.30 (t J= 1.2 Hz, 1 H), 8.33 (d J= \ A Hz, 1 H), 8.44 (dt J=8.0; 1.9 Hz, 1 H), 8.55 (d J= 5.2 Hz, 1 H), 8.68 (dd J= 4.8; 1.6 Hz, 1 H), 9.16 (s, 1 H), 9.28 (d J= 2.2 Hz, 1 H), 10.61 (s, 1 H).
Example 14
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-thiophen-2- yl)pyrimidin-2-yl]amino]-phenyl]benzamide
Figure imgf000022_0001
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-2-pyrimidinyl)- amino]phenyl]benzamide (0.30 g, 0.69 mmol) was suspended in
anhydrous dioxane (15 ml), PyBrOP (0.34 g, 0.73 mmol) and 0.29 ml of triethylamine added and stirred at 45 °C temperature under argon for 1 hour. The catalyst PdCI2(PPh3)2 (24.3 mg, 5 -mol%) was added and treated by 2-thienylboronic acid (0.93 mg, 0.73 mmol). After stirring for 1 h at room temperature deaerated aqueous solution of 1 M Na2CO3 (2.1 ml, 2.1 mmol) was added by syringe and stirring was continued for 24 h at 100 °C under argon. Reaction mixture diluted with ethyl acetate (30 ml) and brine (5 % solution) was filtered through celite. Organic phase was separated, washed with brine and dried. After evaporation of solvent under reduced pressure a residue was treated with methanol to obtain 0.16 g (46%) of title compound. Analytical sample could be obtained by flash chromatography (EtOAc:MeOH 10: 1 followed by the eluent with addition of NH4OH). M.p.189-192 °C
1H NMR (DMSO-ofe): 2.20 (s,3H), 2.27 (s,3H), 2.44 (m, 8H), 3.55 (s, 2H), 7.20 (m, 2H), 7.23 (d J= 5.2 Hz, 1 H), 7.43 (d J= 8.3 Hz, 2H), 7.51 (dd J= 8.2; 2.2 Hz, 1 H), 7.73 (dd J= 5.1 ; 1.1 Hz), 7.90 (m, 3H), 7.94 (dd J= 3.8; 1.1 Hz, 1 H), 8.36 (d J=5.2 Hz, 1 H), 8.88 (s, 1 H), 10.13 (s, 1 H).
Example 15
N-[3-([4,5']Bipyrimidinyl-2-amino)-4-methylphenyl]-4-(4-methylpiperazin-1 - ylmethyl)benzamide
Figure imgf000023_0001
4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-2-pyrimidinyl)- amino]phenyl]benzamide (0.30 g, 0.69 mmol) was suspended in anhydrous dioxane (15 ml), PyBrOP (0.34 g, 0.73 mmol) and 0.29 ml of triethylamine added and stirred at 45 °C temperature under argon for 1.5 hour. The catalyst PdCI2(PPh3)2 (24.3 mg, 5 -mol%) was added and the mixture was treated by 5-pyrimidinylboronic acid (0.90 mg, 0.73 mmol) under argon. After stirring for 1 h at room temperature deaerated aqueous solution of 1 M Na2CO3 (2.1 ml, 2.1 mmol) was added by syringe and stirring was continued for 24 h at 100 °C under argon. Reaction mixture diluted with ethyl acetate (30 ml) and brine (5 % solution) was filtered through celite. Organic phase was separated, washed with brine and dried. After evaporation of solvent under reduced pressure a residue was purified by flash chromatography (EtOAc:MeOH 10:1 followed by the eluent with addition of NH4OH) to obtain 0.12 g (35%) of title compound. M.p. 192-194 °C 1 H NMR (DMSO-ofe): 2.18 (s,3H), 2.22 (s,3H), 2.38 (m, 8H), 2.40 (s,3H), 3.53 (s, 2H), 7.21 (d J= 8.5 Hz, 1 H), 7.43 (d J= 8.2 Hz, 2H), 7.47 (dd J= 8.3; 2.0 Hz, 1 H), 7.50(d J= 5.1 Hz, 1 H), 7.90 (d J= 8.3Hz, 2H), 8.12 (d J= 2.0 Hz, 1 H), 7.57 (d J= 5.1 Hz, 1 H), 9.07 (s, 1 H), 9.29 (s, 1 H), 9.45 (s, 2H), 10.16 (s, 1 H).
Example 16
n-2-ylamino)-4-methylphenyl]benzamide
Figure imgf000024_0001
To suspension of 2-(5-amino-2-methylphenylamino)pyrimidin-4-one (1.0 g, 4.6 mmol) and K2CO3 (0,96g, 6,9 mmol) in THF (30 ml) stirred for 1 h benzoyl chloride (0.6 ml, 5.3 mmol) was added and the mixture was stirred for 6 h at room temperature. After evaporation of solvent the remainder was treated with water (40 ml) upon stirring. Solid filtered and washed with water (10 ml) afforded 1.4 g (98%) of N-[3-(4-oxopyrimidin-2-ylamino)-4- methyl-phenyl]benzamide. M.p. 288-290 °C (ethanol)
1H NMR (DMSO-ok): 2.20 (s,3H), 5.73 (d J= 6.4 Hz, 1 H), 7.19 (d J= 8.3 Hz, 1 H), 7.48- 7.68 (m, 5H), 7.95 (m, 2H), 8.10 (s, 1 H), 8.17 (br.s, 1 H), 10.23 (s, 1 H), 1 1.08 (br.s, 1 H).
Example 17
N-[4-Methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]benzamide
Figure imgf000024_0002
N-[3-(4-Oxopyrimidin-2-ylamino)-4-methylphenyl]-benzamide (0.36 g,
1.12 mmol), PyBrOP (0.55 g, 1.18 mmol) and 0.47 ml of triethylamine in anhydrous dioxane (15 ml) was stirred at 45 °C under argon for 0.5 h. To the solution 3-pyridinylboronic acid (145 mg, 1.18 mmol) and catalyst PdCl2(PPh3)2 (39.4 mg, 5 -mol%) was sequentially added under argon. After stirring for 0.5 h at room temperature deaerated aqueous solution of 1 M Na2CO3 (3.4 ml, 3.4 mmol) was added by syringe and stirring was continued for 24 h at 100 °C under argon. Reaction mixture diluted with ethyl acetate (30 ml) and brine (5 % solution). Organic phase was separated, washed with brine (15 ml) and filtered through celite and dried. After evaporation of solvent the residue was crystallized from ethanol to obtain 0.21 g (49%) of amorphous substance with mp.178-182 °C.
[BioMed.Chem.Lett, 201 1 , 21 , 6964 m.p. 190-191 °C]
1 H NMR (DMSO-Ok): 2.22 (s,3H), 7.43 (d J= 5.2 Hz, 1 H), 7.52 (m, 5H), 7.95 (m, 2H), 8.09 (d J= 1.9 Hz, 1 H), 8.48 (dt J= 8.1 ; 1.8 Hz, 1 H), 8.51 (d J= 5.2 Hz, 1 H), 8.68 (dd J= 4.8; 1.8 Hz, 1 H), 8.97 (s, 1 H), 9.29 (d J= 1.9 Hz, 1 H), 10.20 (s, 1 H).
Example 18
phenyl)-4-(6-methyl-3-pyridyl)-2-pyrimidineamine
Figure imgf000025_0001
To suspension of 2-(2-methyl-5-nitrophenylamino)pyrimidin-4-one (0.20 g, 0.81 mmol) in anhydrous dioxane (10 ml) bromo-tris- pyrrolidinophosphonium hexafluoro-phosphate (PyBrOP, 0.46 g, 0.99 mmol) and triethylamine (0.33 ml, 2.37 mmol) were added under argon atmosphere. The mixture was stirred at room temperature for 2 h. The catalyst - bis(tri-phenylphosphine)-palladium(ll) chloride (29 mg, 5 mol-%) and 6-methyl-3-pyridyl boronic acid (0.13 g, 0.95 mmol) were added. After stirring for 0.5 h at room temperature Na2CO3 water solution (1 mol/L, 4.0 ml) was added dropwise and the mixture was refluxed for 24 h under argon. The mixture was evaporated till dryness, dissolved in ethyl acetate and washed with brine. Organic phase was dried and evaporated under reduced pressure. The product was subjected to flash chromatography on silica gel (dichloro methane: aceonitril 2: 1 ) to obtain 0.12 g (46%) of title compound, m.p. 172-173°C. 1H NMR (DMSO-Ok): 2.43 (s, 3H), 2,54 (s, 3H), 7.42 (d, J= 8.4 Hz, 1 H), 7.52 (d J=8.3 Hz, 1 H), 7.55 (d J=5.2; 2.2 Hz, 1 H), 7.89 (dd J=8.4; 2.4 Hz, 1 H), 8.39 (dd J= 8.3; 2.2 Hz, 1 H), 8.60 (d J= 5.2 Hz, 1 H), 8.81 (d J= 2.4 Hz, 1 H), 9.22 (m, 2H).
Example 19
-(2-Methyl-5-nitrophenyl)-4-(6-methyl-3-pyridyl)-2-pyrimidineannine
Figure imgf000026_0001
To suspension of 2-(2-methyl-5-nitrophenylamino)pyrimidin-4-one (0.20 g, 0.81 mmol) in anhydrous dioxane (10 ml) bromo-tris- pyrrolidinophosphonium hexafluoro-phosphate (PyBrOP, 0.46 g, 0.99 mmol) and triethylamine (0.33 ml, 2.37 mmol) were added under argon atmosphere. The mixture was stirred at room temperature for 2 h. The catalyst - bis(tri-phenylphosphine)-palladium(ll) chloride (29 mg, 5 mol-%) and 6-methyl-3-pyridyl boronic acid (0.13 g, 0.95 mmol) were added. After stirring for 0.5 h at room temperature Na2CO3 water solution (1 mol/L, 4.0 ml) was added dropwise and the mixture was refluxed for 24 h under argon. The mixture was evaporated till dryness, dissolved in ethyl acetate and washed with brine. Organic phase was dried and evaporated under reduced pressure. The product was subjected to flash chromatography on silica gel (dichloro methane: aceonitril 2: 1 ) to obtain 0.12 g (46%) of title compound, m.p. 172-173°C.
1H NMR (DMSO-Ok): 2.43 (s, 3H), 2,54 (s, 3H), 7.42 (d, J= 8.4 Hz, 1 H), 7.52 (d J=8.3 Hz, 1 H), 7.55 (d J=5.2; 2.2 Hz, 1 H), 7.89 (dd J=8.4; 2.4 Hz, 1 H), 8.39 (dd J= 8.3; 2.2 Hz, 1 H), 8.60 (d J= 5.2 Hz, 1 H), 8.81 (d J= 2.4 Hz, 1 H), 9.22 (m, 2H).
Example 20
N-(2-Methyl-5-nitrophenyl)-4-(5-pyrimidinyl)-2-pyrimidineamine
Figure imgf000027_0001
To suspension of 2-(2-methyl-5-nitrophenylamino)pyrimidin-4-one (0.20 g, 0.81 mmol) in anhydrous dioxane (10 ml) bromo-tris- pyrrolidinophosphonium hexafluoro-phosphate (PyBrOP, 0.43 g, 0.92 mmol) and triethylamine (0.33 ml, 2.37 mmol) were added under argon atmosphere. The mixture was stirred at room temperature for 2 h. The catalyst - bis(tri-phenylphosphine)-palladium(ll) chloride (29 mg, 5 mol-%) and 5-pyrimidyl boronic acid (0.12 g, 0.97 mmol) were added. After stirring for 0.5 h at room temperature Na2CO3 water solution (1 mol/L, 4.0 ml) was added dropwise and the mixture was refluxed for 24 h under argon. The mixture evaporated till dryness was dissolved in ethyl acetate and washed with brine. Organic phase was dried and evaporated under reduced pressure till dryness. The residue was triturated with ethanol to obtain 0.14 g (56%) of title compound, m.p. 208-21 1 °C.
1H NMR (DMSO-Ok): 2.43 (s, 3H), 7.52 (d, J= 8.6 Hz, 1 H), 7.66 (d J= 5.2 Hz, 1 H), 7.90 (dd J= 8.6; 2.2 Hz, 1 H), 8.68 (d J= 5.2 Hz, 1 H), 8.77 (d J= 2.2 Hz, 1 H), 9.33 (s, 1 H), 9.34 (s, 1 H), 9.47 (s, 2H).

Claims

Claims
1. 2-(5-Amino-2-methylphenylamino)pyrimidin-4-one
2. 6-Methyl-2-(2-methyl-5-nitrophenylamino)-pyrimidin-4-one
3. 2-(5-Amino-2-methylphenylamino)-6-methylpyrimidin-4-one
4. Methyl 3-(4-oxopyrimidin-2-ylamino)-4-methylbenzoate
5. N-[3-(4-Oxopyrimidin-2-ylamino)-4-methylphenyl]benzamide.
6. 4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-2- pyrimidinyl)amino]phenyl]-benzamide
7. 4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[(4-oxo-6-methyl-2- pyrimidinyl)amino]-phenyl]benzamide
8. 4-Methyl-N-(3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl)-3- (6-0X0-1 , 6-dihydropyrimidin-2-ylamino)benzamide
9. 4-[(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]benzamide monohydrate (imatinib
monohydrate)
10. Use compounds according to claims 1 -9 as intermediates for
preparation phenylaminopyrimidines of formula (IV)
Figure imgf000028_0001
(IV)
wherein:
R is H or CH3
R is H or CH3
Figure imgf000028_0002
(III) an ester group
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