EA040278B1 - METHOD FOR PRODUCING 4-(4-AMINOPHENYL)MORPHOLIN-3-ONE - Google Patents

Description

Technical field

The invention provides a process suitable for production on an industrial scale for the preparation of 4-(4-aminophenyl)morpholin-3-one of formula (I), the main intermediate in the synthesis of rivaroxaban.

Prior Art

Rivaroxaban is used, among other things, as an anticoagulant (blood thinner). It is commonly used to prevent blood clots. In the synthesis of rivaroxaban, the molecule 4-(4aminophenyl)morpholin-3-one (I) is often used as a key intermediate. The economic viability of the industrial synthesis of rivaroxaban is highly dependent on the appropriate synthesis of this key intermediate.

There are several commercially applicable methods for the synthesis of 4-(4-aminophenyl)morpholin-3-one (I). Scheme 1 is based on the method described in US2003153610 A1. 4-(4-aminophenyl)morpholin-3-one (I) is obtained from 4-nitrofluorobenzene (II), at the first stage it is combined with morpholin-2-one (III) in N-methylpyrrolidone; sodium hydride is used as the base. The resulting 4-nitrophenylmorpholinone (IV) is reduced in tetrahydrofuran with palladium on carbon as a catalyst at a temperature of 70°C. This method is not recommended for the case when the reaction is carried out on an industrial scale, the total yield of the two stages is below 7%.

Scheme 1

Patent application WO 2005/026135 A1 (Bayer Healthcare AG) discloses a more economical method. In the synthesis according to scheme 2, N-(2-hydroxyethyl)aniline (V) is reacted with chloroacetyl chloride to obtain 4-phenylmorpholin-3-one (VI). Then 4-(4nitrophenyl)morpholin-3-one (IV) is obtained in the nitration reaction. The nitro compound (IV) is hydrogenated in ethanol at 80° C. to obtain compound (I). Although in this process the overall yield of compound (I) is 52%, the use of the nitration procedure on an industrial scale is problematic, requires special equipment, and has disadvantages in terms of safety.

Scheme 2

According to the method shown in Scheme 3 (Mederski et al.: Bioorganic & Medicinal Chemistry Letters 14, 2004, p. 5817-5822), 4-nitroaniline (VII) is reacted with 2-(2-chloroethoxy)acetyl chloride (VIII) in toluene. The resulting 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (IX) is refluxed with potassium carbonate in acetonitrile to give cyclic 4-(4-nitrophenyl)morpholin-3-one (IV), which is then reduced in the presence of palladium on carbon in methanol to obtain the target compound 4-(4aminophenyl)morpholin-3-one (I). Output data not provided.

2-(2-chloroethoxy)acetyl chloride (VIII) used in this method is not a readily available compound. The acyl chlorides are usually prepared in situ from the corresponding carboxylic acid, using in most cases thionyl chloride, oxalyl chloride, or other acyl chloride-forming reagents. A common feature of these compounds is that during the formation of acyl chloride a significant amount of hydrochloric acid is released, which damages equipment and accessories, pollutes the environment, while the low atomic efficiency of the reaction makes the process unprofitable.

- 1 040278

Scheme 3

Mali et al. (Sustain Chem. Process (2015) 3:11) according to the method according to scheme 4, starting with 2-(2-chloroethoxy)acetic acid (X), catalysis with boric acid gives 2-(2chloroethoxy)-N-(4-nitrophenyl) acetamide (IX) (yield: 50%), then in the presence of a base - sodium hydroxide - under phase transfer conditions, a cyclic compound (IV) is obtained (yield: 90%), then the expected product (I) is obtained by hydrogenation (yield: 75% ). The yield of the whole process is only 33.8%, which is not enough for an economically viable industrial application.

Scheme 4

The methods described above did not produce 2-(2-chloroethoxy)acetic acid (X), however several such methods are known from the literature. In the process of EP 1640373A1, 2-(2-chloroethoxy)acetic acid (X) is obtained by oxidation of 2-(2-chloroethoxy)ethanol (XI). The oxidation is carried out with hydrogen peroxide catalyzed by sodium tungstate. The disadvantage of this method is that carrying out the oxidation with 30% hydrogen peroxide at 90°C is dangerous; moreover, the yield of 19% is far from the requirements of the industry.

According to the method described in WO 2008075152A1, 2-(2-chloroethoxy)ethanol (XI) was oxidized with the Jones reagent (yield: 80%). The disadvantage of this method is that the chromium trioxide in the Jones reagent is extremely toxic to humans and the environment. Disposal of the waste products of the Cr(III) by-product which is abundant and the unreacted Cr(VI) after the reaction in the form of a precipitate is laborious and uneconomical. In addition, another component of the Jones reagent, sulfuric acid at a concentration of 30-40 wt.%, can contribute to the formation of a symmetrical ester as a by-product.

The main object of the present invention is to provide a simple and cost-effective, industrially applicable method for the preparation of 4-(4-aminophenyl)morpholin-3-one, the main intermediate in the synthesis of rivaroxaban.

The essence of the invention

The present invention is summarized in Scheme 5.

Scheme 5

In the method according to the invention, 4-nitroaniline (VII) and 2-(2-chloroethoxy)acetic acid (X) are combined in a direct way in the presence of a catalyst to obtain 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (IX) . At this stage, there is no need for recrystallization, a simple one-pot reaction is carried out and after the esterification of the catalyst, the product (IX) is crystallized directly from the reaction mixture. As a further simplification of the process, the reaction can optionally be combined with the steps for obtaining 2-(2-chloroethoxy)acetic acid (X). Similarly, a one-pot reaction can be carried out by combining step c) and step d). In the method according to the invention dangerous nitration, formation of corrosive and environmentally polluting

- 2,040,278 compounds (eg sulfuric acid, acid chlorides, gaseous hydrogen chloride, chromium trioxide).

Information confirming the possibility of carrying out the invention

Stage a).

In the process according to the invention, 2-(2-chloroethoxy)acetic acid (X) is formed from 2-(2-chloroethoxy)ethanol (XI) in an oxoammonium-catalyzed oxidation under phase transfer conditions. Alkali and alkaline earth metal hypochlorites, preferably aqueous solutions of sodium hypochlorite or calcium hypochlorite, are used as a stoichiometric oxidizing agent, and the oxidation of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical (TEMPO) is catalyzed; (2,2,6,6tetramethylpiperidin-1-yl)oxyl).

In an embodiment of the present invention, 2-(2-chloroethoxy)ethanol (XI) is dissolved in an aprotic organic solvent, an aqueous solution of an oxidizing agent - sodium hypochlorite or calcium hypochlorite - and (2,2,6,6-tetramethylpiperidine- 1-yl)oxyl catalyst, then the biphasic mixture is stirred vigorously until the reaction is complete while maintaining the pH in the range of 8 to 12.

In another embodiment of the present invention, the aprotic organic solvent may be selected from aliphatic or aromatic halogenated hydrocarbons, aliphatic or aromatic hydrocarbons, aliphatic ketones, aliphatic ethers, aliphatic esters, aliphatic nitriles, for example, the solvent may be dichloromethane, toluene, tetrahydrofuran , methyl isobutyl ketone, ethyl acetate, acetonitrile, preferably dichloromethane.

The reaction proceeds optimally at a pH in the range of 8 to 12. Outside this range, catalysis slows down or even stops. Either a base is added at the same time as the stoichiometric oxidizing agent, or the system is buffered with a weak base to maintain the correct pH. As the base, hydroxides of alkali and alkaline earth metals, hydrogen carbonates, carbonates, hydrogen phosphates, dihydrophosphates and phosphates and their aqueous solutions can be used. Preferably, the reaction mixture is buffered with sodium hydrogen carbonate as is.

The TEMPO catalyst can be used in the reaction in an amount ranging from 0.1 to 200 mol%, preferably in the range from 0.5 to 2 mol%. The temperature during the addition is set in the range of 0 to 30°C, preferably in the range of 20 to 25°C. After the addition, stirring of the mixture is continued while the TEMPO catalyst decomposes most of the remaining excess hypochlorite and then the trace amounts of hypochlorite are decomposed using a suitable reducing agent, preferably sodium metabisulphite or sodium sulfite. The reducing agent is used in an amount ranging from 2.5 to 100 mol.%, preferably in an amount of 2.5 mol.%. After completion of the reaction, the starting material and the catalyst are washed out of the alkaline aqueous phase with a suitable water-immiscible solvent. These solvents may be aliphatic and aromatic halogenated hydrocarbons, aromatic and aliphatic hydrocarbons, aliphatic ketones, aliphatic ethers, aliphatic esters, aliphatic nitriles, for example, the solvent may be dichloromethane, toluene, tetrahydrofuran, methyl isobutyl ketone, ethyl acetate, acetonitrile, preferably dichloromethane.

After removal of the catalyst and starting material, the aqueous phase is acidified with a suitable organic or inorganic Bronsted acid or a solution thereof, preferably concentrated aqueous hydrochloric acid.

After acidification, the product is extracted with a water-immiscible solvent. The extraction solvent may be selected from aliphatic or aromatic halogenated hydrocarbons, aromatic or aliphatic hydrocarbons, aliphatic ketones, aliphatic ethers, aliphatic esters, aliphatic nitriles, for example, the solvent may be dichloromethane, toluene, xylene, tetrahydrofuran, methyl isobutyl ketone, ethyl acetate , acetonitrile, preferably methyl isobutyl ketone. The extracted organic phase was evaporated under reduced pressure to remove said solvent to obtain a pale yellow oil of 2-(2-chloroethoxy)acetic acid (yield: 71%).

Step b).

To the 2-(2-chloroethoxy)acetic acid oily material (X) obtained in step a), 4-nitroaniline (VII) and phenylboronic acid were added as a catalyst. In an embodiment of the present invention, a high boiling solvent forming an aqueous azeotrope, such as xylene or toluene, is added, followed by the addition of a suitable amount of 4-nitroaniline and phenylboronic acid. The amount of 4-nitroaniline is in the range of 0.85 to 1 equivalent based on the 2-(2-chloroethoxy)acetic acid obtained, the amount of phenylboric acid added is in the range of 0.5 to 95 mole %, preferably 5 to 50 mol.%, more preferably it is equal to 25 mol.%.

After adding the starting materials, the reaction mixture is heated to boiling point,

- 3 040278 then the resulting water is removed from the reaction mixture by azeotropic distillation.

After completion of the reaction, an alcohol is added to the mixture to convert the boric acid catalyst into the corresponding ester, thereby making it soluble in the mother liquor during crystallization. This suitable alcohol may have one or two hydroxyl groups and may be selected from those aliphatic and aromatic alcohols which, under these reaction conditions, form a toluene-miscible ester with the catalyst. Preferably, ethylene glycol is used.

After the conversion of the catalyst, the reaction mixture is cooled, then the precipitated crystals are filtered off, washed with toluene and dried in vacuo to obtain 2-(2-chloroethoxy)-N-(4nitrophenyl)acetamide (IX) in the form of a crystalline powder having a color from yellow to light brown (yield: 83% in terms of 4-nitroaniline).

Step c).

In this cyclization step, the product 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (IX) is refluxed in acetonitrile with potassium carbonate according to the method described in Bioorganic & Medicinal Chemistry Letters 14 (2004) 5817-5822 . However, the method described in this article is not suitable for industrial use, as the publication does not provide details. We have developed a simple one-pot procedure for this reaction.

Use at least ten times the amount (ml/g) of acetonitrile and preferably two equivalents of potassium carbonate. Under these conditions at the boiling temperature, the reaction takes 4 hours.

After completion of the reaction, the mixture is cooled and acidified with Bronsted's acid, preferably aqueous hydrochloric acid. Then, in the subsequent evaporation, the solvent is replaced by water, the product is filtered, continuously covering it with water.

To carry out the ring-closing reaction of 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (IX), we also developed another procedure. In another embodiment of the present invention, 2-(2-chloroethoxy)-K-(4-nitrophenyl)acetamide (IX) was refluxed in toluene in the presence of potassium carbonate and PEG-400 (polyethylene glycol 400).

Potassium carbonate was used in an amount of 1 to 5 equivalents, optimally two equivalents. The amount of PEG-400 varied in the range from 1 to 100 mol.%, the optimal amount was 10 mol.%. For the reaction to proceed quickly, the boiling temperature was necessary. At boiling temperature, the reaction is completed in 2 hours.

After complete consumption of the starting material, in the same way as in the case of acetonitrile, the reaction mixture is cooled and acidified with an aqueous solution of hydrochloric acid. The solvent is then replaced with water, the product is washed so that it is permanently covered with water, and 4-(4-nitrophenyl)morpholin-3-one (IV) is obtained in the form of a crystalline powder, the color of which varies from yellow to light brown (yield: 92%).

Step d).

4-(4-nitrophenyl)morpholin-3-one (IV) is dissolved in an aqueous acetic acid solution and then hydrogenated under elevated hydrogen pressure using palladium on carbon as a catalyst.

The concentration of acetic acid may range from 33 to 100%, preferably 50%. You can use the amount of solvent, lying in the range from 10 times to 100 times (ml/g), the optimal was 10 times the amount of solvent. The content of palladium in the palladium-on-carbon catalyst was varied in the range from 1 to 10%, the optimal content was 5%. The reaction can be carried out at a temperature ranging from 15 to 70°C, optimally in the range from 20 to 30°C. The elevated pressure of hydrogen is in the range from 1 to 5 bar, the optimum pressure of 1 bar was sufficient for complete conversion of the nitro compound (IV). After using up all the starting material, the catalyst was filtered off and the solvent was replaced by distillation with 2-propanol, from which the product crystallized.

The resulting 4-(4-aminophenyl)morpholin-3-one (I) can then be used to synthesize rivaroxaban.

The method according to the invention is economically advantageous, the yield of the whole process in the optimum form is 68%, which is higher than the yield of known methods starting with 2-(2-chloroethoxy)acetic acid.

This method of obtaining 4-(4-aminophenyl)morpholin-3-one (I) is safe, since nitration is excluded in the synthesis route according to the invention.

The method protects the environment, unlike the previous methods, it does not use heavy metals and corrosive materials such as chromium trioxide, sulfuric acid and acid chlorides, and does not emit gaseous hydrogen chloride - all these substances are harmful to the environment and human health.

2-(2-Chloroethoxy)-N-(4-nitrophenyl)acetamide (IX) is prepared by a direct reaction from 4nitroaniline and 2-(2-chloroethoxy)acetic acid (X) in the presence of a suitable catalyst. The output of the method using boric acid, known from the literature (Sustain Chem. Process (2015) 3:11),

- 4 040278 is only 50%, in contrast to the method according to the invention using phenylboric acid, where the achieved yield of the entire process is 83%. In addition, recrystallization is not necessary in the process according to the invention, since after the esterification of the catalyst, the product (IX) can be crystallized directly from the reaction mixture.

As a further simplification of the process, it is optionally possible to combine the reaction of step b) with the reaction of step a) to give 2-(2-chloroethoxy)acetic acid (X).

Description of exemplary embodiments of the invention

The following examples are illustrative only and are provided to enable a person skilled in the art to make the present invention. The examples should not be construed as limiting the scope of the present invention.

Example 1 2-(2-Chloroethoxy)acetic acid (X).

150 ml of dichloromethane, 60 ml of tap water, 30.0 ml of 2-(2-chloroethoxy)ethanol (XI), 28.52 g of sodium bicarbonate and 0.22 g of TEMPO catalyst were measured into a sulfonation flask equipped with a condenser, thermometer, drip funnel. Then, at room temperature, 355 ml of an aqueous solution of sodium hypochlorite was added from an addition funnel. The mixture was stirred for half an hour, then 1.34 g of sodium metabisulphite was added to the reaction mixture, the two phases were separated in a separating funnel, then the aqueous phase was washed with 2x10 ml of dichloromethane. After that, the aqueous phase was acidified to pH 1-2 with a 34% hydrochloric acid solution. The resulting aqueous solution was extracted with 5x50 ml of methyl isobutyl ketone. The combined organic extract was washed with 1x20 ml brine, then evaporated under reduced pressure to constant weight.

Weight of pale yellow oil obtained: 21.27 g, yield: 54%.

Example 2 2-(2-Chloroethoxy)acetic acid (X).

150 ml of dichloromethane, 60 ml of tap water, 30.0 ml of 2-(2-chloroethoxy)ethanol (XI), 28.52 g of sodium bicarbonate and 0.22 g of TEMPO catalyst were measured into a sulfonation flask equipped with a condenser, thermometer, drip funnel. Then, at room temperature, 240.0 ml of a solution of 55.62 g of calcium hypochlorite in tap water was added from an addition funnel. The mixture was stirred for half an hour, then 1.34 g of sodium metabisulphite was added to the reaction mixture, the two phases were separated in a separating funnel, then the aqueous phase was washed with 2x10 ml of dichloromethane. After that, the aqueous phase was acidified to pH 1-2 with a 34% hydrochloric acid solution. The resulting aqueous solution was extracted with 5x50 ml of methyl isobutyl ketone. The combined organic extract was washed with 1x20 ml brine, then evaporated under reduced pressure to constant weight.

Weight of pale yellow oil obtained: 28.4 g, yield: 72%.

Example 3 2-(2-Chloroethoxy)-N-(4-nitrophenyl)acetamide (IX).

ml of toluene, 10.00 g of the oily extract of 2-(2-chloroethoxy)acetic acid (X) obtained in one of the previous examples, 8.31 g of 4-nitroaniline and 1.84 g of phenylboronic acid were measured into a sulfonation flask with a volume of 125 ml, equipped with a Dean-Stark nozzle, a condenser and a thermometer. The mixture was heated to boiling point (110-111°C), the reaction was monitored using thin layer chromatography (TLC). After completion of the reaction, the mixture was cooled and 1.00 ml of ethylene glycol was added. Then the mixture was again heated to the boiling temperature and boiled it under reflux for half an hour. After that, the mixture was cooled to a temperature in the range from 0°C to 5°C. The suspension was filtered and washed with toluene. The filtrate was dried to constant weight. Weight of pastel yellow powder obtained: 12.98 g, yield: 83%.

Example 4 4-(4-Nitrophenyl)morpholin-3-one (IV)

100 ml of acetonitrile, 9.35 g of potassium carbonate, 10.00 g of 2-(2-chloroethoxy)-N-(4-hytrophenyl)acetamide (IX) were measured into a sulfonation flask equipped with a KPG stirrer, N2 inlet tube, condenser, dropping funnel and thermometer. The mixture was heated to reflux and maintained at reflux until the reaction was complete (monitored by TLC analysis). Then the reaction mixture was cooled, a solution of 9.4 ml of concentrated hydrochloric acid in 100 ml of tap water was added. The suspension was concentrated by evaporation under reduced pressure until its mass was in the range of 105 g to 115 g, then cooled to a temperature in the range of 20 to 25° C., after which it was filtered and washed with 2x5 ml of tap water. The filtrate was dried under reduced pressure to constant weight. Weight of pastel yellow powder obtained: 7.92 g, yield: 92%.

Example 5 4-(4-Aminophenyl)morpholin-3-one (I).

ml of tap water, 50 ml of acetic acid, 10.00 g of 4-(4-nitrophenyl)morpholin-3-one were measured into an autoclave for hydrogenation. The interior of the autoclave was purged with nitrogen, then 0.50 g of 10% palladium on carbon was measured, after which the interior of the autoclave was filled with hydrogen gas and at a pressure of 1 bar and at a temperature ranging from 20 to 25°C, started mixing. Stirring was continued until the absence of hydrogen could be detected. The reaction mixture was then filtered, the filtrate was evaporated under reduced pressure until a weight ranging from 20 to 30 g was reached, then 100 ml of 2-propanol was added.

- 5 040278 and the resulting suspension was concentrated by evaporation until reaching a mass lying in the range from 50 to 60 g, and then cooled to a temperature lying in the range from 0 to 5°C. The precipitated material was filtered off, washed with 2-propanol, then dried under reduced pressure to constant weight. Weight of white powder obtained: 7.71 g, yield: 89%.

Claims (5)

CLAIM 1. The method of obtaining 4-(4-aminophenyl)morpholin-3-one of formula (I) according to scheme 6, including the following stages: a) 2-(2-chloroethoxy)ethanol of formula (XI) is oxidized to 2-(2-chloroethoxy)acetic acid with an oxidizing agent; b) the resulting 2-(2-chloroethoxy)acetic acid of formula (X) is then reacted with 4-nitroaniline of formula (VII); c) the resulting 2-(2-chloroethoxy)-X-(4-nitrophenyl)acetamide of formula (IX) is then converted to 4(4-nitrophenyl)morpholine-3-one of formula (IV); d) then 4-(4-nitrophenyl)morpholin-3-one of formula (IV) is hydrogenated to give 4-(4-aminophenyl)morpholin-3-one of formula (I), wherein a) in step a), the oxidizing agent is an aqueous solution of sodium hypochlorite or calcium hypochlorite, and the catalyst is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl; b) in step b) a phenylboronic acid catalyst is used; c) in step c) the product 2-(2-chloroethoxy)-M-(4-nitrophenyl)acetamide of formula (IX) is converted to 4-(4-nitrophenyl)morpholin-3-one of formula (IV) in a "one-pot" ' procedures; d) in step d) 4-(4-nitrophenyl)morpholin-3-one of formula (IV) is hydrogenated using a palladium-carbon catalyst under elevated hydrogen pressure to give the desired product 4-(4-aminophenyl)morpholin-3-one of formula (I). 2. The method according to claim 1, characterized in that at stage a) 2-(2-chloroethoxy)ethanol is dissolved, an aqueous solution of an oxidizing agent - sodium hypochlorite or calcium hypochlorite and a catalyst (2,2,6,6-tetramethylpiperidine -1-yl)oxyl, after which the biphasic mixture is stirred until the oxidation reaction is completed, while the pH is maintained in the range from 8 to 12. 3. The method according to claim 1, characterized in that in step b) a solvent is added to the oxidized product obtained in step a), forming an aqueous azeotropic mixture, then 4-nitroaniline and phenylboric acid are added and the resulting water is removed by azeotropic distillation. 4. The method according to claim 1, characterized in that in step c) the product 2-(2-chloroethoxy)-X-(4nitrophenyl)acetamide of formula (IX) is at least a tenfold excess (ml/g) of acetonitrile at least with a twofold excess of potassium carbonate is converted into 4-(4-nitrophenyl)morpholin-3-one formula (IV). 5. The method according to claim 2, characterized in that the amount of 4-nitroaniline of formula (VII) is from 0.85 to 1 equivalent in terms of the resulting 2-(2-chloroethoxy)acetic acid of formula (X). Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2