ITUB20150009A1 - PROCESS FOR THE PREPARATION OF SOFOSBUVIR - Google Patents
PROCESS FOR THE PREPARATION OF SOFOSBUVIR Download PDFInfo
- Publication number
- ITUB20150009A1 ITUB20150009A1 ITUB2015A000009A ITUB20150009A ITUB20150009A1 IT UB20150009 A1 ITUB20150009 A1 IT UB20150009A1 IT UB2015A000009 A ITUB2015A000009 A IT UB2015A000009A IT UB20150009 A ITUB20150009 A IT UB20150009A IT UB20150009 A1 ITUB20150009 A1 IT UB20150009A1
- Authority
- IT
- Italy
- Prior art keywords
- butanol
- reaction
- compound
- sofosbuvir
- give
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 22
- 230000008569 process Effects 0.000 title claims description 22
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 title claims description 20
- 229960002063 sofosbuvir Drugs 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 238000003381 deacetylation reaction Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 7
- 239000012346 acetyl chloride Substances 0.000 claims description 7
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 230000006196 deacetylation Effects 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims 1
- -1 (phenoxy) -phosphorylamino Chemical group 0.000 description 7
- 241000711549 Hepacivirus C Species 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 208000005176 Hepatitis C Diseases 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 208000000624 Esophageal and Gastric Varices Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000749 chronicity Toxicity 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Domanda di brevetto per invenzione industriale dal titolo: Patent application for industrial invention entitled:
?Processo per la preparazione di sofosbuvir?? Process for preparing sofosbuvir
DESCRIZIONE DESCRIPTION
La presente invenzione riguarda un processo per la sintesi di sofosbuvir ed intermedi utili per la sua preparazione. The present invention relates to a process for the synthesis of sofosbuvir and intermediates useful for its preparation.
Sofosbuvir ? un profarmaco utilizzato per il trattamento dell?epatite C. Sofosbuvir? a prodrug used to treat hepatitis C.
L?epatite C ? una malattia infettiva causata dall?Hepatitis C virus (HCV), che colpisce in primo luogo il fegato. L'infezione ? spesso asintomatica, ma la sua cronicizzazione pu? condurre alla cicatrizzazione del fegato e, infine, alla cirrosi, che risulta generalmente evidente dopo molti anni. In alcuni casi, la cirrosi epatica potr? portare a sviluppare insufficienza epatica, cancro del fegato, varici esofagee e gastriche. L'HCV ? trasmesso principalmente per contatto diretto con il sangue infetto, spesso dovuto all'uso di droghe per via endovenosa, a presidi medici non sterilizzati e trasfusioni di sangue. Hepatitis C? an infectious disease caused by the Hepatitis C virus (HCV), which primarily affects the liver. The infection? often asymptomatic, but its chronicity can? lead to scarring of the liver and ultimately to cirrhosis, which is generally evident after many years. In some cases, liver cirrhosis may be lead to developing liver failure, liver cancer, esophageal and gastric varices. The HCV? transmitted primarily by direct contact with infected blood, often due to intravenous drug use, unsterilized medical devices, and blood transfusions.
Il virus dell'epatite C porta ad una infezione cronica nel 50-80% delle persone che lo contraggono, delle quali circa il 40-80% viene trattato. In generale, il trattamento farmacologico ? consigliato nei pazienti con alterazioni epatiche provocate dal virus; il trattamento di riferimento ? una combinazione di interferone-? pegilato e ribavirina, da assumersi per un periodo di 24 o 48 settimane, a seconda del genotipo del virus HCV. Si ? osservato che questa terapia porta a miglioramenti nel 50-60% dei casi. The hepatitis C virus leads to chronic infection in 50-80% of people who contract it, of which about 40-80% are treated. In general, the drug treatment? recommended in patients with liver disorders caused by the virus; the reference treatment? a combination of interferon-? pegylate and ribavirin, to be taken for a period of 24 or 48 weeks, depending on the genotype of the HCV virus. Yup ? observed that this therapy leads to improvements in 50-60% of cases.
Nei fenotipi pi? difficili da trattare, questi due farmaci vengono affiancati da boceprevir e telaprevir, portando il tasso di guarigione dal 40% al 70%. Gli effetti collaterali del trattamento sono frequenti, met? dei pazienti avverte sintomi di tipo influenzale ed un terzo presenta problemi emotivi. Inoltre il trattamento effettuato durante i primi sei mesi risulta pi? efficace rispetto a quando l?epatite C diventa cronica. In the pi? difficult to treat, these two drugs are joined by boceprevir and telaprevir, bringing the cure rate from 40% to 70%. The side effects of the treatment are frequent, met? of patients experience flu-like symptoms and a third have emotional problems. In addition, the treatment carried out during the first six months is more? effective compared to when hepatitis C becomes chronic.
Sofosbuvir ? un farmaco per il trattamento del?epatite C approvato recentemente dall?EMA. Viene assunto per via orale ed agisce con un meccanismo d?azione diretto sul ciclo di vita del virus, sopprimendo la sua replicazione, in quanto, essendo un profarmaco inibitore pan-genotipico dell?RNA polimerasi NS5B RNA-dipendente dell?HCV, pu? essere incorporato nell?HCV RNA dalla polimerasi NS5B e fungere da terminatore di catena. Sofosbuvir ha inoltre mostrato un ridotto numero di complicanze della malattia epatica ed un ridotto numero di effetti collaterali, rispetto ai pazienti trattati con altri trattamenti. Sofosbuvir? a drug for the treatment of hepatitis C recently approved by the EMA. It is taken orally and acts with a direct mechanism of action on the life cycle of the virus, suppressing its replication, since, being a pan-genotypic inhibitor prodrug of the NS5B RNA-dependent HCV RNA polymerase, it can? be incorporated into HCV RNA by NS5B polymerase and act as a chain terminator. Sofosbuvir also showed a reduced number of liver disease complications and a reduced number of side effects, compared to patients treated with other treatments.
Sofosbuvir ? un composto di formula I Sofosbuvir? a compound of formula I
chimicamente noto come isopropil (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-diossopirimidin-1-il)-4-fluoro-3-idrossi-4-metil-tetraidrofuran-2-il]metossifenossi-fosforil]amino]propanoato, commercializzato come Solvaldi? e descritto in US 8,563,530. chemically known as isopropyl (2S) -2 - [[[(2R, 3R, 4R, 5R) -5- (2,4-dioxopyrimidin-1-yl) -4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran -2-yl] methoxyphenoxy-phosphoryl] amino] propanoate, marketed as Solvaldi? and described in US 8,563,530.
US 8,563,530 descrive un processo per la sintesi di sofosbuvir come riportato nei seguenti schemi 1 e 2. US 8,563,530 describes a process for the synthesis of sofosbuvir as reported in the following schemes 1 and 2.
J. Org. Chem., (2011), 76, 8311-8319 descrive un processo per la sintesi di sofosbuvir, come riportato nei seguenti schemi 3 e 4. J. Org. Chem., (2011), 76, 8311-8319 describes a process for the synthesis of sofosbuvir, as reported in the following schemes 3 and 4.
I processi riportati nello stato dell?arte presentano diversi inconvenienti legati alla presenza di due gruppi idrossilici e all?uso di un reagente di Grignard per loro salificazione. La salificazione non ? selettiva e quindi la reazione richiede almeno due equivalenti del reattivo di Grignard che d? luogo al doppio sale pochissimo solubile che a sua volta complica l?andamento della reazione ed il work up. Inoltre la doppia salificazione porta all?ottenimento di quantit? discrete di due principali sottoprodotti che risultano dalla fosforilazione in 3? e in 3?,5?, rendendo difficile la purificazione con rese modeste. The processes reported in the state of the art have various drawbacks linked to the presence of two hydroxyl groups and to the use of a Grignard reagent for their salification. Salification is not? selective and therefore the reaction requires at least two equivalents of the Grignard reagent which gives? gives rise to the double salt with very little soluble content which in turn complicates the course of the reaction and the work up. Furthermore, the double salification leads to the obtainment of quantity? discrete of two main by-products resulting from phosphorylation in 3? and in 3?, 5 ?, making purification difficult with modest yields.
Costituisce oggetto della presente invenzione, un processo per la sintesi di Sofosbuvir che comprende una reazione di deallilazione ed una reazione di deacetilazione a partire da un composto di formula III The object of the present invention is a process for the synthesis of Sofosbuvir which comprises a dealylylation reaction and a deacetylation reaction starting from a compound of formula III
I composti di partenza di formula III del processo oggetto della presente invenzione e la loro preparazione sono descritti nella copendente domanda di brevetto dal titolo ?Composti utili per il trattamento dell?epatite C?, depositata in pari data dalla stessa Richiedente. The starting compounds of formula III of the process object of the present invention and their preparation are described in the copending patent application entitled? Compounds useful for the treatment of hepatitis C ?, filed on the same date by the same Applicant.
Le reazioni di deallilazione e di deacetilazione del processo oggetto della presente invenzione possono essere effettuate in qualsiasi ordine. The dealilylation and deacetylation reactions of the process object of the present invention can be carried out in any order.
In una sua forma di attuazione pertanto il processo oggetto della presente invenzione comprende: In one of its embodiments, therefore, the process object of the present invention comprises:
a) la reazione di deallilazione del composto di formula III a) the dealylylation reaction of the compound of formula III
a dare il composto di formula II to give the compound of formula II
b) la reazione di deacetilazione a dare sofosbuvir. b) the deacetylation reaction to give sofosbuvir.
In un?altra sua forma di attuazione il processo oggetto della presente invenzione comprende: In another embodiment, the process object of the present invention comprises:
b?) la reazione di deacetilazione del composto di formula III b?) the deacetylation reaction of the compound of formula III
a dare il composto di formula IV to give the compound of formula IV
a?) la reazione di deallilazione a dare sofosbuvir. a?) the dealylylation reaction to give sofosbuvir.
Il passaggio di deallilazione del processo oggetto della presente invenzione viene effettuato in presenza di catalizzatori con leganti scelti tra rutenio cloruro, tetradi(trifenilfosfina)palladio(0), palladio su carbone, Pd(dba)2 dppb, Ni(dppp)Cl2, preferibilmente rutenio cloruro; il solvente utilizzato ? polare protico o aprotico, scelto tra alcoli quali metanolo, etanolo, propanolo, isopropanolo, butanolo, sec-butanolo e tert-butanolo, preferibilmente sec-butanolo. The dealylylation step of the process object of the present invention is carried out in the presence of catalysts with ligands selected from ruthenium chloride, tetrad (triphenylphosphine), palladium (0), palladium on carbon, Pd (dba) 2 dppb, Ni (dppp) Cl2, preferably ruthenium chloride; the solvent used? polar protic or aprotic, selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol and tert-butanol, preferably sec-butanol.
Il passaggio di deacetilazione del processo oggetto della presente invenzione viene effettuato in catalisi acida con acidi scelti tra acido cloridrico, acido metansolfonico, acido trifluoroacetico, oppure con cloruro acilico catalitico, ad esempio acetil cloruro, in un solvente protico polare scelto tra metanolo, etanolo, propanolo, isopropanolo, butanolo, secbutanolo e tert-butanolo. The deacetylation step of the process object of the present invention is carried out in acid catalysis with acids selected from hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, or with catalytic acyl chloride, for example acetyl chloride, in a polar protic solvent selected from methanol, ethanol, propanol, isopropanol, butanol, secbutanol and tert-butanol.
Preferibilmente viene utilizzato acetil cloruro in metanolo. Preferably, acetyl chloride in methanol is used.
L?utilizzo dei composti di formula III in cui l?azoto del gruppo pirimidinico ? protetto con un gruppo allile rappresenta l?aspetto caratterizzante del processo oggetto della presente invenzione e consente di incrementare la solubilit? dei derivati nei solventi organici e quindi di facilitarne le trasformazioni chimiche, che avvengono con maggiore selettivit?, ed gli isolamenti e purificazioni. The use of compounds of formula III in which the nitrogen of the pyrimidine group? protected with an allyl group represents the characterizing aspect of the process object of the present invention and allows to increase the solubility. derivatives in organic solvents and therefore to facilitate chemical transformations, which occur with greater selectivity, and isolations and purifications.
In una sua forma di realizzazione preferita il processo oggetto della presente invenzione comprende la reazione di deallilazione del composto di formula III In one of its preferred embodiments, the process object of the present invention comprises the dealylylation reaction of the compound of formula III
con rutenio cloruro in sec-butanolo a dare il composto di formula II with ruthenium chloride in sec-butanol to give the compound of formula II
e la successiva reazione di deacetilazione con acetil cloruro in metanolo a dare sofosbuvir. and the subsequent deacetylation reaction with acetyl chloride in methanol to give sofosbuvir.
Sebbene l?invenzione sia stata descritta nei suoi aspetti caratteristici, modifiche ed equivalenti che sono evidenti all?esperto del ramo sono incluse nella seguente invenzione. Although the invention has been described in its characteristic aspects, modifications and equivalents which are apparent to one skilled in the art are included in the following invention.
La presente invenzione sar? ora illustrata per mezzo di alcuni esempi, che non devono essere visti come limitanti la portata dell?invenzione. The present invention will be now illustrated by means of some examples, which are not to be seen as limiting the scope of the invention.
ESEMPIO 1 EXAMPLE 1
Sintesi di (S)-isopropil 2-((S)-(((2R,3R,4R,5R)-3-acetossi-5-(2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)-fosforilammino)propanoato (composto II) Synthesis of (S) -isopropyl 2 - ((S) - (((2R, 3R, 4R, 5R) -3-acetoxy-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) - il) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate (compound II)
In un pallone di reazione sono stati caricati (2S)-isopropil-2-(((3-acetossi-5-(3-allil-2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)fosforilammino)propanoato (0,2 g, 0,33 mmol), 2-butanolo (2 ml) e rutenio cloruro monoidrato (10 mg, 0,05 mmol), la miscela di reazione ? stata portata alla temperatura di riflusso del solvente e mantenuta in queste condizioni per circa 15-18 ore. A reazione terminata, la temperatura ? stata portata al valore ambiente, il solvente ? stato allontanato mediante distillazione sottovuoto ed il residuo ? stato purificato mediante cromatografia su colonna a dare 0,2 g di (S)-isopropil 2-((S)(((2R,3R,4R,5R)-3-acetossi-5-(2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)-fosforilammino)-propanoato. (2S) -isopropyl-2 - (((3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate (0.2 g, 0.33 mmol), 2-butanol (2 ml) and ruthenium chloride monohydrate (10 mg, 0.05 mmol), the reaction mixture? was brought to the reflux temperature of the solvent and maintained under these conditions for about 15-18 hours. When the reaction is over, the temperature? has been brought to room value, the solvent? been removed by vacuum distillation and the residue? was purified by column chromatography to give 0.2 g of (S) -isopropyl 2 - ((S) (((2R, 3R, 4R, 5R) -3-acetoxy-5- (2,4-dioxo-3) , 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) -propanoate.
1H-NMR (CDCl3, 300 MHz): ? 7,41 (d, 1H), 7,33-7,26 (m, 2H), 7,25-7,12 (m, 3H), 6,17 (d, 1H), 5,51 (d, 1H), 5,21-5,11 (m, 1H), 5,06-4,93 (m, 1H), 4,57-4,51 (m, 1H), 4,30-4,18 (m, 2H), 4,08-3,93 (m, 2H), 2,16 (s, 3H), 1,41-1,13 (m, 12H). 1H-NMR (CDCl3, 300 MHz):? 7.41 (d, 1H), 7.33-7.26 (m, 2H), 7.25-7.12 (m, 3H), 6.17 (d, 1H), 5.51 (d, 1H), 5.21-5.11 (m, 1H), 5.06-4.93 (m, 1H), 4.57-4.51 (m, 1H), 4.30-4.18 ( m, 2H), 4.08-3.93 (m, 2H), 2.16 (s, 3H), 1.41-1.13 (m, 12H).
ESEMPIO 2 EXAMPLE 2
Sintesi di sofosbuvir Synthesis of sofosbuvir
In un pallone di reazione sono stati caricati (S)-isopropil 2-((S)-(((2R,3R,4R,5R)-3-acetossi-5-(2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)-fosforilammino)-propanoato (0,1 g, 0,2 mmol), metanolo (1 ml), acetil cloruro (5 mg, 0,06 mmol) e la miscela di reazione ? stata mantenuta in agitazione alla temperatura ambiente per circa 15-18 ore. A reazione terminata, il solvente ? stato allontanato mediante distillazione sottovuoto ed il residuo ? stato purificato mediante cromatografia su colonna a dare 0,05 g di sofosbuvir. (S) -isopropyl 2 - ((S) - (((2R, 3R, 4R, 5R) -3-acetoxy-5- (2,4-dioxo-3,4-dihydropyrimidin -1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) -propanoate (0.1 g, 0.2 mmol), methanol (1 ml), acetyl chloride (5 mg, 0.06 mmol) and the reaction mixture? was kept under stirring at room temperature for about 15-18 hours. At the end of the reaction, the solvent? been removed by vacuum distillation and the residue? was purified by column chromatography to give 0.05 g of sofosbuvir.
ESEMPIO 3 EXAMPLE 3
Sintesi di (S)-isopropil 2-((S)-(((2R,3R,4R,5R)-5-(3-allil-2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)-fosforilammino)propanoato (composto IV) Synthesis of (S) -isopropyl 2 - ((S) - (((2R, 3R, 4R, 5R) -5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) - il) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate (compound IV)
In un pallone di reazione sono stati caricati (2S)-isopropil 2-(((3-acetossi-5-(3-allil-2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)-fosforilammino)propanoato (0,5 g, 0,8 mmol), metanolo (5 ml), acetil cloruro (0,02 g, 0,25 mmol) e la miscela di reazione ? stata mantenuta in agitazione alla temperatura ambiente per circa 15-18 ore. A reazione terminata, il solvente ? stato allontanato mediante distillazione sottovuoto ed il residuo ? stato purificato mediante cromatografia su colonna a dare 0,3 g di (S)-isopropil 2-((S)-(((2R,3R,4R,5R)-5-(3-allil-2,4-diosso-3,4-diidropirimidin-1(2H)-il)-4-fluoro-4-metiltetraidrofuran-2-il)metossi)(fenossi)-fosforilammino)propanoato. (2S) -isopropyl 2 - (((3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4 -fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate (0.5 g, 0.8 mmol), methanol (5 ml), acetyl chloride (0.02 g, 0.25 mmol ) and the reaction mixture? was kept under stirring at room temperature for about 15-18 hours. At the end of the reaction, the solvent? been removed by vacuum distillation and the residue? was purified by column chromatography to give 0.3 g of (S) -isopropyl 2 - ((S) - (((2R, 3R, 4R, 5R) -5- (3-allyl-2,4-dioxo- 3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate.
1H-NMR (CDCl3, 300 MHz): ? 7,40-7,20 (m, 6H), 6,28-6,17 (m, 1H), 5,92-5,82 (m, 1H), 5,73 (d, 1H), 5,29-5,16 (m, 2H), 5,08-4,99 (m, 1H), 4,57-4,30 (m, 3H), 4,13-4,07 (m, 1H), 4,03-3,87 (m, 1H), 3,78-3,69 (m, 1H), 1,41-1,22 (m, 12H). 1H-NMR (CDCl3, 300 MHz):? 7.40-7.20 (m, 6H), 6.28-6.17 (m, 1H), 5.92-5.82 (m, 1H), 5.73 (d, 1H), 5, 29-5.16 (m, 2H), 5.08-4.99 (m, 1H), 4.57-4.30 (m, 3H), 4.13-4.07 (m, 1H), 4.03-3.87 (m, 1H), 3.78-3.69 (m, 1H), 1.41-1.22 (m, 12H).
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITUB2015A000009A ITUB20150009A1 (en) | 2015-03-05 | 2015-03-05 | PROCESS FOR THE PREPARATION OF SOFOSBUVIR |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITUB2015A000009A ITUB20150009A1 (en) | 2015-03-05 | 2015-03-05 | PROCESS FOR THE PREPARATION OF SOFOSBUVIR |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ITUB20150009A1 true ITUB20150009A1 (en) | 2016-09-05 |
Family
ID=53284377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITUB2015A000009A ITUB20150009A1 (en) | 2015-03-05 | 2015-03-05 | PROCESS FOR THE PREPARATION OF SOFOSBUVIR |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | ITUB20150009A1 (en) |
-
2015
- 2015-03-05 IT ITUB2015A000009A patent/ITUB20150009A1/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2871547C (en) | Uracyl spirooxetane nucleosides | |
| RU2599013C2 (en) | Methods and compositions for inhibiting polymerase | |
| CN108546277B (en) | Novel nucleoside phosphoramidate compounds and uses thereof | |
| JP2012519207A5 (en) | ||
| CN106883279B (en) | A kind of prodrug, preparation method, medical composition and its use | |
| WO2023286844A1 (en) | Compound exhibiting physiological activity such as antiviral activity | |
| EP3239160A1 (en) | Tizoxanide phosphate and alkane sulfonate and pharmaceutical applications thereof | |
| WO2016177300A1 (en) | (2'r)-2'-deoxy-2'-halo-2'-methyl uridine derivative, and preparation method and use thereof | |
| WO2019041317A1 (en) | Method for preparing sofosbuvir fluorolactone intermediate | |
| ITUB20150009A1 (en) | PROCESS FOR THE PREPARATION OF SOFOSBUVIR | |
| CN102850282B (en) | 3-substituted oxy-2-Zinamide compounds and uses thereof | |
| ITMI20101878A1 (en) | PROCEDURE FOR THE PREPARATION OF ERLOTINIB | |
| CN108794517B (en) | Arginase inhibitor and preparation method and application thereof | |
| US8951988B2 (en) | Azidothymidine quinoline conjugated compound, preparation method therefor and application thereof in anti-hepatoma therapy | |
| JPH02108695A (en) | Nucleotide for treatment | |
| EP3419983B1 (en) | Process for the preparation of sofosbuvir | |
| WO2018025195A1 (en) | PROCESS FOR THE PREPARATION OF (Sp)-SOFOSBUVIR AND INTERMEDIATES THEREOF | |
| CN115518058A (en) | Application of N-cycloalkyl substituted aromatic methylamine compound in preparation of antiviral drug, structure and preparation method | |
| CN106977543A (en) | The preparation technology of improved Suo Feibuwei intermediates | |
| JP4731320B2 (en) | Anti-coronavirus agent | |
| WO2020151296A1 (en) | Dinucleotide precursor for drug and preparation method therefor | |
| CN107556248B (en) | Novel neuraminidase inhibitory compound and preparation method and medical application thereof | |
| WO2019043544A1 (en) | Process for the preparation of ixazomib citrate | |
| KR100971486B1 (en) | Adefovir dipivoxil malonate and pharmaceutical composition including the same | |
| ITUB20150064A1 (en) | PROCESS FOR THE PREPARATION OF SOFOSBUVIR |