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US4920218A
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Novel hydroxide mediated FK-506 rearrangement process
Assignee: Merck and Co Inc
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Filing: 1989-09-05
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Granted: 1990-04-24
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Expires: 2009-09-05
Abstract
Abstract A process is described involving an alkaline rearrangement of FK-506 producing a new decarbonylated 22-membered macrocycle rearrangement derivative of FK-506, i.e. C.9, nor-keto FK-506.
Inventors
- 👤 David Askin
- 👤 Todd K. Jones
- 👤 Robert A. Reamer
- 👤 Ralph P. Volante
- 👤 Ichiro Shinkai
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 17:11
CPC Classifications
C; C07; C07D; C07D498/00; C07D498/12; C07D498/18
Claims Analysis
Total Claims: 12
Claim 1
Independent Claim
111 words
A process comprising the steps of: (a) contacting compound 2: ##STR10## wherein R 1 and R 2 are independently H, or an easily removable hydroxy protecting group, with a hydroxide base in an inert aqueous/organic solvent mixture at room temperature in the range of about 0°-25° C. for a sufficient time to form 3; ##STR11## (b) contacting 3 obtained above with an oxidizing agent in an inert organic solvent at 0°-50° C. for a sufficient time to form 4; ##STR12## (c) contacting the above-obtained 4 under mild acidic hydrolysis conditions for a sufficient time to remove R 2 and/or R 1 if either are present, to yield the immunosuppressant 5: ##STR13##
Claim 2
Dependent Claim
111 words
A process comprising the steps of: (a) contacting compound 2: ##STR10## wherein R 1 and R 2 are independently H, or an easily removable hydroxy protecting group, with a hydroxide base in an inert aqueous/organic solvent mixture at room temperature in the range of about 0°-25° C. for a sufficient time to form 3; ##STR11## (b) contacting 3 obtained above with an oxidizing agent in an inert organic solvent at 0°-50° C. for a sufficient time to form 4; ##STR12## (c) contacting the above-obtained 4 under mild acidic hydrolysis conditions for a sufficient time to remove R 2 and/or R 1 if either are present, to yield the immunosuppressant 5: ##STR13##
Claim 3
Dependent Claim
60 words
The process of claim 1 wherein R 1 and R 2 are independently selected from radicals easily hydrolyzable under mild acid conditions selected from C 1 -C 10 acyl or halogenated C 1 -C 10 acyl; C 1 -C 10 halogenated alkyl; SiR 3 , where R is independently C 1 -C 4 linear or branched alkyl, phenyl, or benzyl.
Claim 4
Dependent Claim
15 words
The process of claim 2 wherein said R 1 and R 2 are both triisopropylsilyl.
Claim 5
Dependent Claim
34 words
The process of claim 2, step (a), wherein said hydroxide base is of the formula: M(OH) n , where M is Na, K, Cs, Li, Mg, Ca, Ba and n is 1 or 2.
Claim 6
Dependent Claim
11 words
The process of claim 4 wherein said hydroxide base is LiOH.
Claim 7
Dependent Claim
21 words
The process of claim 1, step (a), wherein said organic solvent is a C 1 -C 10 cyclic or acyclic ether.
Claim 8
Dependent Claim
18 words
The process of claim 1, step (b), wherein said oxidizing agent is lead tetraacetate or an alkali metaperiodate.
Claim 9
Dependent Claim
15 words
The process of claim 1, step (a), conducted in the temperature range of 0°-5° C.
Claim 10
Dependent Claim
15 words
The process of claim 1, step (b), conducted in the temperature range of 20°-25° C.
Claim 11
Dependent Claim
83 words
A process comprising the steps of: (a) contacting compound 2a, wherein "TIPS" is triisopropylsilyl: ##STR14## with lithium hydroxide in aqueous tetrahydrofuran at 0°-5° C. for a sufficient time to form 3a; ##STR15## (b) contacting 3a obtained above with lead tetraacetate in dry benzene at 20°-25° C. for a sufficient time to form 4a; ##STR16## (c) contacting the above-obtained 4a with aqueous HF in acetonitrile at 20°-25° C. for a sufficient time to remove the triisopropylsilyl protecting groups, to yield the immunosuppressant 5: ##STR17##
Claim 12
Dependent Claim
83 words
A process comprising the steps of: (a) contacting compound 2a, wherein "TIPS" is triisopropylsilyl: ##STR14## with lithium hydroxide in aqueous tetrahydrofuran at 0°-5° C. for a sufficient time to form 3a; ##STR15## (b) contacting 3a obtained above with lead tetraacetate in dry benzene at 20°-25° C. for a sufficient time to form 4a; ##STR16## (c) contacting the above-obtained 4a with aqueous HF in acetonitrile at 20°-25° C. for a sufficient time to remove the triisopropylsilyl protecting groups, to yield the immunosuppressant 5: ##STR17##
References Cited (Backward Citations)
JPS6317884A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1993-04-23 | 1993-10-23 | 1994-04-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1997-04-23 | 1997-10-23 | 1998-04-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2001-04-23 | 2001-10-23 | 2002-04-24 | $7700.00 | Window Closed / Lapsed |