ITMI20130273A1 - PROCEDURE FOR THE PREPARATION OF APREPITANT - Google Patents

Description

â € œPROCESS FOR THE PREPARATION OF APREPITANTâ €

The invention relates to an efficient method for the synthesis of Apripitant. This method is very practical and suitable for large-scale production.

Background of the invention

Apripitant 1, whose chemical name is 5 - [[(2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy] -3- (4-fluorophenyl) - 4-morpholinyl] methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one is a neurokinin-1 receptor antagonist (NK1RA) discovered by Merck & Co.

It is the active ingredient of the drug Emend, which is an antiemetic and is used together with other medicines to prevent chemotherapy-induced nausea and vomiting in adults. For injectable use Merck has developed Fosaprepitant, a pro-drug of Apripitant, marketed under the name of Ivemend.

Apripitant and Fosaprepitant have the following structures respectively:

O O

F O H N F O H N OH

F F N NH N N P OH

FON FON O

F F F F F F

F F

<Apripitant 1> Fosaprepitant 2 Apripitant is synthesized through two main phases: i) the formation of the secondary amine of formula 3 and ii) the synthesis of the active ingredient 1 starting from 3.

O F O F O H N F F NH N NH F O FON

F F F F

F F

F F

<3> Apripitant 1

The synthesis of secondary amine 3, which is considered the â € œstarting materialâ € from the regulatory point of view for the preparation of Apripitant, has been extensively treated in the scientific literature (see for example: J. Med. Chem. 1998 , 41, 4607-4614; J. Am. Chem. Soc. 2003, 125, 2129-2135; Org. Process Res. Dev. 2006, 10, 109-117; ibidem 2007, 11, 455-457; and references therein cited).

The absolute stereochemical configuration of the secondary amine 3 is considered in the subsequent â € œstepsâ €.

Apripitant 1 can be obtained from secondary amine 3 essentially by means of two synthesis routes, illustrated in the following scheme.

NH2H

Cl NOF O NH2

N F H

N N O

4 O F O N heating

OR

base

F F

Route A F

F 5

O O F O H N NH F O H N F NH Cl F NH F O Route B N N

6 FON

base

F F F F F F

F F

"Secondary amine" 3 Apripitant 1 The introduction of the â € œtriazolinoneâ € pendant on the amino group of the secondary amine 3 was initially made by means of a two â € œstepâ € protocol (Route A, WO9516679) which includes the N -alkylation with the chloroderivative of formula 4 [methyl ester of 2- (2-chloro-1-iminoethyl) hydrazincarboxylic acid] to give the compound of formula 5 and the cyclization of the latter to Apripitant 1 by heating in xylenes at ebb. The boiling points of the various xylenes (ortho, meta, para) are included in the range between 138 and 144 ° C. According to the procedure described in example 75 of the aforementioned patent application, both the intermediate 5 and the Apripitant 1 obtained from it require chromatographic purification and are obtained with an overall yield of 79%.

A more direct synthesis route (Route B) was subsequently found by Merck & Co. and claimed in patent application WO9965900. This new way involves the alkylation of secondary amine 3 with 3-chloromethyl-1,2,4-triazolin-5-one 6 and, unlike the first, it is believed by Merck & Co. to have the characteristics of suitability for implementation on an industrial scale, for greater efficiency and productivity.

Nevertheless Merck & Co. subsequently filed a patent application (WO03089429) which claims an improvement of the original synthesis (Route A) which provides for the cyclization of intermediate 5 at a temperature of 140-150 ° C. From the general description it is not clear which solvent is (and if it is necessary) that allows to heat the intermediate 5 to 140-150 ° C; in the only example of the experimental part reference is made to toluene which however has a boiling point of 110-111 ° C.

Unexpectedly we found that Apripitant can be obtained in high yields and quality through an efficient and practical process that includes the extraction of 5 in xylene from the reaction mixture, the formation of Apripitant by heating the organic phase and the isolation of 1 directly by filtration of the reaction mixture after the product is crystallized in the mixture itself.

Description of the invention

The object of the present invention is therefore a process for the preparation of Apripitant which includes the following steps:

i) N-alkylation of the compound of formula 3 with the chloroderivative 4 to give 5;

ii) extraction of the intermediate 5 in an aromatic solvent;

iii) thermal cycling of 5 in an aromatic solvent at a temperature between 120 and 135 ° C to give 1;

iv) recovery of 1 by filtration of the reaction mixture of step iii).

Detailed description of the invention

N-alkylation of secondary amine 3 with chlorine derivative 4 to give 5 The secondary amine 3, usually used as a salt (e.g. hydrochloride), is reacted with chlorine derivative 4 in the presence of an organic or inorganic base in a polar aprotic solvent.

The molar ratio between 4 and 3 is generally comprised between 1.0 and 1.5, preferably between 1.1 and 1.3. The base is usually used in molar excess (from 1.5 to 3.0, preferably from 2.0 to 2.8) with respect to 3; when 3 is used in salified form, the molar excess can vary between 2.5 and 4.0, preferably between 3.0 and 3.8.

The organic base is preferably an aliphatic tertiary amine, such as for example triethylamine, diisopropylethylamine, N-methylmorpholine or an aromatic heterocyclic amine, such as for example pyridine, lutidine, collidine. The inorganic base is preferably an alkaline or alkaline earth carbonate or phosphate such as for example potassium carbonate, cesium carbonate, calcium carbonate, sodium phosphate. Preferred aprotic polar solvents are acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide.

Extraction of intermediate 5 in aromatic solvent

The solvent is preferably an aromatic, or predominantly aromatic, non-toxic or low toxic solvent (class ICH 2 or 3), having a boiling point greater than or equal to 120 ° C as meta-xylene (1,3-dimethylbenzene), para-xylene (1,4-dimethylbenzene), ortho-xylene (1,2-dimethylbenzene), ethylbenzene, anisole, or a mixture thereof. Particularly preferred is the use of xylene (for pharmaceutical use) commercially available in bulk and which typically contains variable quantities of each of the dimethylbenzene and ethylbenzene isomers. The volume of the aromatic solvent used is between 10 and 30 liters per kg of secondary amine 3, preferably between 15 and 25.

The mixture of the aromatic solvent containing the derivative 5 is typically washed with water and the aqueous phase separated and discarded without the need for counter-extraction.

Thermal cycling of 5 in aromatic solvent to give 1

The above solution of derivative 5 in an aromatic solvent is then heated to a temperature between 120 and 135 ° C, preferably between 124 and 128 ° C, for a time generally between one hour and eight hours, preferably between three and five hours. The reaction is considered terminated when the conversion of intermediate 5 into Apripitant 1 is greater than 95% (HPLC monitoring). The temperature range 120-135 ° C is particularly critical for obtaining Apripitant 1 suitable for use as an active ingredient in pharmaceutical compositions. At the temperature of 110 ° C the reaction practically does not proceed, while temperatures in the 140-150 ° C range favor the formation of impurities.

Recovery of 1 by filtration of the suspension

Apripitant 1 precipitates directly from the reaction mixture during cooling, which usually takes place over a period of 1 to 8 hours, at a temperature of 5Ã · 40 ° C, and the suspension is then stirred for a period of 2Ã · 6 hours before filtration.

The suspension is then filtered or centrifuged, and washed with the aromatic solvent previously used or with an aliphatic hydrocarbon such as hexane, cyclohexane, n-heptane, petroleum ether, or with a mixture thereof.

After drying under vacuum, Apripitant 1 is typically obtained with a yield greater than 80% and with a chromatographic purity greater than 99.0%.

Apripitant 1 thus obtained was used for the synthesis of Fosaprepitant without the need to carry out any purification; if necessary, however, the quality of the active ingredient can benefit from crystallization or treatments with solvents or a mixture of solvents.

The process which is the subject of this patent application, as well as allowing to obtain Apripitant 1 in high yields and quality, is very simple and efficient and suitable for production on an industrial scale. In fact, the whole sequence of operations described above can be, in most cases, carried out with a single reactor. In fact, once the N-alkylation reaction of the secondary amine 3 with the chloroderivative 4 to give 5 is finished, the reaction mixture is treated with the aromatic solvent and water, with extraction of the intermediate 5 in the organic phase and preferential distribution of the polar aprotic solvent in the aqueous phase. Typically the organic phase having a lower density than the aqueous one, the latter can be easily discharged from the bottom of the reactor and the organic phase can be washed again with water for the desired number of times (with the possibility of analytically evaluating, e.g. by means of GC, the optimal content of residual aprotic polar solvent).

The invention is now further illustrated by the following example. One-pot summary of Apripitant 1

3 (1.053 kg as hydrochloride, 2.211 mol), 4 (0.463 kg, 2.740 mol) and DMSO (21.0 l) are loaded into a suitable reactor. The mixture is stirred at 25 ° C and then DIPEA (1.453 l, 8.175 mol) is charged. The mixture is stirred at 25 ° C for 8 hours and the disappearance of 3 is checked by HPLC analysis. Xylene (21.0 l) is added, demi water (15.8 l) is added, stirred for 10 minutes and the phases. Three other washes with water (identical volumes) of the organic phase are carried out. After washing, the organic phase containing the intermediate 5 is heated to 125 ° C for 4 hours. The disappearance of 5 is checked by HPLC analysis. The reaction mixture is cooled in 2 hours to 25 ° C: during the cooling the product precipitates. The mixture is stirred at 25 ° C for 4 hours. The suspension is sent to a centrifuge and the product panel is washed with xylene (2.1 l) and n-heptane (5.3 l). The product is discharged and dried under vacuum (p <40 mbar) at 40 ° C for 20 hours. 1.00 kg of Apripitant 1 is obtained.

Claims (6)

CLAIMS 1. Procedure for the preparation of Apripitant of formula 1 OR F O H N F N NH FON F F F F. 1 comprising the following steps: i) N-alkylation of the compound of formula 3 F O F. NH F O F F F. F. 3 with the methyl ester of 2- (2-chloro-1-iminoethyl) hydrazincarboxylic acid of formula 4 NH2 H. Cl NO No. 4 O to give the compound of formula 5 F O NH F2H N N O F O N OR F F F F 5 ; ii) extraction of the compound of formula 5 in an aromatic solvent; iii) thermal cycling of the compound of formula 5 to give Apripitant 1; iv) recovery of aprepitant 1 by filtration of the reaction mixture of step iii); characterized in that step iii) is carried out at a temperature of between 120 and 135 ° C. 2. The process of claim 1 wherein the aromatic solvent has a boiling point greater than or equal to 120 ° C. 3. The process of claims 1 or 2 wherein the aromatic solvent is selected from meta-xylene, para-xylene, ortho-xylene, ethylbenzene, anisole, or a mixture thereof. 4. The process of claim 3 wherein the aromatic solvent is selected from meta-xylene, para-xylene, ortho-xylene, or a mixture thereof. 5. The process according to any one of the preceding claims in which step iii) is carried out at 124-128 ° C. The process according to any one of the preceding claims in which steps i), ii) and iii) are carried out in a single reactor. Milan, February 26, 2013