HRP20250049T1 - Procesi i međuprodukti u pripremi velikih količina hemisukcinata 2,4,6-trifluor-n-[6-(1-metil-piperidin-4-karbonil)-piridin-2-il]-benzamida - Google Patents
Procesi i međuprodukti u pripremi velikih količina hemisukcinata 2,4,6-trifluor-n-[6-(1-metil-piperidin-4-karbonil)-piridin-2-il]-benzamida Download PDFInfo
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Claims (11)
1. Proces za pripremu spoja formule:
[image]
sadrži korake:
i. obrada piperidin-4-karboksilne kiseline u uvjetima reduktivne aminacije koja sadržava formaldehid i mravlju kiselinu u vodi s naknadnom obradom vodenom otopinom HCl, nakon čega slijedi vodena destilacija i dodavanje acetonitrila, uz ponovljeno razrjeđivanje/destiliranje dok sadržaj vode ne bude veći od 0,2 %, što se određuje Karl Fischerovom analizom, i to kako bi se dobio kruti hidroklorid 1-metilpiperidin-4-karboksilne kiseline;
ii. obrada hidroklorida 1-metilpiperidin-4-karboksilne kiseline sredstvom za kloriranje kao što je tionil klorid u klorobenzenu kako bi se dobio klorid 1-metilpiperidin-4-karboksilne kiseline;
iii. obrada klorida 1-metilpiperidin-4-karboksilne kiseline N,N-dietilaminom u klorobenzenu koji sadržava trietilamin uz naknadnu neutralizaciju organskog sloja i naknadnu obradu vodenom otopinom HCl u izopropanolu kako bi se dobio kruti hidroklorid hidrat N,N-dietil-1-metil-piperidin-4-karboksamid;
iv. obrada hidroklorid hidrata N,N-dietil-1-metil-piperidin-4-karboksamida mineralnom lužinom kao što je vodena otopina NaOH u nepolarnom otapalu kao što je metil-tert-butil eter uz naknadno ispiranje vodom, odvajanje faza i destilaciju organskog otapala dok sadržaj vode ne bude veći od 0,1 % masenog udjela, što se određuje Karl Fischerovom analizom, i to kako bi se dobio N,N-dietil-1-metil-piperidin-4-karboksamid;
v. naknadna obrada N,N-dietil-1-metil-piperidin-4-karboksamida (6-brom-2-piridil)litijem u nepolarnom organskom otapalu kao što je metil-terc-butil eter uz naknadnu ekstrakciju dobivene mješavine vodom i prikladnim organskim otapalom, kao što je n-butanol, odvajanje faza i ponovljenu destilaciju organskog otapala dok sadržaj vode ne bude veći od 0,2 % masenog udjela, što se određuje Karl Fischerovom analizom, i to kako bi se dobio (6-brom-2-piridil)-(1-metil-4-piperidil)metanon;
vi. obrada (6-brom-2-piridil)-(1-metil-4-piperidil)metanona vodenom otopinom HBr i naknadnom ekstrakcijom n-butanolom, nakon čega slijedi ponovljena destilacija organskog otapala dok sadržaj vode ne bude veći od 0,3 %, što se određuje Karl Fischerovom analizom, i to kako bi se dobio kruti hidrobromid (6-bromo-2-piridil)-(1-metil-4-piperidil)metanon;
vii. obrada hidrobromida (6-brom-2-piridil-1-metil-4-piperidil)metanona otopinom NH3 u etilen glikolu uz prisutnost katalizatora Cu2O pri otprilike 80 °C tijekom otprilike 2 sata, uz naknadna ispiranja vodom, zasićenom vodenom otopinom NaCl i 20-postotnom vodenom otopinom NaOH i naknadnu ekstrakciju nepolarnim aprotonskim otapalom, kao što je metil-terc-butil eter, odvajanje faza i obradu organske faze s 5 % masenog udjela ugljika;
viii. filtracija navedene mješavine, razrjeđivanje prikladnim polarnim alkoholnim otapalom, kao što je izopropanol, i ponovljena destilacija organskog otapala dok sadržaj vode ne bude veći od 0,2 %, što se određuje Karl Fischerovom analizom, uz naknadnu obradu dobivenog ostatka izopropanolom, vodom i 20 % masenog udjela otopine HCl, pri čemu je koncentracija vode u dobivenoj suspenziji barem 2 %, filtraciju dobivene suspenzije i sušenje u vakuumu pri 40 °C tijekom 16 – 24 sata kako bi se dobio kruti dihidroklorid dihidrat (6-amino-2-piridil)-(1-metil-4-piperidil)metanon;
ix. obrada dihidroklorida dihidrata (6-amino-2-piridil)-(1-metil-4-piperidil)metanona u klorobenzenu sa 6 % masenog udjela otopine NaOH u vodi pri otprilike 54 °C tijekom otprilike 30 minuta, uz naknadno odvajanje faza i vakuumsku destilaciju vodene otopine kako bi se dobio (6-amino-2-piridil)-(1-metil-4-piperidil)metanon;
x. naknadna obrada (6-amino-2-piridil)-(1-metil-4-piperidil)metanona kloridom 2,4,6-trifluorobenzojeve kiseline u klorobenzenu pri otprilike 100 °C tijekom otprilike 4 sata, uz naknadno hlađenje, punjenje acetonitrilom i zagrijavanje dobivene suspenzije pri 80 °C tijekom otprilike 1 sat, a zatim prikupljanje dobivene krutine filtracijom, i to kako bi se dobio kruti hidroklorid 2,4,6-trifluor-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamid;
xi. obrada hidroklorida 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamida zasićenom vodenom otopinom Na2CO3 u metil-terc-butil eteru;
xii. obrada mješavine iz prethodnog xi. koraka otopinom SiO2 uz naknadnu filtraciju, obradu ugljikom, filtraciju i isparavanje, razrjeđivanje etanolom i destilaciju dok sadržaj vode ne bude veći od 1 %, što se određuje Karl Fischerovom analizom, i to kako bi se dobio 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamid;
xiii. obrada 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamida u etanolu otopinom od 0,5 ekvivalenata jantarne kiseline u etanolu pri otprilike 55 °C tijekom najmanje 3 sata pri sobnoj temperaturi, a zatim naknadno prikupljanje krutine filtracijom kako bi se dobio kruti hemisukcinat 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamid.
2. Proces za pripremu spoja formule:
[image]
sadrži korake:
i. obrada piperidin-4-karboksilne kiseline u uvjetima reduktivne aminacije koja sadržava formaldehid i mravlju kiselinu u vodi s naknadnom obradom vodenom otopinom HCl, nakon čega slijedi vodena destilacija i dodavanje acetonitrila, uz ponovljeno razrjeđivanje/destiliranje dok sadržaj vode ne bude veći od 0,2 %, što se određuje Karl Fischerovom analizom, i to kako bi se dobio kruti hidroklorid 1-metilpiperidin-4-karboksilne kiseline;
ii. obrada hidroklorida 1-metilpiperidin-4-karboksilne kiseline sredstvom za kloriranje kao što je tionil klorid u klorobenzenu kako bi se dobio klorid 1-metilpiperidin-4-karboksilne kiseline;
iii. obrada klorida 1-metilpiperidin-4-karboksilne kiseline N,N-dietilaminom u klorobenzenu koji sadržava trietilamin uz naknadnu neutralizaciju organskog sloja i naknadnu obradu vodenom otopinom HCl u izopropanolu kako bi se dobio kruti hidroklorid hidrat N,N-dietil-1-metil-piperidin-4-karboksamid;
iv. obrada hidroklorid hidrata N,N-dietil-1-metil-piperidin-4-karboksamida mineralnom lužinom kao što je vodena otopina NaOH u nepolarnom otapalu kao što je metil-tert-butil eter uz naknadno ispiranje vodom, odvajanje faza i destilaciju organskog otapala dok sadržaj vode ne bude veći od 0,1 % masenog udjela, što se određuje Karl Fischerovom analizom, i to kako bi se dobio N,N-dietil-1-metil-piperidin-4-karboksamid;
v. naknadna obrada N,N-dietil-1-metil-piperidin-4-karboksamida (6-brom-2-piridil)litijem u nepolarnom organskom otapalu kao što je metil-terc-butil eter uz naknadnu ekstrakciju dobivene mješavine vodom i prikladnim organskim otapalom, kao što je n-butanol, odvajanje faza i ponovljenu destilaciju organskog otapala dok sadržaj vode ne bude veći od 0,2 % masenog udjela, što se određuje Karl Fischerovom analizom, i to kako bi se dobio (6-brom-2-piridil)-(1-metil-4-piperidil)metanon;
vi. obrada (6-brom-2-piridil)-(1-metil-4-piperidil)metanona vodenom otopinom HBr i naknadnom ekstrakcijom n-butanolom, nakon čega slijedi ponovljena destilacija organskog otapala dok sadržaj vode ne bude veći od 0,3 %, što se određuje Karl Fischerovom analizom, i to kako bi se dobio kruti hidrobromid (6-bromo-2-piridil)-(1-metil-4-piperidil)metanon;
vii. obrada hidrobromida (6-brom-2-piridil-1-metil-4-piperidil)metanona u dvofaznoj mješavini vode i toluena krutim KOH tijekom otprilike 3 sata uz naknadno odvajanje organskog sloja i isparavanje otapala kako bi se dobio (6-brom-2-piridil-l-metil-4-piperidil)metanon;
viii. obrada (6-bromo-2-piridil-1-metil-4-piperidil)metanona 2,4,6-trifluorobenzamidom u toluenu koji sadržava K2CO3, vodu, Pd(OAc)2 i Xantphos pri otprilike 70 °C tijekom otprilike 12 sati, dok sadržaj (6-bromo-2-piridil)-(1-metil-4-piperidil)metanona ne bude veći od 0,1 % na temelju HPLC-a, uz naknadno razrjeđivanje reakcijske mješavine vodom i EtOAc, naknadnu obradu silikagelom modificiranim tiourejom pri 60 °C tijekom otprilike 8 sati, uz naknadnu filtraciju kako bi se dobila otopina 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamida;
ix. obrada otopine 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamida u etil acetatu otopinom od otprilike 0,5 ekvivalenata jantarne kiseline otopljene u etanolu pri otprilike 55 °C tijekom otprilike 3 sata, uz naknadno hlađenje na sobnu temperaturu tijekom otprilike 10 sati, y zatim prikupljanje dobivene krutine filtracijom kako bi se dobio kruti hemisukcinat 2,4,6-trifluoro-N-[6-(1-metilpiperidin-4-karbonil)-2-piridil]benzamid.
3. Proces prema zahtjevu 1 ili 2, pri čemu se reakcije izvode primjenom metodologije obrade serije.
4. Proces prema zahtjevu 3, pri čemu je proizvedena serija na razini procesa.
5. Proces prema zahtjevu 4, pri čemu proizvedena serija iznosi barem 1 kilogram.
6. Proces prema zahtjevu 4, pri čemu proizvedena serija iznosi barem 10 kilograma.
7. Proces prema zahtjevu 4, pri čemu proizvedena serija iznosi barem 100 kilograma.
8. Spoj formule:
[image]
9. Spoj prema zahtjevu 8 koji je kristalan i koji je naznačen time što uzorak rendgenske difrakcije praha uz uporabu CuKα zračenja čiji je maksimum pri kutu difrakcije 2-theta od 8,3° u kombinaciji s jednim ili više vrhova odabranih iz skupine koja se sastoji od kutova od 16,6°, 23,5° i 33,7° (redom ± 0,2°).
10. Upotreba spoja prema zahtjevu 8 u pripremi spoja formule:
[image]
ili njegove farmaceutski prihvatljive soli.
11. Upotreba spoja prema zahtjevu 8 u pripremi spoja formule:
[image]
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| Application Number | Priority Date | Filing Date | Title |
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| US201962871965P | 2019-07-09 | 2019-07-09 | |
| EP20751396.1A EP3996713B1 (en) | 2019-07-09 | 2020-07-06 | Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate |
| PCT/US2020/040881 WO2021007155A1 (en) | 2019-07-09 | 2020-07-06 | Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| HRP20171742T4 (hr) | 2009-04-02 | 2021-08-06 | Colucid Pharmaceuticals, Inc. | 2,4,6-trifluor-n-[6-(1-metilpiperidin-4-karbonil)piridin-2-il]benzamid, namijenjen liječenju migrene oralnom ili intravenskom primjenom |
| TWI829107B (zh) * | 2019-07-09 | 2024-01-11 | 美商美國禮來大藥廠 | 大規模製備2,4,6-三氟-n-[6-(1-甲基-哌啶-4-羰基)-吡啶-2-基]-苯甲醯胺半琥珀酸鹽的方法及中間體，以及2,4,6-三氟-n-[6-(1-甲基-哌啶-4-羰基)-吡啶-2-基]-苯甲醯胺醋酸鹽之製備 |
| AU2022270144A1 (en) | 2021-05-07 | 2023-10-26 | Eli Lilly And Company | Taste masked compostions of 2,4,6-trifluoro- n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2- ylj-benzamide hemisuccinate, and orally disentegrating tablet comprising the same |
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