Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• This invention relates to novel processes for producing chromane compounds, preferably chroman-2-yl acetic acid compounds and amino substituted chroman-2-yl acetic acid esters which are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors. Further the invention relates to processes for resolving chiral intermediates or final products to provide desired enantiomers.
• R is H or an alkyl group.
• the process comprises the following reactions (a) through (d):
• R 1 group is a hydrogen atom or a removable amino protecting selected from the group consisting of BOC, t-butoxycarbonyl, and the like,
• R is H or an alkyl group.
• the process is used to prepare a compound according to the formula:
• the processes herein relate to producing chromane compounds, preferably chroman-2-yl acetic acid compounds and amino substituted chroman-2-yl acetic acid esters which are intermediates for producing therapeutic agents, or are themselves therapeutic agents, for disease states in mammals that have disorders caused by or impacted by platelet dependent narrowing of the blood supply.
• one preferred embodiment provides a process that utilizes a 6-nitro coumarin compound (available from Aldrich) and in the first step reduces the 6-nitro group to a substituted amino group and reduces the 3-4 alkene bond to produce a 6-(tert-butoxy- carbonylamino)-2-chromanone compound as follows:
• the reduction of the nitro group and the cyclic 3-4 alkene bond are conducted in a single step.
• palladium on carbon or the like may be used in a solvent such as THF to reduce both the nitro group and the cyclic alkene bond.
• di- tert-butyl-dicarbonate is added to reaction mixture along with the THF and results in protecting the amino group as it is formed.
• a lower hydrogen pressure and temperature may be used initially followed by increasing of the hydrogen pressure and the temperature to reduce the cyclic alkene bond.
• the carbonyl group (2-oxo group) of the protected 2-chromanone from the above step can be reduced to a 2-hydroxychromane by utilizing a DIBAL-H reduction process or the like as .follows:
• the 2-hydroxy chromane is then condensed with a (carbethoxymethylene)- triphenylphosphorane compound in the presence of a base such as sodium ethoxide in an acceptable solvent such as toluene at about 50-100 °C, preferably about 65-90 °C, and more preferably about 80 °C to afford the acetate.
• a base such as sodium ethoxide
• an acceptable solvent such as toluene
• the protecting group on the amine group can then optionally be removed with an acceptable acid such as trifluoroacetic acid at about 40-80 °C, preferably 50-70 °C, and more preferably about 60 °C to yield the free amine as follows:
• the ethyl group can be replaced by H or another esterifying group selected from lower alkyl, lower alkenyl, lower alkynyl, 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 pages 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 or after the coupling step.
• the above process can be modified to produce a formyl, propyl or butyl side chain or the like, by utilizing a different triphenylphosphorane starting material.
• the compounds disclosed herein find 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, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc.
• 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.
• an agonist such as thrombin
• the GP llb/IIIa binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation.
• the compounds produced according to the methods disclosed herein may used as intermediates for producing therapeutic compounds or as compounds that may be administered in combination or in concert with other therapeutic or diagnostic agents.
• the compounds produced by the intermediates according to the disclosure herein 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 used in above processes are commercially available from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or may be readily synthesized by known procedures, for example, 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 otherwise indicated, or is well-known in literature available in the art. Further, the above procedures of the processes described herein 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 well-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.
• blocking groups are well known in the art.
• removal of amino or acid blocking groups by procedures such as acidification or hydrogenation are well-known in the art.
• the two-position acid ester group is attached to a chiral carbon which may optionally be resolved to produce a racemic mixture enriched in either the R or S enantiomers or completely resolved into a substantially pure composition of one of the enantiomers.
• Conventional processes may be utilized to resolve the enantiomers.
• compositions and Formulations may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this disclosure and are presently contemplated. 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. For example, reaction of the free acid or free base form of a compound of the structures recited above 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. Alternatively, 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 solution was then heated to about 50°C and the pressure of hydrogen was increased to about 4 bar G for about 5 hours.
• the reaction was essentially complete (the area ratio by HPLC between the amount of 6-nitro-coumarin starting material and the amount of 6-(t-butoxy-carbonylamino)-2-chromanone product was not more than about 3%)
• the mixture was cooled to room temperature.
• the suspension was filtered and the cake was washed with 30 Kg of tetrahydrofuran.
• the filtrate was distilled under reduced pressure (T ⁇ 60°C) by adding about 23 Kg of toluene and distilling off about 8 Kg of the solvent.
• the medium was then heated to reflux until complete dissolution.
• the mixture was slowly cooled down and stirred at room temperature for about 2 hours or more.
• Methyl alcohol (11.4 Kg) was then slowly added (T ⁇ -50°C), and upon completion of the addition, the reaction mixture was slowly warmed up to about -10°C. When this temperature was obtained, 12 Kg of celite and 15.6 Kg of water were added. The mixture was further warmed-up to 20°C and maintained under good agitation at that temperature for at least 30 minutes. The suspension was filtered and the cake was washed 3 times with 76.85 Kg of dichloromethane. The filtrate and washes were combined and the solvent was distilled off under reduced pressure (T ⁇ 50°C) until the minimum stirrable volume was reached (about 40 L).
• Toluene (36.3 Kg) was added to the reactor and the solvents were distilled until minimum stirrable volume was achieved. This operation was repeated 3 times. Finally, 52 Kg of toluene was added and distilled under reduced pressure until the residual volume was about 132 L. The reaction mixture was then cooled to room temperature to yield 6-(t- butoxycarbonylamino)-2-hydroxychromane in a toluenic solution.
• Example 2 To the toluenic solution of Example 2, above, was added 17.53 Kg of (carbethoxymethylene)triphenylphosphorane (50.32 mole, corresponding to 1:1 equivalents of the amount of 6-(t-butoxycarbonylamino)-2-chromanone used as the initial starting material in Example 2) and 16 g of sodium ethoxide. The reaction mixture was then heated to about 80°C and stirred at 80°C for at least about 2 hours. The evolution of the reaction was then checked by TLC and HPLC. An additional amount of sodium ethoxide (48 g) was added and the mixture was maintained at about 80°C for about 24 hours with stirring. After cooling the reaction mixture to room temperature, 57.11 Kg of silica gel and 91 Kg of toluene were added to the reaction medium which was stirred for at least 1 hour at about 20°C.
• (carbethoxymethylene)triphenylphosphorane 50.32 mole, corresponding to 1:1 equivalents of the amount of 6-(t
• the silica gel was filtered and washed twice with 122 Kg of toluene. The filtrate and the washes were pooled and the solvents were distilled off under reduced pressure (T ⁇ 50°C) until the residue solution had a volume of about 100 L. The residue was cooled down to about 25°C to result in a 100 L toluenic solution of ethyl [6-(t-butoxy carbonylamino)chroman-2-yl]acetate.
• Example 3 To the toluenic solution of Example 3, above, was added 25 Kg of trifluoro acetic acid (219.26 mole). The solution was then heated up to about 60°C for at least one hour. The solution cooled down to about 40°C and the solvents were distilled off (T ⁇ 50°C) under reduced pressure until the volume of the residue was about 100 L.
• Example 4 The 80 L of the toluenic solution of Example 4, above, was cooled to 19°C and 9.67 L of 6.2 M hydrochloric acid in ethyl alcohol was slowly added in order to maintain the temperature between 10 and 20°C.
• the crystals were maturated under stirring for at least 16 hours at the same temperature, filtered and washed with 40 L of toluene.
• the product was dried for at least 16 hours under reduced pressure while maintaining the temperature between 45 and 50°C to afford about 8.50 Kg (31.34 mole) of ethyl [6-amino-2-chroman- 2-yl]acetate hydrochloride. Yield about 68.7% for production steps from 6-(t- butoxycarbonylamino)-2-chromanone to ethyl [6-amino-2 ⁇ chroman-2-yl]acetate hydrochloride salt.
• reaction mixture was then heated to about 50°C and the pressure of hydrogen was increased to about 60 psi.
• TLC was used to monitor the progress of the reaction, and the reaction was complete in about 15 hours.
• the reaction mixture was cooled to room temperature and purged 3 times with nitrogen before it was discharged from the reactor.
• the catalyst and molecular sieves were removed by filtration through a layer of celite and the filtration cake was washed with 1.0 L of tetrahydrofuran.
• the rate of addition was adapted in order to keep the temperature between -50°C and -65°C (exothermic).
• the reaction mixture was stirred for 1 hour after the DIBAL-H was added.
• the 870 mL of methanol was then slowly added (T ⁇ -50°C).
• the reaction mixture was warmed up, and at about -20°C, and 790 g of celite and 970 mL of water were added.
• the mixture was further warmed-up to room temperature and maintained under good agitation at that temperature for about 40 minutes.
• the suspension was filtered and the cake was washed with 10.0 L of methylene chloride in three washings. The filtrate and the washings were combined and the solvent was removed under reduced pressure (T ⁇ 50°C).
• Example 8 To the toluenic solution of Example 8, above, was added 1350 g of (carbethoxymethylene)triphenylphosphorane (95%) and 2.1 g of sodium ethoxide. The reaction mixture was then heated to about 80°C and stirred at 80°C for 2 hours. An additional 3.2 g of sodium ethoxide was added and the temperature maintained with stirring for 18 hours. TLC analysis was used to monitor the evolution of the reaction from time to time. The reaction mixture was stirred at 80°C for an additional 3 hours after the addition. After cooling the reaction mixture to room temperature, 3750 g of silica gel and 70L of toluene were added to the reaction medium which was stirred for 2 hours before filtration.
• silica gel and 70L of toluene were added to the reaction medium which was stirred for 2 hours before filtration.
• the silica gel was washed with 2 x 12 L of toluene (total of 24 L of toluene). The filtrate and the washes were combined and the solvent was distilled off under reduced pressure (T # 60°C) until the residue solution had a volume of about 7 L.
• the mixture was cooled down to room temperature and about 10 L of 10% (w/w) aqueous sodium hydrogen carbonate was slowly added until the pH was above 7.
• the solution was stirred for 20 minutes.
• the organic and aqueous layers were separated and the aqueous layer was extracted with 3 L of toluene.
• the combined organic layers were washed with 3 L of brine, dried over sodium sulfate, and filtered.
• the toluene solvent was removed by distillation under reduced pressure (at T ⁇ 60°C) until the residue was about 6

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• 2001
  • 2001-06-01 WO PCT/US2001/018014 patent/WO2001094331A2/en not_active Application Discontinuation
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