Process for the preparation of 1,4-dihydro-4-oxoquinoline-2-carboxylates and 4-aminoquinoline compounds therefrom

Abstract

Methods for the preparation of alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylic acid esters are described herein.

Description

Technical Field

[0001] The present invention relates to a method for preparing certain 1,4-dihydro-4-oxoquinoline-2-carboxylic acid esters. In particular, the invention relates to the improved preparation of 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylic acid esters and the subsequent conversion of the oxoquinoline esters to 4-aminoquinoline compounds (including the acids and their esters).

Background Art

[0002] 4-Ureido-5,7-dihalo-quinoline-2-carboxylate compounds, particularly diphenylureido-dichloroquinurenic acid (DCUKA) compounds and their esters, have been reported to have analgesic activity and be useful for the treatment of chronic pain and alcohol dependence, as well as for the prevention of relapse in alcoholics. One difficulty in the commercial development of 4-ureido-5,7-dihalo-quinoline-2-carboxylate compounds has been the harsh conditions required for the preparation of 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate, an intermediate in the synthesis of 4-ureido-5,7-dihalo-quinoline-2-carboxylate compounds. The published approach for preparing DCUKA ester compounds (e.g., methyl ester or ethyl ester) is illustrated for the ethyl (Et) ester in Scheme 1. Reaction A in Scheme 1 below involves heating a mixture of 3,5-dichloroaniline 1 and diethyl acetylenedicarboxylate (e.g., 2 in tetrahydrofuran (THF)) at about 70 °C to obtain Michael adduct 3. Reaction B involves heating Michael adduct 3 in diphenyl ether solvent at about 250 °C to obtain ethyl 5,7-dichloro-1,4-dihydro-4-oxoquinoline-2-carboxylate 4. Next, the ester 4 is reacted with chlorosulfonyl isocyanate in acetonitrile, followed by quenching with hydrochloric acid (collectively reaction C) to obtain ethyl 4-amino-5,7-dichloro-quinoline-2-carboxylate 5, which is then reacted with diphenylcarbamoyl chloride in the presence of NaH in dimethylformamide (DMF) to obtain the DCUKA ethyl ester (reaction D), or alternatively, the DCUKA acid can be isolated by in situ hydrolysis of the ester group if desired. Reaction B in Scheme 1 is a potential obstacle to the commercial-scale production of DCUKA compounds due to the high temperature of the reaction, the expense of the solvent, and the difficulties in product purification and solvent recovery. The methods described herein address this problem.

[0003] [Chemical Formula] SUMMARY OF THE INVENTION

[0004] The following describes a method for preparing an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate of formula IV herein. This method involves reacting a dialkyl 1-(3,5-dihalophenylamino)ethylene-1,2-dicarboxylate compound of formula III with P in methanesulfonic acid in a heated continuous flow reactor 2 O 5 (often called the Eaton's reagent) to cyclize and form an alkyl 1,4-dihydro-4-oxoquinoline-2-carboxylate of formula IV. Optionally, a co-solvent such as dichloromethane can be included with the Eaton's reagent. A method for preparing a diphenylureido-dihaloquinurenic acid ester of formula VI from an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate of formula IV is also described. Diphenylureido-dihaloquinurenic acid alkyl esters (e.g., DCUKA ethyl ester) are analgesics useful for the treatment of chronic pain and alcohol dependence, and for the prevention of relapse in alcoholics. Scheme 2 summarizes the synthesis of a diphenylureido-dihaloquinurenic acid alkyl ester of formula VI by the method described herein.

[0005] [Chemical Formula]

[0006] In the compounds of formula I, II, III, IV, V and VI of Scheme 2, each X is independently a halogen, for example, F, Cl, Br or I, and each R is a C 1 ~C 4 alkyl group, for example, methyl (Me), ethyl (Et), propyl (Pr), isopropyl (iPr), butyl (Bu), etc. In one preferred embodiment, each X is Cl. In another preferred embodiment, each R is ethyl. In yet another preferred embodiment, each X is Cl and each R is ethyl.

[0007] In Scheme 2, reaction (a) is typically a Michael addition reaction that involves adding a dialkyl acetylenedicarboxylate of formula II to a heated solution of a 3,5-dihaloaniline of formula I. The dialkyl 1-arylamino-ethylene-1,2-dicarboxylate Michael adduct of formula III can be isolated and purified, and can be used in crude form in reaction (b).

[0008] The previously reported cycloacylation of compound 3 (formula III where each X is Cl and each R is ethyl) by Tabakoff et al. is entirely thermally driven by heating a solution of compound 3 at about 250 °C in a high boiling point solvent such as diphenyl ether (shown as reaction A in Scheme 1). This reaction is typically carried out in a batch reactor and may be difficult to carry out in a flow reactor due to the high temperature and relatively low solubility of the product. The high temperature required for the reaction also poses safety problems. Under the high temperature conditions of the reaction, any aniline present in the reaction will react with the ester group to form an amide, so compound 3 must not contain relatively unreacted 3,5-dichloroaniline (compound 1).

[0009] In the method described herein, the cycloacylation of the Michael adduct of formula III to form a 1,4-dihydro-4-oxoquinoline compound of formula IV, reaction (b) of Scheme 2, is carried out at a temperature much lower than conventional thermal cycloacylation using P 2 O 5 (e.g., about 7 to about 10 weight % (wt%) of P in methanesulfonic acid 2 O 5 , also known as Eaton's reagent). As described herein, reaction (b) is carried out in a flow reactor using neat Eaton's reagent as the sole solvent or using Eaton's reagent with a hydrocarbon co-solvent or a halogenated hydrocarbon co-solvent.

[0010] The use of Eaton's reagent has been reported by Zewge et al. (J. Org. Chem., 2007, 71: 4276-4279) for the cycloacylation of aniline derivatives having other substitution patterns on the phenyl ring, while the cycloacylation reaction with 3,5-disubstituted-aniline Michael adducts such as compound 3 in Scheme 1 has not been reported or suggested. In fact, Zewge et al. reported that the cycloacylation of aniline derivatives with Eaton's reagent does not proceed effectively in the presence of a co-solvent, and aniline derivatives having a meta substituent provide a complicated reaction profile (footnote 15), and in the case of the meta-methoxyaniline compound (footnote 22), it has a yield of only 30% of the desired product. Therefore, the effective cycloacylation of the 3,5-dihaloaniline Michael adduct of formula III with Eaton's reagent is unexpected. Even more surprisingly, considering the very negative results reported by Zewge et al. using a co-solvent, a co-solvent can be included with Eaton's reagent in the flow reaction.

[0011] Another unexpected advantage of using Eaton's reagent in the cycloacylation reaction (b) is that a relatively high level (up to 25% or more) of the unreacted dihaloaniline of formula I (e.g., compound 1) can be present during cycloacylation without significantly inhibiting the reaction. Thus, in one preferred embodiment, an isolated crude product of formula III obtained from the Michael addition, reaction (a), containing a significant amount of the unreacted aniline of formula I is used in the cycloacylation without further purification other than isolating the crude product from the solvent used in the Michael addition reaction.

[0012] The crude product of formula IV obtained from the cycloacylation reaction can be isolated by grinding the product-containing portion of the effluent from the flow reactor (e.g., by adding the effluent to cold water) to obtain the crude 1,4-dihydro-4-oxoquinoline of formula IV as a granular solid precipitate. The granular solid is then purified by slurrying the precipitate while gently heating it in a solvent (e.g., acetonitrile, methanol, or isopropanol, preferably isopropanol or acetonitrile) (e.g., at about 40 °C) to drive impurities into the liquid phase, and then recovering the remaining solid from the slurry (e.g., by filtration) to obtain a sufficiently purified (more than 90% by HPLC) compound of formula IV.

[0013] Reaction (c) of Scheme 2 converts the 1,4-dihydro-4-oxoquinoline of formula IV to the 4-aminoquinoline compound of formula V by reaction of a 1,4-dihydroquinoline compound with chlorosulfonyl isocyanate in an aprotic solvent (e.g., acetonitrile). The crude 4-aminoquinoline product can be purified by gently heating the product in a solvent (e.g., ethyl acetate, ethanol, or isopropanol) (e.g., at about 50 °C) to drive impurities into the liquid phase and recovering the remaining solid from the slurry to obtain a sufficiently purified (more than 90% by HPLC) compound of formula V.

[0014] Reaction (d) of Scheme 2 is the conversion of the 4-aminoquinoline compound of formula V to the diphenylureido-dihaloquinurenic acid ester of formula VI by reaction with diphenylcarbamoyl chloride in the presence of a base (e.g., sodium hydride) in a polar aprotic solvent (e.g., dimethylacetamide, "DMAc").

[0015] The following non-limiting embodiments are provided to illustrate the methods described herein.

[0016] The first embodiment is a method for preparing an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate. This method includes the following consecutive steps.

[0017] (i) A solution containing a compound of formula III dissolved in a reagent containing about 7 to about 10 wt% of P 2 O 5 is fed through a continuously flowing heated reactor coil heated at a selected temperature in the range of about 65 to about 75 °C at a feed rate sufficient to provide a residence time of about 15 to 40 minutes in the heated coil at a concentration of about 0.15 to about 0.25 grams of the compound of formula III per mL of reagent, thereby heating the first solution, and collecting the effluent flowing out of the heated coil containing the alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate of formula IV.

[0018]

Chemical formula

[0019]

Chemical formula

[0020] Also, this method can, if desired, include the purification of the ester of formula IV. The purification is carried out as follows.

[0021] (iv) A suspension containing the precipitate obtained from step (iii) in a solvent (for example, about 3 to about 10 mL of solvent per 1 g of precipitate) is stirred at a temperature in the range of about 40 to 50 °C for at least about 1 hour, followed by (v) Recovering the undissolved solid particles containing the purified ester of formula IV from the suspension (for example, by filtration or centrifugation), wherein the solvent is an organic solvent selected from the group consisting of acetonitrile, methanol, isopropanol, and combinations of two or more thereof. For the purification of the ester of formula IV, acetonitrile and isopropanol are preferred solvents.

[0022] A second embodiment is a method for preparing an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate, which comprises the following successive steps.

[0023] (i) A solution containing about 15 to about 60 wt% of the dihaloaniline of formula I in an aprotic solvent (for example, tetrahydrofuran (THF), 2-methyl THF, etc.) is contacted with at least about 0.9 equivalent of the dialkyl acetylenedicarboxylate of formula II at a selected temperature of about 70 to about 100 °C for about 6 to about 24 hours to form a compound of formula III,

[0024]

Chemical formula

[0025] [Chemical formula] (iv) The effluent collected in step (ii) is added to cold water in an amount of about 5 volumes or more per volume of the effluent while stirring, while maintaining the water temperature at about 15 °C or lower, to form a precipitate containing the ester of formula IV, and (v) The precipitate is collected (for example, by filtration or centrifugation). Here, in formula I, formula II, formula III and formula IV, each X is independently a halogen atom (for example, Cl), and each R is independently C 1 ~C 4 alkyl (for example, Et). Optionally, step (iii) can be carried out in the presence of a hydrocarbon co-solvent or a halogenated hydrocarbon co-solvent (for example, dichloromethane).

[0026] The method of the second embodiment can also optionally include purifying the ester of formula IV. The purification is carried out as follows.

[0027] (vi) A suspension containing the precipitate obtained from step (v) in a solvent (for example, about 3 to about 10 mL of solvent per 1 g of precipitate) is stirred at a temperature in the range of about 40 to 50 °C for at least about 1 hour, where the solvent is selected from the group consisting of acetonitrile, methanol, isopropanol, and combinations of two or more thereof, and then (vii) The undissolved solid particles containing the purified ester of formula IV are recovered from the suspension (for example, by filtration or centrifugation). Acetonitrile and isopropanol are preferred solvents for purifying the ester of formula IV, as in the first embodiment.

[0028] The third embodiment performs steps (i), (ii), and (iii) of the first embodiment, and then (iv) The ester of formula IV is purified by stirring a suspension of the precipitate obtained from step (iii) in a solvent at a temperature in the range of about 40 to 50 °C for at least about 1 hour, wherein the first solvent is selected from the group consisting of acetonitrile, methanol, isopropanol, and combinations of two or more thereof (acetonitrile and isopropanol are preferred solvents for purifying the ester of formula IV), and then (v) Recovering undissolved solid particles containing the purified ester of formula IV from the suspension, (vi) A solution containing the purified ester of formula IV in a polar aprotic solvent (e.g., acetonitrile, THF, 2-methyl-THF) is contacted with chlorosulfonyl isocyanate at a temperature of about 40 to about 80 °C until the evolution of carbon dioxide gas ceases, (vii) To the solution from step (vi), an acid (e.g., a strong acid such as HCl) in a C 1 ~C 4 alcohol (e.g., methanol, ethanol, isopropanol, propanol, butanol, etc.) is added, and the resulting acidic mixture is heated at a temperature of about 65 to about 75 °C (e.g., about 70 °C) to form the 5,7-dihalo-4-aminoquinoline-2-carboxylic acid ester of formula V (preferably, the alcohol is selected to have the same alkyl substituent as R),

[0029] [Chemical formula] (viii) Isolating the ester of formula V, (ix) A solution containing the ester of formula V isolated in step (viii) in a polar aprotic solvent (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, propylene carbonate, combinations of two or more thereof) is contacted with diphenylcarbamoyl chloride in the presence of a base to form the diphenylureido-dihaloquinurenic acid ester of formula VI,

[0030] [Chem.] Here, the base is selected from the group consisting of alkali metal hydroxides (e.g., LiOH, KOH, or NaOH) and alkali metal hydrides (e.g., NaH or KH), preferably, the base is NaH (e.g., 60% NaH) or NaOH, and (x) isolating the diphenylureido-dihaloquinurenic acid ester of formula VI, Here, in formula I, formula II, formula III, formula IV, formula V, and formula VI, each X is independently a halogen atom (e.g., Cl), and each R is independently C 1 ~C 4 alkyl (e.g., Et), a method for preparing an alkyl diphenylureido-dihaloquinurenate. Optionally, step (iii) can be carried out in the presence of a hydrocarbon cosolvent or a halogenated hydrocarbon cosolvent (e.g., dichloromethane).

[0031] The ester of formula V can be isolated in step (viii) by any desired method. In some embodiments, the ester of formula V can be isolated in step (viii) by adjusting the pH of the acidic mixture of step (vii) to about 9 to about 10 to form a second precipitate comprising the ester of formula V, and the second precipitate is then recovered, for example, by filtration or centrifugation.

[0032] The method of the third embodiment can also include, if desired, purifying the ester of formula V. The purification is carried out as follows.

[0033] (a) A suspension of the ester of formula V isolated in step (viii) in a solvent (e.g., about 5 to about 10 mL of solvent per 1 g of the ester of formula V) is stirred at a temperature in the range of about 40 to 50 °C for at least about 1 hour, where the third solvent is C 2 ~C 3 alcohol (e.g., ethanol or isopropanol), C 2~C 3 selected from the group consisting of alkyl acetates (e.g., ethyl acetate or isopropyl acetate), and combinations thereof, (b) After cooling the suspension of step (a) to a temperature of about 20 - 25 °C, recovering the undissolved solid particles containing the purified ester of formula V from the suspension (such as by filtration or centrifugation). Ethanol, isopropanol and ethyl acetate are preferred solvents for purifying the ester of formula V.

[0034] The diphenylureido-dihaloquinurenic acid ester of formula VI can be isolated in step (x) by any desired method. In some embodiments, the ester of formula VI is isolated in step (x) by adding the solution from step (ix) with stirring to about 28 - about 30 volumes of an aqueous acid (e.g., 10 wt% acetic acid) to form a precipitate containing the ester of formula VI, which precipitate is then recovered, for example, by filtration or centrifugation.

[0035] If desired, the method of the third embodiment can similarly include the purification of the diphenylureido-dihaloquinurenic acid ester of formula VI. The purification is carried out as follows.

[0036] (c) Forming a solution containing the ester of formula VI isolated in step (x) in a solvent mixture comprising a water-immiscible solvent or at least one water-immiscible solvent (e.g., dichloromethane, ethyl acetate / ethanol mixture, methyl-t-butyl ether, 2-methyl-THF), and subsequently washing the solution successively with an aqueous base and then an aqueous acid, (d) Removing all the residual solvent from the solution of step (c) to recover a residue containing the ester of formula VI, (e) Stirring a suspension in a solvent containing the residue from step (d) (e.g., about 5 - about 10 mL of solvent per 1 g of residue) at a temperature in the range of about 40 - 50 °C for at least about 1 hour, where the solvent comprises one or more C 2 ~C 3 alcohols (e.g., ethanol, propanol, or isopropanol), and (f) After cooling the suspension from step (e) to a temperature of about 20 - 25 °C, undissolved solids or particles containing the purified ester of formula VI are recovered from the suspension (e.g., by filtration or centrifugation). Ethanol and isopropanol are preferred solvents for purifying the ester of formula VI.

[0037] The fourth embodiment performs steps (i), (ii), (iii), (iv) and (v) of the second embodiment, and then (vi) The suspension containing the precipitate obtained from step (v) in a solvent is stirred at a temperature in the range of about 40 - 50 °C for at least about 1 hour to purify the ester of formula IV, wherein the second solvent is selected from the group consisting of acetonitrile, methanol, isopropanol, and combinations of two or more thereof, (vii) Undissolved solid particles containing the purified ester of formula IV are recovered from the suspension of step (vi), (viii) The solution containing the purified ester of formula IV is contacted with chlorosulfonyl isocyanate in a polar aprotic solvent (e.g., acetonitrile) at a temperature of about 40 - about 80 °C until the evolution of carbon dioxide gas ceases, (ix) C 1 ~C 4 A strong acid (e.g., HCl) in an alcohol (e.g., methanol, ethanol, isopropanol, propanol, butanol, etc.) is added to the solution of step (viii), and the resulting acidic mixture is heated at a temperature of about 65 - about 75 °C (e.g., about 70 °C) to form the 5,7-dihalo-4-aminoquinoline-2-carboxylic acid ester of formula V (preferably, the alcohol is selected to have the same alkyl substituent as R),

[0038] [Chemical formula] (x) The ester of formula V is isolated, (xi) A solution containing the ester isolated in step (x) in an aprotic polar solvent (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, propylene carbonate, or a combination of two or more thereof) is contacted with diphenylcarbamoyl chloride in the presence of a base to produce a diphenylureido-dihaloquinurenic acid ester of formula VI,

[0039]

Chemical formula

[0040] The ester of formula V can be isolated in step (x) by any desired method. In some embodiments, the ester of formula V is isolated in step (x) by adjusting the pH of the acidic mixture of step (ix) to about 9 - 10 to form a second precipitate containing the ester of formula V, and then the precipitate is recovered, for example, by filtration or centrifugation.

[0041] The method of the fourth embodiment can also, if desired, include the purification of the ester of formula V. The purification is carried out as follows.

[0042] (a) A second suspension containing the ester of formula V isolated in step (x) in a solvent (e.g., about 5 to about 10 mL of solvent per gram of the ester of formula V) is stirred at a temperature in the range of about 40 to 50 °C for at least about 1 hour, where the solvent is selected from the group consisting of C 2 ~C 3 alcohols (e.g., ethanol or isopropanol), C 2 ~C 3 alkyl acetates (e.g., ethyl acetate or isopropyl acetate), and combinations thereof (preferably ethanol, isopropanol, or ethyl acetate). (b) After cooling the suspension from step (a) to a temperature of about 20 to 25 °C, the undissolved solid particles containing the purified ester of formula V are recovered from the suspension (by filtration, centrifugation, etc.).

[0043] The diphenylureido-dihaloquinurenic acid ester of formula VI can be isolated in step (xii) by any desired method. In some embodiments, the ester of formula VI is isolated in step (xii) by adding the solution from step (xi) with stirring to an aqueous acid (e.g., 10 wt% acetic acid) up to about 26 to about 30 volumes to form a precipitate containing the ester of formula VI, and the precipitate is recovered, for example, by filtration or centrifugation.

[0044] If desired, the method of the third embodiment can similarly include the purification of the diphenylureido-dihaloquinurenic acid ester of formula VI. The purification is carried out as follows.

[0045] (c) A solution containing the ester of formula VI isolated in step (xii) in a water-immiscible solvent (dichloromethane, ethyl acetate, methyl-t-butyl ether, methyl ethyl ketone, combinations thereof, etc.) is formed, and the solution is successively washed with an aqueous base and then an aqueous acid. (d) Remove the solvent from step (c) to recover a residue containing the ester of formula VI, (e) Stir a suspension in a solvent containing the residue from step (d) (e.g., about 5 to about 10 mL of a fifth solvent per 1 g of the second residue) at a temperature in the range of about 40 to 50 °C for at least about 1 hour, where the solvent is one or more C 2 ~C 3 alcohol (e.g., ethanol, propanol, or isopropanol, preferably ethanol or isopropanol), (f) After cooling the suspension of step (e) to a temperature of about 20 to 25 °C, recover the undissolved solid particles containing the purified ester of formula VI from the suspension (e.g., by filtration or centrifugation).

[0046] If desired, the purified ester of formula VI can be converted by hydrolysis to the corresponding carboxylic acid (e.g., DCUKA) or its salt. Further, the carboxylic acid or carboxylate salt can be converted to an addition salt with a strong acid such as p-toluenesulfonic acid so that the heterocyclic nitrogen of diphenylureido-dihaloquinurenic acid is protonated.

Brief Description of the Drawings

[0047]

Figure 1

Mode for Carrying Out the Invention

[0048] As described above, the previously reported procedure for the synthesis of DCUKA ethyl ester and methyl ester (shown in Scheme 1 for the ethyl ester) was to treat 3,5-dichloroaniline 1 with diethyl acetylenedicarboxylate 2 in THF under reflux conditions to obtain the Michael adduct 3, which was then 2In (O), it starts with a four-step process that involves cyclizing by heat at 250 °C to obtain ethyl 5,7-dichloro-1,4-dihydro-4-oxoquinoline-2-carboxylate 4. Next, ester 4 is treated with chlorosulfonyl isocyanate under reflux conditions to obtain 4-aminoquinoline 5. Then, the amino group of compound 5 is reacted with diphenylcarbamoyl chloride in DMF in the presence of NaH to obtain the target DCUKA ethyl ester 6. Ester 6 and its corresponding acid (where the ethyl group, Et, is replaced by H) are analgesics and are useful for the treatment of chronic pain and alcohol dependence, among other related pathologies.

[0049] This specification includes the use of a solution of phosphorus pentoxide in methanesulfonic acid (also known as the Eaton reagent) for the cycloacylation reaction, eliminates the need for high temperatures in the cycloacylation reaction, and describes an important advancement in the synthesis of DCUKA esters suitable for use under flow reactor conditions.

[0050] <Azamichael reaction (a) of Scheme 2> As exemplified by the preparation of compound 3 (Formula III where each X is Cl and each R is Et), the aza-Michael reaction involves dropping a THF solution of about 1.1 equivalents (eq) of diethyl acetylenedicarboxylate 1 into a THF solution of about 1 eq of 3,5-dichloroaniline 2, and then heating the resulting mixture at about 70 °C for several hours (h), e.g., about 4 - 7 h, to produce the crude Michael addition product 3 as a mixture of cis and trans isomers. Compound 3 was obtained with a conversion of about 75% (based on the consumption of 3,5-dichloroaniline 1) under these conditions, and this reaction was not improved even when heated for 24 h. Unless otherwise stated, the conversion was determined by HPLC area under the curve (AUC) measurement as described elsewhere in this specification. The conversion to compound 3 can be further increased to about 98% by adding an additional 0.5 eq of diethyl acetylenedicarboxylate and heating at 70 °C for an additional about 22 h. However, since diethyl acetylenedicarboxylate is not thermally stable and decomposes with significant energy release, it is preferred to limit the charge of diethyl acetylenedicarboxylate to less than 1 equivalent (e.g., about 0.9 eq) for safety reasons. When about 75% of 3,5-dichloroaniline (measured by HPLC) is consumed, THF is removed by distillation, and the crude mixture of Michael adducts can be used directly in the subsequent cycloacylation reaction to produce compound 4 as described below. This procedure was found to be suitable for the production of Michael adduct materials on a multi-kilogram scale.

[0051] <Cycloacylation (b) of Scheme 2> The cycloacylation step to form a compound of Formula IV, such as compound 4 (Formula IV where x is Cl and R is Et), was originally carried out in diphenyl ether at 250 °C. Attempts to perform this reaction in a continuous flow reactor under such conditions to provide a more practical large-scale synthesis led to the partial precipitation of the cyclization product from diphenyl ether in the reactor system, causing dangerous conditions due to high backpressure. To avoid this problem, alternative cycloacylation methods were investigated.

[0052] The cycloacylation of the compound of formula III (e.g., compound 3) and its compatibility with highly acidic Eaton's reagent were investigated on a small scale by a bulk reaction of compound 3 with neat Eaton's reagent at a concentration of about 4 - 6 mL of Eaton's reagent per gram of compound 3 (also referred to as 4 - 6 volumes of Eaton's reagent for convenience). The reaction was carried out at 60 °C, and the reaction was monitored by high-performance liquid chromatography (HPLC). The HPLC results showed the consumption of compound 3 with the formation of a new peak without significant by-products.

[0053] The small-scale bulk cycloacylation was successful, and this procedure was investigated and further optimized under flow conditions. The cycloacylation of compound 3 (having two meta-chloro substituents) with neat Eaton's reagent proceeded surprisingly well under flow conditions even with crude compound 3 containing 20 - 25% unreacted dichloroaniline (compound 1). The flow reaction provided a significantly higher conversion rate (e.g., 85 - 95% based on the initial amount of compound 3) compared to the bulk cycloacylation reaction of compound 3 (which provided only about 75% conversion after about 2 hours of heating and no further increase in conversion thereafter). Unexpectedly, a co-solvent (e.g., dichloromethane) did not significantly inhibit the cycloacylation reaction under flow conditions, in contrast to the results reported by Zewge et al. (footnote 15) which showed that the co-solvent almost stopped the reaction within at least the 20-hour reaction time frame investigated.

[0054] Advantageously, crude compound 3 containing about 75 mol% of 3 and about 20 - 25% unreacted 3,5-dichloroaniline 1 can be utilized in cycloacylation with Eaton's reagent without significant inhibition from the unreacted aniline compound. For example, in a reaction using about 10 g of crude compound 3 dissolved in about 40 mL (4 volumes) of Eaton's reagent at 70 °C, with a residence time of 20 minutes and a back pressure of about 15 pounds per square inch (psi), a crude product containing about 73% of 4 and about 22% of 3,5-dichloroaniline was obtained based on AUC measurements from HPLC data, indicating that compound 3 in the crude starting material was very highly converted to compound 4 (e.g., over 95%).

[0055] As described above, under flow reactor conditions, the cycloacylation reaction also proceeds surprisingly well using a co-solvent added to the Eaton's reagent. This is in stark contrast to what was reported in a similar cycloacylation using Eaton's reagent and co-solvents (toluene, xylene, sulfolane) in a bulk reaction at solvent-to-Eaton's reagent ratios of 1:1 and 2:1 (reported by Zewge et al. to be extremely slow, with the best conversion being only about 3% after 20 hours at 100 °C using a 1:1 toluene / Eaton's reagent (Zewge et al., footnote 15)).

[0056] <Isolation of the Compound of Formula IV> As shown by the formation of Compound 4 in the reaction of crude Compound 3 with Eaton's reagent, the crude product from the cycloacylation reaction (Reaction (b) in Scheme 2) can be easily isolated as a granular solid by trituration, for example, by adding the product-containing effluent to cold (e.g., 0 - 15 °C) water (typically about 5 - 20 volumes of water per volume of effluent) with vigorous stirring (typically over several minutes to several hours), allowing the product to precipitate, then filtering to recover the precipitate, and drying the recovered precipitate under vacuum. Optionally, the water can contain a base to neutralize or partially neutralize methanesulfonic acid and any phosphoric acid that may form upon addition of the effluent to the water. This trituration procedure can be used even when a co-solvent such as dichloromethane is present in the effluent.

[0057] The crude precipitate, which may still contain some unreacted Compound 3, a significant amount of unreacted 3,5-disubstituted aniline 1, and some by-products, can be further purified by slurrying the crude Compound 4 in an aqueous solution of a basic salt such as sodium acetate (e.g., about 5 - 20 mL of salt solution per gram of crude Compound 4). Alternatively, or in addition, the crude Compound 4 can be purified using an organic solvent in which the product has moderate to low solubility, e.g., C 1 ~C 3It can be purified by slurrying the solid in alcohol (e.g., methanol or isopropanol) or acetonitrile. With isopropanol and acetonitrile, a purity of up to 95% can be obtained, and a recovery rate of up to 90% of the theoretical amount of the target product in the crude solid product can be obtained.

[0058] <Amination (c) of Scheme 2> Using the available high-quality Compound 4, the evaluation of the amination reaction was initiated. Chlorosulfonyl isocyanate was added to a suspension of Compound 4 in acetonitrile at 23 °C. According to the literature, chlorosulfonyl isocyanate is one of the most reactive isocyanates, but no exotherm was observed during the addition. After the addition was complete, the mixture was heated to reflux (about 75 - 80 °C) for about 1 hour, during which the reaction was monitored by HPLC. When the temperature reached about 40 - 45 °C, the reaction mixture became a clear brown solution, and continuous evolution of CO 2 was observed, which stopped at a temperature of about 65 - 70 °C. A new broad peak appeared in the HPLC profile, and at the same time, Compound 4 was consumed. At this point, the mixture was cooled to about 35 - 40 °C, 1.5 M HCl in methanol was added, and then it was further heated to reflux at about 70 °C for 1 hour to quench the intermediate product formed in the first reaction and release the 4-aminoquinoline product, Compound 5. The progress of the reaction to release the product was confirmed by the appearance of a new peak in the HPLC profile accompanied by the disappearance of the broad peak.

[0059] <Isolation of the compound of formula V> As part of the initial optimization, 0.5 N NaOH was added directly to the reaction mixture at 0 - 5 °C, and the pH of the mixture was adjusted to about 9 - 10 as measured with a pH meter. The resulting thick slurry was filtered, washed with water to recover a yellowish-brown filter cake, which was conditioned at 40 - 45 °C. The HPLC purity of the filter cake was evaluated to be about 88%, and no disappearance of the product in the filtrate and washings was observed.

[0060] Since some transesterification from ethyl to methyl was observed with HCl in methanol, this procedure was modified to use HCl-ethanol instead. Thus, the alcohol used in the quench solution preferably has the same alkyl group as the ester in the reaction product. To enhance the safety of the method, it is preferred to add chlorosulfonyl isocyanate to the solution of compound 5 at about 70 °C instead of 23 °C, whereby the generation of CO 2 during the entire addition is controlled. According to this procedure, crude compound 5 is isolated in a maximum yield of 93% and a maximum purity of 90%.

[0061] <Purification of the crude compound of formula V> The crude compound 5 was easily purified by slurrying in various solvents including ethanol, isopropanol, and ethyl acetate. For example, when slurried in 3 - 5 volumes of isopropanol (i.e., 3 - 5 mL per 1 g of the crude product), about 85% of compound 5 was recovered with a purity of 94 - 97% as measured by HPLC. Similar results were obtained with 3 - 5 volumes of ethanol, although the recovery rate was slightly lower (64 - 72%) and the purity was slightly higher (98 - 99%). Slurry purification with about 3 - 10 volumes of ethyl acetate gave the highest recovery rate (88 - 90%) with an HPLC purity of 93 - 97%.

[0062] <Carbamylation ((d) in Scheme 2)> The carbamylation of the compound of formula V to produce the diphenylureido-dihaloquinurenic acid ester of formula VI is exemplified by the conversion of compound 5 to DCUKA ethyl ester 6. The carbamylation is carried out by adding diphenylcarbamoyl chloride to a solution of the compound of formula V, such as compound 5, in a polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), propylene carbonate (PC), etc., in the presence of an alkali metal hydroxide such as NaOH or an alkali metal hydride such as NaH. DMAc is the preferred solvent for this reaction and 60% sodium hydride is the preferred base.

[0063] A number of bases were evaluated for this reaction. Both lithium hexamethyldisilazide and sodium hexamethyldisilazide (LiHMDS and NaHMDS) in THF solvent resulted in the loss of compound 5 as determined by HPLC. Instead, the acid form of compound 5 (where Et is replaced by H) was formed without the formation of the desired DCUKA ethyl ester compound 6. Similar results were also observed with potassium tert-butoxide and sodium ethoxide. Weaker bases such as pyridine, diisopropylethylamine in toluene, and cesium carbonate in DMF were also unable to give the desired product, similar to solvent-free pyridine.

[0064] The use of NaH in THF was also unsuccessful, but the reaction was effective in DMF, DMAc, NMP, and propylene carbonate (PC). The use of NaOH and LiOH in DMAc did result in the formation of compound 6. NaOH gave a conversion rate of 85 - 90%, but a longer reaction time (16 hours) was required. LiOH gave a conversion rate of only 25% in DMAc. Overall, the use of 60% NaH in DMAc solvent provided a shorter reaction time, the highest conversion rate, and the best safety for large-scale batches because DMAc is essentially inert in the presence of NaH. In summary, 60% NaH in DMAc provided the target product with a conversion rate of over 95% within 1 hour after complete addition of the base.

[0065] <Isolation and purification of the compound of formula VI> The quenching method was evaluated at the completion of the carbamylation reaction as confirmed by HPLC. First, the reaction mixture was gradually charged into cold water (0 - 5 °C) to precipitate the product. This procedure does work, but some hydrolysis of the ester group can occur, so to avoid hydrolysis of the ethyl ester in Compound 6, it is desirable to quench the reaction in an acidic solution such as 10 wt% acetic acid (AcOH). The crude yield of the product after filtration to recover the filter cake was consistently about 85 - 90% with a purity of about 85 - 90% by HPLC. To remove the by-product DCUKA acid generated during the reaction, an acid / base workup followed by crystallization or slurry washing purification was developed. For example, the crude filter cake can be dissolved in about 10 volumes of dichloromethane (DCM), washed with about 3 volumes of 0.5 M NaOH solution, and then washed with about 3 volumes of 0.3 M citric acid solution, which removes some of the impurities observed by HPLC. Alternatively, 60 volumes of 75% / 25% v / v EtOAc / MEK can be used to dissolve the crude DCUKA acid instead of DCM.

[0066] Alternatively, crystallization and slurry purification methods were developed to purge two unknown impurities observed in the crude product. Slurry purification with isopropanol (IPA) and ethanol (EtOH) was effective in removing impurities and the overall recovery was good. After removing DCM and drying, the crude Compound 6 was suspended in about 10 volumes of IPA or EtOH, slurried at 40 °C overnight, and then cooled to 23 °C. Filtration afforded Compound 6 of high purity (over 98%) from both IPA and EtOH, 1 The 1H-NMR spectrum showed no additional peaks except for the solvent.

[0067] Crystallization initiated by solvent swap from DCM to EtOH also provided high-purity compound 6 because this material is relatively insoluble in EtOH. Alternatively, a mixture of EtOAc and MEK can be used to dissolve the crude DCUKA acid, and this solvent combination can be removed by solvent swap with EtOH as in the case of DCM. The organic phase was subjected to distillation at 45 °C to reduce the volume level of DCM from the initial volume to about 4 - 5 times, and then EtOH was continuously added dropwise while further removing DCM during distillation. After adding about 6 volumes of EtOH, the mixture was maintained at about 70 °C for about 45 minutes, 1 and a DCM to EtOH ratio of about 1:22 was obtained as determined by 1H-NMR analysis. The resulting slurry was slowly cooled to 20 °C and maintained at 20 °C overnight. Filtration followed by HPLC analysis of the filter cake confirmed that both impurities were completely removed. Overall, this isolation and purification method gave compound 6 with a recovery rate of about 65% and a purity of over 98%.

[0068] As yet another alternative, DCM can be excluded from the crystallization method for the compound of formula VI (e.g., compound 6). Several solvents as alternatives to DCM such as EtOAc / EtOH, EtOAc / THF, EtOAc / MEK were screened. Solvent ratios of 80 / 20 - 60 / 40 were screened. From all the solvents screened, only EtOAc / MEK was successful in dissolving compound 6 at 50 volumes at a 75 / 25 ratio of EtOAc / MEK.

[0069] <Hydrolysis of the compound of formula VI to form the acid of formula VII> The compound of formula VI can be hydrolyzed to the corresponding salt of formula VII or the acid of formula VIII.

[0070]

Chemical formula

[0071] If desired, an addition salt of diphenylureido - dihaloquinenic acid can be formed by treating the salt of formula VII with a strong acid such as excess p - toluenesulfonic acid (TSOH) to form an addition salt of formula IX.

[0072]

Chemical formula

[0073] <Design of a Flow Reactor for Cycloacylation> The attached figure schematically shows a reactor 10 for performing a cycloacylation reaction. The reactor 10 includes a feed pipe 12 having an inlet section 14, a regulating coil section 22, a reactor coil section 24, and an outlet section 26. The inlet section 14 is in fluid flow connection with a pump 18, and the pump is in fluid flow connection with the regulating coil section 22. The regulating coil section 22 is in fluid flow connection with the reactor coil section 24. The regulating coil section 22 and the reactor coil section 24 are housed within a heated chamber 20. The reactor coil section 24 is in fluid flow connection with the outlet section 26. In operation, the reaction mixture is filled into a reactant reservoir 16, drawn into the pump 18 through the inlet section 14 of the pipe 12, discharged from the pump 18 into the regulating coil section 22, where the reaction mixture flows into the reactor coil section 24, and then flows out from the heated chamber 20 into a discharge reservoir 28 through the outlet section 26 of the pipe 12.

[0074] In use, the flow of the reaction mixture is in the direction of the broad arrow A. The heated chamber 20 is heated to a temperature sufficient to heat the contents of the reaction coil section 24 to the desired reaction temperature. The total internal volume of the regulating coil section 22 and the reactor coil section 24 is selected, in combination with the liquid delivery rate of the pump 18, to provide the desired residence time for the reaction mixture within the heated chamber 20. Typically, the pipe 12 is initially filled with a reaction solvent, which is displaced by the reaction mixture as the liquid delivery progresses. The effluent that does not contain any product from the cycloacylation reaction is typically discarded before collecting the effluent containing the product. To maintain the liquid delivery efficiency, the reactant reservoir 16 can be refilled as needed or additional reactant reservoirs can be connected to the pump 18 as one reservoir is depleted. In the final stage of operation, the solvent can be pumped through the pipe 12 to displace the reaction mixture that remains in the reactor at the end.

[0075] The following non-limiting examples are provided to illustrate certain aspects and features of the methods described herein.

Example

[0076] Experimental procedure Both the reagents and solvents were purchased from commercial suppliers and used upon receipt. 1 The 1H-NMR spectra were obtained using a BRUKER AVANCE 300 or AVANCE 500 spectrometer at 300 MHz and 500 MHz. Tetramethylsilane from the NMR solvent was used as an internal standard. The HPLC analysis was performed using a VARIAN PROSTAR instrument.

[0077] <HPLC Analysis Method> Column: WATERS XBRIDGE PHENYL, 3.5 μM, 4.6 × 150 mm Detector wavelength: 254 nm, Flow rate: 1.0 mL / min, Mobile phase A: 0.05% formic acid in water, Mobile phase B: 0.05% formic acid in acetonitrile, Diluent (acetonitrile for reactions (a), (b) and (c); acetonitrile and 0.1% TFA for reaction (d)) The elution gradient is shown in Table 1.

[0078] [Table 1]

[0079] [Example 1. Aza-Michael Reaction for the Formation of Compound 3] 3,5-Dichloroaniline 1 (100.0 g, 0.617 mol, 1.0 eq) was charged into a 1-liter three-necked jacketed reactor equipped with a mechanical stirrer, a reflux condenser, and a temperature probe, followed by THF (700 mL, 7 volumes). Next, diethyl acetylenedicarboxylate 2 (126.0 g, 0.741 mol, 1.2 eq) was added to this reactor neat. The addition of diethyl acetylenedicarboxylate was carefully monitored for any exotherm. After the addition was complete, the resulting mixture was stirred at about 70 - 75 °C while the reaction was monitored by HPLC (about 1 μL of the reaction mixture was dissolved in 1.5 mL of MeCN, and 5 μL of that was injected into the HPLC column). The endpoint of the reaction was selected such that at least 75% of 3,5-dichloroaniline (retention time: RT = 14.8 min) was converted to compound 3 (RT = 17.5 min) based on HPLC curve area under the curve (AUC) measurement. When this conversion was achieved, the reflux condenser was replaced with a distillation head and THF was removed under reduced pressure. The endpoint of the THF distillation was 1 determined by 1H-NMR. The 1H-NMR of the resulting product 1 was consistent with the structure of compound 3.

[0080] [Example 2. Continuous flow synthesis of compound 3] <A. Flow reactor design> A fluid pump was connected to a 340-foot coil of 1 / 8-inch outer diameter (about 3.18 mm), 0.069-inch inner diameter (about 1.75 mm) stainless steel tubing inside a heating unit. This tubing provided a volume of 3.1 mL for preheating the reaction mixture and a volume of about 247 mL to provide a residence time suitable for the reaction mixture in the heating coil of the reactor. Using a feed rate of about 4.1 mL / min, a residence time of about 60 minutes (min) can be achieved. The heater temperature can be set to the desired temperature for the flow reaction. Preferably, a backpressure regulator is connected in-line to help maintain a smooth flow rate.

[0081] <B. Operation of the Flow Reactor> Since it is impossible to use a piston pump with a corrosive solvent, a peristaltic pump (e.g., WATSON-MARLOW 530S pump) was used for this reaction. This is because the durable tubing inside this pump is suitable for use in such a highly corrosive environment. For the reaction in solvent-free Eaton's reagent, the substrate compound 3 was dissolved in Eaton's reagent in a reservoir, while the reactor coil was pre-filled with methanesulfonic acid and heated to the desired reaction temperature (e.g., 70 °C). Then, the reaction mixture was pumped from the reservoir through the flow reactor coil at a rate sufficient to achieve the desired residence time (e.g., 15 - 40 minutes) in the heated coil. Immediately after pumping all of the reaction mixture from the reservoir into the coil, a chase of at least one coil volume of methanesulfonic acid was pumped through the coil to ensure complete elution of all of the reaction mixture from the heated coil. After exiting the heated coil for the isolation of compound 4, the effluent containing the cyclized product was collected. The reactor was pre-filled with a co-solvent (e.g., DCM) instead of methanesulfonic acid, and the same procedure was followed for the reaction using Eaton's reagent and the co-solvent, except that the chase was at least one coil volume of the co-solvent instead of methanesulfonic acid.

[0082] <C. 54 g Test Reaction and 20-Minute Target Residence Time> It is impossible to use a piston pump with a corrosive solvent. Therefore, a COLE-PARMER L / S peristaltic pump was used for this reaction because the durable tubing used in this assembly was specially made for a peristaltic pump. The reactor was filled with DCM and heated to 70 °C at an internal pressure of 50 - 70 psi. Compound 3 (54 g) was dissolved in DCM (216 ml, 4 volumes), and Eaton's reagent (211 ml, 4 volumes) was added. The solution of compound 3 was pumped through the reactor, followed by pumping DCM as the chase solvent. After adjusting the pumping rate, the residence time was shown to be 23 minutes using a timer and a graduated cylinder. The resulting reaction mixture was collected and subjected to HPLC analysis of the reaction mixture, which showed 85.5% AUC of compound 4, 5.8% AUC of a by-product with a retention time (RT) of 1.05 minutes, and 4.2% AUC of compound 3.

[0083] <Reaction of 230 g using a target residence time of 20 minutes> For this flow synthesis, a Watson-Marlow 530S peristaltic pump was used to obtain a higher flow rate. The reactor was filled with DCM and heated to 70 °C at an internal pressure of 50 - 70 psi. Compound 3 (230 g) was dissolved in DCM (920 ml, 4 volumes), and Eaton's reagent (920 ml, 4 volumes) was added. The solution of Compound 3 was pumped through the reactor, followed by pumping DCM as a chaser solvent. Using a stopwatch, the residence time was shown to be 19.25 minutes. The resulting reaction mixture was recovered and subjected to HPLC analysis of the reaction mixture, which showed 84.9% AUC of Compound 4 and 4.7% AUC of the 1.05 RT by-product, with 0.6% AUC of Compound 3 remaining. During pumping, the flow rate test showed only 7 mL / min due to backflow into the pump. At the end of this reaction method, the average residence time was determined to be approximately 32 minutes.

[0084] <E. Reaction of 10 g using a target residence time of 20 minutes> For this flow synthesis, a Watson-Marlow 530S pump was used. The reactor was filled with methanesulfonic acid and heated to 70 °C without a backpressure regulator. Crude Compound 3 containing some residual Compound 1 was diluted with Eaton's reagent (40 ml, 4 volumes). The solution of Compound 3 was pumped through the reactor, followed by pumping methanesulfonic acid as a chaser solvent. Using a stopwatch, the residence time was 16.5 minutes, indicating that it was less than the target residence time of 20 minutes. The resulting reaction mixture was recovered and subjected to HPLC analysis of the reaction mixture, which showed 73.7% AUC of Compound 4 and 20.7% AUC of Compound 1.

[0085] <F. Reaction of 10 g using the target residence time of 20 minutes> For this flow synthesis, a WATSON-MARLOW 530S pump was used. The reactor was filled with methanesulfonic acid and heated to 70 °C using a back pressure regulator set at 15 psi to enable a constant and smooth flow of the output. The crude compound 3 containing compound 1 was diluted with Eaton's reagent (40 ml, 4 volumes). The solution of compound 3 was fed through the reactor, and then methanesulfonic acid was fed as a chaser solvent. Using a stopwatch, the residence time was 16 minutes, indicating that it was less than the target residence time of 20 minutes. The resulting reaction mixture was recovered and subjected to HPLC analysis of the reaction mixture, which showed 72.7% AUC of compound 3 and 22.3% AUC of compound 1.

[0086] <G. Isolation and purification> The flow reaction mixture (199 g in 1.1 L) was charged at a rate of 40 mL / min into water (2.4 L, 12 volumes) cooled to -5 °C in a jacketed reactor while maintaining the batch temperature below 15 °C. Once completely added, the batch was warmed to 23 °C and stirred for an additional 0.5 hour. The batch was then filtered to recover the solid. After completely removing the solvent, the pH of the filtrate was approximately 0. The filter cake was slurried with a 28 wt% NaOAc solution (2.1 L, 2×5 volumes) to adjust the pH of the cake to approximately 5 - 6. Next, the filter cake was washed with water (2.0 L, 2×5 volumes) to remove inorganic salts. The cake was conditioned under vacuum and then transferred to a glass tray and further conditioned in a vacuum oven at 35 - 40 °C until a constant weight of the cake was reached. The filter cake, mother liquor, and washings were analyzed by HPLC. The crude weight of the filter cake was 197.8 g with a purity of 67% by HPLC.

[0087] [Example 3. Amination of Compound 4 to Produce Compound 5] A four-necked 1 L jacketed reactor equipped with a mechanical stirrer, a temperature probe, and a reflux condenser was charged with Compound 4 (50 g, 1 eq, 0.175 mol), and then acetonitrile (MeCN, 500 mL, 10 volumes) was charged at 23 °C. The slurry was heated to 70 °C, and chlorosulfonyl isocyanate (17 mL, 1.1 eq, 0.192 mol) was slowly added dropwise over 1 hour using a syringe pump (0.26 min / mL). Controlled evolution of CO 2 was observed during the addition of the isocyanate. After complete addition, the mixture was stirred at 70 °C for an additional 30 minutes. Samples were taken before and after the addition of chlorosulfonyl isocyanate to monitor the consumption of Compound 4 (RT: 14.1 min) to the first intermediate product (RT: 15 - 20 min) by HPLC. Upon complete conversion, 1.5 M HCl-EtOH (163 mL, 1.4 eq, 3.2 volumes) was added dropwise at 70 °C over 1 hour using a syringe pump (2.5 mL / min). Tracking this addition by HPLC, the intermediate disappeared at 15 - 20 min and a new peak appeared at 11.6 min. Subsequently, the batch was vacuum distilled at 50 - 55 °C (internal temperature) to reduce the batch volume to approximately 1 / 2. The resulting slurry was then cooled to 0 °C, and the pH (1 - 2) was adjusted to approximately pH 9 - 10 using 0.5 N NaOH (165 mL, 1.04 eq, 3.2 volumes). The resulting thick slurry was warmed to 5 °C, stirred for an additional 0.5 hour, and filtered to recover the filter cake. Both the filter cake and the filtrate were analyzed by HPLC. The filter cake, Compound 5, was conditioned in a vacuum oven at 45 - 50 °C overnight. The dry weight of the isolated crude product was 46.1 g (crude yield = 93%, purity: 90%).

[0088] The crude compound 5 (31 g) was charged into a four-necked 250 mL jacketed reactor equipped with a mechanical stirrer, a temperature probe, and a reflux condenser. EtOAc (155 mL, 5 volumes) was charged into the reactor, and the slurry was stirred at 23 °C for 10 minutes, then heated to 50 °C and stirred for 14 hours. After 14 hours, the mixture was slowly cooled to 23 °C with stirring. This slurry was filtered to recover the filter cake, and both the filter cake and the filtrate were analyzed by HPLC. The filter cake was further conditioned at 40 - 45 °C for 4 hours to obtain 25.3 g of compound 4 with a purity of 95.8% in an 82% yield by HPLC.

[0089] [Example 4. Carbamylation for Producing Compound 6] Compound 5 (10 g, 0.035 mol, 1 eq) was added to a four-necked 500 L jacketed reactor equipped with a mechanical stirrer and a temperature probe, and then DMAc (70 mL, 7 volumes) was added. After cooling the resulting solution to 5 °C, diphenylcarbamoyl chloride (9.8 g, 0.042 mol, 1.2 eq) was added as a solid all at once. This solution was stirred at 5 °C for 10 minutes, and then NaH (60%, 2.8 g, 0.2462 mol, 2 eq) was added portionwise at 5 °C over 1 hour. After the addition was complete, the dark red mixture was stirred for an additional 1 hour. The progress of the reaction was monitored by HPLC. A 10 wt% AcOH solution (280 mL, 4 volumes based on the volume of DMAc) was added to another three-necked 1 L jacketed reactor equipped with a mechanical stirrer and a temperature probe and cooled to about 5 °C. Then, the DMAc solution was slowly fed into the 10 wt% AcOH solution to quench the intermediate product and precipitate the crude compound 6 by maintaining the internal temperature near 5 °C. After complete quenching, the slurry (pH = 3) was stirred at 5 °C for an additional 30 minutes and then filtered to recover the filter cake. The filter cake was washed with water (2 × 140 ml, 2 × 2 volumes), and the filter cake, filtrate, and washings were analyzed by HPLC. The recovered filter cake was further conditioned in a vacuum oven at 45 - 50 °C overnight to obtain 14.6 g (87%) with a purity of 87% by HPLC.

[0090] The crude compound 6 (42 g) was charged into a three-necked 1 L jacketed reactor, and DCM (420 mL, 10 volumes) was added to dissolve the material. Once completely dissolved, 0.5 N NaOH (125 mL, 3 volumes) was added to the reactor, and the mixture was stirred vigorously for about 5 - 10 minutes, after which stirring was stopped to allow phase separation. The organic phase was recovered, returned to the reactor, and the washing with 0.5 N NaOH was repeated three times. When the washing with 0.5 N NaOH solution (3×3 volumes) was completed, the organic layer was washed with 0.3 M citric acid (125 mL, 1×3 volumes). After each washing, both the organic and aqueous phases were analyzed by HPLC, and it was shown that the impurity at 16.7 minutes was partially purged by the base wash, but in addition to the impurity at 15.9 minutes, it still remained in the organic phase.

[0091] The organic phase (400 mL) was transferred to a 500 mL reactor equipped with a mechanical stirrer, thermocouple, addition funnel, and Dean-Stark condenser, and heated slowly to 45 °C to remove DCM. When about 6 volumes of DCM were removed, EtOH was continuously added dropwise to maintain 6 volumes of solvent in the simple distillation flask while removing DCM by distillation. The temperature of the mixture was slowly raised to 70 °C with a constant dropwise addition of EtOH, during which crystallization / precipitation was observed. A total of about 250 mL of EtOH (6 volumes) was added, and the mixture was maintained at 70 °C for about 45 minutes. 1 1H-NMR confirmed a 22:1 ratio of EtOH:DCM and the successful exchange of most of the DCM into EtOH.

[0092] The slurry was slowly cooled to 20 °C over 1 hour and maintained at 20 °C overnight with stirring. The slurry was then filtered to recover the solid, and both the filter cake and the filtrate were analyzed by HPLC. From the HPLC data of the filter cake, the purging of both impurities with RT of 15.9 minutes and 16.7 minutes in EtOH was confirmed. The filter cake was further conditioned in a vacuum oven at 50 °C for 4 hours to obtain 27.4 g of purified compound 6 with a purity of over 98% and a yield of 65% by HPLC.

[0093] In another preparation, Compound 5 (20.0 g, 0.07 mol, 1 equivalent) was dissolved in DMAc (140 mL, 7 volumes) and cooled to 5 °C in a four-necked 1000 L jacketed reactor equipped with a mechanical stirrer and a temperature probe. Diphenylcarbamoyl chloride (19.6 g, 0.084 mol, 1.2 eq) was added as a solid all at once to the solution of Compound 5. The resulting reaction solution was stirred at 5 °C for 15 minutes, and then NaH (60%, 5.6 g, 0.52 mol, 2 eq) was added portionwise at 5 °C over 1 hour. After the addition was complete, the resulting brown mixture was stirred for an additional 1 hour. The progress of the reaction was monitored by HPLC and completed after 1 hour. Another three-necked 1 L jacketed reactor equipped with a mechanical stirrer and a temperature probe was charged with a 10 wt% AcOH solution and cooled to 5 °C. The main reaction mixture was slowly added at 5 °C into the 10 wt% AcOH solution (560 mL, 4 volumes based on DMAc) to precipitate crude Compound 6 by keeping the internal temperature around 5 °C. When the reaction mixture was completely quenched, the resulting slurry (pH = 3) was stirred at 5 °C for an additional 30 minutes and then filtered to recover the filter cake. The filter cake was washed with water (2 × 280 mL, 2 × 2 volumes based on DMAc), and the filter cake, filtrate, and washings were analyzed by HPLC. The recovered filter cake was further conditioned in a vacuum oven at 45 - 50 °C overnight (20 hours) to obtain 33.2 g (98.5%) of Compound 6 with a purity of 86%.

[0094] The crude Compound 6 was divided into two portions. That is, portion I (16.6 g) was charged into a three-necked 1 L jacketed reactor and dissolved in ethyl acetate:methyl ethyl ketone (825 mL, 75:25, 50 volumes) at 50 °C. Once completely dissolved, the solution was cooled to about 22 °C and 0.5 N NaOH (50 mL, 3 volumes) was added to the mixture with vigorous stirring for about 5 - 10 minutes, after which stirring was stopped to allow phase separation. The organic phase was recovered, returned to the reactor, and washed three times with 0.5 N NaOH. Next, the organic layer was washed with 0.3 M citric acid (50 mL, 1 × 3 volumes). After each washing, both the organic and aqueous phases were analyzed by HPLC.

[0095] The washed organic phase (700 mL) was transferred to a 1 L reactor equipped with a reactor jacket and slowly heated to 40 °C under vacuum to reduce the amounts of ethyl acetate and methyl ethyl ketone to about 6 volumes. Then, ethanol (170 mL, 10 volumes) was added to the reactor and the mixture was distilled again to 6 volumes. The final mixture was cooled to about 22 °C. The resulting slurry was filtered, washed with 250 mL (15 volumes) of ethanol, and then dried in a vacuum oven at 40 °C for 3 days to obtain white solid Compound 6 (10.77 g, 64% yield, 91.6% purity).

[0096] [Example 5. Base Hydrolysis for Producing Compound 7]

[0097] [Chemical Formula]

[0098] Compound 6 was hydrolyzed with sodium hydroxide to form the sodium salt, Compound 7. The reaction conditions were demonstrated using a GMP lot (Run 8, Table 1) on a 100 g scale. The reaction proceeded using 2 eq of NaOH and was completed within 3 hours at 50 °C on a 100 g scale (see the 100 g scale runs in Table 2). After this time, the reaction mixture was cooled to room temperature and filtered. The solid was slurried with methanol (2.5 volumes) and water (7.5 volumes). The pH of the slurry was adjusted to 5 using glacial acetic acid, the mixture was stirred overnight, then the pH was adjusted to 5 again, the slurry was filtered, washed with methanol (2 volumes), and dried in a vacuum oven at 45 °C overnight to obtain the desired product in 89% yield (88 g). As shown in Table 2, various conditions were similarly screened, all of which resulted in high conversion to Compound 7.

[0099] [Table 2]

[0100] [Example 6. Formation of Tosylate Addition Salt, Compound 8]

[0101] [Chemistry]

[0102] The formation of Compound 8 was achieved by adding approximately 2 equivalents of p-toluenesulfonic acid to Compound 7. As shown in Table 3, various reaction conditions were investigated. As an illustration of the method, a 200 g scale run (Table 3) is provided. The dried Compound 7 material was slurried in ethyl acetate (1.2 L, 6 volumes) and warmed to approximately 40 °C. A 2.1 M aqueous solution of p-toluenesulfonic acid (prepared from 160 g of p-toluenesulfonic acid monohydrate dissolved in 240 mL of water) was added to the ethyl acetate slurry, which was then stirred at 40 °C for 10 hours and then cooled to 10 °C over 1 hour. Proton NMR at this point showed an approximately 80% conversion to the desired salt. The slurry was then warmed again to 40 °C and further treated with a 2.1 M p-TsOH solution (100 mL, 40 g p-toluenesulfonic acid in 60 mL of water), stirred at 40 °C for 2 hours, and then proton NMR showed complete conversion to the tosylate addition salt. The slurry was then cooled to 10 °C over 1 hour, aged at 10 °C for 1 hour, and then filtered. The filter cake was washed with ethyl acetate (2 × 400 mL, 2 × 2 volumes) and dried at 45 °C to obtain 220 g of the desired product in 84% yield.

[0103]

Table 3

[0104] Preferred embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the present invention. Variations of these preferred embodiments may become apparent to those skilled in the art upon reading the above description. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by the applicable law. Further, all combinations of the above elements in all possible variations are included in the present invention unless otherwise indicated herein or clearly inconsistent with the context.

Claims

1. A process for preparing an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate, comprising the following consecutive steps, namely, (i) A first solution containing a compound of formula III dissolved in a reagent containing 7 to 10 wt% of P in methanesulfonic acid is passed through a heated continuous flow reactor coil at a selected temperature in the range of 65 to 75 °C at a concentration of 0.15 to 0.25 grams of the compound of formula III per mL of the reagent, and heated by feeding at a liquid feed flow rate sufficient to provide a residence time of 15 to 40 minutes in the heated coil, and recovering an effluent flowing out from the heated coil containing an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate of formula IV. ２ O ５ ​ 【Chemical 1】 【Chemical Formula 2】 (ii) adding the effluent recovered from step (i) to at least 5 volumes of water per volume of the effluent while maintaining the water temperature at 15 °C or lower and with stirring to form a first precipitate containing the ester of formula IV, and (iii) recovering the first precipitate comprising, wherein in Formula III and Formula IV, each X is independently a halogen atom and each R is independently C １ -C ４ alkyl.

2. The process according to claim 1, wherein each X is a chlorine atom.

3. The process according to claim 1, wherein each R is ethyl.

4. The process according to claim 1, wherein each X is a chlorine atom and each R is ethyl.

5. The process according to claim 1, wherein the first solution further comprises a hydrocarbon co-solvent or a halogenated hydrocarbon co-solvent.

6. The process according to claim 5, wherein the co-solvent comprises dichloromethane.

7. The following steps, namely (iv) stirring a first suspension containing the first precipitate obtained from step (iii) in a first solvent at a temperature in the range of 40 to 50 °C for at least 1 hour, and (v) recovering undissolved solid particles containing the purified ester of formula IV from the first suspension further comprising, wherein the first solvent is selected from the group consisting of acetonitrile, methanol, isopropanol, and combinations of two or more thereof, the process according to claim 1.

8. The process according to claim 7, wherein the first suspension contains 3 to 10 mL of the first solvent per gram of the first precipitate.

9. A process for preparing an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate, comprising the following consecutive steps, namely, (i) contacting a first solution containing 15 to 60 wt% of a dihaloaniline of formula I in a first solvent with at least 0.9 equivalent of a dialkyl acetylenedicarboxylate of formula II at a selected temperature of 70 to 100 °C for 6 to 24 hours to form a compound of formula III, 【Chemical 3】 (ii) removing the first solvent to form a first residue containing the compound of formula III (iii) A second solution containing the first residue from step (ii), dissolved in a reagent containing 7 to 10 wt% of P in methanesulfonic acid, is passed through a heated continuous flow reactor coil at a selected temperature of 65 to 75 °C at a concentration of the first residue of 0.15 to 0.25 grams per mL of the reagent, and heated by pumping at a liquid feed flow rate sufficient to provide a residence time of 15 to 40 minutes in the heated coil, and collecting the effluent flowing out of the heated coil, which contains an alkyl 5,7-dihalo-1,4-dihydro-4-oxoquinoline-2-carboxylate of formula IV. ２ O ５ ​ 【Chemical Formula 4】 (iv) adding the effluent recovered from step (iii) to at least 5 volumes of water per volume of the effluent while maintaining the water temperature at 15 °C or lower and with stirring to form a first precipitate containing the ester of Formula IV, and (v) recovering the first precipitate comprising, wherein in Formula I, Formula II, Formula III and Formula IV, each X is independently a halogen atom, and each R is independently C １ -C ４ alkyl, and the first solvent is an aprotic solvent. (Claim 10) (Claim 9) The method according to claim 9, wherein each X is a chlorine atom. (Claim 11) (Claim 9) The method according to claim 9, wherein each R is ethyl. (Claim 12) (Claim 9) The method according to claim 9, wherein each X is a chlorine atom and each R is ethyl. (Claim 13) (Claim 9) The method according to claim 9, wherein the second solution further contains a hydrocarbon cosolvent or a halogenated hydrocarbon cosolvent. (Claim 14) (Claim 13) The method according to claim 13, wherein the cosolvent contains dichloromethane. (Claim 15) (Claim 15) A method for preparing a diphenylureido-dihaloquinurenic acid alkyl ester, comprising performing steps (i), (ii), (iii), (iv) and (v) of claim 7, and then (vi) contacting a third solution containing the purified ester of Formula IV in a polar aprotic solvent with chlorosulfonyl isocyanate at a temperature of 40 to 80 °C until the generation of carbon dioxide gas ceases, (vii) adding an acid dissolved in C １ to C ４ alcohol, heating the resulting acidic mixture at a temperature of 65 to 75 °C to form a 5,7-dihalo-4-aminoquinoline-2-carboxylic acid ester of formula V [Chemical Formula 5] (viii) isolating the ester of Formula V, (ix) contacting a fourth solution containing the ester of Formula V isolated in step (viii) in a second polar aprotic solvent with diphenylcarbamoyl chloride in the presence of a base to form a diphenylureido-dihaloquinurenic acid alkyl ester of Formula VI, ​ (wherein the base is selected from the group consisting of alkali metal hydroxides and alkali metal hydrides), and (x) isolating the diphenylureido-dihaloquinurenic acid alkyl ester of Formula VI including, wherein in Formula I, Formula II, Formula III, Formula IV, Formula V, and Formula VI, each X is independently a halogen atom, and each R is independently C １ ~C ４ alkyl. (Claim 16) (Claim 15) The method according to claim 15, wherein each X is a chlorine atom and each R is ethyl. (Claim 17) (Claim 15) The method according to claim 15, wherein the first solution in step (i) further contains a hydrocarbon cosolvent or a halogenated hydrocarbon cosolvent. (Claim 18) (Claim 17) The method according to claim 17, wherein the cosolvent contains dichloromethane. (Claim 19) (Claim 19) Before step (ix), (a) stirring a second suspension containing the ester of Formula V isolated in step (viii) in a third solvent at a temperature in the range of 40 to 50 °C for at least 1 hour, and (b) cooling the second suspension to a temperature of 20 to 25 °C and then recovering undissolved solid particles containing the purified ester of formula V from the second suspension, further comprising a step of purifying the ester of formula V, wherein the third solvent is C ２ - C ３ alcohol, C ２ - C ３ The method according to claim 15, selected from the group consisting of alkyl acetates and combinations thereof.

20. In step (x), the fourth solution from step (ix) is added to 26 to 30 volumes of aqueous acid with stirring to form a third precipitate containing the ester of formula VI, and then the ester of formula VI is recovered by filtration or centrifugation, whereby the diphenylureido-dihaloquinurenic acid alkyl ester of formula VI is isolated, the method according to claim 15.

21. The method according to claim 20, comprising dissolving the third precipitate in a mixture of ethyl acetate and methyl ethyl ketone, and then reducing the volumes of ethyl acetate and methyl ethyl ketone by distillation to crystallize the compound of formula VI.

22. The compound of formula III in step (i) is formed by contacting a first solution containing 15 to 60% by weight of dihaloaniline of formula I with at least 0.9 equivalent of dialkyl acetylenedicarboxylate of formula II at a selected temperature of 70 to 100 for 6 to 24 hours to form a compound of formula III, 【Chemical Formula 7】 The compound of formula III is used in step (i) without further purification, the method according to claim 15.

23. Performing steps (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), and (x) of claim 15, and then (xi) a method of forming a diphenylureido-dihaloquinurenate of formula VII, comprising hydrolyzing the compound of formula VI with an aqueous base. 【Chemical 8】 [In formulas I, II, III, IV, V, VI, and VII, each X is independently a halogen atom, and each R is independently C1-C4 alkyl. ]

24. Performing steps (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), and (xi) of claim 23, and then (xii) a method of forming diphenylureido-dihaloquinurenic acid of formula VIII, comprising neutralizing the compound of formula VII with a strong acid. [Chemical Formula 9] [In Formulas I, II, III, IV, V, VI, VII, and VIII, each X is independently a halogen atom, and each R is independently C1-C4 alkyl.]

25. Performing steps (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), and (xi) of claim 23, and then (xiii) A method for forming an addition salt of diphenylureido-dihaloquinurenic acid p-toluenesulfonic acid of Formula IX, comprising contacting the compound of Formula VII with at least 2 equivalents of p-toluenesulfonic acid. 【Chemical Formula 10】 [In Formulas I, II, III, IV, V, VI, VII, and IX, each X is independently a halogen atom, and each R is independently C1-C4 alkyl.]

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