# US 2017/0283390 A1 · Processes for preparing antiviral compounds

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- Number: US 2017/0283390 A1
- Document ID: US20170283390A1
- Status: Published application
- Kind: A1
- Application number: 15/582,224
- Filed: 2017-04-28
- Published: 2017-10-05
- Earliest claimed: 2014-06-11
- Assignees: Gilead Pharmaset LLC
- Applicants: Gilead Pharmaset LLC
- Inventors: Kevin M. Allan; Shinji Fujimori; Lars V. Heumann; Grace May Huynh; Katie Ann Keaton; Christopher M. Levins; Ganapati Reddy Pamulapati; Benjamin James Roberts; Keshab Sarma; Martin Gerald Teresk; Xiang Wang; Scott Alan Wolckenhauer
- Web page: https://patentgrep.com/patent/US20170283390A1

## CPC

- C07D 311/78: Ring systems having three or more relevant rings
- A61P 31/14: for RNA viruses
- C07C 49/755: a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
- C07C 49/80: containing halogen
- C07C 49/82: containing hydroxy groups
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 491/052: the oxygen-containing ring being six-membered
- C07C 2602/10: the other ring being six-membered, e.g. tetraline
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present disclosure provides processes for the preparation of a compound of formula: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

## Claims

### Claim at position 1

-55. (canceled)

### Claim 56

A method for preparing a compound of formula (I-a), stereoisomer thereof, or mixture of stereoisomers thereof:
comprising the steps of:
(a) cyclizing a compound of formula (L):
under conditions sufficient to yield a compound of formula (K):
and
(b) brominating the compound of formula (K) under conditions sufficient to yield a compound of formula (I-a),
wherein Z is hydrogen, halo, —OSO2R1, —BF3−, —B(OR2)2, —CO2H, or —NR13 wherein R1 is alkyl, haloalkyl, aryl or substituted aryl, and R2 is alkyl.

### Claim 57 (depends on 56)

The method of claim 56, wherein the reaction conditions of step (a) comprise a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, and acetonitrile.

### Claim 58 (depends on 56)

The method of claim 56, wherein the reaction conditions of step (a) comprise a temperature of from about 20° C. to about 80° C.

### Claim 59 (depends on 56)

The method of claim 56, wherein the reaction conditions of step (a) comprise at least one of a palladium catalyst, a carbonate salt, and a phosphine reagent.

### Claim 60 (depends on 56)

The method of claim 56, wherein the reaction conditions of step (b) comprise a brominating reagent selected from the group consisting of pyridiniumtribomide, bromine, and N-bromosuccinimide.

### Claim 61 (depends on 56)

The method of claim 56, wherein the reaction conditions of step (b) comprise a solvent selected from the group consisting of dichloromethane, methanol, and a mixture thereof.

### Claim 62 (depends on 56)

The method of claim 56, wherein the reaction conditions of step (b) comprise a temperature of about 20° C.

### Claim 63 (depends on 56)

The method of claim 56, wherein the compound of formula (L):
is prepared by contacting a compound of formula (M):
with a compound of formula (N):
under conditions sufficient to yield the compound of formula (L),
wherein X1 is a leaving group, Y1 is hydrogen, halo or trifluoromethanesulfonate, and Z is hydrogen, halo, —OSO2R1, —BF3−, —B(OR2)2, —CO2H, or —NR13 wherein R1 is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and R2 is alkyl.

### Claim 64 (depends on 63)

The method of claim 63, wherein X1 is halo, —OH, or —S(O)2R3, and R3 is alkyl, haloalkyl, or aryl, and the aryl is optionally substituted with halo, alkyl, or haloalkyl.

### Claim 65 (depends on 63)

The method of claim 63, wherein the reaction conditions comprise a solvent selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and aceteonitrile.

### Claim 66 (depends on 63)

The method of claim 63, wherein the reaction conditions comprise a temperature of from about 20° C. to about 70° C.

### Claim at position 13

-134. (canceled)

### Claim 135

A compound of formula (L):
wherein Z is hydrogen, halo, —OSO2R1, —BF3−, —B(OR2)2, —CO2H, or —NR13 wherein R1 is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and R2 is alkyl.

### Claim 136 (depends on 135)

The compound of claim 135, wherein Z is bromo.

### Claim 137

(canceled)

### Claim 138 (depends on 63)

The method of claim 63 where the compound of formula (M):
is prepared by reacting a compound of formula (M′):
with isopropylmagnesium chloride in THF and N-methoxy-N-methyl acetamide to form formula (M); wherein X1 is a leaving group and Y1 is hydrogen, halo or trifluoromethanesulfonate.