# US 2008/0306145 A1 · Preparation Of Ginkgolide And F-Seco-Ginkgolide Lactols

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- Number: US 2008/0306145 A1
- Document ID: US20080306145A1
- Status: Published application
- Kind: A1
- Application number: 11/791,422
- Filed: 2005-11-23
- Published: 2008-12-11
- Earliest claimed: 2004-11-23
- Assignees: The Trustees of Columbia University in the City of New York
- Inventors: Koji Nakanishi; Nina Berova; Katsunori Tanaka
- Web page: https://patentgrep.com/patent/US20080306145A1

## CPC

- C07D 493/22: in which the condensed system contains four or more hetero rings
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to synthesis of C11 natural ginkgolide derivatives and C11 f-seco-gingkolide derivatives from the corresponding lactols which are selectively obtained using NaBH4.

## Claims

### Claim 1

A compound having the structure:
wherein R1 is H or —OR8,
where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10,
where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms; Z is carbon, oxygen, sulfur or nitrogen; Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10—OSR10, —N(R10)(R10) or —NR10SO2R10,
where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)COR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13, or triethylsiloxy,
where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, or cycloalkyl or aryl group having 3 to 10 carbon atoms;
wherein R6 is H or —OR8,
where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
wherein R7 is —CH3;
wherein R3 is O and R5 is selected from H, OH, —C(CH3)—C(O)—O(CH3), (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclic, amino, amido, alkoxy, alkenyloxy, alkynyloxy, —O-aryl, —O-(alkyl)(C1-C10), (—NH-alkyl, —N(alkyl)2, —NH2, -alkyl-C(O)(OH), -alkyl-OH, -alkyl-(NH2), halide, CX3 where X is a halide, indole radical, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10, where A, Z, Ar and R10 are defined as above, or
wherein R5 is O and R3 is selected from OH, —C(CH3)—C(O)—O(CH3), (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclic, amino, amido, alkoxy, alkenyloxy, alkynyloxy, —O-aryl, —O—(C2-C10 alkyl) (C1-C10), (—NH-alkyl, —N(alkyl)2, —NH2, -alkyl-C(O)(OH), -alkyl-OH, -alkyl-(NH2), halide, CX3 where X is a halide, indole radical, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10, where A, Z, Ar and R10 are defined as above,
or an optically pure enantiomer, diastereomer, tautomer or salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, having the structure:

### Claim 3 (depends on 1)

The compound of claim 1, having the structure:

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound has the structure:

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound has the structure:

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound has the structure:

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound has the structure:

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound has the structure:

### Claim 9

A process for preparing the compound of claim comprising:
(a) exposing a compound having the structure:
wherein R1 is H or —OR8,
where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, O-A-Ar, or —R10,
where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms; Z is carbon, oxygen, sulfur or nitrogen; Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, —C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10, —OSR10, —N(R10)(R10), or —NR10SO2R10,
where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)CR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13 or triethylsiloxy,
where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, or (C2-C5) alkynyl, or a cycloalkyl or aryl group having 3 to 10 carbon atoms;
wherein R6 is H or —OR8,
where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino; and
wherein R7 is —CH3,
to NaBH4 in a suitable solvent to produce a lactol derivative; and
(b) reacting the lactol derivative product of step (a) with an agent suitable to produce the compound.

### Claim 10 (depends on 9)

The process of claim 9, wherein the suitable solvent in step (a) is MeOH.

### Claim 11

(canceled)

### Claim 12 (depends on 9)

The process of claim 9, wherein the suitable agent is a carboxcylic acid, an alkylating reagent or an acid halide.

### Claim 13 (depends on 1)

A process for preparing the compound of claim 1 comprising:
(a) exposing a compound having the structure:
wherein R1 is H or —OR8,
wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10,
where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms; Z is carbon, oxygen, sulfur or nitrogen; Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, —C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10—OSR10N(R10)(R10), or —NR10SO2R10,
where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)COR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13, or triethylsiloxy,
where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, or cycloalkyl or aryl group having 3 to 10 carbon atoms; and
wherein R15 is H or halide, and R16 is —C(CH3)—C(O)—OCH3,
to NaBH4 in a suitable solvent so as to produce a second compound having the structure:
(b) reacting the lactol product of step (a) with an agent suitable to produce a compound having the structure:
wherein R3 is O and R5 is selected from H, OH, —C(CH3)—C(O)—O(CH3), (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclic, amino, amido, alkoxy, alkenyloxy, alkynyloxy, —O-aryl, —O-(alkyl)(C1-C10), (—NH-alkyl, —N(alkyl)2, —NH2, -alkyl-C(O)(OH), -alkyl-OH, -alkyl-(NH2), halide, CX3 where X is a halide, indole radical, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10, where A, Z, Ar and R10 are defined as above, or
wherein R5 is O and R3 is selected from OH, —C(CH3)—C(O)—O(CH3), (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclic, amino, amido, alkoxy, alkenyloxy, alkynyloxy, —O-aryl, —O—(C2-C10 alkyl) (C1-C10), (—NH-alkyl, —N(alkyl)2, —NH2, -alkyl-C(O) (OH), -alkyl-OH, -alkyl-(NH2), halide, CX3 where X is a halide, indole radical, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10, where A, Z, Ar and R10 are defined as above; and
(c) joining R16 and R15 to form a lactone.

### Claim 14 (depends on 13)

The process of claim 13, wherein the suitable solvent in step (a) is MeOH.

### Claim 15

(canceled)

### Claim 16 (depends on 13)

The process of claim 13, further comprising the step of exposing the compound produced in step (a) to p-phenylbenzoic acid, EDC and DMAP so as to resolve the enantiomers before step (b).

### Claim 17

(canceled)

### Claim 18

A process for preparing a compound having the structure:
comprising reacting
wherein R1 is H or —OR8,
wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10,
where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms; Z is carbon, oxygen, sulfur or nitrogen; Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, —C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10, —OSR10, —N(R10)(R10), or —NR10SO2R10,
where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)COR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13, or triethylsiloxy,
where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, or cycloalkyl or aryl group having 3 to 10 carbon atoms; and
wherein R15 is H or halide, and R16 is —C(CH3)—C(O)—OCH3,
with NaBH4 in a suitable solvent.

### Claim 19 (depends on 18)

The process of claim 18, wherein the compound produced is:
and the process comprises reacting:
with NaBH4 in a suitable solvent.

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22

A process for preparing a compound having the structure:
comprising:
a) exposing a compound having the structure:
to p-phenylbenzoic acid, DEC, DMAP, at a suitable temperature so as to produce a compound having the structure:
b) separating the compounds produced in step a); and
c) exposing the products of step b) to a suitable hydrolyzing agent so as to produce the compound.

### Claim 23 (depends on 22)

The process of claim 22, wherein the hydrolyzing agent is K2CO3 in a suitable solvent.

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26 (depends on 1)

A method of making a composition comprising admixing an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 27 (depends on 1)

A composition comprising the compound of claim 1 and a carrier.