WO2001087871A2

WO2001087871A2 - Methods for producing amino substituted chromanes and intermediates therefor

Info

Publication number: WO2001087871A2
Application number: PCT/US2001/015687
Authority: WO
Inventors: Robert Scarborough; Panos Kalaritis; J. Guy Steenrod; George Yiannikouros
Original assignee: Millennium Pharmaceuticals, Inc.
Priority date: 2000-05-17
Filing date: 2001-05-16
Publication date: 2001-11-22
Also published as: AU2001264613A1; WO2001087871A3

Abstract

Disclosed are processes for producing chromane compounds, preferably 2-(6-aminochroman-2-yl) acetic acid esters which are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors.

Description

METHODS FOR PRODUCING AMINO SUBSTITUTED CHROMANES AND

INTERMEDIATES THEREFOR

Field of the Invention

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. Therefore, there is a need for improved processes for producing compounds that are useful as intermediates in processes for producing platelet aggregation inhibitors. There is a particular need for improved processes for making compounds having the benzo ring of the benzopyrans substituted by an amino group or a protected amino group. Such intermediates are useful for coupling with a carbonyl group to produce a carboxamide link and result in compounds that are useful platelet aggregation inhibitors or in intermediates for forming platelet aggregation inhibitors. Also needed is a process to produce relatively inexpensively large quantities of chromone intermediates that are useful for being resolved by conventional processes to produce benzopyran or 2-chromane derivatives wherein the chiral center at the two position of the saturated pyran ring portion of the bicyclic ring structure can be resolved into racemic mixtures (R/S) that are enriched with one of the R or S enantiomers or to produce substantially pure compositions of a single enantiomer (R or S enantiomer). Due to inherent losses of up to 50% or more of the starting materials (assuming a 50/50 R/S racemate) during enantiomeric resolution, there is a need for a process which is efficient enough to be scaled to an industrial level for inexpensively producing large quantities of a desired intermediate compound or large quantities of final 2-(chroman-2-yl) acetic acid ester compounds that are useful in the anticoagulant field.

Accordingly, there continues to be a need for a process that is adaptable to commercially scaleable production of such chromanes. Summary of the Invention

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. In accordance with a preferred embodiment, there is provided a process for making a compound according to the formula

wherein R is H or an alkyl group, comprising:

(a) reducing the 2-postion carbonyl group of the dihydrocoumarin with a reducing compound or compounds to reduce a ring carbonyl group of a lactone to a hydroxy group, to form 2-hydroxychromane as follows:

(b) condensing the hydroxychromane compound produced in (a) above with (carbethoxymethylene)-triphenylphosphorane in the presence of an ethoxide base with heating to afford the acetate compound as follows: ethoxide base

(carbethoxymethylene)- triphenylphosphorane

(c) acetylating the compound produced in (b) above using a Friedel Crafts acylation to provide an acetyl group on the chromane ring and yield ethyl 2-(6- acetylchroman-2-yl)acetate as follows:

(d) converting the 6-acetyl group of the product of (c) to a N-hydroxyimino- ethyl group by reacting the 6-acetyl compound with hydroxyamine hydrochloride to yield racemic (2R/2S) ethyl 2-[6-(N-hydroxyiminoethyl)chroman-2-yl]acetate, as follows:

(e) converting the 6-(N-hydroxyimino-ethyl) group of the product of (d) to an amino group via a Beckman re-arrangement followed by heating in alcohol, cooling the mixture to about room temperature, and adding concentrated HX, where X is a halogen, in ethyl acetate or EtOH to the mixture to form an insoluble amine hydrohalide salt and yield ethyl 2-[6-aminochroman-2-yi]acetate hydrohalide (hydrochloride) as follows:

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.

In a preferred embodiment, 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:

wherein 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. In further embodiments, one of the enriched components is racemized and then re-resolved to increase the yield of the desired enantiomer. Detailed Description of the Preferred Embodiments As mentioned above, 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. In certain preferred embodiments, 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.

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 preferred processes disclosed 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. During the synthesis of these compounds, amino or acid functional groups may be protected by blocking groups to prevent undesired reactions with these groups during certain procedures. Use of other blocking groups or protecting groups known in the art, but not described specifically herein are also contemplated. The application and removal of such blocking groups by procedures such as acidification or hydrogenation are known in the art. Preferred Process of Preparing Ethyl (6-amino-chroman-2-yl)acetate

In accordance with a preferred embodiment, there is provided a process that utilizes coumarin as a starting material to produce a racemate or enriched (2S or 2R) ethyl (6-amino-chroman-2-yl)acetate as set forth in reaction Scheme I below.

SCHEME I

Optionally the 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. In the first step, there is a process that utilizes a dihydrocoumarin (Aldrich D10,480-9, for example) starting material. In the first step 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:

DIBAL-H

di -chl oromethane

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. For example, as illustrated below: sodium ethoxide

(carbethoxymethylene)- triphenylp o sphorane

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:

As an optional step, 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:

When the selective hydrolysis by the lipase is conducted in an aqueous basic solution

(preferably a buffer solution) with lipase PS 30 and the insoluble ester racemate is agitated with stirring 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 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 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.

Depending upon whether the desired enantiomer is the (2S) or the (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:

wherein, as illustrated, a catalytic amount of sodium ethoxide, potassium ethoxide or similar catalytic base in R¹OH (preferably EtOH) is utilized until racemization is completed (usually for 4-8 hours at about 45°C, longer at room temperature). After acidification with 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. Optionally 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.

Either the racemate or the separated (2S) or (2R) enantiomer from the optional chiral resolution step (for illustration purposes only the 2S enantiomer is show being converted below) the (6-(N-hydroxyimino-ethyl) group of the title compound is subjected to a Beckman re-arrangement to ultimately form a 6-amino group by using an agent such as PCI₅ followed by heating in an alcohol. After cooling of the mixture to room temperature concentrated HCI in EtOH, or another strong mineral acid, may be added to the mixture to form an insoluble amine hydrohalide salt. An organic solvent such as ethyl acetate may also be added to the mixture, the filtrate can be collected and washed with ethyl acetate. Evaporation to remove the solvent will yield ethyl 2-[(2S) 6-aminochroman-2-yl]acetate hydrohalide (hydrochloride) as follows:

While an ethyl group was used to form the ester of the acetic acid side chain, the ethyl group can be replaced by H or another esterifying group selected from lower alkyl (C C₈), lower alkenyl (C₁-C₈), lower alkynyl (C C₈), phenyl, cinnamyl or other ester groups.

In either event, 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.

Further, 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. 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. 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. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the preferred compounds and practice the claimed methods. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

EXAMPLES Example 1 Production of 2-hydroxy-chromane (1)

A 22 L 3-necked RB flask, equipped with a thermocouple, mechanical stirrer, addition funnel, gas bubbler and a dry-ice acetone cooling bath, was charged under nitrogen atmosphere with 7.20 L of dry dichloromethane and 2.0 Kg (13.50 moles) of dihydrocoumarin and cooled to -70°C . To this stirring mixture slowly was added via the addition funnel 9.50 L (14.25 moles) of DIBAL-H in toluene in such a rate that the temperature would not exceed -60°C. After completion of the addition (about 4.5 hours), the mixture was stirred for an additional 45 minutes at -70°C. TLC analysis (hexane/ethyl acetate 4:1 ) indicated complete reaction.

In a separate 50 L glass reactor a solution of 20.0 L of water and 4.0 L (about 42 moles) of concentrated hydrochloric acid (37% w/v) was prepared. The chilled DIBAL-H reaction mixture was then slowly added to a stirring hydrochloric acid solution in the 50 L reactor at room temperature. The rate of addition was kept such that the temperature was allowed to rise to between 25 and 30°C. At these temperature a smooth decomposition of the diisobutyl aluminum complexes was observed. The 22 L 3-necked RB flask was rinsed with 5.0 L of dichloromethane and the wash was added to the stirring mixture in the 50 L reactor. After about 30 minutes of vigorous stirring the layers were allowed to separate. The organic bottom layer was removed and the aqueous layer was back- extracted with 5.0 L of dichloromethane. The combined organic layers were equally divided into two 20 L carboys and dried over 1.0 Kg of anhydrous sodium sulfate (0.5 Kg each) for one hour. The organic solution was separated by filtration and each of the sodium sulfate was washed with 1.0 L of dichloromethane. The filtrates were combined to provide approximately a 28 L composition of chroman-2-ol in the organic solvents of the reaction (dichloromethane (about 19 L) and toluene (about 7 L)). Example 2 Production of ethyl 2-(chroman-2-yl)acetate (2)

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. With stirring, 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 product was distilled at 158°C and 0.75 mm Hg pressure to afford 2.33 Kg (11.07 moles, 81.8% yield) of colorless liquid. After cooling to room temperature the residue was mixed with 1.0 L of 5% ethyl acetate in hexanes and the precipitate formed was filtered and rinsed with and additional 500 mL of 5% ethyl acetate in hexanes. The combined filtrates were concentrated by rotary evaporation and the residue was transferred into a 1 L RB flask. The distillation was done in the same way described above to afford an addition 234 g (8.2% additional yield) of ethyl (chroman-2-yl)acetate. The combined yield is about 89% (based on the 13.50 moles of dihydrocoumarin starting material) of ethyl 2-(chroman-2- yl)acetate (2.564 Kg, 12.0 moles). Example 3

Production of ethyl 2-(6-acetylchroman-2-yl) acetate (3)

To a 50 L reactor under nitrogen was charged 222 L of dichloromethane and while stirring 13.4 Kg (100.4 moles of aluminum chloride was added in portions. The stirring suspension was cooled to -5°C and 7.39 Kg (35.1 moles) of the chroman-2-yl acetic acid ester (produced as in Example 2) dissolved in 6.0 L of dichloromethane was added at -5°C over 10 minutes. To this stirring mixture was added 3.16 Kg (40.3 moles) of acetyl chloride at 0°C over 2.5 hours. During the addition the reaction temperature rose to 2.5°C. 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. Following the removal of the aqueous layer, the combined organic extracts were added back into the reactor followed by the addition of 30 L of 1 :1 mixture of brine/water. The mixture was stirred for 15 minutes and allowed to separate for 30 minutes. The bottom organic layer was removed and concentrated by rotary evaporation to afford 9.1 Kg (34.7 moles) which corresponds to a 99% yield of ethyl 2-(6-acetylchroman-2-yl)acetate with respect to the chroman-2-yl acetic acid starting material. The product was obtained as a viscous oil which upon standing crystallized into a white solid. Example 4 Production of ethyl 2-[6-(N-hydroxyimino-ethyl)chroman-2-yl)acetate (4)

A 50 L reactor was charged under nitrogen with 27.3 L of absolute ethanol, 9.1 K g (34.7 moles) of ethyl 2-(6-acetyl-chroman-2-yl)acetate and 5.8 Kg (69.4 moles) of sodium bicarbonate. To this stirring mixture was added 3.6 Kg (52.0 moles) of hydroxyamine hydrochloride in portions. Formation of carbon dioxide resulted in foaming and the hydroxyamine hydrochloride was added gradually to control the degree of foaming. The mixture was stirred at room temperature for 6 hours. TLC analysis (hexanes/ethyl acetate 7:3) indicated complete reaction. The mixture was added to 50.0 L of stirring distilled water at room temperature. The product precipitated and was filtered into a vacuum funnel. 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.

A 200 L reactor was charged with 30.5 L of tetrahydrofuran. 12.2 Kg (44.0 moles) of the wet racemic ethyl 2-[6-(N-hydroxyimino-ethyl)chroman-2-yl)acetate from Example 4 and 91.5 L of distilled were sequentially added. With the aid of a pH controller, the pH of the stirring mixture was adjusted to 8 with an aqueous NaOH solution and the temperature was set to about 37°C. To this mixture was added 1.22 Kg of a PS 30 lipase (PS 30 from Pseudomonas Cepacia, Amano Enzyme Co., LTD, Lombard, IL). 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. After filtration and solvent removal by rotary evaporation 6.2 Kg (51% yield) of the ethyl 2-[(2R)-6-(N-hydroxyimino-ethyl)chroman-2-yl]acetate chiral ester was collected.

The basic filtrates containing the enriched (2S) enantiomer were transferred into the 200-L reactor and carefully with the aid of a pH controller the pH was adjusted to about 3.5 by a slow addition of 8.2 L of 3 N hydrochloric acid. The formed white suspension was collected by vacuum filtration and thoroughly rinsed with 30.5 L of distilled water. The product was transferred into six trays and dried in a vacuum oven at 60°C to afford 4.8 Kg (42% yield) of ethyl 2-[(2S)-6-(N-hydroxyimino-ethyl)chroman-2-yl]acetate as a white solid. Example 6

Optional racemization of ethyl 2-[(2R)-6-(N-hydroxyimino-ethyl)chroman-2-yl]acetate for recycling to increase yield of (2S) enantiomer

A 22 L 3-necked RB flask equipped with a heating mantle, condenser, overhead mechanical stirrer and thermocouple was charged with 12.4 L of ethanol, 6.2 Kg (22.4 moles) of the enriched ethyl 2-[(2R)-6-(N-hydroxyimino-ethyl)chroman-2-yl]acetate obtained in Example 5 and 420 mL (1.12 moles) of sodium ethoxide, 21% w/w in ethanol. The mixture was heated to 45°C and it became a clear solution (the pH of the reaction is 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 indicated complete reaction (initial OD = -98° and the final was +1° rotation). To the mixture was then added 80 mL of acetic acid and the mixture was allowed to cool to room temperature before the mixture was divided equally into two 20 L carboys containing 9.0 L of distilled water each. The two carboys were closed and shaken. The precipitate that was formed was filtered into a vacuum funnel. The combined portions of the filtered precipitate were rinsed with 6.8 L of distilled water to yield the racemic ethyl 2-[6-(N-hydroxyimino-ethyl)chroman-2- yljacetate as an overweight white solid. Essentially 100% of the starting material appeared to be conserved and the racemate was collected wet for recycling through the Example 5 enzyme resolution procedure. Example 7

Production of racemic, enriched (2S) or enriched (2R) ethyl 2-(6-aminochroman-2- yl)acetate

About 4.6 Kg of the dried enriched ethyl 2-[(2S)-6-(N-hydroxyimino-ethyl)chroman- 2-yl]acetate is obtained from Example 5. Alternatively, 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 50 L reactor was charged under nitrogen with 30.0 L of dichloromethane and 10.1 Kg (54.3 moles) of phosphorus pentachloride (95%). The stirring mixture was cooled to -5°C and the 4.6 Kg portion of the dried (2S), (2R) or (2R/2S) ethyl 2-(6-(N- hydroxyimino-ethyl)chroman-2-yl)acetate was added in small portions at such a pace that the temperature did not exceed 20°C. The mixture was stirred for 1 hour at room temperature.

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.

To the room temperature reaction mixture was added 10.0 liters of ethyl acetate. After stirring the reaction mixture for one hour the white suspension was filtered and the filter cake was washed with 5.0 L of ethyl acetate. The solvent filtrates were concentrated by rotary evaporation until very little solvent remained. This was filtered and this filter cake was added to the other filter cake. The combined white solid was washed with 5.0 L of ethyl acetate. The white solid was dried in a vacuum oven at 50°C to afford 4.4 Kg (87% yield) of either of the (2S), (2R) or (2R/2S) ethyl (6-aminochroman-2-yl)acetate. Example 8

Optional production of racemic, enriched (2S) or enriched (2R) ethyl 2-(6-aminochroman- 2-yl)acetate hydrochloride salt

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. Then 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. The solvent filtrates are concentrated by rotary evaporation until very little solvent remains and this solvent mixture is stirred and filtered. The resulting filter cake is added to the first filter cake. The combined white solid is washed with 5.0 L of ethyl acetate. The white solid is dried in a vacuum oven at about 50°C to afford 4.4 Kg (87% yield) of the (2R/2S) ethyl 2-(6-aminochroman-2-yl)acetate hydrochloride salt.

¹H-NMR (250 MHz, DMSO- 6),9.97 (s,(br), 3H), 7.05 (m, 2H, 6.80 (m, 1 H), 4.42 (qd, J = 7.5 Hz, 1.2 Hz, 1 H), 4.14 (q, J = 6.7 Hz, 2H), 2.88 (ddd, J = 16.5 Hz, 10.4 Hz, 5.2 Hz, 1 H), 2.80 (dd, j = 11.3 Hz, 6.7 Hz, 1 H), 1.70 (m, 4H), 1.22 (t, J = 6.7 Hz, 3H)

¹³C-NMR (62.9 MHz, DMSO-d6), 170.2, 153.4, 123.9, 123.1 , 121.9, 117.3, 72.6, 60.1 , 39.7, 25.9, 23.7, 14.1. Example 9 Production of Toluenic Solution of racemic (2R/2S) ethyl 2-(6-aminochroman-2-yl) acetate from the 6-amino hydrochloride salt

At room temperature the 1 Kg of ethyl 2-(6-aminochroman-2-yl)acetate hydrochloride salt of Example 8 is added to 6 L of toluene with stirring and 10% (w/w) aqueous sodium hydrogen carbonate is slowly added until the pH is above 7 and all of the salt has dissolved in the reaction mixture. The solution is stirred for about 15 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted twice with 2 L of toluene. The combined organic layers are distilled off under reduced pressure (T < 50°C) until the residue is about 6 L to yield a toluenic solution of ethyl 2-(6- aminochroman-2-yl)acetate.

¹H-NMR (400 MHz, CDCI₃) 6.61 (d, J = 8.9 Hz, 1 H), 6.46 (dd, J = 8.9 Hz, 2.5 Hz, 1 H), 6.40 (d, J = 2.5 Hz, 1H), 4.37 (qd, J = 7.5 Hz, 1.2 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2H), 3.22 (s, 2H), 2.81 (ddd, J = 16.5 Hz, 5.2 Hz, 4.1 Hz, 1 H), 2.58 (dd, J = 15.4 Hz, 7.4 Hz, 1 H), 2.02 (dm, J = 13.5 Hz, 1 H), 1.75 (m, 1 H), 1.07 (t, J = 7.2 Hz, 3H). ³C-NMR (100 MHz, CDCI₃) 107.9, 147.5, 139.4, 122.1 , 117.3, 115.9, 115.0, 72.1 , 60.6, 40.6, 27.3, 24.5, 14.2.

The examples given above are non-limiting in that one of ordinary skill in view of the above will readily envision other permutations and variations on these procedures without departing from the principal concepts, such permutations and variations being considered as falling within the scope of the invention as disclosed herein in reference to preferred embodiments.

Claims

WHAT IS CLAIMED IS:

1. A process for making a compound according to the formula

wherein R is H or an alkyl group, comprising:

(b) condensing the hydroxychromane compound produced in (a) above with (carbethoxymethylene)-triphenylphosphorane in the presence of an ethoxide base with heating to afford the acetate compound as follows:

triphenylphosphorane

(e) converting the 6-(N-hydroxyimino-ethyl) group of the product of (d) to an amino group via a Beckman re-arrangement followed by heating in alcohol, cooling the mixture to about room temperature, and adding concentrated HX, where X is a halogen, in ethyl acetate or EtOH to the mixture to form an insoluble amine hydrohalide salt and yield ethyl 2-[6-aminochroman-2-yl]acetate hydrohalide (hydrochloride) as follows:

Cone. HX

2. The process according to Claim 1 , further comprising forming the free acetic acid side chain or performing a transestehfication process step to provide a compound of the formula:

wherein R is selected from H, lower alkyl, lower alkenyl, lower alkynyl, phenyl, and cinnamyl.

3. The process according to Claim 2, wherein the acid or ester compound is obtained as a salt.

4. The process according to Claim 2, wherein the carbonyl reducing compound in (a) is DIBAL-H; the solvent in (b) is toluene at a temperature of about 50-100 °C; the ethoxide base in (b) is sodium ethoxide; the acetylation in (c) is done in dichloromethane at a temperature of about - 20-25°C; the Friedel Crafts reaction in (c) uses acetyl chloride and 2.0 to 4.0 equivalents of aluminum chloride as the Lewis Acid; the reaction in (d) is performed in ethanol at a temperature of about 15°C to about 40°C; and the Beckman rearrangement in (e) is performed using PCI₅

5. The process according to Claim 1 , wherein the carbonyl reducing compound in (a) is DIBAL-H; the solvent in (b) is toluene at a temperature of about 50-100 °C; the ethoxide base in (b) is sodium ethoxide; the acetylation in (c) is done in dichloromethane at a temperature of about - 20-25°C; the Friedel Crafts reaction in (c) uses acetyl chloride and 2.0 to 4.0 equivalents of aluminum chloride as the Lewis Acid; the reaction in (d) is performed in ethanol at a temperature of about 15°C to about 40°C; and the Beckman rearrangement in (e) is performed using PCI₅.

6. The process according to claim 1 , for making a compound according to the formula:

. HCI

7. The process of Claim 1 , further comprising 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:

wherein 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.

8. The process according to Claim 7, wherein the resolving process fruther comprises: filtering the basic solution to separate it from solids formed during the resolution; putting the solids, comprising lipase biomass and enriched (2R>2S) enantiomer ester, remaining in the filter; and recovering the hydrolyzed acid (2S>2R) by neutralizing the filtrate to reform a water-insoluble free acid from the salt and recover enriched (2S) enantiomer.

9. The process according to Claim 8, further comprising rinsing the solids remaining in the filter with ethyl acetate solvent or similar solvent, filtering the solvent, and evaporating the solvent to recover enriched (2R) enantiomer.

10. The process according to Claim 8, further comprising re-esterifying the enriched (2S>2R) acid followed by racemizing the ester by exposing the enriched ester to a basic alcoholic solution in the alcohol corresponding to the ester or in an inert solvent.

11. The process according to claim 10, wherein the racemizing comprises using a catalytic amount of sodium ethoxide, potassium ethoxide in ethanol, until the desired degree of racemization is completed at a temperature of from about 20°C to about 60°C, as follows:

acidifying the mixture with an acid to quench the base and form a soluble salt with the base; and adding a volume of water 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, and recovering the ester as a precipitate.

12. The process according to claim 11 , comprising conducting the racemization at a temperature of about 45°C.

13. The process according to Claim 8, further comprising re-esterifying the enriched (2R>2S) acid followed by racemizing the ester by exposing the enriched ester to a basic alcoholic solution in the alcohol corresponding to the ester or in an inert solvent.

14. The process according to claim 13, wherein the racemizing comprises using a catalytic amount of sodium ethoxide, potassium ethoxide in ethanol, until the desired degree of racemization is completed at a temperature of from about 20°C to about 60°C, as follows:

15. The process according to claim 14, comprising conducting the racemization at a temperature of about 45°C.