Antifungal compound process
The present invention relates to a process for preparing compound 1 that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compound 1 or 1a and substituted derivatives thereof.
1. A process to prepare compound 1 or 1a, or a mixture thereof; or a salt of compound 1 or 1a, or a mixture thereof:
the process comprising nitromethylating a compound of formula 15:
to provide a compound of formula 17 or 17a,
or a mixture thereof; and
converting a compound of formula 17 or 17a,
or a mixture thereof, to compound 1 or 1a, or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.
2. The process of claim 1 comprising:
(i) reducing a comnound of formula 17 or 17a,
or a mixture thereof, to provide a compound of formula 19 or 19a,
or a mixture thereof;
(ii) forming the tetrazole of a compound of formula 19 or 19a,
or a mixture thereof, to provide a compound of formula 9 or 9a,
or a mixture thereof; and
(iii) arylating a compound of formula 9 or 9a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.
3. A process to prepare compound 1 or 1a, or a mixture thereof; or a salt of compound 1 or 1a, or a mixture thereof:
the process comprising:
(i) arylating a compound of formula 15,
to provide ketone
(ii) nitromethylating ketone 16,
to provide nitro-alcohol 18 or 18a,
or a mixture thereof;
(iii) reducing nitro-alcohol 18 or 18a,
or a mixture thereof, to provide amino-alcohol 20 or 20a
or a mixture thereof; and
(iv) forming the tetrazole of amino-alcohol 20 or 20a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.
4. The process of claim 1 comprising:
(i) arylating a compound of formula 17 or 17a,
or a mixture thereof, to provide nitro-alcohol 18 or 18a,
or a mixture thereof;
(ii) reducing nitro-alcohol 18 or 18a,
or a mixture thereof, to provide amino-alcohol 20 or 20a,
or a mixture thereof; and
(iii) forming the tetrazole of amino-alcohol 20 or 20a
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.
5. The process of claim 1 comprising:
(i) reducing a compound of formula 17 or 17a,
or a mixture thereof, to provide a compound of formula 19 or 19a,
or a mixture thereof;
(ii) arylating a compound of formula 19 or 19a,
or a mixture thereof, to provide amino-alcohol 20 or 20a,
and
(iii) forming the tetrazole of amino-alcohol 20 or 20a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.
6. A process to prepare compound 1 or 1a, or a mixture thereof; or a salt of compound 1 or 1a, or a mixture thereof:
the process comprising:
(i) arylating a compound of formula 15,
to provide ketone 16,
(ii) forming the cyanohydrin of ketone 16,
to provide nitrile 24 or 24a,
or a mixture thereof;
(iii) reducing nitrile 24 or 24a
or a mixture thereof, to provide amino-alcohol 20 or 20a,
or a mixture thereof; and
(iv) forming the tetrazole of amino-alcohol 20 or 20a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl; and
R′ is H or trimethylsilyl.
7. A process to prepare compound 1 or 1a, or a mixture thereof; or a salt of compound 1 or 1a, or a mixture thereof:
the process comprising:
cyanating a compound of formula 15,
to provide a compound of formula 23 or 23a,
or a mixture thereof; and
converting a compound of formula 23 or 23a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl; and
R′ is H or trimethylsilyl.
8. The process of claim 7 comprising:
(i) reducing a compound of formula 23 or 23a,
or a mixture thereof, to provide a compound of formula 19 or 19a,
or a mixture thereof;
(ii) arylating a compound of formula 19 or 19a,
or a mixture thereof, to provide amino-alcohol 20 or 20a,
or a mixture thereof;
(iii) forming the tetrazole of amino-alcohol 20 or 20a,
or a mixture thereof, to provide compound 1 or 1a
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl; and
R′ is H or trimethylsilyl.
9. The process of claim 7 comprising:
(i) reducing a compound of formula 23 or 23a,
or a mixture thereof, to provide a compound of formula 19 or 19a,
or a mixture thereof;
(ii) forming the tetrazole of a compound of formula 19 or 19a,
or a mixture thereof, to provide a compound of formula 9 or 9a,
or a mixture thereof;
(iii) arylating a compound of formula 9 or 9a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl; and
R′ is H or trimethylsilyl.
10. The process of claim 7 , comprising:
(i) arylating a compound of formula 23 or 23a,
or a mixture thereof, to provide nitrile 24 or 24a,
or a mixture thereof;
(ii) reducing nitrile 24 or 24a,
or a mixture thereof, to provide amino-alcohol 20 or 20a,
or a mixture thereof;
(iii) forming the tetrazole of amino-alcohol 20 or 20a,
or a mixture thereof, to provide compound 1 or 1a,
or a mixture thereof;
wherein R is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl; and
R′ is H or trimethylsilyl.