Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-07-11
2004-06-29
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S404000, C549S405000
Reexamination Certificate
active
06756403
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel processes for producing chromane compounds, preferably chroman-2-yl acetic acid compounds and amino substituted chroman-2-yl acetic acid esters which are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors. It further relates to processes for resolving chiral intermediates or final products to provide desired enantiomers.
BACKGROUND OF THE INVENTION
One process for making chromanes from coumarin derivatives is described in U.S. Pat. No. 5,731,324 at pages 101-103. The unprotected amino derivative bicyclic compound is shown on page 147. However, that process involves chromatography as a purification step, which does not scale well commercially.
SUMMARY OF THE INVENTION
In accordance with one preferred embodiment, there is provided a process for making a compound, or a salt thereof, having a general formula:
wherein R is C
1
-C
8
alkyl and n=0 to about 3. The method comprises (a) through (f) below:
(a) reacting phenol and beta-keto glutaric add in H
2
SO
4
/Ethanol with heat, followed by pouring the reaction mixture onto ice water, extracting into organic solvent and evaporating as follows:
(b) hydrogenating the chromenone product from (a) above to produce the corresponding chromanone:
(c) nitrating the chromanone from (b) as follows:
(d) resolving the racemic mixture using a lipase enzyme, as follows:
(e) hydrogenating the 4-carbon to remove the oxo group and convert the nitro group to an acetamido group as follows:
(f) acidifying the product from (e) above to recover the amine followed by addition of concentrated HCl to produce the HCl salt as follows:
In accordance with one preferred embodiment, there is provided a process for making a compound, or a salt thereof, having a general formula:
wherein R is C
1
-C
8
alkyl and n=0 to about 3. The method comprises (a) through (g) below:
(a) reacting 2-hydroxyacetophenone and diethyloxalate in the presence of sodium ethoxide followed by addition of concentrated sulfuric acid to make the bicyclic ring system as follows:
(b) hydrogenating the chromen-4-one to form the chromen-4-one as follows:
(c) performing a chain extension by first making the free acid, followed by reacting with borane-methyl sulfide complex to form the 2-hydroxymethyl derivative, followed by replacing the hydroxy group with a tosyl group and reacting the tosyl derivative with a cyanide salt to form a 2-cyano derivative, followed by acidifying the cyano derivative in concentrated acid and esterifying the 2-acid group as follows:
(d) nitrating the product from (c) above to form the 6-nitro group as follows:
(e) resolving the racemic mixture using a lipase enzyme, as follows:
(f) hydrogenating the 4-carbon to remove the oxo group and convert the nitro group to an acetamido group as follows:
(g) acidifying the product from (f) above to recover the amine followed by addition of concentrated HCl to produce the HCl salt as follows:
In accordance with one preferred embodiment, there is provided a process for making a compound, or a salt thereof, having a general formula:
wherein R is C
1
-C
8
alkyl and n=0 to about 3. The method comprises (a) through (e) below:
(a) reacting nitrophenol and diethyl ester of maleic add with methane sulfonic acid under heating as follows:
(b) performing a chain extension by first making the free aid, followed by reacting with borane-methyl sulfide complex to from the 2-hydroxymethyl derivative, followed by replacing the hydroxy group with a tosyl group and reacting the tosyl derivative with a cyanide salt to form a 2-cyano derivative, followed by acidifying the cyano derivative in concentrated acid and esterifying the 2-acid group as follows:
(c) resolving the racemic mixture using a lipase enzyme, as follows:
(d) hydrogenating the 4-carbon to remove the oxo group and convert the nitro group to an acetamido group as follows:
(e) acidifying the product from (d) above to recover the amine followed by addition of concentrated HCl to produce the HCl salt as follows:
In accordance with one preferred embodiment, there is provided a process for making a compound, or a salt thereof, having a general formula:
wherein R is C
1
-C
8
alkyl and n=0 to about 3. The process comprises (a) through (g) below:
(a) nitrating the chromen-4-one at the 6-position as follows:
(b) reacting the product from (a) above with TBSOTf to form a benzopyrillium salt as follows:
(c) adding the ketene enol to the benzopyrillium salt from (b) above as follows:
(d) acidifying the product from (c) above to complete the addition of the substituent at the 2-position on the 6-nitro-4-oxochromane ring as follows:
(e) resolving the racemic mixture using a lipase enzyme, as follows:
(f) hydrogenating the 4-carbon to remove the oxo group and convert the nitro group to an acetamido group as follows:
(g) acidifying the product from (f) above to recover the amine followed by addition of concentrated HCl to produce the HCl salt as follows:
The compositions formed according to the above methods preferably comprise about 75% to about 100% of a single (2R) or (2S) enantiomer of 6-aminochroman-2-yl acetic acid or an ester thereof.
In preferred embodiments, the lipase is from
Pseudomonas cepacia
, is the PS 30 lipase, is stabilized by cross-linking with alpha keto glutarate and the like, or is the stabilized PS 30 enzyme ChiroCLEC-PC.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In view of the shortcomings of the known process mentioned above, there is a need for improved processes for producing compounds that are useful as intermediates in processes for producing platelet aggregation inhibitors. There is a particular need for Improved processes for making compounds having the phenyl ring of the benzopyrans substituted by an amino group or a protected amino group. Such intermediates are useful for coupling with a carbonyl group to produce a carboxamide link and result in compounds that are useful platelet aggregation inhibitors or intermediates for forming platelet aggregation inhibitors. Also needed is a process to produce relatively inexpensively large quantities of chromone intermediates that are useful for being resolved by conventional processes to produce benzopyran or chromane derivatives wherein the chiral center at the two position of the saturated pyran ring portion of the bicyclic ring structure can be resolved into racemic mixtures (R/S) that are enriched with one of the R or S enantiomers or to produce substantially pure compositions of a single enantiomer (R or S enantiomer). Due to inherent losses of up to 50% or more of the starting materials (assuming a 50/50 R/S racemate) during enantiomeric resolution, there is a need for a process which is efficient enough to be scaled to an industrial level for inexpensively producing large quantities of a desired intermediate compound or large quantities of final chroman-2-yl acetic acid ester compounds that are useful in the anticoagulant field.
Accordingly, there continues to be a need for a process that is adaptable to commercially scaleable production of such chromanes. One or more of the foregoing needs may be met using the processes described herein and the compounds and intermediates made thereby.
The disclosure herein presents novel processes for producing chromane compounds, preferably chroman-2-yl acetic acid compounds and amino substituted chroman-2-yl acetic acid esters which are intermediates for producing therapeutic agents, or are themselves therapeutic agents, for disease states in mammals that have disorders caused by or Impacted by platelet dependent narrowing of the blood supply.
In particular, disclosed are processes that utilizes a Simonis Chromone cyclizing step with a phenol starting material and glutarate ketone under acidic condition (P
2
O
5
, phosphorous oxychloride or H
2
SO
4
). Preferably, sulfuric acid and absolute ethanol are utilized to produce the acetic add ethyl ester at the 2-position as follows:
wherein R is a subs
Briggs Barbara
Kanter James
Mullins John J. G.
Ruhter Gerd
Udodong Uko
Eli Lilly and Company
Knobbe Martens Olson & Bear LLP
Owens Amelia
LandOfFree
Methods for producing chiral chromones, chromanes, amino... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for producing chiral chromones, chromanes, amino..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for producing chiral chromones, chromanes, amino... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3364879