SA109300353B1 - New Process for the Synthesis and New Crystalline form of Agomelatine and Pharmaceutical Compositions Containing it - Google Patents

Abstract

Abstract: The present invention relates to a process for the synthetic synthesis and new crystalline form of a compound of Formula (I): Pharmaceuticals.

Description

New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it Full description Background of the invention This application is a partial application of Application No. oY ) and which was filed in the Kingdom of Saudi Arabia on 1 / Y / AH corresponding to “A / ¥ / Xero M.” The present invention relates to a process for the synthetic synthesis of agomelatine ¢ or: ºN-[2-(7- methoxy-1-naphthyl)ethyljacetamide © ¢ of formula (1): NHCOMe MeO CO 7 The present invention also relates to the crystal form of the formula TT of agomelatine; and a process for its preparation and compositions containing it. agomelatine » that is, N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide has valuable pharmacological properties.

0 in fact; agomelatine has a dual trait. Where on the one hand; Co-receptors of the melatoninergic system and on the other hand »; An antagonist of the 5-1117 receptor. These properties provide activity in the central nervous system, ey central nervous system, in particular v seasonal affective and seasonal disorders, severe depression, in the treatment of acute depression, cardiovascular and cardiovascular disorders, sleep disorders and sleep disorders 5 and resulting exhaustion insomnia, insomnia, “digestive system diseases, gastrointestinal pathologies, obesity, appetite disorders from traveling by plane across different time zones,” and appetite disorders. obesity©, its preparation, and therapeutic use per EP Specification No. + agomelatine, then Mala D was described in view of the pharmacological value of the compound; It was necessary to be able to obtain it by means of a process of producing agomelatine that could actually be converted to an industrial scale and result in Jaa industrial composition and an excellent degree of purity. agomelatine It was also important to be able to obtain its production completely; This thus offers valuable advantages in terms of filtration and ease of formulation. In agomelatine there is a description of preparation 0154977488 and in the specification of European patent application No.

JV; It gives an average yield of less than 7-methoxy-1-tetralon in eight steps; It begins with, followed by conversion to aromatic compound and saponification ¢ ethyl bromoacetate The process involves the effect with 0 acetyl chloride followed by reduction; then concentrate ¢ (7-methoxy-1-naphthyl)acetonitrile to produce, in six steps, (7-methoxy-1-naphthyl)acetonitrile in particular; The preparation quickly shows difficulties in carrying out the process; This cooled 0 reaction and by converting to the industrial scale

Primarily to the problems of reproducing the first step, which is the activity of cthyl bromoacetate on 7-methoxy-1-tetralone according to the Réformatsky reaction yielding: .ethyl (7-methoxy-3,4-dihydro-1(2H) )-naphthalenelidene)ethanoate furthermore; The next conversion step is always: ethyl (7-methoxy-3,4-dihydro- 1(2H)-naphthalenelidene)ethanoate ~~© a non-toxic aromatic compound produced after Al "C 0 to 1 1 of Os on 8 p. 1. The references describe obtaining (7-methoxy-1-naphthyl)acetonitrile in three steps of fag from 7-methoxy-1-tetralon by means of LICH,CN activity followed by deacetylation. hydrogen using: DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and finally dehydration in an acid medium (Synthetic Communication, 2001, 31(4), 621-629) 0 The total yield is average (ZY) + with leg cell in particular The DDQ used in Jeli The dehydrogenation and reflux of benzene necessary in the third step does not meet industry requirements in terms of cost and environment. The patent is a new industrial synthesis process that produces agomelatine by reproduction and without the need for laboratory purification; and produces 2800061006 with a purity compatible with its use as an active yo catalyst. Specification EP No. 0 44977488; By direct condensation of the cyano compound with: 7-methoxy-1-tetralon in addition; It was necessary that the concentrate obtained could be subjected to an aromatic conversion process to produce:

ec without the need for harsh conditions; And that (7-methoxy-1-naphthyl)acetonitrile reactors can be used that are compatible with industrial requirements in terms of cost and environment. It forms an ideal synthesis medium that meets the requirements of (7-methoxy-1-naphthyl)acetonitrile. It is clear that And that it is a substrate for the conversion step to an aromatic compound. 0 7-methoxy-1-tetralon Direct synthesis of in acetonitrile or acetonitrile compounds The direct concentration reactions of tetralonates with condensation © TRAY ET have been described References In particular, the specification for US Patent Application No. 6-fluoro-1-tetralone with an intermediate cyanomethyl phosphonate which connects to a cyano resulting in a tetralon with an acetonitrile condensation describes 4711 directly with the following reaction. A mixture of isomers of acetonitrile produces a concentration of “7-methoxy-1-tetralon by applying to 0:1 the smallest ratio according to the “endo” form in which the largest ratio is represented. exo” constitutes Figure

CN CN

0

MeO MeO | MeO

CH,CN ) + 3 "exo" major portion "endo" minor portion Such a mixture requires the following critical transmutation conditions that are not compatible with the requirements. industrial agomelatine with the aim of carrying out the installation of yo

Yai.

General description of the invention

At this Ads pall, the patent applicant devises a new industrial synthesis process that allows obtaining:

(7-methoxy-1 -naphthyl)acetonitrile from 7-methoxy-tetralon » by sale) production without the need for laboratory purification; And in just two steps using:

(7-methoxy-3.,4-dihydro-1-naphthalenyl)acetonitrile 8 devoid of impurity “0»©” of formula (IT) CN MeO | 1 , whose impurity cannot be compromised To convert to the following aromatic compound under operating conditions compatible with industrial requirements in order to carry out the synthesis of agomelatine. To investigate more accuracy; The present invention relates to a process for the synthetic synthesis of a compound of formula (): NHCOMe MeO CO ' | Yo and is characterized by 7-methoxy-1-tetralone of formula (111): 0 MeO am) y:(1V) of the formula cyanoacetic acid reacts with

HO

- (IV) 0

HV) of a compound of formula Bae under conditions in which the water formed is removed; In the presence of a quantity of + - 0 R

R—NH, hil V) 0 Can be different or the same group; Each represents an sR SR group where © 0-(. alkyl is substitutable or non-substituted”; 0 is an aryl group or a linear or branched (C3-Cio) alkyl group aryl (Ce) To produce, after filtration and washing with a basic solution: (VI) of the formula (7-methoxy-3,4-dihydro-1-naphthalenelacetonitrile

CN

MeO

CC! 0 The compound ZY allyl in the presence of a hydrogen compound removes ane with (VI) where the compound of the formula reacts with the formula (711?):

A

CN

MeO

CC 1 a in the medium of Raney nickel ethanol in the presence of hydrogen, which is then subjected to reduction with the production of a compound, hydrochloric acid, then to a salt using Lad; and converts to ammoniacal ethanol (VID) of the formula NH, MeO (VIII),

CC He 1 2 which is exposed successively to sodium acetate activity and then to acetic anhydride producing the compound of formula (1); which separates in the form of a solid; where: - aryl is understood to mean a naphthyl 0 phenyl or a biphenyl group « Ve - the expression 'substituted' which predominates in the expressions ' aryl ' and 'alkyl aryl' indicates that | For scented parts of these groups can be replaced by from 1 to ? from identical or different selected combinations of linear or branched (Ci-Cs) alkyl or “Ae fill and hydroxy and linear or branched (C1-Cg) alkoxy; - An allyl compound is understood to be any molecule that contains who? to 01 carbon atoms” may contain in addition to 1 © oxygen atoms ; It contains the group: -CH)-CH=CH, | 00 at least one. Yat

To investigate more accuracy; In the reaction of converting a compound of formula (I) to a compound of formula (V1) the water formed is removed by dilution. Preferably a reaction solvent with a boiling point greater than or equal to that of water is used; It is more preferable to form an azeotrope with water toluene s « xylene (fie » ie anisole ethylbenzene 0 ' ¢ or cyclohexene 0 » tetrachloroethylene or mesitylene 2. It is preferable to carry out the conversion of the compound of formula (111) to A compound of formula (VI) by toluene reflux or

. toluene, particularly with xylene reflux

In the reaction of converting a compound of formula (TT) to a compound of formula (71); One of the 8 SR groups of Sad) used usefully has a (j,©-:0) linear or branched alkyl group; The other represents an aryl alkyl group or aryl and more specifically Seal) the preferred catalyst of the formula (Va)

yab atam a 3 hil (Vp Ya 0 where R , is an unsubstituted or unsubstituted phenyl group; in particular phenyl dc sans is unsubstituted. The R, group is preferred is the hexyl group, and the preferred value of n is 1.10 The preferred catalyst to be used in the conversion of the compound of formula (I) to the compound of formula (VI) according to the process of the invention is benzylammonium heptanoate of formula :(1X) 000+ Wipe Sim 0 Yai.

01 N solution after filtering and washing with (V1) is useful; Then the compound of the formula gad and a is obtained in the form of (NH4OH rut 01) AH” and (5:) 011; Or “KOH 5” NaOH Jae organic or mineral base. Sodium hydroxide special with solution or toluene with reflux (VI) to formula compound (VI) It is preferable to perform the conversion of the formula compound. toluene; More specifically with the reflux of ©xylene it is notched in (VII) to the compound of formula (VI) preferred to be used in the conversion of the compound of formula (ial) and in the form of AL,O3 and « nickels + platinum and palladium or supports, for example, oxide form on carbon palladium 7710 to 1 of cade is used in the manner. palladium more specifically palladium on carbon. preferably; Palladium Ive Jo especially uses any and at

0 on carbon in amounts ranging from 1 to 0007 by weight of the catalyst by weight of the substrate” and more specifically Je the hydrogen Jae is preferred to be used in the reaction to convert the compound of formula (VI) to the compound of formula ( VID) is an allyl compound and more specifically allyl acrylate or allyl glycidyl ether and the preferred allyl acrylate for the process according to the invention is allyl methacrylate.

1 usefully”; The conversion of a compound of formula (VI) (a compound of formula (VU) is performed according to a process of the invention at a temperature from Ye. to a' $a' and in particular from Ye to ad 0 ¢ More informatively at 00 then It is useful that the conversion of the compound of formula (VII) to the compound of formula (1) takes place in an alcoolic medium “in particular in ethanolic medium .

Yan.

1 This process is of particular importance for the following reasons: Exclusively 'in the scope of' (VI) of the formula 'endo' the process allows obtaining a compound (determined in the form of synthetic ede lil). This result is completely surprising as the references related to the type of (Tetrahedron, 1966.22, 3021-3026) 'endo'['cxo' bia] frequently obtained ammonium acetates as a catalyst for the reaction instead of (V) The result is according to the compound of formula eo - (Bull.Soc.Chim.Fr., 1949, 884-890) currently used in these reactions.

JAY where das transcends high (VI) to formula compound (TT) is formula compound conversion rate - 7905 ad ; Which does not exceed the rate of acetic acid in contrast to the rate that can be observed by using to convert the compound of formula (71) to an allyl in the presence of a hydrogen compound remove eae The use of - fully complies with industrial requirements in terms of cost environment; In contrast to (VI) the formula 0 compound currently in use. quinones are limited to, especially product-free, ' (VI) Furthermore, the process allows the formula compound the corresponding reduction of the formula (?): : CN

meO,

XX), industrial. Glas obtained in the ade that was made (VID) to the formula compound (VI) finally the formula compound conversion rates -

A 0 navigator 'its moment is high as it exceeds

Yq.

AR

<> Dehydrogenation of the compound of formula (VII) has been described in the presence of Raney nickel in ammoniated ethanol medium Med. Chem., 1994,37(20),3231-3239) ammoniacal ethanol medium 0 but requires conditions that are difficult to apply on an industrial scale: the reaction is heated at 10 “C for 11 dele and the final yield is less than TA moreover ; One of the main drawbacks of the reaction is the formation of conjugated © compound “bis” of formula (61E): N H MeO 2 OMe (XD) NS and the difficulty in controlling the conversion rate of said nonconfluence. The process by which Lash presented dl 3¢ allows obtaining a compound of formula (VII) with a purity less than ; 7 under experimental conditions consistent with industrial requirements; As long as the reaction takes place at a temperature from Te to £0 “m to give a yield of 729.0 that exceeds 250 and a chemical purity that exceeds Oe - the step of introducing the amide group allows the amidation to be carried out in an alcoolic medium, especially in an ethanolic medium ethanolic medium; The compound of formula (1) can easily separate in a quantitative production, which is astonishing as a reaction of this type is not very compatible with this solvent in which a competing consumption of acetic anhydride is expected. 1 - The compound of formula (VI) is ) which is obtained according to the process of the invention is new and useful as an intermediate in the synthesis of agomelatine, and the compound undergoes Adee conversion to an aromatic compound followed by reduction and conjugation with acetic anhydride.

vy according to the process described above. In agomelatine of the invention in the crystalline form 1 th 1 as it relates to its production in the form of sale) well and can be sink sl actually; It is important to be able to obtain a complete form. The field allows the previous patent application | Macla Co. (accessed in Yous er al. (Journal of Medicinal Chemistry, 1992, 35(8),1484-1486) © : a specific crystalline form described in 4 agomelatine. Tinant et al. (Acta Cryst., 1994, C50, 907-910 well 23ak in agomelatine crystalline form then; the applicant has developed a process to obtain and exhibit advantages in terms of filtration and ease of 0 and can be reproduced completely; which As a result, the formulation. AXS DS§ Noise aberration for the step: 0 and it is a step that takes place at a temperature of 0100 °C and od \eo monoclinic crystal lattice system.

NAR p Yat.

Vi. 72/0 Area Collection: -

A Number of molecules in the unit cell: - Nm 1 Quantity of unit cells: i.e. = 7 art -

Janes VAY = 1 : Density - One of the advantages of obtaining the crystalline form is that it allows rapid and particularly effective concentration © as well as the preparation of pharmaceutical formulations having a coherent and reproducible composition and is particularly useful when the formulations are used for oral administration mouth. On it; The shape obtained is sufficiently stable to allow prolonged storage without . oxygen certain conditions with respect to temperature; low humidity; or levels of 0. A pharmacological study of the obtained form showed that it has significant Lag activity related to the Lad central nervous system related to the microcirculation; He can verify that the 17-crystal form of agomelatine is useful in the treatment of stress, sleep disorders, anxiety, severe depression, seasonal affective disorders, and diseases. Cardiovascular pathologies ‒ diseases of the digestive system ‒ insomnia and jet lag across different time zones; schizophrenia; panic attacks; depression, “appetite disorders,” obesity, insomnia, “pain, psychological disorders,” and epilepsy; diabetes mellitus; Yq.

ve and various disorders related to senile dementia, senile dementia, Parkinson's, Parkinson's disease, cmemory loss, cmigraine amnesia, and migraines in the field of . cerebral circulation disorders and in cerebral circulation disorders » Alzheimer's Alzheimer's use in the treatment of dysfunction (Sa agomelatine) shows that the crystal form [1] of Jalil al is immune; it can also be used in the treatment of Alba; sexuality; because it Contains the properties of inhibiting ovulation Cancer. sleep «disorders

Gains and time zone air travel insomnia and insomnia pathologies 0 . Obesity, obesity, appetite disorders, and appetite disorders as agomelatine. The invention also relates to pharmaceutical compositions containing the crystalline form 11 of L with one or more suitable inert, non-toxic excipients. Among the combinations, Jd is the special component; Compositions suitable for oral administration; Pharmaceutical Ang according to the invention may be mentioned; on or tops; or granules; Gal, parenteral (intravenous or subcutaneous), nasal administration Ve, or sublingual tablets; or as softgel capsules; opportunities for emulsification; downloads; and creams;

ALE and paints; skin gel; injectable preparations; drinkable suspensions and biodegradable pastes. The effective dose can be adjusted according to the nature and severity of the disturbance; Method of administration, age and weight of the patient. 1 g per day in one or more doses. 1 to 11 mg. The dose varies from 0

Detailed Description The examples given below illustrate the invention but do not in any way define it. Example 1:N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide Step A: (7-Methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile in a 1760 L aise reactor put 88.0 kg of 7-methoxy-1-tetralon » and 01.7 kg of

cyanoacetic acid and 19.1 kg of acid in toluene in the presence of 0.7 kg of benzylamine. The mixture is heated at the return temperature. When the starting substrate is completely disappeared from the mixture and 0 is filtered, the precipitate obtained is washed with toluene, then the obtained filtrate is washed with a solution of sodium hydroxide 1 p with water until it becomes neutral. After A) the solvent

0 By evaporation, the solid resulting from the ethanol / water mixture (Y JAY) is recrystallized to produce the product mentioned in the title with a yield of 790 and a chemical purity of more than 795. Melting point: 0-186, then. Step b: (7-methoxy-1-naphthyl)acetonitrile in a 170 liter reactor 1.6 kg of 70 palladium is placed on carbon in toluene » which

It is heated at reflux temperature; Then 91.1 kg of: (7-methoxy-3 4-dihydro-1-naphthalenyl)acetonitrile dissolved in “toluene” is added to the side of 17.7 kg of “allyl methacrylate.” The reaction continues at Reflux heat followed by evaporation phase chromatography. When all of the starting substrate 00 has disappeared into the surrounding medium and filtered off. after removal

Yq.

Vv to produce (80/01) / water ethanol by evaporation; the solid resulting from the 794. toluene mixture recrystallized the product mentioned in the title with a yield of 791 and a chemical purity that exceeds AT. Melting point: 2-(7-Methoxy-1-naphthyl)ethanamine hydrochloride: step c to see a kilogram of the compound obtained in step b is added; and 1101 in a reactor © ammonium hydroxide is stirred Safe 110 and ¢ ethanol in Raney nickel?a kg of 0 is estimated at © innocent, then it is converted to 660 hydrogen pressure, then the mixture is under hydrogen pressure, adding Alig ¢ ethyl acetate when it disappears The whole starting substrate; the solvent is evaporated; and the resulting precipitate is dissolved in After filtration; the precipitate obtained 1171. hydrochloric acid is washed from a solution of 1 8? in an oven to produce the product mentioned in the title with a yield of 795,3 and a purity (Cala) Then ethyl acetates on it 0.759.5 chemical exceeds VEY. Melting point:

Dangerous N-[2-(7-methoxy-1-naphthyl)ethylJacetamide d: 411 kg of J gaan is added to it in the atmosphere step, to which 1 kg of the compound is added, then 1 kg of YA in liters . The mixture is stirred and then 1 0001 reactor is added ethanol in 0 sodium acetate of water 1 0001 reaction mixture at reflux and the amount of precipitated acetic anhydride (ALS) obtained ets is added The reaction mixture is left to return to ambient temperature

Yas.

YA clay, 1.5 liters + to produce the product mentioned in Al-Atwan with a yield of 0 clef ethanol Jada and washed with . 7 5 a3 Chemist with more than YeA degree | for fusion

N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide :¥ Example (7-Methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile if step © and 1.7 kg From « 7-methoxy-1-tetralone in kg of AO, Qa +760 is added in a reactor of 111 kg in the presence of toluene in heptanoic acid in kg of 1,085 and cyanoacetic acid the mixture at the reflux temperature. When the starting substrate material is completely gone, the mixture, cyan + aniline, is cooled, then the filtrate obtained from toluene is washed and filtered. The precipitate obtained is then washed with water until it becomes neutral. after removing ON sodium hydroxide on it using solution 0 to yield the product (+ /A+)/water ethanol solvent by evaporation; The resulting solid is recrystallized from a mixture

S88 and a chemical purity that exceeds TAY mentioned in the title with a melting point product: 0-4 then. (7-methoxy-1-naphthyl)acetonitrile Step B: 1. The procedure is as in Step B of the example. 0

EIN Melting Point: 2-(7-Methoxy-1-naphthyl)ethanamine hydrochloride : Step C

Yat.

Xi The procedure is as in step c of example 1. Melting point: A Y Hd C

N-[2-(7-methoxy-1-naphthyl)ethyl acetamide Step D: The procedure is as in Step D of the example 1. © Melting point: A M

N-[2-(7-methoxy-1-naphthyl)ethyl|acetamide from IT ?: crystal form JE! Data were recorded using a Burker AXS D8 diffractometer with a high degree of analysis with the following variables: Theta angle? Between ? 3 and 50 pf step by step, 6 and Ve step. The N-[2-(7-methoxy- 1-naphthyl)ethyljacetamide powder obtained in Example 1 0 is applied to the transition synthesis support. X-rays are emitted from a copper tube (0.540 01-ACuKy h). The composition contains a frontal colorimetric device (crystal) 111(66) and a powered solid state detector - (MXP-DI, Moxtec-SEPH) The composite is well crystallized: the beamwidth at half-height is of the order of 70. 09 theta). Then determine the following variables: Vo - monoclinic crystal lattice system. - Lattice system variables: F - T =p cA as =B AV EVAT=Ccc 7 - Area group: A Yan.

Y.

A The number of molecules in the monocyte: mg YO Tablet each contains a dose of 0001 Formula for preparation © g Yo Yo Example compound ? 7 g Lactose monohydrate 1 g Magnesium stearate Corn 7 g Ls Assa 1100D 1/1 4 g | 0001 Formula for the preparation of Ve g YO compound Example 3?

Yat.

Lactose monohydrate 7 g. WY Magnesium stearate g

Povidone 5 g Silica Anhydrous Colloid T 01 Sodium cellulose glycolate ~~ © g Stearic acid 1 g

Yan.

Claims (1)

YY - - claimants 1,' - compound of formula (VI): (7-methoxy-3,4-dihydro-[-naphthalenyl)-acetonitrile .; For use as an intermediate in the synthesis of agomelatine.