DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION

(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM INTERMEDIATE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of the invention and manner in which the same is to be performed.
FIELD OF INVENTION
The present invention relates to a process for the preparation of [N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2-yl]carbamic acid 1-chloroethyl ester compound of Formula (I).

Formula (I)
The compound of Formula (I) is a key intermediate in the preparation of Isavuconazonium sulfate of Formula (II).

Formula (II)

The present invention also relates to one-pot process for the preparation of Isavuconazonium sulfate of Formula (II).
BACKGROUND OF THE INVENTION
Isavuconazonium sulfate, is the prodrug of Isavuconazole, and it is an azole antifungal agent used for the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazonium Sulfate is very soluble in water over the pH range 1-7. Isavuconazonium sulfate is being marketed in the US under the brand name Cresemba®.

US 6,812,238 of Basilea discloses a process for the preparation of compound of Formula (I) by the reaction of 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) with 1-Chloroethyl chloroformate in presence of diisopropylamine in dichloromethane, followed by adding Boc-sarcosine in the presence of DMAP and in diethylether to produce [N-methyl-N-3-((tert-butoxycarbonylmethylamino) acetoxymethyl)-pyridin-2-yl]carbamic acid 1-chloro-ethyl ester of Formula (I).

The process is as shown in scheme-I below:

The disadvantage of the above processes is due to the strong acylation ability of the acid chloride, both N-acylation and O-acylation can occur, even if the reaction is carried out at a low temperature, the following by-product is unavoidable.

US ‘238 further also discloses the preparation of Isavuconazonium sulfate of Formula (II) by reacting Isavuconazole compound of formula (V) with compound of formula (I) in acetonitrile and in the presence of NaI to give compound of formula (VIII) which is treated with mineral acid to give Isavuconazonium sulfate Formula II.

The disadvantage of the above process is the compound Formula VIII contains more number of impurities and it needs multiple purifications for their elimination.

CN 110551064 discloses a process for the preparation of compound of Formula (I) by the reaction of 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) with Boc-sarcosine in presence of THF, DMAP and DCM to produce 3-(tert-butoxycarbonylmethylamino)acetoxymethyl)-2-methyl aminopyridine of Formula (IV), which is further reacted with 1-chloroethyl chloroformate in presence of Na2CO3 and DCM.

The process is as shown in scheme- II below:

The disadvantage of the above processes is as it was aforementioned the problem of di-acylation already, even this methodology would furnish the di-acylation and therefore, the following impurities formation is quite inevitable.

Therefore, there is always a need for the alternative preparative route, which provides the desired compound of Formula (I) in high yield with high purity and without forming by-products and completing isolation of desired compound of Formula (I).

The present invention is to resolve the above problems, surprisingly found that the compound of Formula (III) is reacted with Boc-sarcosine in presence of a base and an amide solvent to provide compound of Formula (IV) in pure form without forming by-products, which is further reacted with chloroethyl chloroformate in presence of a base and a solvent followed by separating layers using an acid to produce compound of Formula (I) with high purity and yield and removes unreacted compound of Formula (IV). The compound of formula (I) is involved in the one-pot process of Isavuconazonium sulfate, which is commercially feasible provides high yield and having purity >99% (HPLC).

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a process for the preparation of N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy) methyl) pyridin -2-yl]carbamic acid 1-chloroethyl ester compound of Formula (I) in high yield with purity and without forming by-products.

Formula (I)

Another object of the present invention is to provide a one-pot process for the preparation of Isavuconazonium sulfate of Formula (II).

Formula (II)

SUMMARY OF THE INVENTION
The main embodiment of the present invention is to provide a process for the preparation of compound of Formula (I) with high purity,

Formula (I)
which comprises:
(i) reacting of compound of Formula (III);

Formula (III)
with Boc-sarcosine or a salt thereof; in presence of a base and in an amide solvent to produce compound of Formula (IV);

Formula (IV)
(ii) separating the layers,
(iii) reacting compound of Formula (IV) with chloroethyl chloroformate in the presence of a base and a solvent to produce reaction mass;
(iv) adding an acid for removing unreacted intermediate compound of formula (IV);
(v) isolating the compound of Formula (I) in pure form.

In yet another embodiment of the present invention is to provide a one-pot process for the preparation of Isavuconazonium sulfate of Formula (II) having purity > 99%,

Formula (II)

which comprises:
a) reacting Isavuconazole of formula (V);

Formula (V)
with a compound of formula (I);

Formula (I)

in a solvent, in the presence of an alkali metal halide to give compound of formula (VI);

Formula (VI)
wherein X is Cl, Br or I;
b) reacting the compound of formula (VI) with trifluoroacetic acid to give compound of formula (VII);

Formula (VII)
c) converting the compound of formula (VII) to Isavuconazonium sulfate of Formula (II) having purity > 99%.

DETAILED DESCRIPTION OF THE INVENTION
The present invention related to a process for the preparation of N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2-yl]carbamic acid 1-chloroethyl ester compound of Formula (I), in high yield and purity without forming by-products.

The process comprises, reacting compound of formula (III) with Boc-sarcosine in the presence of a base, a coupling agent in an amide solvent to provide compound of formula (IV). The compound of Formula (IV) is reacted with chloroethyl chloroformate in the presence of a base and a solvent to produce a reaction mixture, followed by separating the layers, adding an acid to the organic layer for removing unreacted intermediate compound of Formula (IV) and the compound of Formula (I) is isolated with high purity and yield.

The base as used in the above reaction comprising an organic base comprises pyridine, piperidine, dimethylaminopyridine, picolines, diisopropyl ethylamine, triethyl amine and the like or mixtures thereof or an inorganic base comprises NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, sodium hydride, potassium tert- butoxide, sodium tert-butoxide, magnesium hydroxide and the like or mixtures thereof.

The amide solvent used in the above reaction comprises N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoramide, and N-acetyl pyrrolidine and the like or mixtures thereof.

The coupling agent is selected from carbodiimides or salt thereof such as N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC); imidazoliums or salt thereof; such as 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyl-di-(1,2,4-triazole) (CDT); uronium or guanidinium salts such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); phosphonium salts such as benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP or Castro's reagent), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 7-azabenxotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP); alkyl phosphonic acid anhydrides such as T3P etc.

The solvent used in the above reaction comprises an ether such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.

The acid used in the above reaction comprises inorganic acid selected from the group consisting of sulfuric acid, nitric acid or hydrochloric acid, phosphorus acid, phosphoric acid or mixtures thereof.

In yet another embodiment of the present invention, a one-pot process for the preparation of Isavuconazonium sulfate comprises, the reaction of Isavuconazole of formula (V) with the compound formula (I) in a solvent, in the presence of a catalyst and alkali metal halide to give formula (VI), which is treated with trifluoroacetic acid in a solvent to give compound of formula (VII) which is salt exchanged by an anion exchange resin to give Isavuconazonium sulfate (II) with high purity i.e > 99% (HPLC).

The process of the present invention is depicted below scheme:

The alkali metal halide used in the coupling comprises lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide.

The catalyst used in the coupling comprises tetrabutylammonium bromide (TBAB), tetrabutylammonium hydroxide, triethylbenzylammonium chloride, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide.

The solvent used in the above reaction comprises tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; butyronitrile, propionitrile, ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.

The anion exchange resin used for salt exchange comprises a strong base anion (SBA) resin.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1: PREPARATION OF COMPOUND OF FORMULA (IV):
In a RBF, 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) (50.0 g) and DMF (100 mL) were charged at 20-30ºC. The above reaction mixture was stirred for 5 min at 20-30ºC, then cooled to 0-5ºC. A solution of N-Boc-sarcosine (102.68 g) & DMAP (13.26g) in DMF (150 mL) were dissolved at 0-5ºC. The above reaction mixture was stirred for 10 min at 0-5ºC. EDC.HCl (84.24 g) was added at 0-5ºC and the reaction mixture was maintained at 0-5ºC for 2-4 h and monitored the reaction for unreacted 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III). In a separate round bottom flask water (3500 mL) was taken to cooled to 0-5ºC and the reaction mass was added over a period of ~30 min then allowed the reaction temperature to reach 20-30ºC. The reaction was maintained at this temperature for 2-3h. The reaction mass was filtered over Buchner funnel under vaccum at 20- 30ºC, then continued to suck dry. The wet cake was washed with isopropyl alcohol and dried at 20-30ºC for 10-12 h.

Yield: ~80-90% (85-95 g) and progress of the reaction was monitored on HPLC purity (Limit: NLT 99.0, 0.97 RRT ~NLT 0.5%; 1.08 RRT NLT 0.1% and 1.3 RRT 0.5%).

EXAMPLE-2: PREPARATION OF COMPOUND OF FORMULA (I):
In a RBF, 3-(tert-butoxycarbonylmethylamino)acetoxymethyl)-2-methyl aminopyridine of compound of Formula (IV also referred as DES-CECF) (50.0 g) at 20-30ºC and MDC (400 mL) was charged and the resulting mixture was stirred for 10±5 min at 20-30ºC then cooled to 0- 5ºC. Sodium carbonate (50 g) was added and stirred for 5-10 min at 0-5ºC.1-Chloroethyl chloroformate (24.0 g) was added to reaction mass over a period of 10-20 min and stirred the reaction mass for 8 h at 0-5ºC, then monitored the reaction for unreacted compound of Formula (IV). It should be less than 25%. The reaction mass was filtered and washed with DCM (100 mL). To the filtrate sodium bicarbonate solution (prepared from 54.0 g NaHCO3 + DM water 1000 mL) was added and stirred for 15-30 min at 20-30°C. The layers were separated and the organic layer was collected. Charged organic layer and 10% Aq. Phosphorous acid solution (400 mL) into the above RBF and stirred for 10±5 min and then layers were separated and collected the organic layer. The organic layer was concentrated under reduced pressure below 40ºC to obtain the compound of Formula (I) as pale yellow color liquid.
Yield: ~ 40g and HPLC purity: > 99.0 %

EXAMPLE-3: PREPARATION OF COMPOUND OF FORMULA (I):
In a RBF, 3-(tert-butoxycarbonylmethylamino)acetoxymethyl)-2-methyl aminopyridine of compound of Formula (IV) (50.0 g) at 20-30ºC and MDC (400 mL) was charged and the resulting mixture was stirred for 10±5 min at 20-30ºC then cooled the reaction mixture to 0- 5ºC. Pyridine (56 g) was added at 0-5ºC and stirred for 5-10 min at 0-5ºC. 1-Chloroethyl chloroformate (24.0 g) was added to reaction mass at 0-5ºC over a period of 10-20 min and stirred for 8 h at 0-5ºC, the reaction was monitored for unreacted compound of Formula (IV). It should be less than 25%. Reaction mass was filtered and residue was washed with of DCM (100 mL). To the filtrate, sodium bicarbonate solution (prepared from 54.0 g NaHCO3 + DM water 1000 mL) was added, stirred for 15-30 min at 20-30°C. Settled for 10±5 min at 20-30ºC, layers were separated. Organic layer was added with 10% Aq. phosphorous acid solution (400 mL), stirred for 10±5 min, layers were separated and organic layer was collected. Concentrated the above organic layer under reduced pressure below 40ºC to obtain the compound of Formula (I) as pale yellow color liquid.
Yield: ~55g and HPLC purity: > 99.0 %.

EXAMPLE-4: PREPARATION OF ISAVUCONAZONIUM SULFATE OF FORMULA (II)
A. PREPARATION OF COMPOUND OF FORMULA (VI)
Compound of Formula I (190 g) was added to acetonitrile (500 ml) at 20-30°C under nitrogen atmosphere. The reaction mixture was stirred for 10-15 minutes to give a clear solution. Compound of Formula V (100 g), sodium bromide (70.63g) and TBAB (7.37 g) were added to the reaction mixture. Temperature was raised to 45-55°C and maintained for 20 hours. Reaction mixture was filtered on Hyflow and washed the bed with acetonitrile (200 ml). The reaction mass was distilled, MDC (1000 ml) was added to the concentrated mass and stirred for 15-20 min. Reaction mass was washed with purified water (2x1500 ml) and 10% sodium chloride solution (2x1000 ml). Organic layer was treated with carbon to give a wet material (VI) and it is used as such in the next step for the preparation of Formula (VII).

B. PREPARATION OF COMPOUND OF FORMULA (VII)
Purified water (500 ml) was added to the MDC solution containing Formula (VI) (~200g) at 20-30°C. The mixture was cooled to 0-10°C. Trifluoroacetic acid (1000 ml) was added at 0-10°C. Reaction mass temperature was raised to 20-30°C and maintained for 3 hrs. After completion of the reaction, the reaction mass was washed with water (2x3000 ml) at 20-30°C. The organic layer was treated with carbon to give Formula VII (Isavuconazonium TFA Salt), which is used as such in the preparation of Formula (II).

C. PREPARATION OF COMPOUND OF FORMULA (II)
The MDC layer contains Formula (VII, ~200g, Isavuconazonium TFA Salt) was Concentrated and dissolved in purified water (400 ml). The aqueous solution contains Formula-(VII) was passed through Indion GS 300 Resin to exchange from Isavuconazonium TFA salt to Isavuconazonium Sulfate at 20-30°C. To the obtained aqueous solution, acetonitrile (12500 ml) was added at 20-30°C and cooled to -10 to -15°C. Added seed material of Isavuconazonium Sulfate (1.0g) at -10 to -15°C and continued stirring for 30 hours. Raised the temperature to 0-5°C. Filtered and dried the product to afford crystalline Isavuconazonium Sulfate of compound of Formula (II) having HPLC Purity >99%. ,CLAIMS:WE CLAIM:
1. A process for the preparation of compound of Formula (I) with high purity, which is an intermediate of Isavuconazonium sulfate (II);

Formula (I)
comprises:
(i) reacting a compound of Formula (III);

Formula (III)
with Boc-sarcosine or a salt thereof; in presence of a base and an amide solvent to produce compound of Formula (IV);

Formula (IV)
(ii) reacting compound of Formula (IV) with chloroethyl chloroformate in presence of a base and a solvent to produce a reaction mass;
(iii) adding an acid for removing unreacted intermediate compound (IV);
(iv) isolating the compound of Formula (I) in pure form.

2. The process as claimed in claim 1, wherein the base comprises organic base such as pyridine, piperidine, dimethylaminopyridine, picolines, diisopropyl ethylamine, triethyl amine and the like or mixtures thereof; or an inorganic base such as NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, magnesium hydroxide and the like or mixtures thereof.

3. The process as claimed in claim 1, wherein the amide solvent comprises N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoramide, and N-acetyl pyrrolidine and the like or mixtures thereof.

4. The process as claimed in claim 1, wherein the solvent comprises an ether selected from tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.

5. The process as claimed in claim 1, wherein the acid comprises sulfuric acid, nitric acid or hydrochloric acid, phosphorus acid, phosphoric acid or mixtures thereof.

6. A one-pot process for the preparation of Isavuconazonium sulfate of Formula (II),

Formula (II)
which comprises:
(i) reacting Isavuconazole of formula (V);

Formula (V)
with compound of formula (I);

Formula (I)
in a solvent, in the presence of alkali metal halide to give compound of formula (VI);

Formula (VI)

wherein X is Cl, Br or I;
(ii) reacting the compound of formula (VI) with trifluoroacetic acid to give compound of formula (VII);

Formula (VII)
(iii) converting compound of formula (VII) to Isavuconazonium sulfate of Formula (II).

7. The process as claimed in claim 7, wherein the alkali metal halide comprises lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide.

8. The process as claimed in claim 7, wherein step-(i) is carried out in the presence or absence of a catalyst comprises tetrabutylammonium bromide (TBAB), tetrabutylammonium hydroxide, triethylbenzylammonium chloride, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide.

9. The process as claimed in claim 7, wherein the compound of formula (VII) is salt exchanged by an anion exchange resin to give Isavuconazonium sulfate (II) with high purity i.e > 99% (HPLC).