US4897475A
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Process for synthesis of 5α-cholest-8(14)-en-3β-ol-15-one and other 15-oxygenated sterols
Assignee: Rice University
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Filing: 1988-02-05
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Granted: 1990-01-30
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Expires: 2008-02-05
Abstract
Abstract A process for preparing 15-oxygenated sterols, such as 3 beta -hydroxy-5 alpha -cholest-8(14)-ene-15 one, comprising converting 7-dehydrocholesterol to 3 beta -benzoyloxycholesta-5,7-diene, converting the 3 beta -benzoyloxycholesta-5,7-diene to a 3 beta -benzoyloxy-5-cholesta-7,14-diene, converting the 3 beta -benzoyloxy-5-cholesta-7,14-diene to a 3 beta -benzoyloxy-14 alpha , 15 alpha -epoxy-5-cholest-7-ene and converting the 3 beta -benzoyloxy-14 alpha , 15 alpha -epoxy-5-cholest-7-ene to a 15-oxygenated sterol. Preferably, the 3 beta -benzoyloxy-cholesta-5,7-diene is converted to a 3 beta -benzoyloxy-5-cholesta-7,14-diene by (i) contacting 3 beta -benzoyloxy-cholesta-5,7-diene, in a solvent at a temperature of at most about -55 DEG C, with HCl at a concentration of at least about 2.0 M for a time sufficient to convert the 3 beta -benzoyl-oxycholesta-5,7-diene to a 3 beta -benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3 beta -benzoyloxy-5-cholesta-8,14-diene; and (iii) recovering the 3 beta -benzoyloxy-5-cholesta-7,14-diene.
Inventors
- 👤 George J. Schroepfer, Jr.
- 👤 William K. Wilson
- 👤 Ker-Shi Wang
- 👤 Alemka Kisic
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 16:16
CPC Classifications
C; C07; C07J; C07J71/00; C07J71/0005; C07J71/001; C07J71/0021; C07J9/00
Claims Analysis
Total Claims: 52
Claim 1
Independent Claim
76 words
A process for converting 3β-benzoyloxycholesta-5,7-diene to 3β-benzoyloxy-5-cholesta-7,14-diene comprising: (i) forming a first reaction mixture by contacting 3β-benzoyloxycholesta-5,7-diene, in a solvent at a temperature of at most about -55° C., with HCl at a concentration is said solvent of at least about 2.0M for a time sufficient to convert said 3β-benzoyloxycholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; and (iii) recovering said 3β-benzoyloxy-5-cholesta-7,14-diene.
Claim 2
Dependent Claim
76 words
A process for converting 3β-benzoyloxycholesta-5,7-diene to 3β-benzoyloxy-5-cholesta-7,14-diene comprising: (i) forming a first reaction mixture by contacting 3β-benzoyloxycholesta-5,7-diene, in a solvent at a temperature of at most about -55° C., with HCl at a concentration is said solvent of at least about 2.0M for a time sufficient to convert said 3β-benzoyloxycholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; and (iii) recovering said 3β-benzoyloxy-5-cholesta-7,14-diene.
Claim 3
Dependent Claim
11 words
The process according to claim 1, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5α-cholesta-7,14-diene.
Claim 4
Dependent Claim
11 words
The process according to claim 1, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5β-cholesta-7,14-diene.
Claim 5
Dependent Claim
15 words
The process according to claim 1, wherein said HCl concentration is from 2.0M to 2.5M.
Claim 6
Dependent Claim
15 words
The process according to claim 4, wherein said temperature is from -65° to -75° C.
Claim 7
Dependent Claim
26 words
The process according to claim 1, wherein said HCl is introduced as a gas into said reaction mixture to a concentration of from 2.0 to 2.5M.
Claim 8
Dependent Claim
21 words
The process according to claim 1, wherein said solvent comprises a mixture of CHCl 3 and CH 2 Cl 2 .
Claim 9
Dependent Claim
24 words
The process according to claim 7, wherein said solvent mixture consists of CHCl 3 and CH 2 Cl 2 in approximately a 3:1 ratio.
Claim 10
Dependent Claim
26 words
The process according to claim 1, further comprising the step of removing HCl from said reaction mixture through a sodium hydroxide trap prior to said neutralizing.
Claim 11
Dependent Claim
14 words
The process according to claim 1, wherein said base is concentrated NH 4 OH.
Claim 12
Dependent Claim
80 words
A process according to claim 1, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is converted to 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene a process comprising (i) forming a solution of 3β-benzoyloxy-5-cholesta-7,14-diene and ether by heating a mixture thereof and subsequently cooling said solution; (ii) forming a second reaction mixture by adding to said solution a mixture comprising an amount of MCPBA and NaHCO 3 effective to form and to inhibit the decomposition of said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene; and (iii) cooling said second reaction mixture to collect said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene.
Claim 13
Dependent Claim
11 words
The process according to claim 11, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5α-cholesta-7,14-diene.
Claim 14
Dependent Claim
11 words
The process according to claim 11, wherein said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene is 3β-benzoyloxy-14α,15α-epoxy-5α-cholest-7-ene.
Claim 15
Dependent Claim
11 words
The process according to claim 11, wherein said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene is 3β-benzoyloxy-14α,15α-epoxy-5β-cholest-7-ene.
Claim 16
Dependent Claim
11 words
The process according to claim 11, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5-β-cholesta-7,14-diene.
Claim 17
Dependent Claim
16 words
The process according to claim 11, wherein said second reaction mixture further comprises said diethyl ether.
Claim 18
Dependent Claim
27 words
The process according to claim 11, wherein said second reaction mixture is cooled to about 5° C. for approximately 1 hour to form crystals of said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene.
Claim 19
Dependent Claim
32 words
The process according to claim 11, wherein the ether used in the solution is selected from the group consisting of dibutyl ether, tert-butyl ether, diisopropyl ether, tert-butyl methyl ether, and diethyl ether.
Claim 20
Dependent Claim
30 words
The process according to claim 11, wherein the solution of step (i) is a solution of 3β-benzoyloxy-5-cholesta-7,14 diene and a solvent selected from the group consisting of dichloromethane and chloroform.
Claim 21
Dependent Claim
15 words
The process according to claim 11, wherein said solution is cooled to about ambient temperature.
Claim 22
Dependent Claim
18 words
The process according to claim 1, wherein prior to obtaining said 3β-benzoyloxy-5-cholesta-7,14-diene, said 3β-benzoyloxy-cholesta-5,7-diene is converted to 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene.
Claim 23
Dependent Claim
24 words
The process according to claim 1, further comprising the step of monitoring said first reaction mixture to determine when to neutralize said reaction mixture.
Claim 24
Dependent Claim
13 words
The process according to claim 22, wherein said monitoring is accomplished by chromatography.
Claim 25
Dependent Claim
16 words
The process of claim 1, wherein said 3β-benzoyloxycholesta-5,7-diene is obtained by reacting 7-dehydrocholesterol with benzoyl chloride.
Claim 26
Dependent Claim
70 words
The process of claim 24, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is converted to 3β-benzoyloxy-14α, 15αepoxy-5-cholest-7-ene a process comprising: (i) forming a solution of 3β-benzoyloxy-5-cholesta-7,14-diene and diethyl ether by heating a mixture thereof and subsequently cooling said solution; (ii) forming a second reaction mixture by adding a mixture comprising MCPBA and NaHCO 3 to said solution, and cooling said second reaction mixture to form said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene; and (iii) collecting said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene.
Claim 27
Dependent Claim
27 words
The process of claim 25, wherein said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene is converted to 5-cholest-8(14)-en-3βol-15 one by reacting said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene with a mineral acid in an organic solvent.
Claim 28
Dependent Claim
11 words
An intermediate useful in the production of 3β-benzoyloxy-14α, 15α-epoxy-5α-cholest-7-ene, comprising 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene.
Claim 29
Dependent Claim
11 words
An intermediate useful in the production of 3β-benzoyloxy-14α, 15α-epoxy-5α-cholest-7-ene, comprising 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene.
Claim 30
Dependent Claim
136 words
A process for converting 3β-benzoyloxy-cholesta-5,7-diene to 3β-hydroxy-5-cholest-8(14)-en-15-one comprising the steps: (i) forming a first reaction mixture by contacting 3β-benzoyloxy-cholesta-5,7-diene, in a solvent, with HCl at a temperature of at most about -55° C. and a concentration in said solvent of at least about 2.0M for a time sufficient to convert said 3β-benzoyloxy-cholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing said reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; (iii) forming a solution of 3β-benzoyloxy-5-cholesta-7,14-diene and ether and subsequently cooling said solution; (IV) forming a second reaction mixture by adding to said solution a mixture comprising an amount of MCPBA and NaHCO 3 effective to form and to inhibit the decomposition of said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene, cooling said second reaction mixture to collect said 3β-benzoyloxy14α-15α-epoxy-5-cholest-7-ene and (v) converting said 3β-benzoyloxy-14α,15 α-epoxy-5-cholest-7-ene to said 3β-hydroxy-5-cholest-8(14)-en-15-one.
Claim 31
Dependent Claim
136 words
A process for converting 3β-benzoyloxy-cholesta-5,7-diene to 3β-hydroxy-5-cholest-8(14)-en-15-one comprising the steps: (i) forming a first reaction mixture by contacting 3β-benzoyloxy-cholesta-5,7-diene, in a solvent, with HCl at a temperature of at most about -55° C. and a concentration in said solvent of at least about 2.0M for a time sufficient to convert said 3β-benzoyloxy-cholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing said reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; (iii) forming a solution of 3β-benzoyloxy-5-cholesta-7,14-diene and ether and subsequently cooling said solution; (IV) forming a second reaction mixture by adding to said solution a mixture comprising an amount of MCPBA and NaHCO 3 effective to form and to inhibit the decomposition of said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene, cooling said second reaction mixture to collect said 3β-benzoyloxy14α-15α-epoxy-5-cholest-7-ene and (v) converting said 3β-benzoyloxy-14α,15 α-epoxy-5-cholest-7-ene to said 3β-hydroxy-5-cholest-8(14)-en-15-one.
Claim 32
Dependent Claim
11 words
The process according to claim 28, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5α-cholesta-7,14-diene.
Claim 33
Dependent Claim
11 words
The process according to claim 28, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5β-cholesta-7,14-diene.
Claim 34
Dependent Claim
15 words
The process according to claim 28, wherein said HCl concentration is from 2.0M to 2.5M.
Claim 35
Dependent Claim
15 words
The process according to claim 31, wherein said temperature is from -65° to -75° C.
Claim 36
Dependent Claim
26 words
The process according to claim 28, wherein said HCl is introduced as a gas into said reaction mixture to a concentration of from 2.0 to 2.5M.
Claim 37
Dependent Claim
21 words
The process according to claim 28, wherein said solvent comprises a mixture of CHCl 3 and CH 2 Cl 2 .
Claim 38
Dependent Claim
24 words
The process according to claim 34, wherein said solvent mixture consists of CHCl 3 and CH 2 Cl 2 in approximately a 3:1 ratio.
Claim 39
Dependent Claim
26 words
The process according to claim 28, further comprising the step of removing HCl from said reaction mixture through a sodium hydroxide trap prior to said neutralizing.
Claim 40
Dependent Claim
14 words
The process according to claim 28, wherein said base is concentrated NH 4 OH.
Claim 41
Dependent Claim
12 words
The process according to claim 28, wherein said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene is 3β-benzoylox-14α,15α-epoxy-5α-cholest-7-ene.
Claim 42
Dependent Claim
13 words
The process according to claim 28, wherein said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene is 3β-benzoyloxy-14α, 15α-epoxy-5β-cholest-7-ene.
Claim 43
Dependent Claim
15 words
The process according to claim 28, wherein said second reaction mixture further comprises said ether.
Claim 44
Dependent Claim
21 words
The process according to claim 28, wherein prior to obtaining said 3β-benzoyloxy-5-cholesta-7,14-diene in step (i), said 3β-benzoyloxy-cholesta-5,7-diene is converted to 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene.
Claim 45
Dependent Claim
23 words
The process according to claim 28, further comprising the step of monitoring said reaction mixture to determine when to neutralize said reaction mixture.
Claim 46
Dependent Claim
13 words
The process according to claim 42, wherein said monitoring is accomplished by chromatography.
Claim 47
Dependent Claim
32 words
The process according to claim 28, wherein the ether used in the solution is selected from the group consisting of dibutyl ether, tert-butyl ether diisopropyl ether, tert-butyl methyl ether, and diethyl ether.
Claim 48
Dependent Claim
30 words
The process according to claim 28, wherein the solution of step (iii) is a solution of 3β-benzoyloxy-5-colesta-7,14 diene and a solvent selected from the group consisting of dichloromethane and chloroform.
Claim 49
Dependent Claim
15 words
The process according to claim 28, wherein said solution is cooled to about ambient temperature.
Claim 50
Dependent Claim
102 words
The process according to claim 28, further comprising the separation of said 3β-hydroxy-5-cholest-8(14)-en-15-one by using a two-phase recrystallization procedure which comprises (i) forming a second solution of alcohol, water and a saturated hydrocarbon with the mixture resulting from said converting step, (ii) heating said second solution to form a two-phase system, wherein the first phase contains said saturated hydrocarbon and the second phase contains an alcohol/water mixture, (iii) cooling said second solution to to promote the formation of crystals at an interface between said first and second phases which crystals contain said 3β-hydroxy-5-cholest-8(14)-en-15-one substantially free of impurities, and (iv) collecting said 3β-hydroxy-5-cholest-8(14)-en-15-one.
Claim 51
Dependent Claim
12 words
The process according to claim 47, wherein said saturated hydrocarbon is hexane.
Claim 52
Dependent Claim
11 words
The process according to claim 47, wherein said alcohol is methanol.
References Cited (Backward Citations)
US4202891A
Cited
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