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US 2019/0119205 A1Published application
Method for preparing treprostinil and intermediate therefor
AssigneeYonsung Fine Chemical Co., Ltd.
InventorsHyun Ik SHIN, Hyoseon LEE, Kyung Jin LEE, Kee Young LEE, Changyoung OH
Life of this patent
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Abstract
The present invention relates to a cost-effective and efficient method for preparing treprostinil with high purity, and an intermediate therefor.
Claims18
A method for preparing a compound of the following formula (1), which comprises the steps of:
- (i) converting an alkyl halide or alkenyl tin of the following formula (3) to its cuprate, and subjecting the cuprate to stereoselective 1,4-addition to an α, β-unsaturated ketone of the following formula (2) to obtain a compound of the following formula (4);
- (ii) subjecting a ketone group of the compound of the following formula (4) to methenylation to obtain a compound of the following formula (5);
- (iii) deprotecting a diol protecting group of the compound of the following formula (5) to obtain a compound of the following formula (6);
- (iv) converting a diol of the compound of the following formula (6) to a cyclic carbonate to obtain a compound of the following formula (7);
- (v) deprotecting a phenol protecting group of the compound of the following formula (7) to obtain a compound of the following formula (8);
- (vi) subjecting the compound of the following formula (8) to intramolecular Friedel-Crafts allylic alkylation to obtain a compound of the following formula (9);
- (vii) subjecting the compound of the following formula (9) to hydrogenation to obtain a compound of the following formula (10);
- (viii) subjecting the compound of the following formula (10) to alkylation with a compound of the following formula (1) to obtain a compound of the following formula (12);
- and
- (ix) hydrolyzing an ester group of the compound of the following formula (12);
- wherein,
- represents a single or double bond between carbon atoms,
- R1 represents hydrogen or halogen,
- R2 represents hydrogen or a hydroxyl protecting group,
- R3 represents a C1-C6 alkyl group,
- PG1 and PG2 represent a hydroxyl protecting group each independently or in combination,
- X represents halogen or Sn(R4)3,
- R4 represents a C1-C6 alkyl group,
- Y represents α-OR5:β-H or α-H:β-OR5,
- R5 represents hydrogen or a hydroxyl protecting group,
- Z represents a C1-C6 alkyl group, and
- X′ represents halogen.
19 more elements
A compound of the following formula (8):
- wherein,
- represents a single or double bond between carbon atoms,
- R1 represents hydrogen or halogen,
- Y represents α-OR5:β-H or α-H:β-OR5,
- R5 represents hydrogen or a hydroxyl protecting group, and
- Z represents a C1-C6 alkyl group.
3 more elements
A method for preparing a compound of the following formula (8), which comprises the steps of:
- (i) converting an alkyl halide or alkenyl tin of the following formula (3) to its cuprate, and subjecting the cuprate to stereoselective 1,4-addition to an α, β-unsaturated ketone of the following formula (2) to obtain a compound of the following formula (4);
- (ii) subjecting a ketone group of the compound of the following formula (4) to methenylation to obtain a compound of the following formula (5);
- (iii) deprotecting a diol protecting group of the compound of the following formula (5) to obtain a compound of the following formula (6);
- (iv) converting a diol of the compound of the following formula (6) to a cyclic carbonate to obtain a compound of the following formula (7);
- and
- (v) deprotecting a phenol protecting group of the compound of the following formula (7):
- wherein,
- represents a single or double bond between carbon atoms,
- R1 represents hydrogen or halogen,
- R2 represents hydrogen or a hydroxyl protecting group,
- PG1 and PG2 represent a hydroxyl protecting group each independently or in combination,
- X represents halogen or Sn(R4)3,
- R4 represents a C1-C6 alkyl group,
- Y represents α-OR5:β-H or α-H:β-OR5,
- R5 represents hydrogen or a hydroxyl protecting group, and
- Z represents a C1-C6 alkyl group.
13 more elements
A compound of the following formula (9):
- wherein,
- represents a single or double bond between carbon atoms,
- R1 represents hydrogen or halogen,
- Y represents α-OR5:β-H or α-H:β-OR5,
- R5 represents hydrogen or a hydroxyl protecting group, and
- Z represents a C1-C6 alkyl group.
3 more elements
A method for preparing a compound of the following formula (9), which comprises a step of subjecting a compound of the following formula (8) to intramolecular Friedel-Crafts allylic alkylation:
- wherein,
- represents a single or double bond between carbon atoms,
- R1 represents hydrogen or halogen,
- Y represents α-OR5:β-H or α-H:β-OR5,
- R5 represents hydrogen or a hydroxyl protecting group, and
- Z represents a C1-C6 alkyl group.
3 more elements
A method for preparing a compound of the following formula (10), which comprises a step of subjecting a compound of the following formula (9) to hydrogenation:
- wherein,
- represents a single or double bond between carbon atoms,
- R1 represents hydrogen or halogen,
- Y represents α-OR5:β-H or α-H:β-OR5,
- R5 represents hydrogen or a hydroxyl protecting group, and
- Z represents a C1-C6 alkyl group.
3 more elements
Dependencies are inferred from the claim text.