FR2555582A1 - PROCESS FOR THE PREPARATION OF 4- (2-PHENOXYETHYL) -1,2,4-TRIAZOLONE - Google Patents

Abstract

IMPROVED PROCESS FOR THE PREPARATION OF 5-ETHYL-4- (2-PHENOXYETHYL) -1,2,4-TRIAZOLONE, A USEFUL INTERMEDIATE IN THE SYNTHESIS OF 1,2,4-TRIAZOLONES ANTIDEPRESSORS, AN EXAMPLE OF WHICH IS 23-4- ( 3-CHLOROPHENYL) -1-PIPERAZINYLPROPYL - 5-ETHYL-4- (2-PHENOXYETHYL) -2H-1,2,4-TRIAZOL-3 (4H) -ONE, ALSO KNOWN AS NEFAZODONE. THE IMPROVED PROCESS IS SHORTER AND GIVES A HIGHER EFFICIENCY THAN THE PREVIOUS PROCESS AND THE STARTING MATERIALS ARE CHEAP AND EASILY AVAILABLE.

Description

PROCESS FOR THE PREPARATION OF 4- (2-PHENOXYETHYL) -1,2,4-TRIAZOLONE

  The invention describes an improved, more economical process for the synthesis of a chemical intermediate (I) of interest to the cossate (1) intended to be used for the manufacture of the antidepressant agent

  consisting of 2- {3- [4- (3-chlorophenyl) -1-piperazinyl] propyl} -5-ethyl-

  4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one, which is also known

under the name of nefazodone.

ci Q xN N O nefazodone

  This intermediate product, 5-ethyl-4- (2-phenoxyethyl) -1,2,4-

  triazolone, of formula I is also known under the name of MJ 14814 and its current synthesis described in example 5 of the application under treatment SN 06/509 266 is indicated in diagram 1. An overall yield of 33 % for scheme 1 is planned from the yield calculations of the individual stages in stage 5 of the current request

treatment.

Diagram 1 f f OH \ step I

(1) C2H5

OH + -------- OI

(1) (2) (3)

0O step 2

OCHIO + R2H20 1) .2NNH2

(5) 2) BC1

  A _ step 3 A1203 11 (4) .Bam j [F ll-C-O] {avé 45 [ô A (9)

EIOB I

NH20 tOHEtape4B step 5 JNC 3 5

(8) L 7)

  O (9) RO0 é () t type 6 (1; Mi 14814) As can be seen in diagram 1, the preparation of MJ 14814 starts from phenol and ethyl acrylate, dangerous material having a vapor pressure high. This process has been successfully scaled up and used many times to give MJ 14814 with an overall yield of 25-30% based on phenol.

  MJ 14814 is transformed into nefazodone (MJ 13754)

  depressant, as described in the current request cited above. This conversion involves the reaction of MJ 14814 with 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine (10) hydrochloride

(10)

  The preparation of MJ 14814 by diagram 1 involves six steps and

  the isolation of four intermediaries, two of which are necessary liquids

  sit a purification by vacuum distillation.

  On the contrary, the improved process described below comprises four stages which only involves the isolation of three intermediates, all of which are solids, with an overall yield of 40 to 55% in MJ 14814 to relative to phenol. By comparison, the method of the prior art represented by diagram 1, is a longer process requiring more manpower and providing MJ 14814 with a much higher yield.

weaker.

  The following references relate to the steps making up the process

  currently described herein.

  1. Dow Technical Bulletin "Developmental 2-Ethyl-2-Oxazoline XAS-1454 Ethyloxazoline: An intermediate for Aminoethylation". This reference describes the synthesis of N- (2-phenoxyethyl) propionamide,

  intermediate compound of the process according to the invention.

  2. W. Reid and A. Czack, Ann. 676, pp. 121-129 (1964). This reference teaches the reaction of imidoyl ethers with ethyl carbazate to give amidrazones. Which then cyclize by subsequent heating to 1,2,4-triazoles as described

below in Figure 2.

Diagram 2

NH R

  R OR '+ H2NN CO2R "- R N 2NHCO R" t = I R "ethyl

  However, there is no description of the use of ethers

  N-substituted imidoyl that would be required to obtain the

  N-substituted triazolone sought.

  3. M. Pesson et al., Bull. Soc. Chim., Fr., pp. 1367-71 (1962).

  This reference describes a very low yield synthesis (0.3%) of a triazolone having the desired substitution configuration

  by the procedure described below in diagram 3.

  Diagram 3 N-Ph - 01 O + H2NHCO2Et "- - N ___ OMe_ 2Ph o Efficiency 0.3%

  The authors indicate that the imidoyl ethers of the secondary amides

  are difficult to prepare (page 1364, bottom of the second colon-

  born). Pesson et al. well describe a preparation of a triazolone with the desired substitution configuration but by a synthesis, indicated as scheme 4, which is different from that of the process according to the invention. The synthesis according to the reference begins with an ether

  imidoyl of a primary amide and gives an intermediate carbethoxyhydrazone

  diary which is then reacted with a primary amine.

Diagram 4

Àe0C + 2CO 2Et R - --2 -

R) H + 2 2 EtOH R OEt A R

R

  o It should be noted that the carbazate displaces the imine function in scheme 4, which represents another characteristic which differs from the

process according to the present.

  Pesson et al. also indicate that thioamides are more reactive than amides and give N-substituted amidrazones by reaction with carbazate. However, when the N-substituent is an alkyl, as required by the process according to the invention, we do not observe

  no reaction with ethyl carbazate. Finally, Pesson et al.

  teach the activation of a thiobenzamide with dimethylsulfate, followed by a reaction with the carbazate to obtain a triazolone. AT

  again, it should be noted that no description involving an activa-

  thioamides of alkylcarboxylic acid, structural prerequisite of

present process.

  In summary, references 2 and 3 essentially describe reactions of certain amide derivatives with carbazate esters to ultimately give triazolone products but with distinctive variations in the structural relationship with the product prepared by

  the method according to the present invention.

  The invention relates to an improved synthesis process which can be

  suitable for large-scale preparation of the chemical inter-

  useful medium, 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone.

  The process according to the present invention starts from phenol and 2-ethyl-2-

  oxazoline, inexpensive and readily available raw material. This improved process has the advantage of saving both material and labor costs because it is shorter to implement, it involves less isolation of intermediary and provides a return

higher in product.

  The following table, Figure 5, illustrates the preparation of MJ 14814 from readily available starting materials using the

process according to the invention.

255558 2

Diagram 5 s OH + L f 175 Step 1 H

(1) (V) (IV)

  Amide activation Step 2 (SOX2; He2SO4; 10. POC13; COC12; eta.)

NMC, 2R

  E Step 3 Them I, heat III Step 4

(I; MU 14814)

  yield 40 to 55% In scheme 5, R represents a C1-C4 alkyl; X represents Cl, Br or SO4; Y represents Cl, Br or OR, and activation of the amide indicates the formation of a halide or a reactive imidoyl ester by treatment of the amide with a reactant

  suitable activation such as SOC12, SOBr2, POC13, dimer sulfate

  thyle, phosgene, etc. Step 1 of the diagram described above involves the reaction of

  phenol (1) and 2-ethyl-2-oxazoline (V) to give the intermediate compound

  N- (2-phenoxyethyl) propionamide (IV) diary. The starting materials for step i are commercially available. Step 2, which consists in activating the amide (IV), is accomplished by treating IV with an amide activating reagent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, dimethyl sulfate and

  analogous, to obtain an intermediate halide or imidoyl ester

  re (III). The preferred agents are phosgene or phosphorus oxychloride. Intermediate III is not isolated but it is reacted with an alkyl carbazate of formula H2NNHCO2R, R = methyl is that

  which we prefer, in step 3, to obtain the new precur-

  sor (II), of triazolone. In step 4, the acid addition salt (II) consisting of hydrazinecarboxylate is converted into the base and cyclized to

  the triazolone sought (1) by heating.

  This improved four-step process involves only the isolation of two intermediates (IV and II) in addition to the target compound, I. For comparison, the process applied to date involves six steps and the isolation of four intermediates, two of which are liquids and require purification by vacuum distillation. The reduced handling of intermediaries in the process according to the present invention significantly reduces the costs of the work involved

by manufacturing.

  The synthesis of MJ 14814 as represented in the improved method is preferably carried out in a series of four

  steps from the simplest starting materials (phenol, 2-ethyl-

  oxazoline) to MJ 14814. The steps constituting the process are as follows: (1) Addition of 2-ethyl-2-oxazoline to the hot phenol (150) and heating maintained at approximately 175 for another 16 hours. The oil is

  then soaked in water to give N- (2-phenoxyethyl) propio-

  namide (IV) with a yield of approximately 90%.

  (2) Adding phosgene or phosphorus oxychloride to an IV solution containing a catalytic amount of imidazole in methylene chloride to obtain a hydrochloride solution

  of intermediate imidoyl chloride (III).

  (3) Treatment of the solution of III with a solution of a carbazate

  of alkyl to obtain the alkyl hydrochloride {1- [2-phenoxy-

  ethyl) amino] propylidene} hydrazine carboxylate (II) with a

about 75%.

  (4) The free base of II, resulting from the treatment of II with an alkalizing agent, is heated in solution for several hours

  to give I with a yield of about 75%.

  Description of specific embodiments

  The method according to the invention is illustrated in more detail by the following examples, directed towards the preferred embodiments of the steps of the method described below. These examples should not, however, be interpreted as limiting in any way the scope of the present invention. In the examples which follow, used to illustrate the preceding processes, the temperatures as above are expressed in degrees centigrade (C). Melting points are not corrected. The nuclear magnetic resonance (NMR) spectral characteristics relate to chemical derivatives expressed in parts per million (ppm) and are expressed relative to tetramethylsilane (TMS) which serves as a reference standard. The relative areas reported for the various lines in the H NMR spectral data correspond to the number of hydrogen atoms of a particular functional type of the molecule. The nature of the lines as to their multiplicity is indicated in the form of broad singlet (bs), singlet (s), doublet (d), triplet (t), quartet (q) or multiplet (m). The abbreviations used are: DMSO-d6 (deuterodimethylsulfoxide), CDCl3 (deuterochloroform) and by

  elsewhere, they are conventional. Spectrum descriptions

  infrared (IR) only include the absorption wave numbers (cm-1) having a functional group identification value. IR determinations are used using potassium bromide

  (KBr) as a diluent. Elementary analyzes are reported in percent

weight tage.

EXAMPLE 1

  Methyl carbazate Another name for this commercially available chemical is methyl hydrazinecarboxylate. Methyl carbazate can also be synthesized by adding 85% hydrazine hydrate (58.5 g, 1.00 mole) with stirring with dimethyl carbonate (90.0 g, 1.00 mole) for one 10 minute time frame. The mixture quickly heats up to 64 C and becomes clear. The solution is stirred for another 15 minutes and the volatile products are entrained under vacuum at C. On cooling, the residue solidifies. It is collected on a filter and after drying in air, 69.3 g (76.9%) of solid are obtained.

white, melting point 69.5-71.5 C.

EXAMPLE 2

  N- (2-phenoxyethyl) propionamide (IV) Phenol (13.1 moles) is heated to 150 ° C. and stirred under N2 while 2-ethyl-2-oxazoline (12.2 moles) is added in 1 hour. The mixture is heated to 175 3 C. After 16 hours of heating, the oil

  is cooled to about 140 C and then poured into water (12 liters

  very) with vigorous stirring. The mixture is stirred and cooled and, at approximately 25 ° C., the mixture is seeded with a crystallized amide. The product solidifies and what floats is decanted. The solid residue is stirred with 17 liters of hot water (85 C). The mixture is cooled to C, seeded with the amide and the mixture is refrigerated. The resulting granular solid is collected on a filter, rinsed with several portions of water and allowed to air dry. This gives a

  92% yield, (melting point 61.5-64 C).

EXAMPLE 3

  A. Methyl {1- [2-phenoxyethyl] amino} propylide hydrazine carboxylate (II) hydrochloride Phosgene (57.4 g, 0.58 mole) is added to a solution of N- (2-phenoxyethyl) propionamide (IV , 112.0 g, 0.58 mole) and imidazole (0.4 g, 0.006 mole) in 450 ml of methylene chloride over 1 hour, cooling so that the temperature does not exceed 25 C. The

  The reaction solution is then stirred at 25 for a further 2.5 hours.

  A solution of methyl carbazate (52.5 g, 0.58 mole) in 500 ml of

  methylene chloride is stirred in the presence of 25 g of molecular sieve

  milk for 15 minutes and then the solution is filtered. The filtrate is added under N2 over a period of 0.5 hour to the amide / phosgene solution while cooling to 15 to 20 CO. A bulky precipitate is formed and the mixture is further stirred at 25 ° C. nitrogen. After stirring for a total of 16 hours, the mixture is filtered to isolate a solid. The solid is stirred in 750 ml of methylene chloride for 15 minutes, refiltered and then dried under vacuum at 65 C for 2 hours, which gives 135 g (77%) of white solid, (melting point 150-154 C) . Recrystallization of the product from isopropanol gives an analytically pure product, melting point

157-159 C.

  On analysis, it is found that the product obtained has the formula C13H19N303, HCl and the following values are obtained: C H N Cl - calculated.

  .. 51.74 6.68 13.92 11.75 - found ....... 51.73 6.76 13.94 11.78 NRM (DMSO-d6): 1.15 (3, t C7 , 5 Hz]); 1.28 (3, t [7.5 Hz]); 2.74 (2, m); 3.66 (3, s); 3.70 (3, s); 3.81 (2, m); 4.19 (2, m); 6; 98 (3, m); 7.31 (2, m); 9.67 (3, bt [6.8 Hz]); 10.04 (3, bs); 10.40 (3, bs); .. DTD:, 90 (3, bs); 11.72 (3, bs).

  IR (KBr): 695, 755, 1250, 1270, 1500, 1585, 1600, 1670, 1745 and

2900 cm-1.

  By suitable modification of the above procedure (A), thionyl chloride, thionyl bromule, dimethyl sulfate or other amide activating agents can be used instead of phosgene. A slightly different procedure (B) can also be used. B. Methyl {1- [2-phenoxyethyl] amino} propylidene hydrazine carboxylate (basic form II) Phosphorus oxychloride (53.0 g, 0.346 mole) is added slowly to a solution of N- (2-phenoxyethyl) propionamide (IV, 100.0 g, 0.518 mole) in 200 ml of methylene chloride while stirring under nitrogen. This solution is stirred for 4 hours, at the end of which a solution (dried on molecular sieve 4A) of methyl carbazate (46.4 g, 0.518 mole) in 600 ml of methylene chloride is added to the stirred solution over a period of time. 0.5 hour time. The resulting mixture is stirred and heated under moderate reflux, under a nitrogen atmosphere, for 18 hours. The mixture is then stirred with

  1.0 liter of ice water. The layers are separated and the aqueous layers

  its is extracted with an additional 200 ml of methylene chloride.

  The aqueous layer is made basic (pH 12) with an aqueous solution of sodium hydroxide. This causes precipitation of the free basic form of II which is collected by filtration, rinsed with water and dried in air, which gives 75.8 g of product, (melting point

97-99 C).

  Upon analysis, it can be seen that the product obtained has the formula

C13H19N303

  and we get the following values:

C H N

  - calculated ...... 58.85 7.22 15.84 - found ....... 59.02 7.24 15.92 When this free base form of II is used for transformation into I , the preliminary alkalinization step described in example 4 (which will follow) is skipped. The basic form of II is cyclized directly by moderate reflux in xylene according to the mode

example 4.

EXAMPLE 4

  -ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) one (I) Methyl hydrochloride {1- [2-phenoxyethyl] amino} propylidene hydrazine carboxylate (II, 655 , 3 g, 2.17 mole) is stirred vigorously in the presence of 4.0 liters of methylene chloride, 2.4 liters of water and 179.4 g of 50% NaOH (2.24 moles). The layers are separated and the organic layer is dried (K2CO3) and concentrated in vacuo. The residue is stirred in 1.2 l of xylene under moderate reflux for 2.5 hours and the solution is then refrigerated. The solid is collected on a filter, rinsed with toluene and allowed to air dry. 89.5 g (76.9%) of a white crystalline solid are obtained (melting point

134.5-138 C).

  Additional purification can be accomplished as follows. A portion of I (171.2 g, 0.73 mole) is dissolved in a

  boiling solution of 41.0 g (0.73 mole) of KOH in 3.0 liters of water.

  The solution is treated with a Celite filter aid and activated carbon and is filtered. The filtrate is stirred in an ice bath and 37% HCl (61.0 ml, 0.73 mole) is added. The solid is collected on a filter, rinsed with water and dried in air, which gives 166.0 g (97% recovery) of fine white crystalline product, point of

merger 137.5-138 C.

  Of course, the present invention is not limited to the modes of

  realization but it is susceptible of many variants accessible-

  to the skilled person without departing from the spirit of the

vention.

12 2555582

Claims (10)

  1.- Process for the preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-   triazol-3 (4H) -one (I) o which comprises the consecutive stages of: a) reaction of phenol with 2-ethyl-2-oxazoline (V) (v) which gives N- (2phenoxyethyl) propionamide (IV ) O'NX (IV)   b) activation of the amide functional group of compound IV by reaction of compound IV with an amide activating agent, which consists,   for example, thionyl chloride, thionyl bromide, oxy-   phosphorus chloride, phosgene or dimethyl sulfate, so as to produce a halide or an imidoyl ester intermediate of formula III III in which Y is preferably a halogen or an alkoxy group, and X an anion resulting from the reaction between said activation agent amide and compound IV. 13 25'5558 2   c) reaction of the product of step b), without isolation of this compound   se III, with a carbazate ester of formula H2NNHC02R which gives   an {1 - [(2-phenoxyethyl) amine] alkyl acid addition salt   pylidene} hydrazine carboxylate (II) 5. NNHC02R   wherein: R represents lower C1-C4 alkyl; and X represents an anion generally corresponding to the anion of the amide activating agent used in step b); and d) converting compound II into compound I by means of a suitable heat treatment of compound II in its free base form so as to form compound I. 2.- Method according to claim 1, characterized in that   the amide activating agent of step b) is phosgene.   3.- Method according to claim 1, characterized in that   the amide activating agent of step b) is phos- oxychloride   phore. 4.- Method according to claim 1, characterized in that the heat treatment of step d) consists in treating the base at reflux   free of compound II in a suitable inert organic solvent.   5.- Process for the preparation of an alkyl acid addition salt {1 - [(2phenoxyethyl) amine] propylidene} hydrazine carboxylate (II) 3 2YNNHCO 2R C N H.HX   in which: R represents a lower C1-C4 alkyl; and X represents an anion corresponding generally to the agent anion   amide activation used in step b). 14 25S5582   which comprises the consecutive stages of: a) reaction of phenol with 2ethyl-2-oxazoline (V) c (v) which gives N- (2-phenoxyethyl) propionamide (IV) (Iv) b) activation of the amide functional group of compound IV by reaction of compound IV with an amide activating agent, which consists,   for example, thionyl chloride, thionyl bromide, oxy-   phosphorus chloride, phosgene or dimethyl sulfate, so as to produce a halide or an imidoyl ester intermediate of formula III L-XII   c) reaction of the product of step b), without isolation of this compound   sé III, with a carbazate ester of formula H2NNHCO2R which gives   an {1 - [(2-phenoxyethyl) amine] alkyl acid addition salt   pylidene} hydrazine carboxylate (II).   6.- As a new industrial product, addition salt   alkyl acid {1-E [(2-phenoxyethyl) amine] propylidene} hydrazine carboxy-   late (II) NfflC02R NH diX (II) wherein: R represents lower C1-C4 alkyl; and X represents an anion generally corresponding to the anion of   the amide activating agent used in step b).   7.- As a new industrial product, the compound of formula II consisting of methyl {l - [(2-phenoxyethyl) amine] propylidene} hydrazine   carboxylate or its acid addition salt.   8.- As a new industrial product, the compound of formula II consisting of methyl hydrochloride {1 - [(2-phenoxyethyl) amine] propyli dene} hydrazine carboxylate.   9.- As a new industrial product any compound of formu-   the I obtained using the preparation process according to any one of claims 1 to 4.   10.- As a new industrial product any compound of formu-   II obtained using the preparation process according to the claim tion 5.