HRP20220613T1 - Postupak priprave raltegavira - Google Patents
Postupak priprave raltegavira Download PDFInfo
- Publication number
- HRP20220613T1 HRP20220613T1 HRP20220613TT HRP20220613T HRP20220613T1 HR P20220613 T1 HRP20220613 T1 HR P20220613T1 HR P20220613T T HRP20220613T T HR P20220613TT HR P20220613 T HRP20220613 T HR P20220613T HR P20220613 T1 HRP20220613 T1 HR P20220613T1
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- Croatia
- Prior art keywords
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- 238000000034 method Methods 0.000 title claims 17
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 title claims 2
- 229960004742 raltegravir Drugs 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims 15
- 150000003839 salts Chemical class 0.000 claims 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- -1 2-(2-Aminoprop-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6 dihydropyrimidine-4-carboxamide-methanesulfonate Chemical compound 0.000 claims 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 claims 1
- RTZZCYNQPHTPPL-UHFFFAOYSA-N 3-nitrophenol Chemical compound OC1=CC=CC([N+]([O-])=O)=C1 RTZZCYNQPHTPPL-UHFFFAOYSA-N 0.000 claims 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 claims 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 claims 1
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical group OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-UHFFFAOYSA-N 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (19)
1. Postupak priprave raltegavira formule (I) ili njegove farmaceutski prihvatljive soli,
[image]
obuhvaća reakciju nezaštićenog spoja formule (II) u bezvodnom obliku ili u obliku njegove bezvodne soli,
[image]
sa spojem formule (III),
[image]
u kojoj
X = Cl, ili
X = OAr pri čemu je Ar fenilna skupina suspstituirana s jednom ili s više skupina, istih ili različitih jedna od druge, odabranih od sljedećih: halogen (F, Cl, Br ili I), cijano-skupina ili nitro-skupina, ili
X jest supstituent formule (IV):
[image]
u kojoj Z = H (X = IVa) ili Z =
[image]
(X=IVb)
pri čemu je spoj formule (III) korišten u količinama od 1.1 do 1.3 molarna ekvivalenta prema spoju formule (II),
u reakcijskom otapalu i u prisutnosti jedne ili više baza, gdje najmanje jedna od baza ima pKa vrijednost ≥ 7.4, a ukupna količina je u rasponu od 1.5 do 2.9 molarnih ekvivalenata u usporedbi sa spojem formule (II) ili ukupna količina u rasponu od 2.5 do 3.9 molarnih ekvivalenata u usporedbi sa bezvodnom soli spoja formule (II) koji nastaje in situ, te
pri reakcijskoj temperaturi u rasponu od 45 do 75 °C.
2. Postupak prema patentnom zahtjevu 1, naznačen time da sol raltegavira formule (I) jest kalijeva sol.
3. Postupak prema patentnom zahtjevu 1 ili 2, naznačen time da sol spoja formule (II) jest metansulfonatna ili p-toluensulfonatna sol.
4. Postupak prema patentnim zahtjevima 1-3, naznačen time da je u spoju formule (III) X = OAr je odabran iz grupe koja se sastoji od 2-klor-4-nitrofenol, 2,3,4,5,6-pentafluorfenol, 4-nitrofenol, 4-cijanofenol, 3-nitrofenol, 3-klorfenol, 4-bromfenol.
5. Postupak prema patentnim zahtjevima 1-3, naznačen time da je X = Cl ili 4-nitrofenol.
6. Postupak prema patentnim zahtjevima 1-4, naznačen time da najmanje jedna baza ima pKa vrijednost u rasponu od 7.4 do 12.
7. Postupak prema patentnim zahtjevima 1-5, naznačen time da najmanje jedna baza ima pKa vrijednost u rasponu od 8.5 do 11.5.
8. Postupak prema patentnim zahtjevima 1-6, naznačen time da najmanje jedna baza koja ima pKa ≥ 7.4 ima formulu (VI):
NR1R2R3
(VI)
u kojoj
R1, R2 i R3, isti ili različiti jedan od drugog jesu ravnolančana ili razgranata C1-C8 alkilna skupina koja može biti supstituirana sa alkoksi, dialkilamino ili fenilnom skupinom, ili jedna od R1, R2 i R3 jest aromatski heterociklički prsten, ili R1 i R2 uzeti zajedno s dušikovim atomom tvore nearomatski heterociklički prsten.
9. Postupak prema patentnom zahtjevu 8, naznačen time da je baza odabrana iz grupe koja se sastoji od tetrametiletilendiamin, trietilamin, diizopropiletilamin, 4-dimetilaminopiridin.
10. Postupak prema patentnim zahtjevima 1-9, naznačen time da je otapalo odabrano od acetonitril ili toluen ili njihova smjesa.
11. Postupak prema patentnim zahtjevima 1-10, naznačen time da je reakcijska temperatura u rasponu od 55 do 65 °C.
12. Postupak prema patentnom zahtjevu 11, naznačen time da je reakcijska temperatura u rasponu od 50 do 60 °C.
13. Postupak prema patentnom zahtjevu 1, naznačen time da je za pripravu raltegavira formule (I) ili njegove farmaceutski prihvatljive soli,
[image]
koji obuhvaća reakciju spoja formule (IIa) ili (IIb)
[image]
sa spojem formule (III),
[image]
gdje je X definiran kao u patentnom zahtjevu 1.
14. Postupak prema patentnom zahtjevu 13, naznačen time da je spoj formule (III) jest spoj formule (IIIa):
[image]
15. Postupak prema patentnom zahtjevu 13, naznačen time da je spoj formule (III) jest spoj formule (IIIb):
[image]
16. 2-(2-Aminoprop-2-il)-N-(4-fluorbenzil)-5-hidroksi-1-metil-6-okso-1,6 dihidropirimidin-4-karboksamid-metansulfonat formule (IIa)
[image]
17. 2-(2-Aminoprop-2-il)-N-(4-fluorbenzil)-5-hidroksi-1-metil-6-okso-1,6-dihidropirimidin-4-karboksamid-p-toluensulfonat formule (IIb)
[image]
18. 4-Nitrofenoksi-ester 2-[5-metil-1,3,4-oksadiazolil]karbocikličke kiseline formule (IIIb)
[image]
19. Upotreba spoja fromule (IIa) ili (IIb), i/ili (IIIb),
[image]
u postupku priprave raltegravira koji ima sljedeću formulu (I) ili njegove soli.
[image]
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT201700130030 | 2017-11-14 | ||
| EP18807004.9A EP3710445B1 (en) | 2017-11-14 | 2018-11-13 | Process for the preparation of raltegravir |
| PCT/EP2018/081042 WO2019096773A1 (en) | 2017-11-14 | 2018-11-13 | Process for the preparation of raltegravir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20220613T1 true HRP20220613T1 (hr) | 2022-06-24 |
Family
ID=61527266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20220613TT HRP20220613T1 (hr) | 2017-11-14 | 2018-11-13 | Postupak priprave raltegavira |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US11246869B2 (hr) |
| EP (1) | EP3710445B1 (hr) |
| CA (1) | CA3080012A1 (hr) |
| ES (1) | ES2909302T3 (hr) |
| HR (1) | HRP20220613T1 (hr) |
| IL (1) | IL274560A (hr) |
| PL (1) | PL3710445T3 (hr) |
| SI (1) | SI3710445T1 (hr) |
| WO (1) | WO2019096773A1 (hr) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA04003932A (es) | 2001-10-26 | 2004-06-18 | Angeletti P Ist Richerche Bio | Inhibidores de la hidroxipirimidinona carboxamida n-sustituida de la integrasa del virus de inmunodeficiencia humana. |
| UA87884C2 (uk) | 2004-12-03 | 2009-08-25 | Мерк Энд Ко., Инк. | Безводна кристалічна калієва сіль інгібітора віл-інтегрази |
| CA2710987A1 (en) | 2008-01-08 | 2009-07-16 | Merck Sharp & Dohme Corp. | Process for preparing n-substituted hydroxypyrimidinone carboxamides |
| US10259778B2 (en) | 2014-11-10 | 2019-04-16 | Aurobindo Pharma Ltd | Process for the preparation of raltegravir |
-
2018
- 2018-11-13 HR HRP20220613TT patent/HRP20220613T1/hr unknown
- 2018-11-13 US US16/764,026 patent/US11246869B2/en active Active
- 2018-11-13 PL PL18807004T patent/PL3710445T3/pl unknown
- 2018-11-13 ES ES18807004T patent/ES2909302T3/es active Active
- 2018-11-13 CA CA3080012A patent/CA3080012A1/en active Pending
- 2018-11-13 SI SI201830640T patent/SI3710445T1/sl unknown
- 2018-11-13 EP EP18807004.9A patent/EP3710445B1/en active Active
- 2018-11-13 WO PCT/EP2018/081042 patent/WO2019096773A1/en unknown
-
2020
- 2020-05-10 IL IL274560A patent/IL274560A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SI3710445T1 (sl) | 2022-05-31 |
| CA3080012A1 (en) | 2019-05-23 |
| US20200330466A1 (en) | 2020-10-22 |
| WO2019096773A1 (en) | 2019-05-23 |
| EP3710445B1 (en) | 2022-03-16 |
| IL274560A (en) | 2020-06-30 |
| ES2909302T3 (es) | 2022-05-06 |
| EP3710445A1 (en) | 2020-09-23 |
| PL3710445T3 (pl) | 2022-06-20 |
| US11246869B2 (en) | 2022-02-15 |
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