HRP20211553T1 - Postupak za pripravu inhibitora btk - Google Patents
Postupak za pripravu inhibitora btk Download PDFInfo
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- HRP20211553T1 HRP20211553T1 HRP20211553TT HRP20211553T HRP20211553T1 HR P20211553 T1 HRP20211553 T1 HR P20211553T1 HR P20211553T T HRP20211553T T HR P20211553TT HR P20211553 T HRP20211553 T HR P20211553T HR P20211553 T1 HRP20211553 T1 HR P20211553T1
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- 229940124291 BTK inhibitor Drugs 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 46
- 239000011541 reaction mixture Substances 0.000 claims 27
- 238000000034 method Methods 0.000 claims 23
- 239000000203 mixture Substances 0.000 claims 15
- 239000007795 chemical reaction product Substances 0.000 claims 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 11
- 239000003880 polar aprotic solvent Substances 0.000 claims 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 8
- 239000002904 solvent Substances 0.000 claims 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims 6
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims 6
- 239000012071 phase Substances 0.000 claims 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims 5
- 239000000243 solution Substances 0.000 claims 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- 239000002826 coolant Substances 0.000 claims 4
- 238000001816 cooling Methods 0.000 claims 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims 4
- 239000003960 organic solvent Substances 0.000 claims 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 239000007864 aqueous solution Substances 0.000 claims 3
- 238000009835 boiling Methods 0.000 claims 3
- 150000003951 lactams Chemical class 0.000 claims 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 3
- 239000012454 non-polar solvent Substances 0.000 claims 3
- 150000007530 organic bases Chemical class 0.000 claims 3
- 239000012074 organic phase Substances 0.000 claims 3
- 239000007787 solid Substances 0.000 claims 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical group [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 235000019270 ammonium chloride Nutrition 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- -1 ketone bisulfite Chemical class 0.000 claims 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims 1
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 1
- 235000011009 potassium phosphates Nutrition 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
- B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Claims (23)
1. Postupak za pripravu tricikličnog laktama formule 400, njegovih stereoizomera, njegovih geometrijskih izomera, njegovih tautomera i njegovih soli,
[image]
naznačen time, da obuhvaća formiranje reakcijske smjese koja sadrži organsko otapalo, organsku bazu i formule 300 i 310
[image]
i reakcijom reakcijske smjese nastaje smjesa reakcijskog produkta koja sadrži triciklički laktam formule 400,
pri čemu:
R1a, R1b, R2a, R2b, R3a, R3b, R4a i R4b su neovisno odabrani između H i C1−6 alkila;
R5 je odabran između H, C1−6 alkila, cikloalkila, arila, supstituiranog arila, benzila, supstituiranog benzila, heteroarila, supstituiranog heteroarila;
p je 1,2, 3 ili 4; i
q je 1, 2, 3 ili 4.
2. Postupak prema patentnom zahtjevu 1, naznačen time, da p je 1 ili 2, a q je 1 ili 2.
3. Postupak prema patentnom zahtjevu 1 ili patentnom zahtjevu 2, naznačen time, da je organska baza tri-C1−6 alkil amin.
4. Postupak prema patentnom zahtjevu 3, naznačen time, da je organska baza odabrana između 4-metilmorfolina i N-etildiiopropilamina.
5. Postupak prema bilo kojem patentnom zahtjevu od 1 do 4, naznačen time, da otapalo predstavlja polarno aprotično otapalo.
6. Postupak prema patentnom zahtjevu 5, naznačen time, da je otapalo odabrano između N-metilpirolidona i dimetilformamida.
7. Postupak prema bilo kojem patentnom zahtjevu od 1 do 6, naznačen time, da halogen predstavlja Cl.
8. Postupak prema bilo kojem patentnom zahtjevu od 1 do 7, naznačen time, da p je 1, a q je 2.
9. Postupak prema bilo kojem patentnom zahtjevu od 1 do 8, naznačen time, da R1a, R1b, R3a, R3b, R4a, R4b i R5 su H, a R2a i R2b su −CH3.
10. Postupak prema bilo kojem patentnom zahtjevu od 1 do 9, naznačen time, da reakcijska smjesa sadrži od 0,25 do 2 mola po litri, od 0, 5 do 1,5 mola po litri ili od 0,5 do 1 mola po litri formule 300, između 1 i 2 ekvivalenta ili od 1,1 do 1,5 ekvivalenta baze i između 0,7 i 1 ekvivalenta, od 0,75 do 0,95 ekvivalenta ili od 0,8 do 0,9 ekvivalenta formule 310.
11. Postupak prema bilo kojem patentnom zahtjevu od 1 do 10, naznačen time, da je triciklički laktam formule 400 podvrsta formule 160 strukture:
[image]
formula 300 je podvrsta formule 130 strukture:
[image]
i
formula 310 je piperazin-2-on formule 10:
[image]
12. Postupak prema bilo kojem patentnom zahtjevu od 1 do 11, naznačen time, da se formula 300 pripravlja formiranjem reakcijske smjese koja sadrži polarno aprotično otapalo, nepolarno otapalo, fosforni oksiklorid i formulu 320:
[image]
i reakcijom reakcijske smjese nastaje smjesa reakcijskog proizvoda koja sadrži formulu 300.
13. Postupak prema patentnom zahtjevu 12, naznačen time, da je polarno aprotično otapalo dimetilformamid, nepolarno otapalo je diklormetan, molski omjer fosfornog oksiklorida prema formuli 320 iznosi od 1,5:1 do 2,7:1 ili od 1,8:1 do 2,4:1, a molski omjer polarnog aprotičnog otapala prema formuli 320 iznosi od 1,5:1 do 3,5:1 ili od 2:1 do 3:1.
14. Postupak prema patentnom zahtjevu 12 ili patentnom zahtjevu 13, naznačen time, da je spoj 320 podvrsta spoja 321, pri čemu
svaki R1a i R1b je neovisno odabran iz skupine koju čine H i C1−6 alkil;
R2a je −CH3;
R2 je odabran iz skupine koju čine H i C1-6 alkil;
svaki R3a i R3b je H;
p je 1; i
pri čemu se spoj 321 pripravlja formiranjem reakcijske smjese koja sadrži polarno aprotično otapalo, metil magnezijev klorid, bakar (I) klorid i spoj 330 i reakcijom reakcijske smjese nastaje smjesa reakcijskog proizvoda koja sadrži spoj 321 prema sljedećoj reakcijskoj shemi:
[image]
15. Postupak prema bilo kojem patentnom zahtjevu od 12 do 14, naznačen time, da
R1a, R1b, R3a i R3b su H, p je 1, a R2a i R2b su −CH3,
pri čemu je spoj 321 podvrsta spoja 120 koji se pripravlja formiranjem reakcijske smjese koja sadrži polarno aprotično otapalo, metil magnezijev klorid, bakar (I) klorid i spoj 110:
[image]
i reakcijom reakcijske smjese nastaje smjesa reakcijskog proizvoda koja sadrži spoj 120
[image]
16. Postupak prema patentnom zahtjevu 15, naznačen time, da je otapalo tetrahidrofuran, molski omjer metil magnezijevog klorida i spoja 110 u reakcijskoj smjesi iznosi između 1:1 i 2:1 ili od 1,1:1 do 1,4:1, a molski omjer bakar (I) klorida i spoja 110 u reakcijskoj smjesi iznosi od 0,1:1 do 0,5:1 ili od 0,15:1 do 0,25:1.
17. Postupak prema bilo kojem patentnom zahtjevu od 12 do 16, naznačen time, da nadalje obuhvaća pročišćavanje spoja 320, pročišćavanje koje obuhvaća:
(i) formiranje prve reakcijske smjese koja sadrži sirovi spoj 320, organsko otapalo koje se ne miješa s vodom i vodenu otopinu natrijevog bisulfita, i reakcijom prve reakcijske smjese nastaje prva smjesa reakcijskog proizvoda koja sadrži čvrsti ketonski bisulfitni adukt spoja 340:
[image]
(ii) izoliranje čvrstog spoja 340 iz prve smjese reakcijskog produkta,
(iii) formiranje druge reakcijske smjese koja sadrži izolirani spoj 340, vodu, nisko-vrijuće otapalo koje se ne miješa s vodom i natrijev bikarbonat, i reakcijom druge reakcijske smjese nastaje druga smjesa reakcijskog proizvoda koja obuhvata prvu fazu koja sadrži diklorometan i pretežnu količinu pročišćenog spoja 320 koja se nalazi u otopini u prvoj fazi, a druga faza sadrži vodu i
(iv) odvajanje prve faze koja sadrži pročišćeni spoj 320 od vodene faze.
18. Postupak prema patentnom zahtjevu 17, naznačen time, da:
(i) sirovi spoj 320 je u otopini u organskom otapalu koje se ne miješa s vodom, omjer količine vode i mase sirovog spoja 320 u prvoj reakcijskoj smjesi iznosi od 1:1 l/kg do 10:1 l/kg, od 1,5:1 l/kg do 4:1 l/kg ili od 2:1 l/kg do 3:1 l/kg, a ekvivalentni omjer natrijevog bisulfita i spoja 320 u prvoj reakcijskoj smjesi iznosi od 2:1 do 5:1 ili od 3:1 do 5:1;
(ii) druga reakcijska smjesa sadrži omjer količine vode i izolirane čvrste mase 340 od 5:1 l/kg do 15:1 l/kg ili od 7,5:1 l/kg do 10,5:1 l/kg, omjer količine vode i količine nisko-vrijućeg otapala koje se ne miješa s vodom u drugoj reakcijskoj smjesi iznosi od 1:1 do 3:1 ili od 1,5:1 do 2,5:1, a ekvivalentni omjer natrijevog bikarbonata i spoja 340 u drugoj reakcijskoj smjesi iznosi između 1:1 i 2:1, ili od 1,25:1 do 1,75:1, i
(iii) prinos pročišćenog spoja 320 iznosi najmanje 60 % na bazi spoja 330, a čistoća pročišćenog spoja 330 iznosi najmanje 98 % ili najmanje 99 %.
19. Postupak prema patentnom zahtjevu 17 ili patentnom zahtjevu 18, naznačen time, da je organsko otapalo koje se ne miješa s vodom u prvoj reakcijskoj smjesi heksan, i naznačen time, da je nisko-vrijuće otapalo koje se ne miješa s vodom u drugoj reakcijskoj smjesi diklorometan.
20. Postupak prema bilo kojem patentnom zahtjevu od 1 do 11, naznačen time, da
svaki R1a i R1b je neovisno odabran iz skupine koju čine H i C1−6 alkil;
R2a je −CH3;
R2 je odabran iz skupine koju čine H i C1-6 alkil;
svaki R3a i R3b je H;
p je 1; i
pri čemu se spoj 300 pripravlja:
(i) formiranjem prve reakcijske smjese koja sadrži prvo polarno aprotično otapalo, metil magnezijev klorid, bakar (I) klorid, litijev klorid, klorotrimetilsilan i spoj 330:
[image]
i reakcijom spoja 330 nastaje prva smjesa reakcijskog produkta koja sadrži spoj 335, gdje R2a je −CH3
[image]
(ii) brzim hlađenjem prve smjese reakcijskog proizvoda s metanolom kao prvim sredstvom za brzo hlađenje;
(iii) daljnjim brzim hlađenjem drugim sredstvom za brzo hlađenje u vodenoj otopini i dodavanjem nepolarnog otapala koje se ne miješa s vodom u smjesu brzo ohlađenog reakcijskog produkta;
(iv) odvajanjem faza i prikupljanjem organske faze koja sadrži pretežnu količinu spoja 335 i koncentriranjem organske faze nastaje spoj 335 u otopini;
(v) formiranjem druge reakcijske smjese koja sadrži drugo polarno aprotično otapalo, fosforni oksiklorid i otopinu spoja 335, i reakcijom druge reakcijske smjese nastaje druga smjesa reakcijskog proizvoda koja sadrži spoj 301 strukture
[image]
(vi) brzim hlađenjem druge smjese reakcijskog proizvoda s trećim sredstvom za brzo hlađenje u vodenoj otopini; i
(vii) odvajanjem faza i prikupljanjem organske faze koja sadrži pretežnu količinu spoja 301 u otopini.
21. Postupak prema patentnom zahtjevu 20, naznačen time, da je prvo polarno aprotično otapalo tetrahidrofuran, drugo sredstvo za brzo hlađenje je amonijev klorid, nepolarno otapalo koje se ne miješa s vodom je toluen, drugo polarno aprotično otapalo je dimetilformamid, a treće sredstvo za brzo hlađenje je kalijev fosfat.
22. Postupak prema patentnom zahtjevu 20 ili patentnom zahtjevu 21, naznačen time, da:
(i) prva reakcijska smjesa sadrži: od 0,25 do 2 ili od 0,5 do 1,1 mola po litri spoja 330; stehiometrijski suvišak metilmagnezijevog klorida u usporedbi sa spojem 330, molski omjer metilmagnezijevog klorida i spoja 330 između 1:1 i 1,5:1 ili od 1,1:1 do 1,3:1; stehiometrijski suvišak klorotrimetilsilana u usporedbi sa spojem 330, molski omjer klorotrimetilsilana i spoja 330 između 1:1 i 1,2:1 ili od 1,01:1 do 1,1:1; molski omjer bakarnog (I) klorida i spoja 330 od 0,05:1 do 0,2:1 ili od 0,05:1 do 0,15:1; i molski omjer litij klorida i spoja 330 od 0,05:1 do 0,2:1 ili od 0,07:1 do 0,15:1,
(ii) druga reakcijska smjesa sadrži: od 0,5 do 2 mola po litri ili od 0,7 do 1,3 mola po litri spoja 335; i molski omjer fosfornog oksiklorida i spoja 335 od 1,5:1 do 3,1:1 ili od 2,1:1 do 2,6:1, i
(iii) prinos spoja 300 na bazi spoja 330 iznosi najmanje 70 % ili najmanje 75 %, a čistoća spoja 301 iznosi najmanje 85 % ili najmanje 88 %.
23. Postupak prema bilo kojem patentnom zahtjevu od 20 do 22, naznačen time, da R1a i R1b su svaki H, a R2b je −CH3.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662434569P | 2016-12-15 | 2016-12-15 | |
| EP17832491.9A EP3555099B1 (en) | 2016-12-15 | 2017-12-13 | Process for preparing btk inhibitors |
| PCT/EP2017/082723 WO2018109050A1 (en) | 2016-12-15 | 2017-12-13 | Process for preparing btk inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20211553T1 true HRP20211553T1 (hr) | 2021-12-24 |
Family
ID=61007648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| TW (3) | TWI766176B (hr) |
| WO (1) | WO2018109050A1 (hr) |
Families Citing this family (9)
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| WO2018109050A1 (en) | 2016-12-15 | 2018-06-21 | F. Hoffmann-La Roche Ag | Process for preparing btk inhibitors |
| US11100492B2 (en) * | 2018-02-19 | 2021-08-24 | Peter Garrett | General purpose re-loadable card aggregation implementation |
| US20210221792A1 (en) * | 2020-01-16 | 2021-07-22 | Hanmi Pharm Co., Ltd. | Convergent synthesis of poziotinib derivative |
| WO2021164735A1 (en) | 2020-02-20 | 2021-08-26 | Hutchison Medipharma Limited | Heteroaryl heterocyclic compounds and uses thereof |
| CN115715291A (zh) * | 2020-06-18 | 2023-02-24 | 上海华汇拓医药科技有限公司 | 布鲁顿酪氨酸激酶抑制剂及其制备方法 |
| TW202220998A (zh) | 2020-09-21 | 2022-06-01 | 大陸商和記黃埔醫藥（上海）有限公司 | 雜芳基雜環化合物及其用途 |
| WO2022206924A1 (zh) * | 2021-04-02 | 2022-10-06 | 南京明德新药研发有限公司 | 含氮三并环双功能化合物及其制备方法和应用 |
| JP2024517004A (ja) | 2021-05-05 | 2024-04-18 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | Ｂｔｋ阻害剤を調製するための方法 |
| CN113603685A (zh) * | 2021-07-23 | 2021-11-05 | 都创(上海)医药开发有限公司 | Fenebrutinib化合物的晶型及其制备方法和用途 |
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| DE3431541A1 (de) * | 1984-08-28 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | Cis,endo-2-azabicycloalkan-3-carbonsaeure-derivate, verfahren zu deren herstellung, deren verwendung sowie zwischenprodukte bei deren herstellung |
| US7432375B2 (en) * | 2003-03-06 | 2008-10-07 | Eisai R & D Management Co., Ltd. | JNK inhibitors |
| EP1865959A2 (en) * | 2005-03-25 | 2007-12-19 | Glaxo Group Limited | Process for preparing pyridoý2,3-d¨pyrimidin-7-one and 3,4-dihydropyrimidoý4,5-d¨pyrimidin-2(1h)-one derivatives |
| EP2197552B1 (en) * | 2007-09-19 | 2012-11-21 | 4Sc Ag | Novel tetrahydrofusedpyridines as histone deacetylase inhibitors |
| US8440830B2 (en) | 2007-09-19 | 2013-05-14 | 4Sc Ag | Tetrahydro-fused pyridines as histone deacetylase inhibitors |
| CN101781312B (zh) * | 2009-12-30 | 2012-09-26 | 中国科学院广州生物医药与健康研究院 | 一种吲哚衍生物的合成方法 |
| AU2011249912A1 (en) * | 2010-05-07 | 2012-11-29 | Genentech, Inc. | Pyridone and aza-pyridone compounds and methods of use |
| AR088642A1 (es) * | 2011-11-03 | 2014-06-25 | Genentech Inc | Compuestos de piperazina alquilados |
| CA2852964A1 (en) * | 2011-11-03 | 2013-05-10 | F. Hoffmann-La Roche Ag | Bicyclic piperazine compounds |
| UA111756C2 (uk) * | 2011-11-03 | 2016-06-10 | Ф. Хоффманн-Ля Рош Аг | Сполуки гетероарилпіридону та азапіридону як інгібітори тирозинкінази брутона |
| US9076830B2 (en) * | 2011-11-03 | 2015-07-07 | Applied Materials, Inc. | Robot systems and apparatus adapted to transport dual substrates in electronic device manufacturing with wrist drive motors mounted to upper arm |
| US8703953B2 (en) * | 2012-03-09 | 2014-04-22 | Bristol-Myers Squibb Company | Aryl ether-base kinase inhibitors |
| TW201427970A (zh) * | 2012-10-12 | 2014-07-16 | Univ Health Network | 激酶抑制劑及使用其治療癌症的方法 |
| JP6410790B2 (ja) * | 2013-03-14 | 2018-10-24 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | ミトコンドリアアルデヒドデヒドロゲナーゼ−２調節因子およびその使用方法 |
| TWI513371B (zh) * | 2013-07-08 | 2015-12-11 | Lextar Electronics Corp | 整合無線暨有線的照明控制系統 |
| JP6275846B2 (ja) * | 2013-12-05 | 2018-02-07 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 求電子性官能基を有するヘテロアリールピリドン及びアザ−ピリドン化合物 |
| TWI659019B (zh) * | 2014-02-28 | 2019-05-11 | 日商帝人製藥股份有限公司 | 吡唑醯胺衍生物 |
| DE102015206627A1 (de) | 2014-07-09 | 2016-01-28 | Siemens Aktiengesellschaft | Selbstsichernder Umrichter |
| CN111303159A (zh) * | 2014-10-02 | 2020-06-19 | 豪夫迈·罗氏有限公司 | 用于治疗由布鲁顿酪氨酸激酶(btk)介导的疾病的吡唑甲酰胺化合物 |
| MA41169A (fr) * | 2014-12-17 | 2017-10-24 | Acraf | Composés antibactériens à large spectre d'activité |
| PT3233103T (pt) | 2014-12-18 | 2021-01-18 | Principia Biopharma Inc | Tratamento de pênfigo |
| CN107973791B (zh) * | 2015-04-29 | 2020-04-07 | 南京圣和药业股份有限公司 | 稠环或三环芳基嘧啶化合物用作激酶抑制剂 |
| JP6577143B2 (ja) * | 2016-02-29 | 2019-09-18 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | ブルトンチロシンキナーゼの阻害剤を含む剤形組成物 |
| WO2018109050A1 (en) | 2016-12-15 | 2018-06-21 | F. Hoffmann-La Roche Ag | Process for preparing btk inhibitors |
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