Claims:We Claim:
1. A process for the preparation of highly pure 3-Hydroxymethyl-2-(methylamino)pyridine of formula I:

or a salt thereof, which comprises:
a) reacting 2-Chloronicotinic acid of formula III:

or a salt thereof, with a suitable chlorinating agent to produce 2-chloronicotinoyl chloride, followed by reduction with a suitable reducing agent in a suitable solvent to produce (2-chloropyridin-3-yl)methanol of formula II.

and;
b) reacting the (2-chloropyridin-3-yl)methanol of formula II with aqueous methylamine solution in an autoclave to produce 3-hydroxymethyl-2-(methylamino)pyridine of formula I or a salt thereof, and optionally purifying the resulting compound of formula I by recrystallization using a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I or a salt thereof.

2. The process as claimed in claim 1, wherein the chlorinating agents used in step-(a) include, but are not limited to, thionyl chloride, oxalyl chloride, sulphuryl chloride, acetyl chloride, phosphorus pentachloride, 2-chloro-1,3-dimethyl-imidazolinium chloride, cyanuric trichloride and phosphorous oxychloride; wherein the reducing agent used in step-(a) is selected from the group consisting of sodium borohydride, potassium borohydride sodium cyanoborohydride, sodium triacetoxy borohydride, nickel borohydride, zinc borohydride, lithium aluminium hydride, C1-C8-alkyl aluminium hydrides, C2-C16-dialkyl aluminium hydrides, Red-Al, ZnCl2/NaCNBH3, Dibal-H, Vitride; and wherein the solvent used for reduction in step-(a) is selected from the group consisting of water, an alcohol, a ketone, an ester, a halogenated hydrocarbon, and mixtures thereof.

3. The process as claimed in claim 2, wherein the chlorinating agent used in step-(a) is thionyl chloride; wherein the reducing agent used in step-(a) is sodium borohydride; and wherein the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.

4. The process as claimed in claim 1, wherein the aqueous methylamine used in the step-(b) is about 40% to about 80% solution of methylamine in water; and wherein the reaction in step-(b) is carried out under a pressure at about 1 kg/cm2 to about 10 kg/cm2.

5. The process as claimed in claim 4, wherein the aqueous methylamine used in the step-(b) is 40% solution of methylamine in water.

6. A process for the preparation of highly pure 3-Hydroxymethyl-2-(methylamino)pyridine of formula I:

or a salt thereof, comprising reacting (2-chloropyridin-3-yl)methanol of formula II:

with aqueous methylamine solution in an autoclave to produce 3-hydroxymethyl-2-(methylamino)pyridine of formula I or a salt thereof, and optionally purifying the resulting compound of formula I by recrystallization using a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I or a salt thereof.

7. The process as claimed in claim 6, wherein the aqueous methylamine used in the step-(b) is about 40% to about 80% solution of methylamine in water; and wherein the reaction in step-(b) is carried out under a pressure at about 1 kg/cm2 to about 10 kg/cm2.

8. The process as claimed in claim 7, wherein the aqueous methylamine used in the step-(b) is 40% solution of methylamine in water.
, Description:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“NOVEL PROCESS FOR THE PREPARATION OF 3-HYDROXYMETHYL-2-(METHYLAMINO)PYRIDINE”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, B. N. Reddy Colony, Road No. 14,
Banjara Hills, Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel, commercially viable and industrially advantageous process for the production of 3-Hydroxymethyl-2-(methylamino)pyridine with high yield and purity.

BACKGROUND OF THE INVENTION
US Patent No. US 6,812,238 (hereinafter referred as the US’238 patent) discloses a variety of N-substituted carbamoyloxyalkyl-azolium derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. Among them, Isavuconazonium sulfate, which is the prodrug of isavuconazole, acts as an azole antifungal drug. Isavuconazonium sulfate is chemically named as glycine, N-methyl-,[2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1). Isavuconazonium sulfate is represented by the following structural formula:

Isavuconazonium sulfate is approved by FDA for use in the United States for treatment of invasive aspergillosis and invasive mucormycosis. It is orally administered as tablets containing 186 mg of Isavuconazonium sulfate (equivalent to 100 mg of isavuconazole) and as an intravenous injection in a single-dose vial as a sterile lyophilized powder containing 372 mg of Isavuconazonium sulfate (equivalent to 200 mg of isavuconazole).
Various processes for the preparation of Isavuconazonium sulfate, its intermediates and related compounds are described in U.S. Patent Nos. US6812238, US6300353, US7115643 and US7816537; and PCT Publication Nos. WO2011042827A1 and WO2014023623A1; and Drugs of the Future 31(3), 187-195, 2006.
In the synthesis of Isavuconazonium sulfate, the compound, 3-hydroxymethyl-2-(methylamino) pyridine, of formula I:

is a key intermediate.
Various processes for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine were reported in U.S. Patent Nos. US 6812238 and US 8334236; and PCT Publication Nos. WO01/032652 and WO2019/136112.
The US‘238 patent discloses various synthetic routes for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine. The first synthetic route for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine disclosed in the US‘238 patent [see steps (a) to (d) of Example 3 of the US‘238 patent] is depicted in the below Scheme-1:

The synthesis of 3-hydroxymethyl-2-(methylamino)pyridine as described in steps (a) to (d) of Example 3 of the US‘238 patent involves the following reaction steps: a) 2-chloronicotinic acid is reacted with oxalyl chloride in presence of catalytic amount of dimethylformamide in dichloromethane to produce 2-chloronicotinoyl chloride; b) 2-chloronicotinoyl chloride in tetrahydrofuran is reacted with potassium tertiary butoxide to produce tertiary-butyl-2-chloro nicotinate; c) tertiary-butyl-2-chloro nicotinate is reacted with 40% methylamine in presence of methanol to produce tertiary-butyl 2-(N-methylamino)nicotinate; and d) tertiary-butyl 2-(N-methylamino)nicotinate undergoes reduction with Lithium aluminium hydride in the presence of dry tetrahydrofuran followed by usual workup procedure to produce 3-hydroxymethyl-2-(methylamino)pyridine as a residue, which was purified by column chromatography, which was further purified with DCM-hexane to produce pure 3-hydroxymethyl-2-(methylamino)pyridine.
Another synthetic route of 3-hydroxymethyl-2-(methylamino)pyridine disclosed in the US‘238 patent [see steps (e) to (g) of Example 3 of the US‘238 patent] is depicted in the below Scheme-2:

The second synthetic route for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine as described in steps (e) to (g) of Example 3 of the US‘238 patent involves the following reaction steps: a) 2-aminonicotinic acid is reacted with 2-chloro-1,3-dimethyl imidazolinium chloride in the presence of methanol solvent to produce methyl 2-aminonicotinate; b) methyl 2-aminonicotinate is reacted with acetic formic anhydride to produce methyl N-formylamino nicotinate; and c) methyl N-formylaminonicotinate undergoes reduction with Lithium aluminium hydride in the presence of dry tetrahydrofuran followed by usual workup procedure to produce 3-hydroxymethyl-2-(methylamino)pyridine as a residue, which was crystallized with n-hexane to produce pure 3-hydroxymethyl-2-(methylamino)pyridine.
Another synthetic route for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine as disclosed in the US’238 patent [Example 1, step-(a) of US’238 patent] is depicted in the below Scheme-3:

As per the process described in Example 1, step-(a) of the US’238 patent, 3-hydroxymethyl-2-(methylamino)pyridine is prepared by the reduction of N-methylanthranilic acid by a suspension of Lithium aluminium hydride in dry tetrahydrofuran under Argon atmosphere followed by the usual workup procedure to produce yellowish oil, which was purified on a column of silica gel to produce 3-hydroxymethyl-2-(methylamino)pyridine as a colourless oil.
However, the processes for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine described in the aforementioned prior art have the following disadvantages and limitations:
i) the processes involve the use of highly combustible solvents like tetrahydrofuran;
ii) the processes involve the use of explosive and difficult to handle reagents such as Lithium aluminium hydride thereby the making the process undesirable for large-scale operations;
iii) the prior art processes have failed to disclose the purity of the obtained 3-hydroxymethyl-2-(methylamino) pyridine; and
iv) the processes involve the use of tedious and cumbersome column chromatographic purifications and multiple re-crystallizations - methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
The object of the present invention is to provide an improved, cost effective and industrially advantageous process for the preparation of 3-hydroxymethyl-2-(methylamino) pyridine with high purity to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
In one aspect, provided herein is an improved, commercially viable and industrially advantageous process for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine.
The present inventors have found that 3-hydroxymethyl-2-(methylamino)pyridine of formula I can be prepared with high yield and purity by carrying out the reaction of 2-chloronicotnic acid of formula III with a suitable chlorinating agent to produce 2-chloronicotinoyl chloride, followed by reduction of the 2-chloronicotinoyl chloride using a suitable reducing agent in a suitable solvent to produce (2-chloropyridin-3-yl)methanol of formula II, which is finally reacted with 40% aqueous methylamine solution in an autoclave to produce 3-hydroxymethyl-2-(methylamino)pyridine of formula I.
The process for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine of formula II as disclosed in the present invention may be represented by a schematic diagram as depicted below in Scheme-4:
The present invention avoids the problems associated with the processes described in the prior art, and which is more convenient to operate at laboratory scale and on a commercial scale operations.
The process for the preparation of 3-hydroxymethyl-2-(methylamino)pyridine disclosed herein has the following advantages over the processes described in the prior art:
i) the process involves the use of cheaper reducing agents like sodium borohydride thereby making the process cost effective;
ii) the process produces the product with high yield and purity;
iii) the process involves less number of reaction steps thereby making the process industrially advantageous and cost effective;
iv) the process avoids the use of highly combustible solvents like tetrahydrofuran;
v) the process avoids the use of explosive and difficult to handle reagents like Lithium aluminium hydride; and
vi) the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple re-crystallizations.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of highly pure 3-Hydroxymethyl-2-(methylamino)pyridine of formula I:

or a salt thereof, which comprises:
a) reacting 2-Chloronicotinic acid of formula III:

or a salt thereof, with a suitable chlorinating agent to produce 2-chloronicotinoyl chloride, followed by reduction with a suitable reducing agent in a suitable solvent to produce (2-chloropyridin-3-yl)methanol of formula II:

and;
b) reacting the (2-chloropyridin-3-yl)methanol of formula II with aqueous methylamine solution in an autoclave to produce 3-hydroxymethyl-2-(methylamino)pyridine of formula I or a salt thereof, and optionally purifying the resulting compound of formula I by recrystallization using a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I or a salt thereof.
Unless otherwise specified, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
Unless otherwise specified, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC. For example, “room temperature” can refer to a temperature of about 25ºC to about 30ºC.
Unless otherwise specified, the term ‘salt’ as used herein may include acid addition salts and base addition salts.
Unless otherwise specified, the term ‘acid addition salts’, as used herein, include the salts that are derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
The base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium; and organic amines such as ethylamine, tert-butylamine, diethylamine, diisopropylamine and the like.
Exemplary chlorinating agents used in step-(a) include, but are not limited to, thionyl chloride, oxalyl chloride, sulphuryl chloride, acetyl chloride, phosphorus pentachloride, 2-chloro-1,3-dimethyl-imidazolinium chloride, cyanuric trichloride, phosphorous oxychloride and the like. A most specific chlorinating agent used in step-(a) is thionyl chloride.
In another embodiment, the reaction with the chlorinating agent in step-(a) is carried out at a temperature of about 10ºC to about 120ºC, and most specifically at a temperature of about 30ºC to about 90ºC. The reaction time may vary between about 30 minutes to about 10 hours, specifically about 1 hour to about 5 hours, and more specifically about 2 hours to 3 hours.
In another embodiment, the reduction in step-(a) is carried out by reacting with a suitable reducing agent in the presence of a suitable solvent. Exemplary reducing agents used in step-(a) include, but are not limited to, sodium borohydride, potassium borohydride sodium cyanoborohydride, sodium triacetoxy borohydride, nickel borohydride, zinc borohydride, lithium aluminium hydride, C1-C8-alkyl aluminium hydrides, C2-C16-dialkyl aluminium hydrides, Red-Al, ZnCl2/NaCNBH3, Dibal-H, Vitride, and the like. A most preferable reducing agent used in step-(a) is sodium borohydride.
The reduction in step-(a) is carried out in the presence of a suitable solvent. Exemplary solvents used in step-(a) include, but are not limited to, water, an alcohol, a ketone, an ester, a halogenated hydrocarbon, and mixtures thereof.
Specifically, the solvent used for reduction in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. A most preferable solvent used for reduction in step-(a) is water.
In one embodiment, the reduction reaction in step-(a) is carried out at a temperature of about -15ºC to about 50ºC, more specifically at a temperature of about -10ºC to about 30ºC, and most specifically at a temperature of about -5ºC to about 20ºC. The reaction time may vary from about 10 minutes to about 5 hours and most specifically from about 20 minutes to about 4 hours.
The reaction mass containing the (2-chloropyridin-3-yl)methanol of formula II obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula II may be isolated, purified and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula II may be isolated, purified and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation, purification and/or recrystallization of the compound of formula II obtained by the process described herein is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used for work up, isolation and/or recrystallization of the compound of formula II obtained by the process described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.
In one embodiment, the aqueous methylamine used in the step-(b) is about 40% to about 80% solution of methylamine in water; and most preferably 40% solution of methylamine in water.
In another embodiment, the reaction in step-(b) is carried out at a temperature of about 25°C to about 140°C, and most specifically at a temperature of about 60°C to about 130°C. The reaction time may vary from about 2 hours to about 50 hours and most specifically from about 10 hours to about 46 hours.
In another embodiment, the reaction in step-(b) is carried out under a pressure of about 1 kg/cm2 to about 10 kg/cm2.
The reaction mass containing the 3-Hydroxymethyl-2-(methylamino)pyridine of formula I obtained in step-(b) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the 3-Hydroxymethyl-2-(methylamino)pyridine of formula I obtained in step-(b) may be isolated, purified and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for workup, isolation, purification and/or recrystallization of the compound, 3-Hydroxymethyl-2-(methylamino)pyridine, of formula I obtained by the process described herein is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, an ether solvent, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.
The 3-Hydroxymethyl-2-(methylamino)pyridine of formula I obtained by the above processes may be further dried to further lower residual solvents. Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 30°C to about 90°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 10 hours, and more preferably about 3 hours to 6 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The compounds of formula I and II or a salt thereof obtained by the process disclosed herein have a purity of greater than about 90%, specifically greater than about 95%, more specifically greater than about 97%, and most specifically greater than about 98% as measured by HPLC.
According to another aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of highly pure 3-Hydroxymethyl-2-(methylamino)pyridine of formula I:

or a salt thereof, comprising reacting (2-chloropyridin-3-yl)methanol of formula II:

with aqueous methylamine solution in an autoclave to produce 3-hydroxymethyl-2-(methylamino)pyridine of formula I or a salt thereof, and optionally purifying the resulting compound of formula I by recrystallization using a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I or a salt thereof.
The preparation of 3-Hydroxymethyl-2-(methylamino)pyridine of formula I as described in the above process step can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
In one embodiment, the aqueous methylamine used in the above reaction is about 40% to about 80% solution of methylamine in water; and most preferably 40% solution of methylamine in water.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of (2-chloropyridin-3-yl)methanol
Thionyl chloride (800 ml) was added to 2-chloronicotinic acid (200 g) in a reaction flask at room temperature (25-30ºC) and the resulting mixture was stirred for 20 minutes at the same temperature. The resulting mass was heated to reflux temperature (70-80ºC) and then stirred for 2 hours at the same temperature. After completion of reaction, the excess thionyl chloride was removed under vacuum followed by co-distillation with toluene (100 ml x 2) to produce a brown semi-solid (residue). The crude residue was added to a solution of sodium borohydride in water (200g in 2 litres of water) at 0-5ºC and then stirred for about 1-2 hours at the same temperature. After completion of the reaction, the temperature of the reaction mass was raised to 25-30ºC, followed by the slow addition of ammonium chloride (200g) and the reaction mass was stirred for about 30 minutes to about 1 hour at the same temperature. The resulting mass was extracted with ethyl acetate (600 x 2 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (600 ml x 2). The combined organic layers were distilled under reduced pressure to produce 166 g of (2-chloropyridin-3-yl)methanol as an off-white solid (Purity by HPLC: 98.0%).

Example 2
Preparation of 3-Hydroxymethyl-2-(methylamino)pyridine
A mixture of 40% aqueous methylamine (840 ml) and (2-chloropyridin-3-yl)methanol (84 g) were taken into an auto-clave reaction vessel at room temperature (25-30ºC). The resulting mass was slowly heated to 120ºC and maintained at the same temperature for about 40-43 hours under the pressure of 10 Kg/cm2. After completion of the reaction, the resulting mass was cooled to room temperature and excess of methyl amine was removed under vacuum at 120ºC to produce an ash colour semi-solid (residue). To the resulting residue, sodium carbonate (50 g) and water (400 ml) were added and stirred for 20 minutes. To the resulting mass, ethyl acetate (400 ml) was added and stirred for about 10 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (160 ml x 4). The combined organic layers were distilled under reduced pressure to produce 76 g of crude 2-Chloro-3-pyridine methanol as a pale ash colour solid (Purity by HPLC: 95.0%).
Purification:
Diisopropyl ether (190 ml) was added to crude 3-hydroxymethyl-2-(methylamino)pyridine (76 g) in a reaction flask and the resulting mass was heated to reflux temperature, followed by stirring the mass for 1 hour at the same temperature. The resulting mass was cooled to room temperature and then stirred for 1 hour at the same temperature. The precipitated solid was filtered, washed with diisopropyl ether (20 ml x 2) and then air dried the material for 3 to 4 hours to produce 68 g of pure 3-Hydroxymethyl-2-(methylamino)pyridine (Purity by HPLC: 98.0%).