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 LEMBOREXANT INTERMEDIATE

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

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.
FIELD OF INVENTION
The present invention relates to a process for the preparation of salt of cyclopropane pyrimidine carboxylic acid of Formula II, having purity > 95% by HPLC, which is a useful intermediate in the preparation of Lemborexant of Formula I.

Formula I

Formula II
wherein, X comprising a base such as an amine.

BACKGROUND OF THE INVENTION
Lemborexant of Formula (I) is chemically known as (1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-1-carbox amide. It is an orexin receptor antagonist medication, which is used in the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. Lemborexant of Formula (I) is being marketed in the US under the brand name Dayvigo ®.
US 8,268,848 discloses a process for the preparation of Lemborexant of Formula (I) by treating compound (14-2) with tert-butyldiphenylsilyl chloride to produce compound (14-3), which is reacted with 2,4-dimethyl-pyrimidin-5-ol to produce TBDPS protected cyclopropane pyrimidine, which is treated with tetrabutyl ammonium fluoride to produce compound (14-4). Swern Oxidation of compound (14-4) with oxalyl chloride/DMSO gave compound (14-5), followed by treated with sodium chlorite to produce cyclopropane carboxylic acid of Formula (IIA), which is treated with oxalyl chloride to produce cyclopropane carboxyl chloride of Formula (III) followed by reacted with 2-amino-5-fluoropyridine of Formula (IV) to produce Lemborexant of Formula (I).

The process is as shown in scheme-I below:

US 9,416,109 discloses a process for the preparation of Lemborexant of Formula (I) by reacting compound (8) with 2,4-dimethyl-pyrimidin-5-ol to produce compound (10), which is treated with methyl tert-butyl ether to produce compound (11), followed by oxidation with TEMPO to produce compound (12), which is treated with sodium chlorite to produce cyclopropane carboxylic acid of Formula (IIA), which on further reaction with 2-amino-5-fluoropyridine of Formula (IV) in presence of alkyl phosphonic anhydride to produce Lemborexant of Formula (I).

The process is as shown in scheme-II below:

The disadvantage of the above processes is difficulty in isolation of compound IIA, which suffers from low purity of compound IIA and isolation of Lemborexant becomes difficult as being undesired contaminants carry forward.

There is always a need for alternative preparative routes, which for example, involve usage of reagents that are less expensive and/or easier to handle and raw materials which are readily/ commercially available.
The present invention is to resolve the above problems, surprisingly found that the cyclopropane pyrimidine carboxylic acid of Formula IIA can be isolated in pure form by treating with a base to provide corresponding salt of cyclopropane pyrimidine carboxylic acid of Formula II, which is used in the preparation of Lemborexant of Formula I.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide process for the preparation of a salt of cyclopropane pyrimidine carboxylic acid of Formula II having purity > 95% by HPLC.

A further objective of the present invention is to provide a process for the preparation of Lemborexant of Formula (I) using salt of cyclopropane pyrimidine carboxylic acid of Formula (II), which is simple, cost effective and industrially viable.

SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the preparation of a salt of cyclopropane pyrimidine carboxylic acid of Formula (II), having purity > 95% by HPLC,

Formula II
wherein, X comprising a base such as an amine.

which comprises:
(i) providing cyclopropane pyrimidine carboxylic acid of Formula (IIA),

Formula IIA

(ii) treating cyclopropane pyrimidine carboxylic acid of Formula (IIA) with a base to obtain a salt of cyclopropane pyrimidine carboxylic acid compound of Formula (II);
(iii) isolating the salt of cyclopropane pyrimidine carboxylic acid compound of Formula (II) having purity > 95% by HPLC.

In yet other embodiment of the present invention is to provide an improved process for the preparation of Lemborexant of Formula (I),

Formula I
which comprises:
(i) providing the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) having purity > 95% by HPLC,
(ii) reacting the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) with 2-amino-5-fluoropyridine of Formula (IV),


Formula IV

in presence of a coupling agent to produce Lemborexant of Formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

• Figure 1: Illustrates the X-ray powder diffraction pattern of crystalline Form of TBA salt of cyclopropane pyrimidine carboxylic acid of Formula (II) having purity > 95% by HPLC.

• Figure 2: Illustrates the Differential Scanning Calorimetry (DSC) of crystalline Form of TBA salt of cyclopropane pyrimidine carboxylic acid of Formula (II) having purity > 95% by HPLC.

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is related to process for the preparation of the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) having purity > 95% by HPLC, wherein the salt comprising a base such as an amine.

The amine selected from an alkylamine such as tert-butylamine and the like, an arylamine such as benzylamine and the like.

The process comprises, cyclopropane pyrimidine carboxylic acid of Formula (IIA) with a base in presence of a solvent to obtain the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) having purity > 95% by HPLC.

The base used in the above reaction comprising an amine selected from an alkylamine such as tert-butylamine; an arylamine such as benzylamine and the like. 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; an alcohol selected from C1-C10 straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF; an aliphatic hydrocarbon selected from C1-8 carbon atoms containing straight chain or branched chain or cycloalkane, substituted cycloalkane or mixture thereof.

The salt of cyclopropane pyrimidine carboxylic acid of Formula (II) is isolated in pure form by known techniques such as drying under reduced pressure and the like.

Yet another embodiment of the present invention is related to a process for the preparation of Lemborexant of Formula (I).

The process comprises, providing the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) by the process as described above.

The salt of cyclopropane pyrimidine carboxylic acid of Formula (II) is reacted with 2-amino-5-fluoropyridine of Formula (IV) in presence of a coupling agent to produce Lemborexant of Formula (I).

The process is carried out in presence of an acid comprises inorganic acid selected from the group consisting of sulfuric acid, nitric acid or hydrochloric acid, and mixtures thereof.

The process is carried out in presence/ absence of a solvent. 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; an alcohol selected from C1-C10 straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF; an aliphatic hydrocarbon selected from C1-8 carbon atoms containing straight chain or branched chain or cycloalkane, substituted cycloalkane or mixture thereof.

The coupling agent used in the above reaction comprises carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC), N,N'-diisopropylcarbodiimide (DIC); imidazoliums 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.

Lemborexant of Formula (I) is isolated as a solid. Lemborexant of Formula (I) is subjected to purification either by column chromatography or by crystallization by known methods, for example by dissolving in a solvent comprises, methanol, ethanol, propanol, isopropanol, ethyl acetate, methylene chloride, hexane, heptane, cyclohexane, acetone, THF, acetonitrile, methyl-tert-butyl ether, diisopropyl ether, diethyl ether, water or mixtures thereof; and precipitating pure compound by cooling the solution or by adding an anti-solvent comprises, cyclohexane, n-hexane, n-heptane, water etc.

Other embodiment of the present invention is the cyclopropane pyrimidine carboxylic acid of Formula (IIA) used in this invention is prepared according to the process disclosed in US 8268848.

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 salt of cyclopropane pyrimidine carboxylic acid of Formula II:
Cyclopropane pyrimidine carboxylic acid (5 g) was dissolved in ethyl acetate (50 ml) at 20-30°C. Tert-butylamine (1.27 g, 1.1 mole equivalent) was added to reaction mass for 30 min at 20-30°C and stirred for 30 min at the same temperature. Thereafter, the slurry was cooled to 0-5°C and stirred for 2 h at the same temperature. The product was filtered and washed with ethyl acetate (10 ml) at 0-5°C. The wet product was dried at 40-45°C under reduced pressure to yield Cyclopropane pyrimidine carboxylic acid TBA salt.
HPLC purity: > 95%

The Cyclopropane pyrimidine carboxylic acid TBA salt produced by the present invention is characterized by X-ray diffraction pattern having characteristic peaks at 3.04, 5.36, 9.51, 10.75, 11.42, 12.18, 13.22, 14.13, 15.26, 15.86, 16.16, 16.76, 17.82, 18.33, 18.60, 19.21, 20.06, 20.78, 21.62, 22.77, 22.99, 23.16, 24.77, 25.29, 26.45, 26.93, 27.67, 28.23, 28.23, 28.51, 28.86, 29.20, 29.55, 30.17, 31.36, 31.60, 32.20, 32.56, 33.38, 34.15, 35.34, 35.98, 36.56, 37.82 and 39.12 ± 0.2 angle 2?; and DSC having an endothermic peak at 163?C .

EXAMPLE-2:
Preparation of Lemborexant:
Cyclopropane pyrimidine carboxylic acid TBA salt (2.5 g) was added to the ethyl acetate (25 ml) and purified water (25 ml) at 20-30°C. pH was adjusted to 2.0 with 6N hydrochloric acid at 20-30°C and stirred for 30 min. The organic layer was separated and washed with purified water followed by dried over sodium sulfate. Thereafter, 2-amino-5-fluoropyridine (0.67 g) was added to the above organic layer at 20-30°C and cooled to the 0-5°C. N,N-Diisopropylethylamine (1.47 g) was added to the above reaction mass at 0-5 °C and stirred for 10 min at the same temperature. N-propylphosphonic anhydride solution in ethyl acetate solution (T3P, 8.15 g) was added to the reaction mass at 0-5°C. Reaction mass temperature was raised to 20-30°C and stirred for 16 hr. Thereafter, purified water (10 ml) was added and stirred for 20 min. The organic layer was separated and washed with aq. sodium bicarbonate solution followed by aq. sodium chloride solution. Thereafter, the organic layer was treated with charcoal and concentrated completely at below 40°C under reduced pressure to obtained crude Lemborexant. The crude Lemborexant was dissolved in ethyl acetate at 60-65°C and cooled to 40-45°C. n-Heptane was added to the above solution at below 45°C, cooled to 20-30°C and stirred for 2 h. The product was filtered and washed with n-Heptane (5 ml) at 20-30°C. The wet product was dried at 40-45°C under reduced pressure to give Lemborexant.
HPLC purity: > 99%. ,CLAIMS:WE CLAIM:
1. A process for the preparation of a salt of cyclopropane pyrimidine carboxylic acid of Formula (II), having purity > 95% by HPLC,

Formula II
wherein, salt comprising a base,
which comprises:
(i) providing cyclopropane pyrimidine carboxylic acid of Formula (IIA),

Formula IIA
(ii) treating cyclopropane pyrimidine carboxylic acid of Formula (IIA) with a base to obtain a salt of cyclopropane pyrimidine carboxylic acid compound of Formula (II);
(iii) isolating the salt of cyclopropane pyrimidine carboxylic acid compound of Formula (II) having purity > 95% by HPLC.

2. The process as claimed in claim 1, wherein said base comprising alkylamines and arylamines are selected from the group consisting of tert-butylamine and benzylamine.

3. The process as claimed in claim 1, wherein the process is carried out in presence of a solvent selected from the group comprising ethers, alcohol, hydrocarbon solvent, an aliphatic hydrocarbons, water or mixture thereof.

4. The process as claimed in claim 3, wherein said ether selected from the group consisting of tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; wherein said alcohol selected from C1-C10 straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; wherein said hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene; wherein said an aliphatic hydrocarbon selected from C1-8 carbon atoms containing straight chain or branched chain or cycloalkane, substituted cycloalkane; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF or mixture thereof.

5. A process for the preparation of Lemborexant of Formula (I),

Formula I

which comprises:
(i) providing the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) having purity > 95% by HPLC,
(ii) reacting the salt of cyclopropane pyrimidine carboxylic acid of Formula (II) with 2-amino-5-fluoropyridine of Formula (IV)

Formula IV

in presence of a coupling agent to produce compound of Lemborexant of Formula (I).

6. The process as claimed in claim 5, wherein the coupling agent comprising carbodiimides selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC), N,N'-diisopropylcarbodiimide (DIC); imidazoliums selected from the group consisting of 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyl-di-(1,2,4-triazole) (CDT); uronium or guanidinium salts selected from the group consisting of 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 selected from the group consisting of 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 anhydride is T3P etc.

7. The process as claimed in claim 5, wherein the process is carried out in presence of an acid comprising inorganic acid selected from the group consisting of sulfuric acid, nitric acid or hydrochloric acid, and mixtures thereof.

8. The process as claimed in claim 5, further comprising purifying Lemborexant by subjecting Lemborexant to either by column chromatography or by crystallization.