WO2001087871A2 - Procedes de production de chromanes amino substitues et intermediaires correspondants - Google Patents

Procedes de production de chromanes amino substitues et intermediaires correspondants Download PDF

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Publication number
WO2001087871A2
WO2001087871A2 PCT/US2001/015687 US0115687W WO0187871A2 WO 2001087871 A2 WO2001087871 A2 WO 2001087871A2 US 0115687 W US0115687 W US 0115687W WO 0187871 A2 WO0187871 A2 WO 0187871A2
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Prior art keywords
ethyl
acetate
ester
process according
solvent
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PCT/US2001/015687
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English (en)
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WO2001087871A3 (fr
Inventor
Robert Scarborough
Panos Kalaritis
J. Guy Steenrod
George Yiannikouros
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Millennium Pharmaceuticals, Inc.
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Priority to AU2001264613A priority Critical patent/AU2001264613A1/en
Publication of WO2001087871A2 publication Critical patent/WO2001087871A2/fr
Publication of WO2001087871A3 publication Critical patent/WO2001087871A3/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
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring

Definitions

  • This invention relates to processes for producing chromane compounds and amino substituted 2-(chroman-2-yl) acetic acid esters which are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors. Further the invention relates to processes for resolving chiral intermediates or final products to provide desired enantiomers.
  • Background of the Invention One process for making reduced benzopyrans or chromanes from coumarin derivatives is described in U.S. Patent 5,731 ,324 at columns 101-103. However, that process involves chromatography as a purification step, which does not scale well commercially. The unprotected amino derivative bicyclic compound is found on on column 147.
  • the present invention relates to novel processes for producing chromane compounds, preferably amino substituted 2-(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.
  • chromane compounds preferably amino substituted 2-(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.
  • R is H or an alkyl group, comprising:
  • the resulting ester may be converted to its corresponding acid or to another ester by methods known to those skilled in the art. Salts of the acid or ester compounds, including acid halide salts, may also be prepared.
  • the process further comprises resolving the racemic mixture by combining the racemic (2R 2S) ethyl 2-(6-(N-hydroxyiminoethyl)chroman-2- yl)acetate of (d) with an enantiomerically selective ester hydrolyzing lipase material and stirring in aqueous basic solution to resolve the racemic mixture, as follows:
  • the lipase is pseudomonas lipase PS 30 or a glutarate stabilized version and the aqueous basic solution has a pH of about 8 to about 11.
  • one of the enriched components is racemized and then re-resolved to increase the yield of the desired enantiomer.
  • preferred compounds produced using the methods disclosed herein have utility as intermediates for producing therapeutic agents or as therapeutic agents for disease states in mammals which have disorders that are due to platelet dependent narrowing of the blood supply, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, 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 the methods disclosed herein may also be used as intermediates to form compounds that may be administered in combination or concert with other therapeutic or diagnostic agents.
  • the compounds produced by the intermediates according to preferred embodiments 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 according to preferred embodiments 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 starting materials and other reagents used in the processes disclosed are commercially available from chemical vendors such as Aldrich, Lancaster, TCI, Bachem Biosciences, and the like, or may be readily synthesized by known procedures, for example, those present in the chemical literature.
  • amino group can be protonated to isolate the product as an amine acid halide salt or the like.
  • the steps illustrated in Scheme I will now be discussed in detail.
  • the first step there is a process that utilizes a dihydrocoumarin (Aldrich D10,480-9, for example) starting material.
  • the carbonyl group (2-oxo group) of the dihydrocoumarin can be reduced to a 2-hydroxy-chromane compound by utilizing a DIBAL-H reduction process, or any other agents which reduce a carbonyl group to a hydroxy group, as follows:
  • the 2-hydroxy chromane is then condensed with (carbethoxymethylene)- triphenylphosphorane in the presence of a base such as sodium ethoxide in an acceptable solvent such as toluene at about 20-80°C, preferably about 30-65 °C, and more preferably about 35-45 °C to afford the acetate.
  • a base such as sodium ethoxide in an acceptable solvent such as toluene at about 20-80°C, preferably about 30-65 °C, and more preferably about 35-45 °C to afford the acetate.
  • a Friedel Crafts acylation mediated by a Lewis acid such as aluminum chloride is conducted to give the attached acetyl group para to the ring oxygen of the chromane ring.
  • Reaction of the chromane ring with about 1 :1 to 1 :2 equivalents of acetyl chloride in the presence of 2.0 to 4.0 equivalents of aluminum chloride in an acceptable solvent, such as dichloromethane, at a temperature of about -20-25°C, preferably -10-20°C, and more preferably about -5-15°C provides ethyl 2-(6-acetyl-chroman-2-yl)acetate in high yield as follows:
  • the 6-acetyl group can be converted into a N-hydroxyimino-ethyl group by reaction with hydroxyamine hydrochloride in an appropriate solvent such as ethanol at a temperature of about 15°C to about 40°C, ideally at about room temperature, to yield racemic (2R/2S) ethyl 2-[6-(N-hydroxyiminoethyl)chroman-2-yl]acetate, as follows:
  • the racemic (2R/2S) ethyl 2-[6-(N-hydroxyiminoethyl)chroman- 2-yl]acetate can be 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 from Altus, Inc.) as follows:
  • 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 from Altus, Inc.) as follows:
  • the lipase biomass and the enriched (2R) enantiomer can be 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.
  • 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) enantiomer and increase the overall yield of the process.
  • the formation of a racemate from a single enantiomer is 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 chromone 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 as follows:
  • a catalytic amount of sodium ethoxide, potassium ethoxide or similar catalytic base in R 1 OH 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 racemic (2R/2S) ethyl 2-[6-(N-hydroxyiminoethyl)-chroman-2-yl]acetate 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 ethyl group can be replaced by H or another esterifying group selected from lower alkyl (C C 8 ), lower alkenyl (C 1 -C 8 ), lower alkynyl (C C 8 ), phenyl, cinnamyl or other ester groups.
  • the protected amine benzopyran compound or the free amine benzopyran compound can be coupled to a cyanobenzoyl chloride group as described on columns 147 and 148 of U.S. Patent 5,731 ,324, for example
  • the ester group of the acetic acid side chain can be optionally changed, before of after the coupling step.
  • compositions and Formulations The compounds formed according to preferred processes herein may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are contemplated herein. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification. A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art.
  • 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.
  • Example 1 The 28 L filtrates of Example 1 , containing 13.5 moles of chroman-2-ol were transferred into a clean 50 L reactor to perform a Wittig reaction.
  • 5.0 Kg (14.35 moles) of (carbethoxymethylene)triphenylphosphorane was added in portions at room temperature under nitrogen. At the end of the addition the temperature rose to 30 °C.
  • To this stirring solution was then added 125 mL (335 mmoles) of sodium ethoxide 21% w/w in ethanol. The mixture was stirred for two hours at 40°C and TLC analysis (hexane/ethyl acetate 4:1) indicated complete reaction.
  • the mixture was allowed to cool to room temperature followed by the addition of 23 mL (365 mmoles) of acetic acid.
  • the reaction mixture was transferred into two carboys and the solvent was removed by rotary evaporation.
  • the formed precipitate (triphenyl phosphine oxide) was removed by filtration.
  • the collected solid was slurred with 1.0 L of 5% ethyl acetate in hexanes filtered and washed with an addition 1.5 L of 5% ethyl acetate in hexanes.
  • the combined filtrates were concentrated by rotary evaporation and the residue was transferred into a 5 L RB flask containing some glass beads and setup for a high vacuum distillation.
  • the reaction mixture was stirred for an additional 15 minutes at 0°C and, while the reaction mixture was still cold, it was slowly transferred into a 200 L reactor containing 30.0 L (80 moles) of 3N hydrochloric acid and 8.0 L of dichloromethane cooled to -5°C at such a rate that the temperature is kept below 15°C.
  • the 50 L reactor was rinsed with 2.4 L of dichloromethane and added to the 200 L reactor.
  • the mixture was allowed to stir for 15 minutes, and after 30 minutes of separation the bottom organic layer was removed and collected.
  • the aqueous layer was back-extracted with 8.0 L of dichloromethane.
  • Example 5 After rinsing the product with 50 L of distilled water, ethyl 2-[6-(N-hydroxyimino- ethyl)chroman-2-yl)acetate was collected as a overweight white solid. The yield is expected to be 100%, but was not weighed since drying was not necessary in the optional enzymatic hydrolysis steps of Example 5, below.
  • Example 5 Optional enzymatic resolution of racemic ethyl 2-[6-(N-hydroxyimino-ethyl)chroman-2- yl)acetate with a lipase and isolation of (R>S) and (S>R) enantiomer compositions.
  • the pH controller was set up to maintain a pH of about 8 and the peristaltic pump maintained the pH by adding a 3N sodium hydroxide solution. By the end of the third day 7.9 L (22.2 moles) of 3.0 N of sodium hydroxide had been injected.
  • Tetrahydrofuran was removed by rotary evaporation and the pH was adjusted to about 8.
  • the off-white suspension was filtered through a vacuum filter funnel and carefully rinsed with 12.2 L of distilled water.
  • the slightly basic aqueous filtrates contained 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 12.2 L of ethyl acetate was added to it.
  • the ester was dissolved and the solution was allowed to pass through the drain and collected.
  • the insoluble bio-mass was further rinsed with 6.1 L of ethyl acetate and the combined ethyl acetate washes were dried over 500 mg of sodium sulfate.
  • Example 5 About 4.6 Kg of the dried enriched ethyl 2-[(2S)-6-(N-hydroxyimino-ethyl)chroman- 2-yl]acetate is obtained from Example 5.
  • a corresponding amount of dried enriched (2R) or racemic (2R/2S) ethyl 2-[6-(N-hydroxyimino-ethyl)chroman-2-yl]acetate is obtained by taking a portion of the wet (2R) enantiomer from Example 5, or of the (2R 2S) racemate from either of Example 4 or 6, thoroughly rinsing with 30-40 L of distilled water, transferring into six trays and drying in a vacuum oven at 60°C to afford (2R) and (2R/2S) racemic, respectively, ethyl 2-(6-(N-hydroxyimino-ethyl)chroman-2-yl)acetate as a white solid, from which 4.6 Kg of either dried composition is allocated for converting to the 6- amino compound).
  • a 200 L reactor was charged with 20.0 L of absolute ethanol which was chilled to a temperature of -10°C with stirring. Into this stirring solvent was added the mixture from the 50 L reactor. The temperature of the 200 L reactor was brought to reflux and the dichloromethane was removed by condensation. The ethanolic mixture was refluxed for about 6 hours to remove about 18 liters of the ethanol (until foaming of the reaction mixture is observed). The heat was removed and the reaction mixture was allowed to cool to room temperature.
  • Example 7 The procedures as set forth in Example 7 are substantially followed through the step in which the dichloromethane is removed by condensation. At that point the procedure proceeds as follows.
  • the ethanolic mixture is refluxed for about 6 hours to remove about 18 liters of the ethanol (until foaming of the reaction mixture is observed).
  • the heat is removed and the reaction mixture is allowed to cool to room temperature.
  • 10.0 liters of ethyl acetate are added and the mixture is stirred for 15 minutes.
  • To the stirring reaction mixture is slowly added 1.5 L of ethereal HCI and the reaction mixture is stirred for about an hour.
  • the white suspension is filtered and the filter cake is washed with 5.0 L of ethyl acetate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des processus de production de composés de chromane, de préférence des esters d'acide acétique 2-(6- aminochromane2-yl) qui sont des intermédiaires servant à la production d'inhibiteurs d'agrégation plaquettaire et/ou qui sont des inhibiteurs d'agrégation plaquettaire efficaces.
PCT/US2001/015687 2000-05-17 2001-05-16 Procedes de production de chromanes amino substitues et intermediaires correspondants WO2001087871A2 (fr)

Priority Applications (1)

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AU2001264613A AU2001264613A1 (en) 2000-05-17 2001-05-16 Methods for producing amino substituted chromanes and intermediates therefor

Applications Claiming Priority (4)

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US20483700P 2000-05-17 2000-05-17
US60/204,837 2000-05-17
US20876900P 2000-06-02 2000-06-02
US60/208,769 2000-06-02

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0052280A1 (fr) * 1980-11-15 1982-05-26 FISONS plc Procédé pour la préparation de l'amino-3 diacétyl-4,6 phénol ou d'un dérivé de ce composé
US4524217A (en) * 1984-06-08 1985-06-18 Celanese Corporation Process for producing N-acyl-hydroxy aromatic amines
DE3501229A1 (de) * 1985-01-16 1986-07-17 Hoechst Ag, 6230 Frankfurt 7-chlor-6-sulfamoylcumarine, verfahren zu ihrer herstellung und ihre verwendung als heilmittel
WO1996022288A1 (fr) * 1995-01-19 1996-07-25 Eli Lilly And Company ANTAGONISTES DE LA GLYCOPROTEINE IIb/IIIa

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0052280A1 (fr) * 1980-11-15 1982-05-26 FISONS plc Procédé pour la préparation de l'amino-3 diacétyl-4,6 phénol ou d'un dérivé de ce composé
US4524217A (en) * 1984-06-08 1985-06-18 Celanese Corporation Process for producing N-acyl-hydroxy aromatic amines
US4524217B1 (fr) * 1984-06-08 1990-04-03 Celanese Corp
DE3501229A1 (de) * 1985-01-16 1986-07-17 Hoechst Ag, 6230 Frankfurt 7-chlor-6-sulfamoylcumarine, verfahren zu ihrer herstellung und ihre verwendung als heilmittel
WO1996022288A1 (fr) * 1995-01-19 1996-07-25 Eli Lilly And Company ANTAGONISTES DE LA GLYCOPROTEINE IIb/IIIa

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AUTORENKOLLEKTIV: "ORGANIKUM" 1976 , VEB , BERLIN XP002181639 * Electrophilic aromatic substitution, F.C. acylation * page 400 -page 401 *
AUTORENKOLLEKTIV: "ORGANIKUM" 1976 , VEB , BERLIN XP002181640 * Formation of oximes by reaction of carbonyl compounds with hydroxy amine * page 485 *
AUTORENKOLLEKTIV: "organikum" 1976 , VEB , BERLIN XP002181641 * BECKMANN rearrangement of oximes to generate carboxamides * page 706 -page 707 *
COHEN,N. ET AL.: "3,4-Dihydro-2H-1-benzopyran-2-carboxylic Acids and Related Compounds as Leukotriene Antagonists" J.MED.CHEM., vol. 32, no. 8, 1989, pages 1842-1860, XP002181638 WASHINGTON *

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WO2001087871A3 (fr) 2002-04-04

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