Sacubitril intermediate and preparation method thereof
The present invention relates to a sacubitril intermediate and a preparation method thereof. The sacubitril intermediate disclosed herein can be prepared by a deprotection reaction of a compound. In addition, the intermediate can be used as a raw material to synthesize sacubitril.
1. A compound of Formula (V),
wherein:
R 1 is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or 4-methylbenzenesulfonate;
R2 is
with the proviso that when R 1 is phenyl, R2 is not
R 3 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl; and
R 4 is H, —(C 1 -C 4 )alkyl, —(C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkyl-aryl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.
2. The compound of claim 1 , wherein R 1 is phenyl.
3. The compound of claim 1 , wherein R 3 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl or substituted benzyl.
4. The compound of claim 1 , wherein R 4 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triphenylmethyl, tetrahydrofuryl, benzyl or substituted benzyl.
5. The compound of claim 1 , wherein R 2 is —COOH, —COOCH 3 , —COOCH 2 CH 3 , —COOCH(CH 3 ) 2 , —COOC(CH 3 ) 3 , —COOCH 2 Ph, —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH(CH 3 ) 2 , —CH 2 OC(CH 3 ) 3 , —CH 2 OCH 2 Ph, —CH 2 OC(Ph) 3 , —CH 2 OSi(CH 3 ) 3 , —CH 2 OSi(CH 2 CH 3 ) 3 , —CH 2 OSi(CH 3 ) 2 C(CH 3 ) 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH (CH 3 ) 2 , —CONHC (CH 3 ) 3 , —CONHCH 2 Ph or
with the proviso that when R 1 is phenyl, R 2 is —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH(CH 3 ) 2 , —CH 2 OC(CH 3 ) 3 , —CH 2 OCH 2 Ph, —CH 2 OC(Ph) 3 , —CH 2 OSi(CH 3 ) 3 , —CH 2 OSi(CH 2 CH 3 ) 3 , —CH 2 OSi(CH 3 ) 2 C(CH 3 ) 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH (CH 3 ) 2 , —CONHC (CH 3 ) 3 , —CONHCH 2 Ph or
and
wherein each Ph is phenyl.
6. The compound of claim 1 having one of the following structures:
where each Ph is phenyl.
7. The compound of claim 1 , wherein R 2 is
8. The compound of claim 7 , wherein R 1 is phenyl.
9. The compound of claim 7 , wherein R 4 is H.
10. The compound of claim 9 , wherein R 1 is phenyl.
11. A method of preparing a compound of Formula (V):
wherein the compound of Formula (V) is prepared by a deprotection reaction of a compound of Formula (IV):
in the presence of a base or an acid, wherein:
R 1 is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or 4-methylbenzenesulfonate;
R 2 is
with the proviso that when R 1 is phenyl, R 2 is not
R 3 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl;
R 4 is H, —(C 1 -C 4 )alkyl, —(C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkyl-aryl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; and
R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.
12. The method of claim 11 , the compound of Formula (IV) is prepared by a substitution reaction of a compound of Formula (II) with a compound of Formula (III) in the presence of a base;
13. The method of claim 12 , the compound of Formula (II) is prepared by a condensation reaction of a compound of Formula (I);
wherein R 1 is as defined above; and
R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.
14. The method according to claim 11 , wherein the compound of the Formula (IV) is prepared by a process comprising the following steps:
a) preparing a compound of Formula (II) by a condensation reaction of a compound of Formula (I) in the presence of a base,
and
b) preparing a compound of Formula (IV) by a substitution reaction of the compound of Formula (II) with a compound of Formula (III) in the presence of a strong base;
wherein R 1 is phenyl;
R 2 is
R 3 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or benzyl;
R 4 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triphenylmethyl, or tetrahydrofuryl;
R 5 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl or benzyl; and
R 6 is triflate, mesylate or 4-methylbenzenesulfonate.
15. The method of claim 14 wherein the compound of Formula (II) is prepared by a condensation reaction of the compound of Formula (I) with N,N′-carbonyldiimidazole and a compound of Formula (VIII):
in the presence of magnesium chloride and triethylamine, wherein R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.
16. The method of claim 14 , wherein the compound of Formula (II) is prepared by a condensation reaction of the compound of Formula (I) with Meldrum's acid, 4-dimethylaminopyridine, R 5 OH and pivaloyl chloride in the presence of N,N-diisopropylethylamine, R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.