Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid

Patent metadata

Field	Value
Publication number	US-10927116-B2
Application number	US-201815999701-A
Country	US
Kind code	B2
Filing date	Aug 20, 2018
Priority date	Feb 19, 2016
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

The present invention relates to a process for synthesizing a compound of formula (I),

R 1 is phenyl, which is unsubstituted or substituted with one, two or three substituents independently selected from halogen and C 1-6 alkyl; R 2 is C 1-6 alkyl; R 3 is —C x H 2x —; x is 1, 2, 3, 4, 5, 6 or 7; or pharmaceutically acceptable salt or diastereomer thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.

First claim

The invention claimed is:

1. A method for preparing a compound of formula (I),

or a pharmaceutically acceptable salt or diastereomer thereof,
the method comprising the following steps:

a) forming urea (V) via an addition reaction of isocyanate (III) and compound (IV);

b) forming a compound of formula (VI) via a cyclization reaction of urea (V);

c) forming a compound of formula (VII) by protecting the compound of formula (VI)

wherein R is C 1-6 alkyl;
d) forming a compound of formula (VIII) via selective reduction of compound (VII);

e) forming a compound of formula (IX) via hydrolysis of compound (VIII);

f) forming a compound of formula (X) by de-protection of the compound of formula (IX);

g) forming an enantiomeric salt (XVI) of a compound of formula (XIV) or a solvate thereof by addition of Acid in an organic solvent,

wherein Acid is an organic acid selected from: D-(+)-DTTA, L-DTTA, L-tartaric acid, D-DBTA, (+)-CSA, (S)-(+)-1,1′-Binaphthyl-2,2′-diyl hydrogen phosphate, and (R)-(−)-1,1′-Binaphthyl-2,2′-diyl hydrogen phosphate;
h) recovering an enantiomeric compound of formula (XVII) from compound (XVI);

i) forming a compound of formula (XVIII) via bromination of compound (XVII);

j) forming the compound of formula (I) via a substitution reaction between compound (XVIII) and compound (X),

wherein:
R 1 is phenyl, which is unsubstituted or is substituted with one, two or three substituents independently selected from halogen and C 1-6 alkyl;
R 2 is C 1-6 alkyl; and
R 3 is —C x H 2x —, wherein x is 1, 2, 3, 4, 5, 6 or 7.

2. The method according to claim 1 , wherein:
R 1 is chlorofluorophenyl or methylchlorophenyl;
R 2 is methyl or ethyl; and
R 3 is dimethylethylene.

3. The method according to claim 1 wherein the compound of formula (I) is

or a pharmaceutically acceptable salt or diastereomer thereof.

4. A method for preparing a compound of formula (X),

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, the method comprising the following steps:

a) forming urea (V) via an addition reaction of isocyanate (III) and compound (IV);

b) forming a compound of formula (VI) via a cyclization reaction of urea (V);

c) forming a compound of formula (VII) by protecting the compound of formula (VI),

wherein R is C 1-6 alkyl;
d) forming a compound of formula (VIII) via selective reduction of compound (VII);

e) forming a compound of formula (IX) via hydrolysis of compound (VIII);

f) forming a compound of formula (X) by de-protection of the compound of formula (IX),

wherein:
R 3 is —C x H 2x —; and
x is 1, 2, 3, 4, 5, 6 or 7.

5. The method according to claim 4 , wherein R 3 is dimethylethylene.

6. The method according to claim 4 wherein the compound of formula (X) is

or a pharmaceutically acceptable salt or enantiomer thereof.

7. The method according to claim 1 , wherein isocyanate (III) is prepared from a compound of formula (II) in the presence of a base in a solvent with a phosgene reagent, and

wherein the solvent is selected from 2-MeTHF, THF, IPAc, EA, toluene, and DCM.

8. The method of claim 7 , wherein the base is selected from Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 .

9. The method of claim 7 , wherein the phosgene reagent is selected from phosgene, diphosgene and triphosgene.

10. The method of claim 1 , wherein the formation of compound (VI) in b is performed in the presence of an acid in an organic solvent, wherein the solvent is selected from 2-MeTHF, IPAc, EA, toluene, DCM, methanol and ethanol.

11. The method of claim 10 , wherein the acid is selected from boron trifluoride etherate, phosphoric acid, sulphuric acid, HBr and HCl.

12. The method of claim 1 , wherein the formation of compound (VII) in c) is performed in the presence of a base with a protecting reagent in a solvent, wherein the protecting reagent is selected from chloroformates and anhydrides.

13. The method of claim 12 , wherein the solvent is selected from 2-MeTHF, THF, IPAc, EtOAc and DCM.

14. The method of claim 12 , wherein the base is selected from TEA, DIPEA, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 .

15. The method of claim 1 , wherein the formation of compound (VIII) in d) is performed in the presence of a catalytic Lewis acid and a reductive reagent, wherein the catalytic Lewis acid is selected from InCl 3 , YCl 3 , ZnCl 2 , Zn(OAc) 2 and BF 3 -Et 2 O.

16. The method of claim 15 , wherein the reductive reagent is selected from lithium aluminum hydride, sodium dihydro-bis-(2-methoxyethoxy)aluminate, borane dimethylsulfide, phenylsilane and borane tetrahydrofuran complex.

17. The method of claim 1 , wherein compound (IX) in e) is isolated through a work-up procedure, wherein the work-up procedure comprises extraction with an organic solvent to remove the impurities, wherein the organic solvent is selected from TH

Assignees

• Hoffmann La Roche

Inventors

• Chen Junli

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title