Process for preparing {62 -santalol from 3-methylnorcamphor

Claim 2

ALKYLATING 3-METHYLNORCAMPOR WITH B-BROMOPROPIONALDEHYDE ETHYLENE GLYCOL ACETAL;

Claim 3

REACTING THE REACTION PRODUCT OF STEP (1) WITH A METHYLMETALLIC COMPOUND, SUCH AS METHYLLITHHIUM, FOLLOWED BY ACID HYDROLYSIS;

Claim 4

REACTING THE REACTION PRODUCT OF STEP (1) WITH A METHYLMETALLIC COMPOUND, SUCH AS METHYLLITHHIUM, FOLLOWED BY ACID HYDROLYSIS;

Claim 5

admixing endo-3-methyl-exo-3(2-(2,5-dioxacyclopentyl)-ethyl)bicyclo(2.2.1)heptan-2 -one of Step (1) with a methylmetallic compound selected from the group consisting of methyllithium and methylmagnesium bromide in a molar ratio of from about 1:1 to 1:5; in an anhydrous solvent at a temperature of from about 0* to 30* C.; and subsequently admixing the reaction product with an acidic aqueous solution to obtain exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3(3''-oxopropyl)bicyclo -(2.2.1)heptane;

Claim 6

admixing endo-3-methyl-exo-3(2-(2,5-dioxacyclopentyl)-ethyl)bicyclo(2.2.1)heptan-2 -one of Step (1) with a methylmetallic compound selected from the group consisting of methyllithium and methylmagnesium bromide in a molar ratio of from about 1:1 to 1:5; in an anhydrous solvent at a temperature of from about 0* to 30* C.; and subsequently admixing the reaction product with an acidic aqueous solution to obtain exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3(3''-oxopropyl)bicyclo -(2.2.1)heptane;

Claim 7

The process of claim 1 wherein, in Step (1), the strong base is sodium hydride or sodium amide; wherein, in Step (2) the methylmetallic compound is methyllithium; wherein, in Step (4), the dehydrating agent is thionyl chloride; and wherein, in Step (5), the reducing agent is lithium aluminum hydride.

Claim 8

The process of claim 1 wherein, in Step (1), the 3-methylbicyclo(2.2.1)-heptan-2-one is dissolved in a solvent selected from the group consisting of aromatic hydrocarbon solvents, ether solvents, and aliphatic hydrocarbon solvents in a weight ratio of 2-methylbicyclo(2.2.1)heptan-2-one to solvent of from 1:2 to 1:10 and the 3-bromo-1(2,5-dioxacyclopentyl)ethane is dissolved in a solvent selected from the group consisting of aromatic hydrocarbon solvents, ether solvents, and aliphatic hydrocarbon solvents, in a weight ratio of 2-bromo-1(2,5-dioxacyclopentyl)ethane to solvent of from 1:2 to 1:10; wherein, in Step (2), the endo-3-methyl-exo-3(2-(2,5-dioxacyclopentyl)ethyl)bicyclo(2.2.1)heptan-2-one is dissolved in a solvent selected from the group consisting of ether solvents, aromatic hydrocarbon solvents, and aliphatic hydrocarbon solvents in a weight ratio to the solvent of from 1:2 to 1:20; wherein, in Step (3), the exo-2-endo-3-dimethyl-endo-2-hydroxy-3(3''oxopropyl)bicyclo(2.2.1)-heptane is dissolved in a solvent selected from the group consisting of chlorinated hydrocarbon solvents, alcohol solvents, polyol solvents, and ether solvents in a weight ratio to the solvent of from 1:2 to 1:20; wherein, in Step (4), the exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(trans-4''-carbethoxypent-3'' -enyl)bicyclo(2.2.1)heptane and exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(cis-4''-carbethoxypent-3'' -enyl)bicyclo(2.2.1) heptane are dissolved in a solvent selected from the group consisting of chlorinated hydrocarbon solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, and ether solvents in a weight ratio to solvent of from 1:0.5 to 1:20; and wherein, in Step (5), if the reducing agent is lithium aluminum hydride the endo-3-methyl-exo-3-(trans-4''-carbethoxypent-3''-enyl)-2-methylenebicyclo -(2.2.1)heptane and endo-3-methyl-exo-3(cis-4''-carbethoxypent-3''-enyl)-2-methylenebicyclo(2.2.1)-heptane are dissolved in a solvent selected from the group consisting of ether solvents, aliphatic hydrocarbon solvents, and aromatic hydrocarbon solvents in a weight ratio to solvent of from 1:5 to 1:50 and if the reducing agent is sodium in an alcohol solvent, potassium in an alcohol solvent, or lithium in an alcohol solvent, the endo-3-methyl-exo-3(trans-4''-carbethoxypent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane and endo-3-methyl-exo-3(cis-4''-carbethoxypent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane are dissolved in the alcohol solvent of from 1:5 to 1:50.

Claim 9

admixing exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3(3'' -oxopropyl)bicyclo(2.2.1)heptane of Step (2) with (carbethoxyethylidene)triphenyl phosphorane in a molar ratio of from about 1:1 to 1:5 at a temperature of from 0* to 50* C. in an organic solvent to obtain exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(trans-4''-carbethoxypent-3'' -enyl)bicyclo(2.2.1)heptane and exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(cis-4''-carbethoxy-pent-3'' -enyl)bicyclo(2.2.1)heptane;

Claim 10

admixing exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3(3'' -oxopropyl)bicyclo(2.2.1)heptane of Step (2) with (carbethoxyethylidene)triphenyl phosphorane in a molar ratio of from about 1:1 to 1:5 at a temperature of from 0* to 50* C. in an organic solvent to obtain exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(trans-4''-carbethoxypent-3'' -enyl)bicyclo(2.2.1)heptane and exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(cis-4''-carbethoxy-pent-3'' -enyl)bicyclo(2.2.1)heptane;

Claim 11

REACTING THE REACTION PRODUCT OF STEP (2) WITH (CARBETHOXYETHYLIDENE) TRIPHENYLPHOSPHORANE;

Claim 12

REACTING THE REACTION PRODUCT OF STEP (2) WITH (CARBETHOXYETHYLIDENE) TRIPHENYLPHOSPHORANE;

Claim 13

DEHYDRATING THE REACTION PRODUCT OF STEP (3) WITH A DEHYDRATING AGENT, SUCH AS THIONYL CHLORIDE; AND

Claim 14

DEHYDRATING THE REACTION PRODUCT OF STEP (3) WITH A DEHYDRATING AGENT, SUCH AS THIONYL CHLORIDE; AND

Claim 15

admixing exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(trans-4''-carbethoxypent-3'' -enyl)bicyclo- (2.2.1)heptane and exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(cis-4''-carbethoxypent-3''-enyl) -bicyclo(2.2.1)heptane of Step (3) with a dehydrating agent selected from the group consisting of thionyl chloride, phosphorus oxychloride, boron trifluoride, aluminum oxide, sulfuric acid, and p-toluene sulfonic acid in a bicyclic compound to dehydrating agent molar ratio of from about 100:1 to 1:20 in an anhydrous solvent at a temperature of from about -20* to 50* C.; to obtain endo-3-methyl-exo-3-(trans-4''-carbethoxy-pent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane and endo-3-methyl-exo-3-(cis-4''-carbethoxypent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane; and

Claim 16

admixing exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(trans-4''-carbethoxypent-3'' -enyl)bicyclo- (2.2.1)heptane and exo-2-endo-3-dimethyl-endo-2-hydroxy-exo-3-(cis-4''-carbethoxypent-3''-enyl) -bicyclo(2.2.1)heptane of Step (3) with a dehydrating agent selected from the group consisting of thionyl chloride, phosphorus oxychloride, boron trifluoride, aluminum oxide, sulfuric acid, and p-toluene sulfonic acid in a bicyclic compound to dehydrating agent molar ratio of from about 100:1 to 1:20 in an anhydrous solvent at a temperature of from about -20* to 50* C.; to obtain endo-3-methyl-exo-3-(trans-4''-carbethoxy-pent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane and endo-3-methyl-exo-3-(cis-4''-carbethoxypent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane; and

Claim 17

The process of claim 3 wherein the aromatic hydrocarbon solvents are selected from the group consisting of benzene, xylene and toluene; wherein the aliphatic hydrocarbon solvents are selected from the group consisting of pentane, hexane, heptane, octane, cyclopentane, cyclohexane and cyclooctane; wherein the ether solvents are selected from the group consisting of dimethyl ether, diethyl ether, methylethyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane and dioxane; wherein the chlorinated hydrocarbon solvents are selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; wherein the alcohol solvents are selected from the group consisting of methanol, ethanol, propanol, iso-propanol, butanol and pentanol; and wherein the polyol solvents are selected from the group consisting of ethylene glycol, propylene glycol and glycerol.

Claim 18

The process of claim 4 wherein Step (1) is conducted at a temperature of from 80* to 130* C.; wherein Step (3) is conducted at a temperature of 20* to 30* C.; and wherein Step (5) is conducted at a temperature of -10* C. to 5* C.

Claim 19

admixing the endo-3-methyl-exo-3-(trans-4''-carbethoxypent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane and endo-3-methyl-exo-3-(cis-4''-carbethoxy-pent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane of Step (4) with a reducing agent selected from the group consisting of lithium aluminum hydride, sodium in an alcohol solvent, potassium in an alcohol solvent, and lithium in an alcohol solvent, in a bicyclic compound to lithium aluminum hydride molar ratio of from about 1:0.20 to 1:0.5 or a bicyclic compound to sodium in alcohol, potassium in alcohol or lithium in alcohol molar ratio of from about 1:1 to 1:1.5; in an anhydrous solvent at a temperature of from about -50* to 20* C.; to obtain endo-3-methyl-exo-3-(trans-5''-hydroxy-4''-methylpent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane and endo-3-methyl-exo-3-(cis-5''-hydroxy-4''-methylpent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane; wherein all five process steps are conducted in an inert atmosphere.

Claim 20

admixing the endo-3-methyl-exo-3-(trans-4''-carbethoxypent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane and endo-3-methyl-exo-3-(cis-4''-carbethoxy-pent-3''-enyl)-2 -methylenebicyclo(2.2.1)heptane of Step (4) with a reducing agent selected from the group consisting of lithium aluminum hydride, sodium in an alcohol solvent, potassium in an alcohol solvent, and lithium in an alcohol solvent, in a bicyclic compound to lithium aluminum hydride molar ratio of from about 1:0.20 to 1:0.5 or a bicyclic compound to sodium in alcohol, potassium in alcohol or lithium in alcohol molar ratio of from about 1:1 to 1:1.5; in an anhydrous solvent at a temperature of from about -50* to 20* C.; to obtain endo-3-methyl-exo-3-(trans-5''-hydroxy-4''-methylpent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane and endo-3-methyl-exo-3-(cis-5''-hydroxy-4''-methylpent-3''-enyl)-2 -methylenebicyclo(2.2.1)-heptane; wherein all five process steps are conducted in an inert atmosphere.

Claim 21

REDUCING THE REACTION PRODUCT OF STEP (4) WITH A REDUCING AGENT, SUCH AS LITHIUM ALUMINUM HYDRIDE, TO OBTAIN B-SANTALOL, AND NOVEL COMPOUNDS PRODUCED THEREIN ARE DISCLOSED.

Claim 22

REDUCING THE REACTION PRODUCT OF STEP (4) WITH A REDUCING AGENT, SUCH AS LITHIUM ALUMINUM HYDRIDE, TO OBTAIN B-SANTALOL, AND NOVEL COMPOUNDS PRODUCED THEREIN ARE DISCLOSED.