High-purity thienopyrimidine compound and preparation method therefor
A thienopyrimidine compound (a compound of formula N) and a preparation method therefor are provided. Specifically, the preparation method includes the steps of: (a) in a solvent A, reacting, in the presence of an organic base and acyl chloride, a compound of formula N-2 with 3-amino-6-methoxypyridazine to obtain a compound of formula N-1; and (b) in a solvent B, converting, in the presence of a base, the compound of formula N-1 into the compound of formula N. The preparation method does not require toxic and expensive reagents, has mild reaction conditions and a high product purity, and is suitable for industrial production.
1 . A method for preparing a compound of formula N, wherein the method comprises the following steps:
(a) in inert solvent A, in the presence of an organic base and an acyl chloride, subjecting a compound of formula N-2 and 3-amino-6-methoxypyridazine to a condensation reaction, thereby obtaining a compound of formula N-1; and
(b) in inert solvent B, in the presence of a base, subjecting the compound of formula N-1 to a ring-closing reaction, thereby obtaining a compound of formula N;
in each formula, R is C 1-6 alkyl, and R 1 is —NO 2 or —NHCONHOCH 3 .
2 . The method according to claim 1 , wherein in step (b), the base is an inorganic base.
3 . The method according to claim 1 , wherein in step (b), the base is selected from the group consisting of carbonate, phosphate, bicarbonate, hydrophosphate, or a combination thereof.
4 . The method according to claim 1 , wherein in step (b), the base is selected from the group consisting of potassium carbonate, sodium carbonate, caesium carbonate, tripotassium phosphate, or a combination thereof.
5 . The method according to claim 1 , wherein the method comprises one or more features selected from the group consisting of:
a. the organic base is an organic compound containing 1-3 nitrogens and 3-20 carbons;
b. the acyl chloride is selected from phosphorus oxychloride, thionyl chloride, C 1-8 alkyl sulfonyl chloride, C 4-20 aromatic sulfonyl chloride, C 1-8 alkyl acyl chloride, C 4-20 aromatic acyl chloride.
6 . The method according to claim 1 , wherein the organic base is a compound selected from the group consisting of R 2 NH 2 , (R 2 ) 2 NH, (R 2 ) 3 N, 4 to 7 membered heterocyclic alkyl containing N heteroatom, 5 to 6 membered heteroaryl containing N heteroatom, or a combinations thereof, wherein R 2 is C 1-6 alkyl.
7 . The method according to claim 1 , wherein the method comprises one or more features selected from the group consisting of:
a. the organic base is selected from the group consisting of triethylamine, pyridine, or a combination thereof;
b. the acyl chloride is selected from benzenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, or a combination thereof.
8 . The method according to claim 1 , wherein step (a) comprises one or more features selected from the group consisting of:
a. the molar ratio of the compound of formula N-2 to 3-amino-6-methoxypyridazine is 1:1 to 3;
b. the molar ratio of the compound of formula N-2 to the organic base is 1:1.5 to 5;
c. the molar ratio of the compound of formula N-2 to the acyl chloride is 1:1 to 3.
9 . The method according to claim 1 , wherein step (a) comprises one or more features selected from the group consisting of:
a. the molar ratio of the compound of formula N-2 to 3-amino-6-methoxypyridazine is 1:1.4 to 1.6;
b. the molar ratio of the compound of formula N-2 to the organic base is 1:1.4 to 2.1;
c. the molar ratio of the compound of formula N-2 to the acyl chloride is 1:1.4 to 1.6.
10 . The method according to claim 1 , wherein in step (b), the molar ratio of the compound of formula N-1 to the base is 1:0.5 to 3.
11 . The method according to claim 1 , wherein in step (b), the molar ratio of the compound of formula N-1 to the base is 1:0.5 to 2.0.
12 . The method according to claim 1 , wherein in step (b), the molar ratio of the compound of formula N-1 to the base is 1:0.7 to 1.1.
13 . The method according to claim 1 , wherein the compound of formula N is a compound of formula N-a,
14 . An API product comprising the compound of formula N or a salt thereof,
wherein
the purity of the compound of formula N is ≥99.5%; and
the content of both impurity i and impurity f in the API product are ≤0.15; wherein
the impurity i is a compound of formula i,
and impurity f is a compound of formula f
wherein R is NH 2 or C 1-6 alkoxy wherein the compound of formula N or a salt thereof is prepared by a method comprising the following steps:
(a) in inert solvent A, in the presence of an organic base and an acyl chloride, subjecting a compound of formula N-2 and 3-amino-6-methoxypyridazine to a condensation reaction, thereby obtaining a compound of formula N-1; and (b) in inert solvent B, in the presence of a base, subjecting the compound of formula N-1 to a ring-closing reaction, thereby obtaining a compound of formula N; in each formula, R is Ci-6 alkyl, and Ri is —N02 or —NHCONHOCH 3 .
15 . The API product of claim 14 , wherein the purity of the compound of formula N is ≥99.6%, and/or the content of both impurity i and impurity f in the API product is ≤0.10%.