EP4298100A1 - Process for obtaining avapritinib and its intermediates - Google Patents
Process for obtaining avapritinib and its intermediatesInfo
- Publication number
- EP4298100A1 EP4298100A1 EP22759019.7A EP22759019A EP4298100A1 EP 4298100 A1 EP4298100 A1 EP 4298100A1 EP 22759019 A EP22759019 A EP 22759019A EP 4298100 A1 EP4298100 A1 EP 4298100A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- reacted
- iii
- avapritinib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 47
- DWYRIWUZIJHQKQ-SANMLTNESA-N (1S)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine Chemical compound Cn1cc(cn1)-c1cc2c(ncnn2c1)N1CCN(CC1)c1ncc(cn1)[C@@](C)(N)c1ccc(F)cc1 DWYRIWUZIJHQKQ-SANMLTNESA-N 0.000 title claims abstract description 38
- 229950009576 avapritinib Drugs 0.000 title claims abstract description 38
- 239000000543 intermediate Substances 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 141
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 13
- -1 tert-butylsulfinyl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000002516 radical scavenger Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 101100390700 Arabidopsis thaliana FH20 gene Proteins 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 abstract description 4
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 2
- 210000000936 intestine Anatomy 0.000 abstract description 2
- 210000002784 stomach Anatomy 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 239000013078 crystal Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- AXWNAQHKNUHLGI-UHFFFAOYSA-N 1-(4-fluorophenyl)-1-(2-piperazin-1-ylpyrimidin-5-yl)ethanamine Chemical compound CC(N)(C1=CC=C(F)C=C1)C1=CN=C(N=C1)N1CCNCC1 AXWNAQHKNUHLGI-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005580 one pot reaction Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 3
- UFIRISYMYHBEJF-UHFFFAOYSA-N 4-chloro-6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine Chemical compound Cn1cc(cn1)-c1cc2c(Cl)ncnn2c1 UFIRISYMYHBEJF-UHFFFAOYSA-N 0.000 description 3
- JKXCZYCVHPKTPK-UHFFFAOYSA-N hydrate;trihydrochloride Chemical compound O.Cl.Cl.Cl JKXCZYCVHPKTPK-UHFFFAOYSA-N 0.000 description 3
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- FDOMEEULKNYULF-UHFFFAOYSA-N heptane;methanol Chemical compound OC.CCCCCCC FDOMEEULKNYULF-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
- F24F5/00—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater
- F24F5/0007—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning
- F24F5/0017—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning using cold storage bodies, e.g. ice
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
- F24F5/00—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater
- F24F5/0007—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning
- F24F5/0017—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning using cold storage bodies, e.g. ice
- F24F2005/0025—Air-conditioning systems or apparatus not covered by F24F1/00 or F24F3/00, e.g. using solar heat or combined with household units such as an oven or water heater cooling apparatus specially adapted for use in air-conditioning using cold storage bodies, e.g. ice using heat exchange fluid storage tanks
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24F—AIR-CONDITIONING; AIR-HUMIDIFICATION; VENTILATION; USE OF AIR CURRENTS FOR SCREENING
- F24F2221/00—Details or features not otherwise provided for
- F24F2221/54—Heating and cooling, simultaneously or alternatively
Definitions
- the present invention relates to process for obtaining avapritinib(l) and its intermediates.
- GIST gastrointestinal stromal tumors
- WO201 5058129 and W02020210293 disclose the synthesis of the compounds of the Formula (VI) and (V) which compounds contain the structural elements of avapritinib.
- An alternative synthesis of avapritinib(l) is disclosed in the patent application No. CN1 10938077. The process according to the application does not require the separation on a chiral column, in contrast to that disclosed in the basic patent (WO 2015057873).
- the compound of the Formula (VI) is resolved with L-dibenzoyltartaric acid (L-DBTA), and then the salt thus obtained [(ll) * L-DBTA] is reacted with the compound of the Formula (X) also disclosed in the basic patent (WO 2015057873).
- L-dibenzoyl tartrate salt of avapritinib [(l) * L-DBTA] is formed, from which avapritinib (I) is released.
- the Compound of the Formula (VI) was added to ethanol/water/acetic acid mixed solution (preparation method: mixing ethanol, water, Acetic acid was mixed according to the volume ratio of 7:3:1), heated to 70 ° C, and then kept at 70 ° C and added dropwise 1.2 eq. L-DBTA and ethanol/water/acetic acid (volume ratio 7:3: 1 ), the resulting solution was stirred at 70°C for 16 hours, then cooled to room temperature. However, no solids could be collected after cooling to room temperature. There was no crystallization even after stirring at lower temperature 0-5 °C or storing in freezer.
- the patent application No. CN110950872 discloses another possible synthesis of avapritinib (I).
- the starting material for the process is S-1-(4-fluorophenyl)-1-[2- (piperazin-1-yl)pyrimidin-5-yl]ethan-1 -amine (the compound of the Formula (II), which is the S enantiomer of the compound of the Formula (VI)).
- the primary amino group of the starting material is protected with a tert- butyloxycarbonyl group (hereinafter Boc).
- W0202021 0669 discloses a process for the manufacture of avapritinib which does not require a column chromatography process.
- the diastereomeric mixture of the compound of the Formula (V) already known is prepared in a reaction medium from which mainly the S, S-diastereomer of the compound of the Formula (V) is precipitated, and the diastereomeric purity of the latter is increased by recrystallization from heptane-methanol.
- the intermediate thus obtained is reacted with hydrochloric acid to simultaneously remove the two protecting groups to give the intermediate salt (ll * 3,5HCI). This is reacted with the compound of the Formula (X) to get the final avapritinib (I) product.
- the present invention provides a novel process for the preparation of avapritinib (I) via the novel key intermediate the compound of the Formula (IV).
- Another aspect of the invention is the compound of the Formula (IV).
- the key intermediate, the compound of Formula (IV) is prepared by selectively introducing a Boc protecting group from the compound of Formula (VI) known in the literature or by removing the t-butylsulfinyl group from the compound of the Formula (V) also known in the literature (Scheme 1.).
- Another object of the present invention is to provide a process for the preparation of avapritinib (I) via the novel intermediate the compound of the Formula (III).
- a further object of the present invention is the compound of Formula (III), which is a diastereomeric salt of the S enantiomer of the compound of Formula (IV) with the compound of Formula (IX) wherein the meaning of R in Formula (IX) is FI or o-, m- or p- methyl group, and a process for obtaining the compound of the Formula (III), wherein the compound of Formula (IV) is resolved with a D-diaroyltartaric acid derivative [compound of the Formula (IX) in which the meaning of R is FI or methyl in the o-, m- or p-position].
- Another object of the present invention is a process for obtaining avapritinib (I) by converting the compound of the Formula (III) to avapritinib (I) in a one-pot process after removal of the resolving acid (Formula (IX)) and the Boc protecting group by reaction with the compound of Formula (X).
- Another object of the present invention is a process for obtaining avapritinib (I) by 85 releasing the compound of Formula S-(IV) from the compound of Formula (III) and then converting it to avapritinib (I) by reaction with the compound of Formula (X) after removing the protecting group Boc in a one-pot process.
- Another object of the present invention is a process for obtaining avapritinib (I) by 90 removing the resolving acid (Formula (IX)) and the Boc protecting group from the compound of the Formula (III) in a one-pot process, and then reacting the arising trihydrochloride monohydrate of the compound of Formula (II) (ll * 3HCI * H20) with the compound of Formula (X). Concentrated hydrochloric acid is used to remove the Formula (IX) and Boc, thereby a new, unknown form of the compound of Formula (II), 95 trihydrochloride monohydrate of Formula II (I l * 3HCI * H20) is obtained.
- the present invention provides a novel process for the preparation of avapritinib (I) via loo the novel key intermediate of the compound of the Formula (IV).
- the present invention further provides the compound of Formula (IV) and a process for obtaining the compound of the Formula (IV) as shown in Scheme 1.
- the compound of the Formula (IV) can be prepared by two methods, from the starting material of compound (V) or (VI).
- the compound of Formula (IV) is prepared by reacting a solution of the compound of the Formula (V) in an organic solvent with 1 to 6 equivalents, preferably 1 .5 to 2 equivalents of a strong acid, in which reaction the t-butylsulfinyl group can be selectively removed.
- the compound of the Formula (V) is dissolved in an organic solvent, preferably THF, and then excess strong acid is added dropwise, preferably 1.5-2 equivalents of concentrated hydrochloric acid.
- the reaction mixture is adjusted to an alkaline pH, the precipitated crystals are washed with water and, optionally, recrystallized from a C1 -C4 aliphatic alcohol, preferably ethanol, to obtain the compound of the Formula (IV).
- a C1 -C4 aliphatic alcohol preferably ethanol
- an organic solvent preferably THF
- a base for example NaFIC03
- the reaction mixture is cooled to 0-5 0 C and then a solution of di-tert-butyl dicarbonate in an organic solvent, preferably THF, is added dropwise. It is stirred for one hour at room temperature, then after addition of water it is stirred for additional half hour at 0-5 0 C. After the precipitated crystals are filtered off and washed with water, the compound of the Formula (IV) is obtained.
- An object of the present invention is to provide a process for the preparation of avapritinib (I) via the new intermediate, the compound of the Formula (III).
- An object of the present invention is the compound of the Formula (III) which is a diastereomeric salt of the compound of the Formula S-(IV) with compound (IX), wherein R means FI or methyl in the 0-, m- or p- position.
- Another object of the present invention is a process for obtaining the compound of the Formula (III), wherein the compound of the Formula (IV) is resolved with a D-diaroyltartaric acid derivative [compound of the Formula (IX) wherein R in the Formula (IX) means FI or methyl group in the 0-, m- or p-position] (Scheme 2.).
- the compound of the Formula (IX) is preferably D-di-benzoyltartaric acid [(2S,3S)-2,3-bis(benzoyloxy)butanedioic acid (IXa)], or, more preferably D-di- toluyltartaric acid [(2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedicarboxylic acid (IXb)].
- the resulting compound of the Formula (III) is preferably (2S,3S)-2,3-bis (benzoyloxy) butanedioic acid tert-butyl 4- ⁇ 5-[(1S)-1 -amino-1 -(4-fluorophenyl)ethyl]pyrimidine-2- yl ⁇ piperazine-1-carboxylate salt (1 :1) (Ilia), or, more preferably (2S,3S)-2,3-bis(4- methylbenzoyloxy) butanedioic acid tert-butyl4- ⁇ 5-[(1S))-1 -amino-1 -(4- fluorophenyl)ethyl]pyrimidin-2-yl ⁇ piperazine-1-carboxylate salt (1 : 1) (lllb).
- the compound of the Formula (IV) is suspended in a C1- C4 aliphatic alcohol, preferably ethanol, and heated to reflux, and a solution of the compound of Formula (IX) in a C1- C4 aliphatic alcohol, preferably ethanol, is added and stirred at room temperature for 24 hours.
- a solution of the compound of Formula (IX) in a C1- C4 aliphatic alcohol, preferably ethanol is added and stirred at room temperature for 24 hours.
- the precipitated crystals of the compound of the Formula (III) are filtered off, washed with a C1-C4 aliphatic alcohol, preferably ethanol, and then recrystallized from ethanol / C1-C4 aliphatic alcohol.
- the preparation of the compound of the Formula (III) is of key importance, since by the reaction of Scheme 2., the S enantiomer of the compound of the Formula (IV) (S-(IV)) can be separated selectively and on an industrial scale via the compound of the Formula (III), so that avapritinib (I) can be produced without the use of a chromatographic purification step. As a result of the reaction shown in Scheme 2., the S:R ratio of the resulting compound of the Formula (III) is at least 98:2.
- Avapritinib (I) may be prepared from the compound of Formula (III) in three alternative ways according to the present invention.
- the compound of the Formula (III) is reacted with the compound of the Formula (X) after removal of the resolving acid of Formula (IX) and the Boc protecting group in a one-pot process.
- the compound of the Formula (III) is dissolved in an organic solvent, preferably TFIF at room temperature, and then a strong acid is added dropwise, preferably concentrated hydrochloric acid.
- a base preferably N, N-diisopropylethylamine (DIPEA) is added dropwise to the organic phase, and then compound of the Formula (X) is added.
- DIPEA N-diisopropylethylamine
- the reaction mixture is stirred overnight at room temperature and an acid scavenger, preferably saturated NaHCC>3 solution is added.
- the phases are separated, the aqueous phase is extracted with a water-immiscible organic solvent, preferably ethyl acetate, and the combined organic phases are dried and concentrated.
- the residue is stirred with ethyl acetate for 1 hour and the precipitated avapritinib (I) is filtered off.
- the crude final product may be purified by recrystallization.
- avapritinib (I) may be prepared by setting free the Formula S-(IV) from the compound of the Formula (III) and then converting it to avapritinib (I) by reaction with the compound of Formula (X) after removal of the Boc protecting group in a one-pot process.
- the compound of Formula (III) is stirred in a mixture of a water-immiscible organic solvent and water, preferably dichloromethane and water, until dissolved at room temperature and then the mixture is made alkaline.
- the aqueous phase is extracted with a water- immiscible organic solvent, preferably dichloromethane, and the combined organic phases are washed, dried and then concentrated in vacuum.
- the residue is dissolved in an organic solvent, preferably TFIF or ethyl acetate, more preferably TFIF, at room temperature, and then a strong acid is added dropwise, preferably concentrated hydrochloric acid.
- a strong acid is added dropwise, preferably concentrated hydrochloric acid.
- the reaction mixture is stirred for 1 - 24 hours, then water is added, and the mixture is made alkaline.
- the phases are separated, a base, preferably DIPEA, is added dropwise to the organic phase, then the compound of the Formula (X) is added.
- the reaction mixture is stirred overnight at room temperature and an acid scavenger, preferably saturated NaFIC03 solution is added.
- the phases are separated, the aqueous phase is extracted with a water-immiscible organic solvent, preferably ethyl acetate, and the combined organic phases are dried and concentrated. The residue is stirred with ethyl acetate for 1 hour and the precipitated avapritinib (I) is filtered off.
- the crude final product may be purified by recrystallization.
- a third method of preparing avapritinib (I) from the compound of the Formula (III) is to remove the resolving acid of Formula (IX) and the Boc protecting group in a one-pot process; isolating the arising compound: trihydrochloride monohydrate of the compound of the Formula (II) (ll * 3HCI * H20) which is a new salt of the compound of the Formula (II), and then converting the said compound to avapritinib (I) by reaction with the compound of the Formula (X).
- the compound of the Formula (III) is reacted with a mixture of concentrated hydrochloric acid and an organic solvent to obtain the compound of the Formula (N * 3FICrFl20).
- the compound of the Formula (III) is dissolved in an organic solvent, preferably TFIF at room temperature, and then a strong acid, preferable concentrated hydrochloric acid is added dropwise. After stirring the reaction mixture for 1 -24 hours, the precipitated crystals are filtered and after washing with water, the compound of the Formula (M * 3FICI * Fl20) can be collected. Then, by reacting the compound of the Formula (I l * 3HCI * H20) and the compound of the Formula (X), avapritinib (I) is obtained as the final product in the reaction shown in Scheme 4.
- an organic solvent preferably TFIF at room temperature
- a strong acid preferable concentrated hydrochloric acid
- the previously collected salt of the compound of the Formula (II) is suspended in a C1-C4 aliphatic alcohol, preferably ethanol, and then a base, preferably a tertiary amine, more preferably DIPEA, is added dropwise.
- a base preferably a tertiary amine, more preferably DIPEA
- the compound of the Formula (X) is added while stirring, and after stirring for 2.5 hours, water is added. After stirring for an additional 1 hour, the precipitated crystalline avapritinib (I) is filtered and washed with water.
- the crude final product can be purified by recrystallization.
- the crude product is recrystallized from ethanol.
- Example 2 Preparation of tert-Butyl 4-15-H -amino-1 -(4-fluorophenyl)ethyllpyrimidin-2- yl)piperazine-1 -carboxylate (IV) with Method B: 5.0 g (16.59 mmol) of 1 - (4-fluorophenyl)-1 -[2- (piperazin-1 -yl) pyrimidin-5-yl] ethan-1 - amine (VI) is dissolved in 32.5 ml of THF with stirring, then 1.53 g (18.25 mmol) of NaHC03 dissolved in 16 ml of water is added.
- the reaction mixture is cooled to 0-5 ° C and a solution of di-tert-butyl-dicarbonate (3.62 g, 16.59 mmol) in THF (12 ml) is added dropwise. After stirring for 1 hour at room temperature, 50 ml of water is added and the mixture is stirred for further 30 minutes at 0-5 ° C. The precipitated crystals are filtrated and washed with water to obtain 5.76 g (86.5%) of white crystals.
- Example 9 Preparation of Avapritinib (I) with the 3. method: 1.05 g (2.45 mmol) of (1S)-1 -(4-fluorophenyl)-1 -[2- (piperazin-1 -yl)pyrimidin-5- yl]ethan-1 -amine trihydrochloride-hydrate (ll * 3HCI * H20) is suspended in 9.1 ml of ethanol with vigorous stirring at room temperature, then 1.7 ml (1.29 g; 10.0 mmol) of DIPEA is added dropwise, stirred until complete dissolution, and 0.57 g (2.45 mmol) of 4- ⁇ 4-chloropyrrolo [2,1 -f] [1 ,2, 4]triazin-6-yl ⁇ -1 -methyl-1 H-pyrazole (X) is added with stirring.
- the Compound (X) gradually dissolves and meantime the product begins to precipitate.
- the reaction mixture is stirred at room temperature for 2.5 hours, then water (13 ml) is added, and the mixture is stirred for an additional 1 hour.
- the crystals are filtered off and washed with water to obtain 1 .13 g (92.6%) of crude product which is recrystallized from acetonitrile.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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HUP2100077A HU231413B1 (en) | 2021-02-26 | 2021-02-26 | Process for the preparation of avapritinib and intermediates for the process |
PCT/HU2022/050019 WO2022180416A1 (en) | 2021-02-26 | 2022-02-28 | Process for obtaining avapritinib and its intermediates |
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HUE039687T2 (en) * | 2013-10-17 | 2019-01-28 | Blueprint Medicines Corp | Compositions useful for treating disorders related to kit |
JP2022526438A (en) * | 2019-04-12 | 2022-05-24 | ブループリント メディシンズ コーポレイション | (S) -1- (4-Fluorophenyl) -1-(2- (4- (6- (1-methyl-1H-pyrazole-4-yl) pyrrolo [2,1-F] [1,2, 4] Triazine-4-yl) piperazinyl) -pyrimidine-5-yl) Ethane-1-amine crystal form and production method |
CN110950872A (en) * | 2019-12-25 | 2020-04-03 | 武汉九州钰民医药科技有限公司 | Method for preparing targeted anticancer drug avapritinib |
CN110938077B (en) * | 2019-12-25 | 2021-04-27 | 武汉九州钰民医药科技有限公司 | Method for synthesizing Avapritinib |
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