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US 8,524,939 B2Granted
Intermediates for the synthesis of benzindene prostaglandins and preparations thereof
AssigneeChirogate International Inc.
InventorsShih-Yi Wei, Min-Kuan Hsu, Ming-Kun Hsu
Life of this patent
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Abstract
Novel processes for preparing optically active cyclopentanones 1 which are useful for the preparation of benzindene Prostaglandins and novel cyclopentanones are provided. The invention also provides novel processes of preparing benzindene Prostaglandins and novel intermediates for benzindene Prostaglandins.
Claims20
A process for preparing a compound of Formula 1
- wherein P1 is a protecting group for the phenol group;
- P2 and P3 are a protecting groups for the hydroxyl groups;
- is a single or double bond;
- R2 is a single bond or a C1-4-alkylene or —CH2O—;
- and R3 is a C1-7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C1-4-alkyl, a halogen or a trihalomethyl, comprising the steps of:
- (1) reacting a compound of Formula III:
- wherein P1 and P2 are as defined above, with a cuprate derived from the compound of Formula II-1, Formula II-2 or Formula II-3,
- wherein X is a halogen, R4 is a lower alkyl, and P3, , R2 and R3 are as defined above, to form a compound of Formula 1.
5 more elements
The process for preparing a compound of Formula 6,
- wherein P2 and P3 are a protecting group for a hydroxyl group;
- R2 is a single bond or a C1-4-alkylene or —CH2O—;
- and R3 is a C1-7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C1-4-alkyl, a halogen or a trihalomethyl, comprising the steps of:
- (1) reacting a compound of Formula III
- wherein P1 is a protecting group for a phenol group;
- P2 is a protecting group for a hydroxyl group, with a cuprate derived from the compound of Formula II-1, Formula II-2 or Formula II-3:
- wherein —X is a halogen;
- is a single or double bond;
- R2 is a single bond or a C1-4-alkylene or —CH2O—;
- and R3 is a C1-7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C1-4-alkyl, a halogen or a trihalomethyl;
- R4 is a lower alkyl;
- and P3 are a protecting group for a hydroxyl group, to form a compound of Formula 1;
- (2) methylenelation of the ketone radical of compound of Formula 1 to form the methylene compound of Formula 2;
- (3) hydroboration of the compound of Formula 2 with a boron reagent, followed by oxidation with basic hydrogen peroxide to give the alcohol compound of Formula 3
- (4) sulfonylation of the compound of Formula 3 in the presence of a base with a sulfonyl donor to form the compound of Formula 4,
- wherein X1 is a sulfonyl group;
- (5) removing the P1 group to form a compound of Formula 5
- wherein X1 is a sulfonyl group;
- and
- (6) intramolecular alkylation of the compound of Formula 5 to form a compound of Formula 6.
17 more elements
A process for preparing a compound of Formula 6c,
- wherein P2 and P3 are a protecting group for a hydroxyl group;
- R2 is a single bond or a C1-4-alkylene or —CH2O—;
- and R3 is a C1-7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C1-4-alkyl, a halogen or a trihalomethyl, comprising the steps of:
- (1) reacting a compound of Formula III
- wherein P1 is a protecting group for a phenol group;
- P2 is a protecting group for a hydroxyl group, with a cuprate derived from the compound of Formula II-1a, Formula II-2 or Formula II-3:
- wherein X is a halogen;
- R2 is a single bond or a C1-4-alkylene or —CH2O—;
- and R3 is a C1-7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C1-4-alkyl, a halogen or a trihalomethyl;
- R4 is a lower alkyl;
- and P3 is a protecting group for a hydroxyl group, to form a compound of Formula 1c;
- (2) methylenelation of the ketone radical of the compound of Formula 1c with a methylenelation reagent to form the methylene compound of Formula 2c;
- (3) hydroboration of the compound of Formula 2c with a boron reagent, followed by oxidation with basic hydrogen peroxide to give the alcohol compound of Formula 3c
- (4) sulfonylation of the compound of Formula 3c in the presence of a base with a sulfonyl donor to form a compound of Formula 4c:
- wherein X1 is a sulfonyl group;
- (5) removing the P1 group and hydrogenating the double bound in ω-side chain to form a compound of Formula 5c
- and
- (6) intramolecular alkylation of the compound of Formula 5c to form a compound of Formula 6c.
15 more elements
A process for preparing treprostinil, comprising the steps of:
- (1) reacting a compound of Formula IIIa
- wherein P1 is a protecting group for a phenol group;
- P2 is a protecting group for a hydroxyl group, with a cuprate derived from the compound of Formula II-1a, Formula II-2a or Formula II-3a:
- wherein X is a halogen;
- R4 is a lower alkyl;
- and P3 is a protecting group for a hydroxyl group to form a compound of Formula 1d
- (2) methylenelation of the ketone radical of the compound of Formula 1d to form a methylene compound of Formula 2d
- (3) hydroboration of the compound of Formula 2d with a boron reagent, followed by oxidation with basic hydrogen peroxide to give the alcohol compound of Formula 3d
- (4) sulfonylation of the compound of Formula 3d in the presence of a base with a sulfonyl donor to form a compound of Formula 4d
- wherein X1 is a sulfonyl group;
- (5) removing the P1 group to form a compound of Formula 5d
- (6) intramolecular alkylation of the compound of Formula 5d to form a compound of Formula 6d
- (7) removing the P2 and P3 groups to form a compound of Formula 7d
- (8) hydrogenating the double bond in the ω-side chain of compound of Formula 7d to form a compound of Formula 8d
- (9) alkylating the phenol group with an alkylating agent of XCH2CN or XCH2COOR5, wherein X is a halogen;
- R5 is an alkyl, to form a compound of Formula 9d
- wherein Z is —CN or —COOR5;
- and
- (10) hydrolyzing the —CN or —COOR5 radical of the compound of Formula 9d with a base to form treprostinil.
16 more elements
A process for preparing treprostinil, comprising the steps of:
- (1)reacting a compound of Formula IIIa
- wherein P1 is a protecting group for a phenol group;
- and P2 is a protecting group for a hydroxyl group;
- with a cuprate derived from the compound of Formula II-1 a, Formula II-2a or Formula ll-3a:
- wherein X is a halogen;
- R4 is a lower alkyl;
- and P3 is a protecting group for a hydroxyl group, to form a compound of Formula 1d
- (2) methylenelation of the ketone radical of the compound of Formula 1d to form a methylene compound of Formula 2d;
- (3) hydroboration of the compound of Formula 2d with a boron reagent, followed by oxidation with basic hydrogen peroxide to give an alcohol compound of Formula 3d
- (4) sulfonylation of compound of Formula 3d in the presence of a base with a sulfonyl donor to form a compound of Formula 4d
- wherein X1 is a sulfonyl group;
- (5) removing the P1 group to form a compound of Formula 5d,
- (6) intramolecular alkylation of the compound of Formula 5d to form a compound of Formula 6d
- (7) alkylating the phenol group with an alkylating agent of XCH2CN or XCH2COOR5 wherein X is halogen such as Cl, Br, or I;
- R5 is an alkyl, to form a compound of Formula 7D
- wherein Z is —CN or —COOR5;
- and
- (8) removing the P2 and P3 groups to form a compound of Formula 8D
- (9) hydrolyzing the —CN or —COOR5 radical of the compound of Formula 8D with a base to form of Formula 9D
- (10) hydrogenating the double bound in the ω-side chain of the compound of Formula 9D to form treprostinil.
17 more elements
Dependencies are inferred from the claim text.