WO2001092249A2 - Synthese chirale et achirale de chromanes substitues par 2-acyle et leurs derives - Google Patents

Synthese chirale et achirale de chromanes substitues par 2-acyle et leurs derives Download PDF

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WO2001092249A2
WO2001092249A2 PCT/US2001/018016 US0118016W WO0192249A2 WO 2001092249 A2 WO2001092249 A2 WO 2001092249A2 US 0118016 W US0118016 W US 0118016W WO 0192249 A2 WO0192249 A2 WO 0192249A2
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compound
group
process according
acid
formula
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PCT/US2001/018016
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WO2001092249A3 (fr
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James Kanter
Charles Marlowe
John J. G. Mullins
Anjali Pandey
Robert Scarborough
Greg Butke
Barry Jacobsen
Derrick Walker
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Cor Therapeutics, Inc.
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Priority to AU2001268166A priority Critical patent/AU2001268166A1/en
Priority to US10/296,875 priority patent/US20040044225A1/en
Publication of WO2001092249A2 publication Critical patent/WO2001092249A2/fr
Publication of WO2001092249A3 publication Critical patent/WO2001092249A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4

Definitions

  • This invention relates to novel processes for producing racemic or enantiomerically enriched or substantially pure 2-acyl substituted chromone compounds, 2-acyl substituted chromane compounds and their corresponding bicyclic sulfur analogs, which are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors.
  • X is ethyl
  • the acid can be converted to an acyl halide, such as acyl chloride, instead of the ethyl ester by reacting it with SOCI 2 , for example.
  • a further reaction of the acyl chloride with NH 3 can be used to produce the carboxamide.
  • chromene-derivative compounds have been reported as useful intermediates for the production of compounds wherein the phenyl ring of the chromene ring structure is further substituted by a benzoylamino derivative to produce antidepressants. See, for example, U.S. Patent 5,659,051.
  • a 2-chroman-2-yl acetic acid compound racemic starting material when the production of a 2-chroman-2-yl acetic acid compound racemic starting material is desired, such can be accomplished by hydrogenation of a coumarin derivative with a reducing agent under standard reduction conditions or via hydrogenation conditions by using standard catalysts selected from the group comprising diisoamylborane, lithium tri-butoxyaluminohydride, lithium triethylborohydride, lithium trimethoxyaluminium hydride, sodium borohydride, H 2 /Pd/C, and the like. Such catalysts and procedures may be utilized to hydrogenate the double bond in the lactone ring and/or replace the keto group with a hydroxyl group.
  • lithium tri- butoxyaluminohydride, LiAIH 4 , or diisoamylborane (DIABO) may be used as part of such a process step to reduce the two position keto group to a hydroxyl group.
  • the hydroxyl group may then be replaced by an acetic acid side chain by a standard chain extension/replacement reaction of the alcohol intermediate.
  • a standard chain extension/replacement reaction of the alcohol intermediate For example, reaction of the alcohol intermediate with chloroacetate under basic conditions in the presence of pyridine will result in an acetic acid side chain in the two position.
  • the present invention relates to novel processes for producing achiral bicyclic intermediates or intermediates which are a substantially pure single enantiomer or a composition substantially enriched in a single enantiomer of chromans substituted at the 2-position with C.,-C 8 -acyl (branched and straight-chained) groups, such as 2-carboxylic acid compounds, chroman-2-yl acetic acid and propanoic acid, as well as other derivatives and sulfur analogs thereof, such as 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.
  • C.,-C 8 -acyl (branched and straight-chained) groups such as 2-carboxylic acid compounds, chroman-2-yl acetic acid and propanoic acid, as well as other derivatives and sulfur analogs thereof, such as esters, which are intermediates for producing therapeutic agents, or are themselves therapeutic agents, for disease states in
  • n is 0 to 6;
  • R are independently selected from the group consisting of alkyl, alkoxy, lower alkenyl, hydroxy, thio, amino, substituted amino, nitro, halo, and CF 3 ;
  • R 4 is selected from the group consisting of hydroxy, alkoxy, alkenyloxy, halogen, amino, and substituted amino
  • each of Q and Q 1 are independently selected from the -C(-R 2 , -R 3 )-, wherein each of R 2 and R 3 is independently selected from the group consisting of alkyl, alkoxy, alkenyl, hydroxy, thio, nitro, halo, and CF 3 , or R 2 and/or R 3 together with the carbon to which it is attached form a carbonyl group.
  • the method comprises (a) and (b):
  • the Walden catalyst in (a) is selected from the group consisting of PCI 5 , PBr 3 , Pl 3 , PF 3 , SOCI 2 , KOH and Ag 2 O; and (b) comprises use of a basic Walden catalyst or a Friedel Crafts catalyst, wherein the catalyst in (b) is preferably one selected from the group consisting of AICI 3 , NaOH, KOH, sodium carbonate, and potassium carbonate.
  • the second compound is a single (R) or (S) enantiomer
  • the compounds formed are either a (2S) or (2R) compound, or an enriched (2S>2R) or (2R>S) mixture wherein one of the (2S) or (2R) is present at greater than about 70%.
  • the second compound is a mono or diester of 3- halomalonic acid, or a mono or diester of 3-hydroxymalonic acid;
  • Z is oxygen;
  • m is 0 or 1 ; and
  • R is amino or nitro.
  • step (a) of the foregoing process produces a compound having the formula:
  • step (b) comprises:
  • step (b1) acylating the compound from step (a) at chain "a” to form an acyl halide
  • step (b) comprises: (b1) reducing at chain "a” to form a methanol group;
  • step (b) comprises:
  • step (b1) acylating the compound from step (a) at both chains "a” and “b” to form acyl halides
  • step (b) comprises heating the compound from step (a) in the presence of a strong base to form a compound having the formula:
  • either of the last two alternatives may further comprise performing a chain extension to form a compound having the formula:
  • the foregoing compounds may be nitrated if amino or nitro is not already present and/or the compounds reduced to remove the 4-oxo group and reduce the nitro group to amino (if present). The reduction may take place in one or more steps. If an acid is formed, further reaction may be done to obtain a corresponding ester, preferably the ethyl ester.
  • a mono or diester of 3-halomalonic acid, or a mono or diester of 3-hydroxymalonic acid is reacted with 4-hydroxy-3-methylaniline and then cyclized using a strong base.
  • the method may further comprise reducing the compound formed to remove the 3-oxo group.
  • the process comprises reacting a 4-nitrophenoxide compound with a malonic ester compound having the formula:
  • Either process may further comprise reducing (removing) the 4-oxo group and reducing the nitro group to amino. The reduction may be accomplished in one step, or in multiple steps.
  • the process comprises
  • alkyl and “lower alkyl” as used herein refers to a monovalent straight or branched chain radical of from one to about 10 carbon atoms, with one to about six being preferred, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
  • substituted alkyl refers to an alkyl group as just defined, substituted by one or more groups selected from halo, amino, hydroxyl, substiuted amino, nitro, and the like. Examples of such groups include chloromethyl, hydroxyethyl, aminomethyl, and the like.
  • halo or halogen as used herein refer to F, Cl, Br, or I substituents.
  • alkenyl and “lower alkenyl” as used herein refers to a monovalent straight or branched chain radical of from two to six carbon atoms containing a carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1- butenyl, 2-butenyl and the like.
  • alkylthio as used herein is an alkoxy group in which the O has been replaced by S.
  • substituted amino refers to an amino group in which one or more hydrogens have been replaced by alkyl, substituted alkyl, alkenyl or similar groups.
  • the chromane carboxylic acid derivatives can be resolved into racemic mixtures (R/S) that are enriched with one of the R or S enantiomers, or resolved to produce substantially pure (e.g. preferably at least 90% enantiomerically pure, more preferably at least 93%, at least 95%, at least 97%, and at least 99% enantiomerically pure) compositions of a single enantiomer (R or S enantiomer).
  • two compounds having the same molecular formula will have a different spatial relationship of the atoms around a "chiral" carbon atom.
  • One or more of the biological activity, physical properties or chemical properties often differ between the enantiomers to make it such that one enantiomer is a preferred structure. In fact, in nature sometimes only one of the two chiral structures is made.
  • (-)-2-methyl-1-butanol is formed in yeast fermentation of starches and only (-)-malic acid (an asymmetrical alpha-hydroxy diacid compound, HOOC-CH(OH)- CH-COOH) is present in fruit juices. While some simple chiral compounds are available in nature, others may be produced synthetically or may be obtained commercially.
  • a process that utilizes an asymmetrical alpha-hydroxy diacid enantiomer and a phenol derivative as starting materials. Since the acid group that is closer to the carbon atom which is substituted by the hydroxyl group tends to be far more acidic (alpha hydroxy acid group) and more reactive than the more distant acid group (methylene acid group), selective reactions may be used to substantially produce the single desired enantiomer with respect to the chiral 2-position carbon in the ring that is substituted by the acyl group.
  • the alpha hydroxy diacid enantiomer is the (R or S) enantiomer of alpha- hydroxy butanoic acid (malic acid).
  • enantiomer (S), also referred to as (-), of malic acid occurs naturally in fruit juices, but each of the two enantiomers are available separately from commercial suppliers, such as from Aldrich Fine Chemicals.
  • reaction steps can be selected with respect to the alpha-hydroxy acid group or to the methylene acid group to produce either of the desired (R) or (S) enantiomer 2-acyl chromane compounds.
  • the natural malic acid such as from fruit juices is used as the reactant since it tends to be less expensive.
  • n is 0 to 6;
  • X is O or S; R is independently selected from the group consisting of alkyl, alkoxy, alkenyl, hydroxy, thio, amino, substituted amino, nitro, halo, and CF 3 ; m is 0 to 4; (although R 0 . 4 may be used as shorthand for R m where m is 0-4)
  • R 4 is a member selected from the group consisting of hydroxy, alkoxy, thioalkyl, - SH, alkenyloxy, halogen, amino and substituted amino, and each of Q and Q ⁇ are independently selected from the -C(-R 2 , -R 3 )-, wherein each of R 2 and R 3 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, amino, hydroxy, thio, nitro, halo, and CF 3l or R 2 and/or R 3 together with the carbon to which they are attached form a carbonyl group. Examples of procedures to make such compounds are in Schemes I through XIX and the Examples which follow.
  • Schemes involve chiral synthetic techniques and some form racemates which may be resolved, if desired.
  • a phenol or thiophenol derivative is reacted with a chiral or achiral compound R 4 -Q-Q.
  • - CH(halogen)-(CH 2 ) n -C( O)-R 4 (wherein R 4 is a member selected from the group consisting of H, -OH, -SH, halo, amino, substituted amino, thioalkyl, alkoxy, or a similar ring condensation leaving group), in the presence of a Walden catalyst, preferably, NaOH, KOH, sodium carbonate, potassium carbonate, and the like, to provide an ether or thio ether, which is then cyclized to form the bicyclic compound.
  • a Walden catalyst preferably, NaOH, KOH, sodium carbonate, potassium carbonate, and the like
  • the phenol or thiophenol is a phenoxide or thiophenoxide derivative and is reacted with a chiral halogen compound ((S) or (R) enantiomer with respect to the carbon attached to the halogen atom) to produce a substantially (S) or (R) ether.
  • a chiral halogen compound ((S) or (R) enantiomer with respect to the carbon attached to the halogen atom)
  • a process for making such a compound comprising reacting a derivative of phenol, thiophenol, sodium phenoxide, sodium thiophenoxide, and the like, with an the alcohol of the derivative of a chiral hydroxy diacid (or with a derivative of the hydroxy group such as the halide which has displaced the hydroxy groupby virtue of a Walden catalyst without producing a racemate) in the presence of a Walden Inversion Catalyst (preferably NaOH, KOH, sodium carbonate, potassium carbonate, and the like) or after the alpha-hydroxy diacid has been treated with the Walden Inversion Catalyst to form a halide (see catalyst examples below) as follows: metallic base catalyst, e.g., NaOH
  • X is O or S
  • R x is H, or a metallic ion such as K, Na, and the like wherein R is substituent on the phenyl or benzene ring (replacing a hydrogen atom on the ring) such as an amino group (or a protected amino group such as a benzamido or acetamido group) or a group that can be converted to an amino group (e.g., hydrogen, halogen, nitro, and the like), and R 1 is hydrogen, the alkyl core of an alcohol group which can form an ester such as a methylene or ethylene group from methanol or ethanol, or (whether alone or together with its neighboring oxygen atom is a protecting group).
  • the catalyst for the reaction is a Walden Inversion Catalyst, preferably selected from the group consisting of PCI 5 , PBr 3 , Pl 3 , PF 3 , SOCI 2 , KOH or Ag 2 O, or the like, or a combination thereof.
  • the Walden catalysts are PBr 3 and KOH, wherein the alcohol has been treated with PBr 3 under conditions to change the (R or S) enantiomer alcohol into its opposing (S or R) alpha bromide diacid or diester, and is then reacted with the phenol in the presence of the Walden Inversion Catalyst KOH to form a phenoxy derivative.
  • Some of the Walden catalysts may preserve the (R ) or (S) geometry of the alcohol starting material with respect to the carbon to which the alcohol group is attached, while some members of the catalyst group (such as the phosphorus halides) may cause inversion of the geometry (e.g., (S) may be converted to (R), or the inverse).
  • some members of the catalyst group such as the phosphorus halides
  • inversion of the geometry e.g., (S) may be converted to (R), or the inverse.
  • the desired geometry for the ring 2 position of the bicyclic ring can still be obtained.
  • the methylene acid group is esterified and the alpha hydroxy acid group is a -COOH group or can be converted into such a compound. If the more reactive alpha-hydroxy acid group needs protecting while the methylene acid group is further reacted, it may be converted to a carboxamide group, for example, by selectively reacting it with SOCI 2 , followed by reaction with NH 3 under conditions such that the methylene acid (or esterified methylene acid) does not react. Since the alpha-hydroxy acid group is about 100 times more reactive than the methylene acid group, such a reaction is readily accomplished.
  • the carboxamide is formed as follows:
  • acyl halide (acid chloride) is first formed and readily converted to the carboxamide.
  • the methylene acid group can then be optionally acidified, if desired, to remove the ester group.
  • the methylene acid group can be cyclized with the phenyl ring without disturbing the chiral carbon adjacent to the oxygen atom.
  • a Friedel Crafts reaction can be used to form a 4-oxo-2-carboxamide chromane derivative.
  • a preferred Friedel Crafts reaction may be illustrated as follows:
  • each of the (R or S) 2-carboxamide enantiomers is possible, depending upon whether the (R or S) enantiomer of malic acid is used as the starting material. Moreover, by choosing the desired Walden Inversion catalyst, a particular (R ) or (S) enantiomer of the alcohol starting material can be converted to the desired enantiomer prior to reacting it with the phenol.
  • the 2-carboxamide enantiomer obtained may be reacted further in several ways.
  • Such preferred ways including convertintg the 2-carboxamide group to a carboxylic acid group by reacting the compound with sulfuric acid and water, or an ester can be formed by then adding an alcohol such as methanol or ethanol.
  • the carboxamide, acid, or ester chromanone can be reduced to a chromane by hydrogenation, such as by using H 2 /Pd/C and other known hydrogenation agents. Standard reaction conditions can be utilized for such steps.
  • a preferred embodiment involving formation of the acid, then formation of the ethyl ester, followed by reducing the chromanone to a chromane derivative is illustrated as follows:
  • the 2-position carboxamide side chain can be extended to form a longer chain, such as an acetic acid (or acetic acid ester) side chain or a derivative thereof without disturbing the chiral carbon at the two position.
  • a preferred process for making the acetic acid chain is as follows.
  • the carboxamide group is first converted to the acid group and then to the carboxylic acid ester as shown above.
  • the ester group is reduced to the alcohol by using standard reduction or hydrogenation conditions and/or catalysts, for example diisoamylborane, lithium tri-butoxyaluminohydride, lithium triethylborohydride, lithium trimethoxyaluminium hydride, sodium borohydride, and the like.
  • lithium tri-butoxyaluminohydride LiAIH 4 , or diisoamylborane (DIABO) may be used as part of such a process step to reduce the two position ester group to a methanol group.
  • an cyanide compound such as CuCN or KCN to extend the carbon chain, followed by an acid such as HCI in water or alcohol to convert the cyano group to an acid group.
  • the acid group may be reacted with an alcohol under acidic conditions to form an ester.
  • the compound formed above may also be reduced in the same manner to form the chromane enantiomer.
  • the chromanone compound may be reacted with HNO 3 such that the -NO 2 group is directed in high yield to the 6-position.
  • the - NO 2 group if present, is preferably converted to an amino group while the 4-oxo group is removed. This reaction may be shown as follows:
  • chromane is a (2S) or (2R) enantiomer depending upon whether the (R) or (S) enantiomer of the alpha hydroxy alcohol starting material is used.
  • the opposite enantiomer is obtained from the same alpha-hydroxy diacid than is obtained by ring closure which uses the methylene acid group.
  • both acid groups are esterified.
  • the more reactive alpha-hydroxy acid ester group is selectively reduced to the aldehyde or alcohol, preferably to the aldehyde.
  • the methylene acid ester group is then converted to the acid chloride and subsequently to its carboxamide, using the acid chloride and carboxamide formation steps that were described and shown above for the alpha-hydroxy acid group.
  • the above step which is enclosed in square brackets is an optional step which is not required if the first selective reduction formed the alcohol instead of the aldehyde.
  • the alcohol can be further reacted to extend its chain by an additional carbon and converted to an acid group.
  • Such reactions are essentially the same as the above CuCN or KCN step followed by acidification used and shown above for the carboxylic acid side chain extension that was done after ring closure.
  • the alcohol group is extended prior to ring closure, which makes it possible to use a Friedel Crafts ring closure reaction to form a 6-membered ring.
  • the phenyl ring substituents, R may be adjusted or changed and the enantiomeric chromanone compound can be converted to its corresponding chromane compound.
  • the reaction steps may be illustrated as follows:
  • the acid side chain converted to the free acid may be re-esterified with an alcohol and a mineral acid such as EtOH and HCI to yield the desired ester.
  • a mineral acid such as EtOH and HCI
  • the bicyclic ring structure may be optionally formed without adding the nitro group to the starting material.
  • nitration procedures may be utilized such as bromination followed by substitution of the nitro group for the bromine group, for example.
  • the above nitration procedure is straight-forward and is preferred.
  • the chromane nucleus core can be produced from the above ester by reducing the 4-position oxo group, which reduction may also hydrogenate an -NO 2 group on the phenyl portion of the chromanone to its -NH 2 form, unless it is protected with a suitable protecting group, such as benzoylamino group, or the like or unless a selective reagent or conditions are used to promote reduction of one group over the other.
  • a suitable protecting group such as benzoylamino group, or the like or unless a selective reagent or conditions are used to promote reduction of one group over the other.
  • Standard reduction or hydrogenation conditions and catalysts may be utilized, for example diisoamylborane, lithium tri- butoxyaluminohydride, lithium triethylborohydride, lithium trimethoxyaluminium hydride, sodium borohydride, H 2 /Pd/C, and the like, may be utilized to hydrogenate the double bond and/or replace the keto group with a hydrogen atom.
  • lithium tri-butoxyaluminohydride, LiAIH 4 , or diisoamylborane (DIABO) may be used.
  • reaction steps show the conversion of 2-carboxylic acid compound to an acyl halide (chloride in this case) and replacement of the halogen atom with a cyano group, which can then be converted in a later step to an carboxylic acid group to result in an acetic acid side chain:
  • R group is an NO 2 group which can be later converted to an amino group, such group preferably being in the 6 position on the bicyclic ring structure.
  • the 2- acyl-cyanate group can be hydrolyzed to an alpha keto carboxylic acid group by exposure to a strong mineral acid (such as HCI) at ambient temperature as follows:
  • the alpha keto acetic acid group which is now ready for a hydrogenation step.
  • Other known methods of extending the chain from a carboxylic acid to an acetic acid may also be used, including those shown herein.
  • the two keto groups one ring, one pendant
  • the nitro group and the unsaturated bond on the pyran ring if present, are all removed by hydrogenation in a single step which may be monitored by HPLC until the reaction is complete.
  • the hydrogenation is conducted in two steps.
  • the first step is hydrogenation under mild conditions in the presence of an alcoholic solution (such as methanol, ethanol or the like), or in ethyl acetate solution or the like, at about 30 psi of hydrogen for about an hour or two followed by purging the bomb with nitrogen then hydrogen.
  • glacial acetic acid is added to the alcoholic solution of the bomb, the hydrogen pressure is increased to 45-65 psi and the temperature raised to between 50°C to 95°C maintained until the hydrogenation is complete by monitoring of HPLC. While hydrogenation may be visualized as either a one-step or two-step process, it is still a one-pot non-separation step.
  • the overall reaction for a preferred single or multi-step hydrogenation process may be exemplified as follows:
  • This process will provide a good yield of the racemate or a single enantiomer based upon the starting compound and the synthetic route chosen.
  • the amino group such as is formed above can be converted to a salt by using a strong mineral acid such as H 2 SO 4 in an alcohol such as ethanol, followed by HCI in an alcohol such as ethanol to produce the desired ester group and the mineral acid salt of the amine, for example, as follows:
  • esters such as the methyl or propyl ester may likewise be envisioned.
  • esters may be formed directly such as by selecting the appropriate alcohol, or they may be obtained by transesterification.
  • Salts other than hydrocloride including, but not limited to, tartrate, glutamate, lactate, hydrobromide, and other such parmaceutically acceptable salts.
  • Hydrogenation may also reduce the 2-position side chain to hydroxy methyl.
  • the side chain may be extended into an acetic acid group, or into an acetic acid ester group, as follows: wherein R1 is preferably an ethyl ester group.
  • Such reaction may proceed on a racemate or on an enriched or substantially purified single enantiomer, whether such material is obtained from a resolution process or formed directly using chiral synthetic techniques.
  • a tosyl group may be added to the amino group during the same step in which the cyano group replaces the alcohol group.
  • an excess of concentrated HCI can be used to ensure that the tosyl group is removed from the amino group to yield a -NH 2 group.
  • a solution of a more nucleophilic acid such as HBr may be used to remove the tosyl group from the amino group.
  • care should be taken to avoid replacement of the -OH of the carboxylic acid group with a bromine atom to yield an acylbromide.
  • the ester group can be modified with a group which can be utilized to resolve the R or S enantiomers, such as a conventional camphor sulphonic acid derivative, a dibenzoyl tartaric acid derivative, and the like, or by hydrolyzing the ester to an acid with a selective lipase to produce a desired enantiomer, for example, as follows:
  • the efficiency of the enzymatic resolution may be increased by having a 6-nitro group prior to enzymatic resolution and then converting the 6-nitro group to an amino acid group after the enzymatic resolution.
  • the efficiency of the enantiomer resolution step is increased by recycling the R-enantiomer by racemization via subjecting it to at least one ring-opening and closure as a racemization step followed by further resolution of the thus generated racemate to increase the amount of S-enantiomer obtained.
  • the preferred solvent for recrystallization is methanol or isopropyl alcohol.
  • HCI and ethanol may be added to the compound to form the 2-carboxylic acid ethyl ester and an excess of HCI is then utilized to produce the hydrochloride salt of the amino group.
  • a preferred process of resolution using liase is discussed in greater detail later herein.
  • the maleic acid is present in about a 2:1 mole ratio with respect to the phenol.
  • the cyclization is performed at about 75-95°C for about 15-30 h, preferably, at 92°C for about 20 h.
  • the reaction mixture is then cooled; the solid is isolated; the solid is washed with water, a dilute base, and then again with water to provide compound 2 as the product as a yellow solid at about 40-50% yield.
  • the carboxylic acid of compound 2 is converted to an intermediate for converting the carboxylic acid more easily into other derivatives.
  • compound 2 is converted to an acyl chloride 3 by reaction with thionyl chloride, as follows:
  • compound 3 is converted into compound 4 with nucleophilic attack of cyanide ion on the chloride of the acyl chloride 3.
  • the resulting compound 4 is hydrolyzed in acidic conditions to yield ⁇ -keto carboxylic acid 5, as shown below.
  • compound 5 undergoes hydrogenation to convert the nitro group into an amino group.
  • conditions to reduce the nitro group include catalytic hydrogenation and use of chemical reducing agents in acidic solutions.
  • a preferred condition for this conversion is the use of hydrogen in the presence of catalytic palladium/carbon and glacial acetic acid.
  • compound 6 is esterified in acidic ethanol to yield compound 7, as shown below.
  • the ethyl group was used to form the ester of the acetic acid side chain in the last step, the ethyl group can be replaced by hydrogen or another group capable of forming an ester selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl, cinnamyl or other ester groups.
  • the amino group can be protonated to isolate the product as an amine acid halide salt or the like.
  • reaction preferably proceeds by reducing conditions which affect the keto, ester or acid, and nitro groups of compound 8 to yield compound 10, as shown below:
  • the nitro group of compound 8 is reduced to an amino group.
  • Reduction may be accomplished by catalytic hydrogenation or by the use of chemical reducing agents in acidic solution.
  • An example of a reducing agent for this conversion is hydrogen in the presence of catalytic palladium/carbon.
  • reducing the 4-keto group of the chromanone ring system produces a chromane ring system.
  • reducing agents for converting a ketone group to a methylene group are lithium aluminum hydride, lithium tri-butoxyaluminohydride, sodium borohydride, H 2 /Pd/C, and the like.
  • these conditions may also be used to reduce the ester group to a hydroxymethyl group.
  • lithium aluminum hydride, lithium tri-butoxyaluminohydride, or sodium borohydride would reduce both the ketone and the carboxylate ester at the 2-position to a hydroxymethyl group to yield compound 10.
  • Compound 10 is further modified by converting the 2-hydroxy methyl into a chromanylacetic ester 7 thereof, as follows:
  • a tosyl group is added to the amine and a cyanide group replaces the hydroxyl group in one pot to yield compound 11.
  • the tosyl group may be removed concomitant with the hydrolysis of the nitrile to a carboxylate with excess concentrated hydrochloric acid.
  • the hydrochloric acid may be removed from the reaction mixture and recrystallization of the product from isopropyl alcohol.
  • a more nucleophilic acid such as HBr may be used to remove the tosyl group.
  • care must be taken to avoid converting the carboxylic acid into an acyl bromide.
  • compound 11 is esterified in the presence of an alcohol and an acid to yield compound 7.
  • R 2 is an ethyl group that results from acidic ethanol.
  • the ethyl group was used to form the ester of the acetic acid side chain in the last step, the ethyl group can be replaced by hydrogen or another group capable of forming an ester selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl, cinnamyl or other ester groups.
  • the amino group can be protonated to isolate the product as an amine acid halide salt or the like.
  • an embodiment provides a cyclization reaction wherein maleic acid and a phenol react under acidic conditions producing a 4-chromanone, as shown above in Scheme XVII.
  • a preferred phenol is 4- nitrophenol to provide compound 3 as the product.
  • To the yellow solid is added a mixture of H 2 SO 4 /EtOH, preferably at room temperature, to form an ester 8.
  • An organic solution containing the ester 8 is washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum to yield the purified product. Typically, the overall yield of this process is about 85-95%.
  • the diazoketone can be converted into a carboxylic acid group with an additional methylene group from the original substrate in good yield by water and a catalyst such as Ag 2 O, as follows:
  • the process then proceeds by compound 13 undergoing hydrogenation to convert the nitro group into an amino group.
  • conditions to reduce the nitro group include catalytic hydrogenation and use of chemical reducing agents in acidic solutions.
  • a preferred condition for this conversion is the use of hydrogen in the presence of catalytic palladium/carbon and glacial acetic acid.
  • compound 6 is esterified in acidic ethanol to yield compound 7, as shown below.
  • R 2 is an ethyl group that results from acidic ethanol.
  • the ethyl group was used to form the ester of the acetic acid side chain in the last step, the ethyl group can be replaced by hydrogen or another group capable of forming an ester selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl, cinnamyl or other ester groups.
  • the amino group can be protonated to isolate the product as an amine acid halide salt or the like.
  • X is O or S, and R 1 and R are independently selected from the groups as defined previously.
  • X is O and R is
  • R 1 Me, Et or Pr
  • Schemes I and III each show a slightly different procedure to obtain the 4- oxochroman-2-l carboxylate ester depending upon whether 1.25 or 2.5 equivalents of thionyl chloride are added. These procedures may be substituted for each other such that the process having fewer steps is used along with the other steps in Scheme I and vice- versa.
  • X is halide.
  • the lipase resolution steps of Schemes VII and VIII may be omitted by using an (R) or (S) chiral halide to couple with the phenol in the manner of Schemes I, II, III, V, or VI.
  • the nitroso compound of Scheme VII can be directly hydrogenated to the amine without formation of the nitro intermediate.
  • Schemes XI through XV all of which form ethyl 2-(4-oxo-6-nitrochroman-2- yl)acetate are preferably followed by Scheme XVI, or a variant thereof, in whjch the racemates are resolved, the reduced and/or a salt is formed.
  • the order of the steps of Scheme XV are changed such that resolution follows reduction, or that there is a first reduction of either the 4-oxo group or the 6-nitro group, followed by reduction of the other group and resolution of the racemate, which may proceed in either order.
  • salt formation may be omitted.
  • the salt form is preferred in one embodiment of coupling reaction.
  • the reactions may proceed with suitable reagents other than those shown in the Scheme, as are known in the art.
  • the order of some of the reactions in the schemes may be changed, and additional steps of protecting, deprotecting, nitrating, hydrolyzing, esterifying, and the like may be added to the schemes at various points.
  • additional steps of protecting, deprotecting, nitrating, hydrolyzing, esterifying, and the like may be added to the schemes at various points.
  • Such minor alterations are within the scope of the disclosure herein.
  • the esters shown are primarily ethyl esters, other esters may be made, either by use of different solvents and/or reagents in the initial formation reactions or by transesterification.
  • the starting materials used in the disclosed processes are commercially available from chemical vendors such as Aldrich, Lancaster, TCI, Bachem Biosciences, and the like, or may be readily synthesized by known procedures including those present in the chemical literature, or may be made by using procedures such as indicated above.
  • Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where it is otherwise indicated, or where use of non-STP conditions for a procedure is known in the art.
  • Some procedures, reactions, and/or workups which are well known in the art or which are readily available in standard reference texts in the art, including Beilstein and Fieser and Fieser, may not be presented herein owing to their stature of being within the knowledge of one of ordinary skill.
  • the above procedures of the processes may be carried out on a commercial scale by utilizing reactors and standard scale-up equipment available in the art for producing large amounts of compounds in the commercial environment. Such equipment and scale-up procedures are known to the ordinary practitioner in the field of commercial chemical production.
  • amino or acid functional groups may be protected by blocking groups to prevent undesired reactions with the amino group during certain procedures. Procedures for such protection and removal of protecting groups are routine and well known to the ordinary practitioner in this field.
  • racemic chroman-2-yl carboxylic acids and esters or their derivatives and/or intermediates these racemates are preferably resolved to produce a mixture enriched in one of the R or S enantiomers or resolved into a substantially pure composition of one of the enantiomers.
  • processes for resolving the racemic mixtures are provided herein and others are known to those skilled in the art. Additionally, processes for the formation of acid addition salts such as the hydrochloride salt of the 6-position amino acid group on the chromane nucleus are known in the art. Other such salts are also envisioned.
  • the methods disclosed herein relate to processes for producing amidino-substituted benzoyl compounds, wherein the phenyl ring may be substituted with lower alkyl, lower alkoxy, Cl, F, Br, I, and the like, which are intermediates for coupling with bicyclic compounds to produce 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.
  • Some of such methods disclosed herein include processes for producing racemic amino substituted bicyclic compounds such as racemic, 6-amino-chroman-2-yl acetic acid esters, and resolving such bicyclic compounds into either the R or S enantiomer.
  • racemic nitro substituted compounds having the bicyclic structures described below are enzymatically resolved into an enantiomerically rich composition (2R>2S) or (2S>2R).
  • Such resolution is preferably performed using a chirally selective Pseudomonas lipase such PS 30, or a stablized lipase (glutarate stablized, for example) such as the Altus, Inc.
  • ChiroCLEC-PC lipase, or the like may be utilized to resolve the nitro-substituted chromane, hydroxy chromane, or oxo-chromane compounds and the like.
  • One preferred resolution process (shown for a chromone) is as follows:
  • R is a nitro or other electron withdrawing group on the phenyl or benzene ring such as an oxime or halogen group and R1 is hydrogen or the alkyl core of an alcohol group which can form an ester, such as a methylene or ethylene group from methanol or ethanol and n is 0 to 6.
  • R1 is hydrogen or the alkyl core of an alcohol group which can form an ester, such as a methylene or ethylene group from methanol or ethanol and n is 0 to 6.
  • the 2-carboxylic acid group is esterified with a methyl or ethyl group and the R group on the phenyl portion is a member selected from NO 2 , halogen, an oxime derivative or the like. More preferably, R group is an 6-nitro group.
  • PS 30 from Pseudomonas is used to selectively hydrolyze a 2-acyl ester group, or to catalyze selectively esterifying the free acid.
  • PS-30 the S-enantiomer is selectively hydrolyzed and in an aqueous basic/organic solvent can be extracted in the aqueous layer as a basic salt. The aqueous solution can then be neutralized to obtain the free acid.
  • the organic portion of the aqueous/organic solvent extraction is enriched in the R-enantiomer which can then be recovered by heating in a base to form a basic salt that precipitates from the organic solvent.
  • the yield is about 40-50% of 95% or greater purity of the desired crude enantiomer.
  • Essentially 100% pure single enantiomer can be obtained from the 95% or greater crude enantiomer by refluxing the crude enantiomer in methanol.
  • the amount of methanol solvent utilized in the desired purification reflux step can be varied to produce optimum yields of the desired pure enantiomer.
  • the process may proceed with the amino group, the process preferably first proceeds by oxidation of the amino group to a more electron withdrawing nitro group. Alternatively, the reaction is begun with a nitro-substituted material.
  • the amino-compound is reacted with an oxygen source, including but not limited to, O 2 , ozone, or H 2 O 2 , optionally in the presence of a catalyst such as a metal oxide catalyst selected from the group consisting of tungstate, molybdate and vanadate to result in oxidation of the amino group.
  • an effective amount of hydrogen peroxide of from about 1-10, more preferably 1-5 moles of hydrogen peroxide per mole of amino groups is used in an aqueous or partially aqueous solution of a lower alcohol solvent to convert the ring amino group of the Formula I compound to a nitro group on the Formula II compound as follows:
  • Formula I Formula II wherein in each of Formula I and Formula II n is 0 to 6; R is a member selected from the group consisting of alkoxy, alkenyloxy, halogen, amino, substituted amino and the like, and each of Q and Q., are independently selected from the -C(-R 2 , -R 3 )-, wherein each of R 2 and R 3 is independently selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, hydroxy, thio, nitro, halo, and CF 3 , or R 1 and R 2 collectively with the carbon to which they are attached form a carbonyl group.
  • the oxidation of the amino to a nitro group is carried out at a temperature from about 20°C to about 100°C, preferably from about 40°C to about 85°C, more preferably from about 55°C to about 75°C, and most preferably at about 60°C.
  • the oxygenation catalyst for the amino to nitro conversion is a metal oxide catalyst selected from the group consisting of tungstate, molybdate and vanadate.
  • tungstate or water soluble quaternary ammonium tungstates include tungstic acid (H 2 WO 4 ), tungsten trioxide (WO 3 ), tungstenic acid (H 2 WO 4 ), sodium tungstate (Na 2 WO 4 ), potassium tungstate (K 2 WO 4 ), and mixtures thereof.
  • the corresponding molydbates, MoO 3 , H 2 MoO 4 , K 2 MoO 4 , Na 2 MoO 4 , and mixtures thereof, and the corresponding vanadates Va 2 O 5 , HVO 3 , KVO 3 , NaVO 3 , and mixtures thereof may be utilized.
  • the catalyst is typically present at a level of from 0.001 % to 2%, preferably 0.01% to 1% and more preferably from 0.05% to 0.5%, by weight of the aqueous or partially aqueous solution.
  • a chelating agent or heavy metal ion sequestrant such as organic phosphonates, EDTA (ethylene diamine tetra-acetic acid) and the like, may be utilized during the oxidation reaction, preferably diethylenetriamine penta(methylene phosphonate)
  • the mixture is resolved by using an enantiomerically selective ester hydrolyzing agent such as a lipase, preferably a Pseudomonas lipase, most preferably PS 30 or a glutarate stablized version (for example ChiroCLEC-PC lipase for Altus, Inc.).
  • an enantiomerically selective ester hydrolyzing agent such as a lipase, preferably a Pseudomonas lipase, most preferably PS 30 or a glutarate stablized version (for example ChiroCLEC-PC lipase for Altus, Inc.).
  • the selective hydrolysis by the lipase is conducted in an aqueous basic solution (preferably a buffer solution) with lipase PS 30.
  • the insoluble ester racemate is agitated with stirring and the hydrolyzed acid forms a salt that is soluble in the aqueous solution.
  • the solution can be filtered and the hydrolyzed acid (2S) can be recovered from the aqueous solution by neutralizing the solution to reform the water-insoluble free acid from the salt and thus recover the insoluble free acid as a precipitate. Rinsing this precipitate with water will yield the (2S) enantiomer free acid.
  • the lipase biomass and the enriched (2R) enantiomer are preferably recovered by rinsing the biomass with an appropriate solvent such as ethyl acetate, filtering the ethyl acetate solvent and evaporating the solvent to recover the enriched (2R) enantiomer.
  • the less desired enantiomer can be recycled by using a racemization step followed by exposure of the resulting racemate to the lipase to obtain more of the desired (2S) or (2R) enantomer and increase the overall yield of the process.
  • the formation of a racemate from a single enantiomer is preferably accomplished by exposing the enantiomer to a basic alcoholic solution such as a sodium or potassium ethanolate solution in the corresponding alcohol or an inert solvent. Other procedures which open the ring at the ring oxygen of the chromane and then reclose it may also be utilized to produce a racemate from a single enantiomer. By repeating the resolution and racemate forming steps a higher overall yield may be obtained.
  • the racemate forming step may be illustrated in a preferred compound as follows:
  • R or S (Racemate) wherein, as illustrated, a catalytic amount of sodium ethoxide, potassium ethoxide or similar catalytic base in R 1 OH (preferably EtOH) is utilized until racemization is completed, usually for 4-8 hours at about 45°C (longer at room temperature).
  • an acid such as 1 N HCI (preferably acetic acid) to quench the base and form a soluble salt with the base
  • the reaction mixture containing the racemic acid mixture is mixed with a greater volume of water than the volume of the alcohol solvent to render the ethyl ester of the racemic (2R/2S) 6-nitro-chroman-2-yl acetic acid insoluble.
  • the racemic mixture is collected as a precipitate by filtration and is rinsed with water.
  • the crude product can be thoroughly rinsed with water and recystallized in an appropriate solvent to ensure that the sodium or potassium ions are removed from the racemate.
  • the resulting ester racemate can then be recycled by exposure to the lipase to obtain a higher yield of the desired single enantiomer with respect to the initial amount of racemate starting material.
  • the separated (2S>2R) or (2R>2S) enantiomer from the optional chiral resolution step may undergo further reactions as set forth herein, below or above.
  • Such reactions include, but are not limited to chain lengthening, nitration, salt formation, esterification, hydrolysis, and reduction of oxo, nitro and other groups.
  • a compound having the 6-nitro group is hydrogenated to yield back the amino of Formula I as an enriched enantiomer which can be utilized as in intermediate for coupling to a benzoyl compound as described in U.S. patent 5,731 ,324 to provide a specific enantiomerically enriched platelet aggregation inhibitor compound.
  • the hydrogenation process is demonstrated below as follows with the (2S>2R) 6-nitro-chroman-2-yl acetic acid compound, but any bicyclic nitro containing compound of Formula II may be thus hydrogenated back to the Formula I structure after the resolution as follows:
  • the compound can be re-esterified and an amine salt (preferably a hydrohalide) may be formed to precipitate the ester out of what is preferably an organic solvent solution.
  • an alcoholic sulfuric acid solution followed by an alcoholic HCI solution can be utilized for the esterification and forming hydrohalide salt of the amino group, but other esters including the methyl or propyl esters may likewise be used. Salts other than HCI may also be used.
  • the purity of the enantiomer may be optionally improved by recrystallation, HPLC or the like.
  • the preferred solvent for recrystallization is methanol or isopropyl alcohol or a mixture thereof.
  • the acidic alcoholic solutions may be added to the free acid R or S enantiomer compound to form a 2-carboxylic acid ethyl ester (or another ester) and an excess of HCI is then utilized to produce the hydrochloride salt of the amino group, as follows
  • the ethyl group can be replaced by H or another esterfing group selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl, cinnamyl or other ester groups.
  • the compounds produced according to preferred embodiments find utility as intermediates for producing therapeutic agents or as therapeutic agents for disease states in mammals, including those which have disorders that are due to platelet dependent narrowing of the blood vessels, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.
  • Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex llb/IIIa. When a platelet is activated by an agonist such as thrombin, the GPIIb/llla binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation. Thus, intermediate compounds for producing compounds that effective in the inhibition of platelet aggregation and reduction of the incidence of clot formation are useful intermediate compounds.
  • the compounds produced according to preferred embodiments may also be used as intermediates to form compounds that may be administered in combination or concert with other therapeutic or diagnostic agents.
  • using the compounds disclosed herein and/or the compounds formed from coupling such compounds with substituted benzoyl halides and/or other compounds may be co-administered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • the compounds produced from the intermediates may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. Such compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects.
  • Such compounds can be utilized in vivo, ordinarily in mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the above compounds produced according to preferred methods may be isolated and further reacted to substitute a desired group for one or more of the hydrogen atoms on the amino group by a coupling reaction.
  • a coupling reaction of the amino group with an acyl halide compound.
  • compounds such as 5- amidino-thiophen-2-yl carboxylic acid derivatives (or an acyl halide such as the acyl chloride) and 4-amidinobenzoyl chloride may be coupled to ethyl 2-[(2S) 6-aminochroman- 2-yl] acetate (or its hydrochloride salt) to form ethyl 2-[(2S) 6-(5-amidino-2- thiophenoyl)amino-chroman-2-yl]acetate and ethyl 2- ⁇ (2S)-6-[(4-amidinophenyl) carbonylamino]chroman-2-yl ⁇ acetate, or other similar compounds or their derivatives which are known platelet aggregation inhibitors.
  • the compound formed from the coupling reaction may be used as either the salt or the free base, and may be readily interconverted between the two forms by using procedures which include those known in the art as well as reacting the compound with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying.
  • the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt, or one salt form of the product may be converted to another using the same general process.
  • the free base or salts may be purified by various techniques such as recrystallization in a lower alkanol such as methanol, ethanol, propanol, isopropanol and the like, for example, or a mixture thereof.
  • the compound is recovered as the hydrochloride salt and the recrystallization solvent is a 90/10-10/90 mixture of ethanol and isopropanol.
  • Non-toxic and physiologically compatible salts are preferred, although other types of salts may also be used, such as in the processes of isolation and purification.
  • Diagnostic and therapeutic applications of the compounds formed by procedures disclosed herein, including the aforementioned coupling reactions will typically utilize formulations wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug, is combined with one or more adjuvants, excipients, solvents, or carriers.
  • the formulations may exist in forms including, but not limited to tablets, capsules or elixirs for oral administration; suppositories; sterile solutions or suspensions for injectable or parenteral administration; or incorporated into shaped articles.
  • Subjects in need of treatment (typically mammalian) using the compounds disclosed herein and/or the compounds formed from coupling such compounds with substituted benzoyl halides and/or other compounds can be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
  • Formulations are prepared for storage or administration by mixing the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985).
  • Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counter ions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
  • buffers such as phosphate, citrate, acetate and other organic acid salts
  • antioxidants such as
  • Dosage formulations to be used for parenteral administration are preferably sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods known to those skilled in the art. Formulations are preferably stored in lyophilized form or as an aqueous solution. The pH of such preparations are preferably between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts.
  • While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the compounds are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
  • the compounds may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled.
  • the compounds may also be coupled with suitable polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the platelet aggregation inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
  • Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound and formulation, individual determinations may be made to determine the optimal dosage required.
  • the range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • a typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg.
  • the compounds or formulations may be administered several times daily, in a once daily dose, or in other dosage regimens.
  • a compound or mixture of compounds as the free acid or base form or as a pharmaceutically acceptable salt or prodrug derivative (including esters), is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice.
  • a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
  • Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent.
  • a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil.
  • Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice.
  • dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the compounds and formulations may be used alone or in combination, or in combination with other therapeutic or diagnostic agents.
  • the compounds and/or formulations may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • anticoagulant agents such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • the compounds and formulations can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the compounds, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring- post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-organ failure
  • renal dialysis e.g., cardiopulmonary bypass or other oxygenation procedure, plasmapheresis
  • instrumentation e.g. cardiac or other intravascular cathete zation, intra-aortic balloon pump, coronary stent or cardiac valve
  • thrombotic complications associated with instrumentation e.g. cardiac or other intravascular cathete zation, intra-aortic balloon pump, coronary stent or cardiac valve
  • those involved with the fitting of prosthetic devices e.g. cardiac or other intravascular cathete zation, intra-aortic balloon pump, coronary stent or cardiac valve
  • Example 2 Production of 2-(2-nitrophenoxy)-butan-1 ,4-acyl chloride
  • a mechanical stirrer, nitrogen inlet, reflux condenser, heating mantle, vacuum system, and scrubber system for efficient removal of HCI and SO 2 gas which was liberated during the reaction was charged under nitrogen 0.5 moles of thionyl chloride, and 0.2 moles of the diethyl (2-(4-nitrophenoxy)butane-1 ,4- dioate obtained from Example 1 , above.
  • the stirred mixtures was placed under a N 2 flow, which was vented to the scrubber system.
  • the stirred mixture was heated to reflux for 12 hours during which the acylation reaction becomes complete.
  • the resulting solution was placed under vacuum and excess thionyl chloride was removed by evaporation under vacuum.
  • Example 2 The mixture obtained from Example 2 and 300 mL of anhydrous tetrahydrofuran were charged under nitrogen into a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, 500 mL addition funnel, cooling system, and thermowell. The reaction mixture was stirred and cooled to about -60°C, 1.5 moles of AICI 3 were added through the addition funnel and the funnel was rinsed with 25 mL of anhydrous tetrahydrofuran. The solution was stirred for about an hour at -75 °C. The mixture was gradually warmed to room temperature while maintaining stirring, and the reaction was quenched with 80 mL of HCI.
  • An alternate method for making the above captioned compound with respect Example 1 was as follows: A mixture containing 80 g of 4-nitrophenol, 45 g of potassium hydroxide, 200 g of the diethyl ester of 3-bromomalic acid, 750 mL of ethanol and 7.5 mL of Aliquot 336®, a quaternary ammonium compound marked by Aldrich Fine Chemicals, was refluxed for 8 hours. The solvent was concentrated and the residue was taken up with 1.5 L of H 2 O. Extraction was carried out with ethyl ether and the organic phase was washed with a 1 N solution of sodium hydroxide and then with water. It was dried over sodium sulfate and concentrated.
  • the stirred mixture was placed under a N 2 flow, which was vented to the scrubber system.
  • the stirred mixture was heated to reflux for 12 hours during which the reaction became complete.
  • the resulting solution was placed under vacuum and excess thionyl chloride was removed by evaporation under vacuum.
  • the resulting product 1-(2-(4-nitrophenoxy)-4-ethyl butanoate) acyl chloride (below) was obtained in about 95% yield.
  • the stirred mixture was placed under a N 2 flow, which was vented to the scrubber system.
  • the stirred mixture was heated to reflux for 12 hours during which the reaction became complete.
  • the resulting solution was placed under vacuum and excess thionyl chloride was removed by evaporation under vacuum.
  • Example 6 Using the carboxamide product of Example 6, the procedures of Example 3, above, were followed except that the final step of adding EtOH and concentrated HCI was ' eliminated. Such procedures yield about 40 g of the 6-nitro-4-oxo-chroman-2-yl carboxamide product (about 75% yield).
  • the carboxamide product of Example 7 was added to concentrated H 2 SO 4 in 300 mL of EtOH under standard ester forming conditions to yield the ethyl ester.
  • the yield was about 40 g of the 6-nitro-4-oxo-chroman-2-yl carboxylic acid ethyl ester product (about 95% yield).
  • Example 11 The (S) diethyl malonate of Example 9 (1 mole) was added to 250 mL of anhydrous EtOH and 1 mole of concentrated HCI (essentially anhydrous) was added to the mixture with stirring. The temperature was raised to 60° C. with stirring and was maintained at this temperature for up to 3 hours with continuous stirring(until HPLC indicates that all of the alcohol had been converted to its halide derivative). The solution was cooled to 0° C. and filtered to remove inorganic salts. The EtOH solvent was then evaporated off under vacuum to yield about 208.5 g of crude (R) diethyl 2-chlorosuccinate (1 mole). The solid was rinsed with cold (0° C.) distilled water to remove inorganic materials . Optionally the diester was re-suspended in EtOH for combination with a metallic oxide to produce an ether derivative.
  • Example 11 The (S) diethyl malonate of Example 9 (1 mole) was added to 250 mL of anhydrous EtOH and 1 mole
  • the aqueous mixture was extracted with 4 x 150 mL of acetone and the organic layers were combined and extracted with 2 x 100 mL of a dilute aqueous NaOH solution to remove the excess phenol.
  • the pH of the organic layer was adjusted to 7.0 with acetic acid and the solvent was evaporated under vacuum to yield a reddish-orange oil which includes the (2S) diethyl succinate phenyl ether intermediate (below).
  • the (2S) diethyl succinate phenyl ether of Example 13 in 250 mL of EtOH was added in small portions to an aqueous NaOH solution at 135° C. while maintaining a pH of 9.0.
  • the mixture was stirred continuously and the temperature was raised to 145°C. while the pH was maintained at 9.0 by alternatively adding 1 N NaOH or concentrated acetic acid.
  • the mixture was stirred at this temperature and 25 mL of EtOH was added every 15 minutes until HPLC indicated that all of the ether had been cyclized to yield the chromanone.
  • the solution was cooled to 100° C. and acetic acid was added to consume the NaOH until a pH of 7.0 was obtained.
  • the aqueous mixture was extracted with 4 x 150 mL of ethyl acetate and the organic layers were combined.
  • the organic layer was extracted once with 100 mL of distilled water and the organic layer was concentrated to an orange/red solid or oil by evaporation under vacuum, which includes the crude (2S) ethyl chroman-4-one 2-carboxylate (or its corresponding (2S) 4-hydroxy derivative).
  • Examples 9-16 were repeated with the corresponding thiophenol starting materials and the corresponding thioether and bicyclic thio derivatives were obtained in substantially the same yields.
  • the NaOH was used to cause the o-cresol to be more soluble in water and to cause the resulting 2-hydroxy-5-nitroso-toluene to be soluble in the water so long as it remains as an aqueous alkaline solution.
  • the mixture was cooled to 2°C and maintained at that temperature for one hour with stirring.
  • a total of .765 moles of H 2 SO 4 as an aqueous solution (.765 moles dissolved in 240 mL of water) which had been chilled to 0°C was gradually added with stirring at such a rate as to maintain the temperature of the resulting mixture below 5°C.
  • the 5-nitroso compound was to be converted to a 5-nitro compound by oxidation without further ring substitution, a higher yield of the nitro compound can be obtained by changing the washing steps to merely rinsing the filter cake once with 25 mL of ice water.
  • the resulting crude nitroso compound can be used as the reactant for the oxidation step and the resulting nitro compound which was insoluble in water can be separated from any residual o-cresol by washing it with water after the oxidation step.
  • the crude filter cake obtained in Example 25, above was added to 250 mL of H 2 O, 50 mL of toluene and 150 g of ammonium molybdate in a 2 liter round bottom flask.
  • the mixture was heated to reflux (about 100°C.) and maintained at reflux while a 500 mL aliquot of 3% by weight aqueous solution of hydrogen peroxide was added. Alternatively, 50 mL of a 30% by weight solution may be added. After the hydrogen peroxide had been added, the mixture was maintained at reflux for 4 hours. The solution was removed from heat and filtered while hot and the supernatant was set aside. The filter cake was washed three times with 100 mL of hot water, dried and set aside.
  • Example 26 The crude filter cake obtained in Example 26, above is placed in a hydrogenator, and the 4-position nitroso group (or nitro group) was reduced to an amine group with H 2 /Pd/C in a hydrogenator with EtOH and toluene as the solvent.
  • the reaction was monitored by HPLC until essentially 100% conversion was obtained.
  • the resulting phenolic amine and solvent were removed from the hydrogenator, placed in a one liter 3 neck RB flask, and heated to about 60°C with stirring. To the stirring mixture was added a sufficient amount of aqueous 1 N NaOH or sodium carbonate to raise the pH above 8. HPLC monitoring was used to indicate conversion of substantially all of the phenol to the phenoxide and then the organic solvent was removed under reflux with vacuum. After removing the organic solvent, a sufficient amount of 1 N HCI was added to the reaction mixture adjust the pH of the basic solution to about 9 and provide an aqueous basic solution of 2-methyl-4-amino-phenoxide. (about 85-90% yield).
  • a room temperature solution of 40 g of ammonium acetate in 400 mL of ethanol is adjusted to a pH of about 6.0 by the addition of acetic acid.
  • To this solution is added 10 g of diethyl 3-keto-glutarate. The mixture is stirred at room temperature for 1 1/2 hours.
  • the reaction mixture is concentrated to less than 100 mL under reduced pressure at a temperature below 30°C, and the concentrated solution is adjusted to a pH of about 9.0 by the addition of aqueous saturated potassium carbonate and then extracted twice with 200 ML portions of CH 2 CI 2 .
  • the aqueous phase is adjusted to a pH of about 10 by adding an aqueous saturated potassium carbonate solution and is extracted twice with 200 mL of methylene chloride.
  • the organic extracts are combined, washed once with a saturated solution of sodium chloride in water and dried over anhydrous sodium sulfate to yield about 9 g of a crude oily diethyl 3-aminoglutarate product.
  • Example 29 To a reaction vessel cooled to about -0°C is added the organic layer of Example 29. To this mixture is slowly added 50 mmoles of sodium nitrophenoxide with stirring. After addition of the sodium nitrophenoxide the reaction mixture is allowed to slowly come to room temperature and 50 mmoles of pyridine is added with stirring. The reaction mixture is stirred at room temperature for 6 hours and the organic solvents are removed under reduced pressure. The off-white cake is diluted with 100 mL of ice water and stirred for 1-2 hours at ice bath temperature. The mixture is stored cold overnight and filtered cold to yield about 20 g of an off-white powder.
  • Examples 29 and 30 can be performed using 4- amino-3H-4,5-dihydropyran-2,6-dione as the material which is diazotized and reacted with nitrophenoxide.
  • the resulting product is heated in the presence of water to obtain diethyl 3-(4-nitrophenoxy)pentane-1 ,5-dioate, the product of Example 30.
  • the 20 g of product from Example 30 is added to a reaction vessel and 80 g of concentrated sulfuric acid (cooled to about 5-15°C) is slowly added to reaction vessel. While maintaining this temperature by cooling to 5 to 15°C in 5 portion is slowly added 20 g of phosphorous pentoxide.
  • the resulting solution (pale orange/brown) is stirred at about 10°C for about 30 minutes and then allowed to slowly want to room temperature (10 to 15 minutes).
  • the reaction mixture is quenched by slowly pouring the reaction mixture over 300g of ice and 125 mL of water and stirred for 1-2 hours at ice bath temperature. A yellow gum is formed which slowly turns to a yellow tan powder.
  • the yellow tan powder is dissolved 200 mL of ethyl acetate and 100 mL of water.
  • the organic layer is separated and the aqueous layer extracted with two 100 mL portions of ethyl acetate.
  • the organic layers are combined and the organic solvent removed under reduced pressure.
  • the off- white cake is washed with two 50 mL portions of cold water.
  • the cake is added to 150 mL of water and shaken for 1 hour, stored cold overnight and filtered cold to yield an off-white powder.
  • the off-white powder is dried under vacuum to yield about 17 g of 6- nitrochroman-4-one acetic acid ethyl ester.
  • the reaction was monitored periodically by GO When the chloronitrobenzene was completely consumed (3.5 hours) the deep black suspension was diluted with tert-butyl methyl ether (600 mL) and stirred with 10% aqueous ammonium chloride 9150 mL) with ice cooling. The black 2-phase suspension was treated with decolorizing carbon (2 g) and filtered through a pad of celite.
  • the reaction mixture was cooled to ambient temperature and then cooled with ice water whereby off-white powder deposited slowly during 2-3 hours.
  • the precipitate was filtered off, washed with 4-5 mL hexane/acetone (1 :1 ) and air dried. Further drying in the vacuum oven at 45-50°C for 16 hours gave 2g of off-white powder with LC purity of 96%.
  • the mother liquor was evaporated to a yellow pasty powder. Ice water was added (20 ML) and the precipitated powder was filtered, washed with water 92 L) and 2 ML of acetone/hexane 91 :1) and vacuum dried in the oven at 45-50°C for 16 hours to get another 1.5 g of off-white powder with LC purity of 95%. Total isolated yield (46%).
  • Examples 35-38 provide one preferred procedure for resolving racemic mixtures.
  • a racemic mixture of ethyl 2-(6- nitrochroman-2-yl) acetate is resolved.
  • Other similar compounds having different substitutions on the ring may also be resolved by a process similar to that exemplified below.
  • the organic layer was separated from the aqueous layer and the aqueous layer was extracted twice with 2 L of toluene. The organic layers and extracted organic portions were combined to provide an alcohol/toluene solution.
  • the alcohol/toluene solution of the nitro compound was made basic with sodium carbonate to precipitate the compound as a sodium salt.
  • the solid was added to 2 liters of water and sufficient 1 N HCI was added to precipitate crude 6-nitro- chroman-2-yl acetic acid from the aqueous solution. The acid is esterified in absolute ethanol and the solvent is evaporated to obtain ethyl 2-(6-amino-chroman-2-yl)acetate in quantitative yield.
  • a 50 L reactor was charged with 8 L of tetrahydrofuran, and 1 Kg (4.0 moles) of the wet racemic ethyl 2-(6-amino-chroman-2-yl)acetate (obtained as in Example 35) and 9 L of distilled water were sequentially added.
  • the pH of the stirring mixture was adjusted to 8 with a 3.0 N aqueous NaOH solution and the temperature was set to about 37°C.
  • To this 37°C mixture was added 20 g of a PS 30 lipase (PS 30 from Pseudomonas cepacia, Amano Enzyme Co., LTD, 1157 North Main Street, Lombard, IL 60148).
  • the pH controller was set up to maintain a pH of about 8 and the peristaltic pump was set to maintain the pH by adding up to 750 mL of 3N sodium hydroxide solution.
  • the container of NaOH only had 750 mL (2 moles) of 3.0 N sodium hydroxide (corresponds to roughly 50% of the moles ' of racemate) and this amount of NaOH was injected with in 24 hours, which indicates that at least 50% of the ester had been hydrolyzed and formed a sodium salt.
  • the THF was removed by rotoevaporation, the off-white suspension was adjusted to a pH of about 8 with NaOH and was then filtered through a vacuum filter funnel and carefully rinsed with 1 L of distilled water.
  • the slightly basic aqueous filtrates containing the enriched (2S) enantiomer were combined and kept.
  • the drain of the funnel containing the enriched (2R) enantiomer and solid bio-mass was sealed and 1 L of ethyl acetate was added to it. The ester and some free acid were dissolved and the solution was allowed to pass through the drain and collected.
  • the insoluble bio-mass was further rinsed with 500 mL of ethyl acetate and the combined ethyl acetate washes were dried over 50 mg of sodium sulfate. After filtration and solvent removal by rotary evaporation, about 52% yield of the ethyl 2-((2R>S) 6-nitro-chroman-2-yl)acetate or free acid is collected.
  • the bomb was purged 3 times with nitrogen and then 3 times with hydrogen, pressurized to 70 psi hydrogen, and heated to 80°C while stirring.
  • the reaction was monitored by TLC to indicate when the nitro groups had been hydrogenated, after which the reaction mixture was cooled to room temperature.
  • the mixture was emptied from the bomb, and the bomb was rinsed with anhydrous ethanol which was added to the mixture, both of which were filtered through a celite bed.
  • the catalyst and sieves were washed one time with 200 mL of ethanol.
  • the filtrate and wash were combined and placed in a 20 L RB flask to which a catalytic amount of HCI was added. This mixture was heated to form the ethyl ester.
  • the mixture was heated to 45°C and became a clear solution (the pH of the reaction was checked and adjusted to at least 10, by adding additional sodium ethoxide). The mixture was stirred at 45°C for 6 hours. Analysis of the reaction by rotation was utilized to indicate complete reaction (an increase of about 3 degrees of rotation). To the mixture was then added 8 mL of acetic acid and the mixture was allowed to cool to room temperature before the mixture was added to 1 L of distilled water and shaken. The precipitate that was formed was filtered into a vacuum funnel. The combined portions of the filtered precipitate were rinsed with 500 mL of distilled water to yield' the racemic ethyl (6-nitro- chroman-2-yl)acetate as a solid. Essentially 100% of the starting material appeared to be conserved and the racemate was collected wet for recycling through the Example 36 enzyme resolution procedure.
  • a hydrogenation apparatus was charged with ethyl 6-nitrochroman-4-one-2- carboxylate (6 g) (Example 40), acetic anhydride (3.5 mL), 10% palladium on carbon (1 g), powdered 3A molecular sieves (4.0 g), and glacial acetic acid (30 mL). After purging several times with nitrogen, the apparatus was purged several times with hydrogen. Under continuous stirring, the apparatus was maintained at about 70 psi with hydrogen and about 80°C for about 10-12 h. The apparatus was then cooled to about 50 °C, evacuated of hydrogen, and purged several times with nitrogen.
  • Trifluroroacetic acid (3.5 mL) was added to the mixture, then the apparatus was resealed, purged several times with hydrogen, and pressurized to 70 psi with hydrogen. The stirred reaction mixture was heated to 80°C until the reaction was complete by HPLC (intermediate:product ⁇ 3%). The reaction mixture was then cooled to room temperature. After filtering the mixture through Celite, the catalyst and molecular sieves were washed with 10 mL aliquots of glacial acetic acid, and the washes were combined with the filtrate. The combined filtrates were concentrated by distillation to yield an oil. The oil was dissolved in ethyl acetate and washed with saturated NaHCO3.
  • aqueous fraction was extracted with ethyl acetate, then made acidic with concentrated HCI and extracted several times with ethyl acetate.
  • the combined organic fractions were combined and concentrated to a solid.
  • the solid was washed with acetonitrile, filtered, and dried to afford ethyl 6-acetamido-2-chroman-2- carboxylate (about 3.5-4.0 g) as a white solid.

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Abstract

L'invention porte sur des procédés de production de composés acyle 4-oxo-chroman-2-yl (2S) ou (2R) et de composés acyle chroman-2-yl, d'esters ou d'amides de ceux-ci ainsi que de leurs dérivés. Ces procédés peuvent impliquer la synthèse chirale ou achirale, de préférence couplée à une procédure de résolution. Ces composés, notamment les esters de l'acide acétique (2S) ou (2R) sont utiles comme intermédiaires pour produire des inhibiteurs de l'agrégation plaquettaire et/ou sont eux-mêmes de puissants inhibiteurs de l'agrégation plaquettaire. L'invention porte également sur des procédés de fabrication de dérivés de ces compositions améliorées, pratiquement pures, d'intermédiaires uniques d'énantiomères (2R) ou (2S) ou de processus de production de produits finaux ou de sels à partir de ces énantiomères désirés.
PCT/US2001/018016 2000-06-02 2001-06-01 Synthese chirale et achirale de chromanes substitues par 2-acyle et leurs derives WO2001092249A2 (fr)

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WO2005073212A1 (fr) * 2004-01-30 2005-08-11 Mitsubishi Gas Chemical Company, Inc. Procede servant a produire un compose chromane
WO2009027081A2 (fr) * 2007-08-28 2009-03-05 Ratiopharm Gmbh Procédé pour préparer des dérivés de diacide pentanoïque
CN102382091A (zh) * 2011-09-05 2012-03-21 浙江大学 一种合成多取代色酮类化合物的方法
CN105503626A (zh) * 2015-12-12 2016-04-20 常州大学 一种2-氨基-4-氯-6-甲氧基苯酚的合成方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005073212A1 (fr) * 2004-01-30 2005-08-11 Mitsubishi Gas Chemical Company, Inc. Procede servant a produire un compose chromane
US7615650B2 (en) 2004-01-30 2009-11-10 Mitsubishi Gas Chemical Company, Inc. Process for producing chroman compound
WO2009027081A2 (fr) * 2007-08-28 2009-03-05 Ratiopharm Gmbh Procédé pour préparer des dérivés de diacide pentanoïque
WO2009027081A3 (fr) * 2007-08-28 2009-06-11 Ratiopharm Gmbh Procédé pour préparer des dérivés de diacide pentanoïque
CN102382091A (zh) * 2011-09-05 2012-03-21 浙江大学 一种合成多取代色酮类化合物的方法
CN102382091B (zh) * 2011-09-05 2014-07-09 浙江大学 一种合成多取代色酮类化合物的方法
CN105503626A (zh) * 2015-12-12 2016-04-20 常州大学 一种2-氨基-4-氯-6-甲氧基苯酚的合成方法

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