FI81785B - PROCEDURE FOR FRAMSTATION OF AV 5-EECL-4- (2-PHENOXYETHYL) -2H-1,2,4-TRIAZOL-3 (4H) -ON. - Google Patents

Description

1 81785

The present invention relates to an improved, more economical process for the synthesis of a valuable intermediate (i) IC / i ίο ^ λο intermediate used for the antidepressant 2- {3- [4- (3-15 chlorophenyl) -1-piperazinyl] propyl} -5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4 -triazol-3 (4H) -one, also known as nefazodone, having the following formula 20 / r \ V ~ (0) \ H /

Nefatsodone 25

The intermediate prepared by the process of the invention, i.e. 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one of formula I, is also known as MJ 30 14814 and its currently used synthesis, shown in Example 5 of U.S. Patent Application 06 / 509,266, is shown in the following Scheme 1. From the yields of the individual steps of Example 5 of said patent application, it can be calculated that the total yield is 33%.

2,81785

Scheme 1 ®- * M 'ssi <g ^ ~ A «« / -IX. „4 OC_Hc> f (1) (2) 2 5 (3)

Step 2 1) H ~ NNHn 0 2 2. il 2) HCl

OH + H2NNH2.H2O V

(5) L ·

Step 3 Al.O, / - \ u

* <OVo ^ A

o V ^ y nhnh2 \ Ä (4) -HCl

NIINH

^ (6) Step 4A

r v ί r

Step 5 __ Step 4B / ^ Ä \ JL

'-' (8) L (7) i /

O

© - ° "V

N — y 0 (9)

h2o ®0H

Step 6 (I; MJ 14814) 381785

As shown in Scheme 1, the starting materials for the preparation of MJ 14814 are phenol and ethyl acrylate, an unpleasant substance having a high vapor pressure. The production scale of this process has been successfully increased, the process has been used repeatedly with a total yield of MJ 14814 of 25-30% based on phenol.

MJ 14814 is converted to the antidepressant nefazodone (MJ 13754) as described in the aforementioned U.S. patent application. In this modification, MJ 14814 is reacted with 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine hydrochloride of formula (10) -N- (C1) - (Ci) (10) 15 Cl \ ^ y -HCl

The preparation of MJ 14814 according to the scheme comprises six steps and four isolated intermediates, two of which are liquid and must be purified by vacuum distillation.

The process of the invention, on the other hand, comprises four steps with only three isolated intermediates, all of which are solids, giving a total yield of MJ 14814 of 40-55% based on phenol. Compared to this improved process, the prior art process of Scheme 1 is a longer and more laborious process in which the yield of MJ 14814 is much lower.

The following references deal with the various steps of the method 30 of the invention: 1. Dow Technical Bulletin; "Developmental 2-Ethyl-2-Ox-azoline XAS-1454 Ethyloxazoline: An Intermediate for Aminoethylation". This reference describes the synthesis of N- (2-phenoxy-35-ethyl) propionamide as an intermediate in the process of the invention.

4 81 785 2. Reid, W. and Czack, A., Ann. 676, (2964), ss. 121-129. This reference describes the reaction between imidoyl ethers and ethyl carbazate to give amidrazones, which are then further cyclized by heating as shown in Scheme 2.

Figure 2

NH NH

X A.

1Q R OR '+ H2NNHCO2R "-> R NHNHCC ^ R" - *

HN NH

R "= ethyl o 15 However, the reference does not disclose the use of N-substituted imidoyl ethers which would be necessary to obtain the desired N-substituted triazolone.

3. Pesson, M. et al., Bull. Soc. Chim., Fr. (1962), ss.

20 1367-1371. This reference describes a very low yield (0.3%) triazolone synthesis in which the desired substitution occurs as described in Scheme 3 below.

Scheme 3 25 N "Ph + H9NNHC0 ~ Et A ®0H H ^ 'OMe 2 2 -> -> -»

N-N

30 1 I

N NH

Yield 0.3% /

Ph »'

O

According to the authors of the article, the preparation of imidoyl ethers of secondary amides is difficult (p. 1364, 35 second column from below). Pesson et al. present as desired

II

The preparation of the triazolone substituted in this way, which, however, takes place by the synthesis shown in the following Scheme 4 and thus differs from the synthesis according to the present invention. In the synthesis disclosed in the publication, the starting material is the imidoyl ether of the primary amide and the intermediate is carbethoxyhydrazone, which is then reacted with the primary amine.

Figure 4 10 NH p

Jf · HCl + H NNHCO Et _10 ^ NNHCC ^ Et R - ^^ OEt EtOH R ^ QEt

R v = - N

R'NH „I · is -r2 * .✓V” R · n

It should be noted that the carbazate replaces the imine group in Scheme 4, which is another feature that distinguishes the process of the invention from the process described in the publication.

Pesson et al. also show that thioamides are more reactive than amides and react with carbazate to form N-substituted amidrazones. However, if the N-substituent is alkyl, as in the process of the invention, no reaction with ethyl carbazate has been observed. Finally, Pesson et al. describe the activation of thiobenzamide with dimethyl sulfate followed by reaction with carbazate to give the triazolone product. Here again, however, no mention is made of the activation of alkyl carboxylic acid thioamides, which is a structural condition in the process according to the invention.

In summary, the above-mentioned references 2 and 3 mainly describe the reactions between certain amide derivatives and carbazate esters to give triazolone products; however, the reactions described are clearly different from the process of this invention.

This invention relates to an improved synthetic method applicable to the large-scale preparation of a useful chemical intermediate, 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone. The process according to the invention uses phenol and 2-ethyl-2-oxazoline as starting materials, which are cheap and readily available raw materials. The process according to the invention is advantageous in terms of both raw material and labor costs, as it is shorter, requires fewer intermediate isolation steps and yields the product in higher yields.

15 The following reaction scheme, i.e. Scheme 5, illustrates MJ

Preparation of 14814 by the process of this invention using readily available starting materials.

Scheme 5 * cir O O Of (1) (V) (IV) 25 Amide activation

Step 2 (SOX2; Me2O2; POCl2; COCl-V, etc.) NNHCO-R ”

30 ^ "O * h2nnhco2r '^ Tr-Y

-HX C Step 3 .HX

(11) \ (C) (III)

heating L J

Step ^ (I; MJ 14814)

Yield 40 - 55% 35 li 81 785 7

In Scheme 5, R is C 1 -C 4 alkyl, X is Cl, Br or SO 4, Y is Cl, Br or OR, and the activation of the amide is accomplished by forming a reactive imidoyl halide or ester by treating the amide with a suitable activator such as SO 2 Cl 2, SOBr 2, POCl 3. , dimethyl sulfate, phosgene, etc.

In step 1 of the above scheme, phenol (1) is reacted with 2-ethyl-2-oxazoline (V) to give N- (2-phenoxyethyl) propionamide (IV). The starting materials for Step 1 are commercially available. In step 2, the amide (IV) is activated by treating compound IV with an amide activating reagent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, dimethyl sulfate or the like to give imidoyl halide or imidoyl ester intermediates. Preferred activators are phosgene and phosphorus oxychloride. Intermediate III is not isolated but is reacted in step 3 with an alkyl carbazate of the formula H 2 NHNCO 2 R, where R is preferably methyl, to give a new triazolone precursor (II). In step 4, the hydrazinecarboxylate acid addition salt (II) is converted to the free base form, which is cyclized by heating to the desired triazolone product (I).

This improved four-step process involves the isolation of two intermediates (IV and II) in addition to the final product (I). By way of comparison, the current process involves six steps and requires the isolation of four intermediates, two of which are liquid and must be purified by vacuum distillation. The reduced handling of intermediates in the process of this invention significantly reduces manufacturing labor costs.

The synthesis of MJ 14814 according to this improved method is preferably performed in a series of four steps starting from the simplest starting materials (phenol, 8,881,785 2-ethyloxazoline) to MJ 14814. The steps of the method are as follows: 1) Add 2-ethyl-2-oxazoline to hot (150 °) to phenol and the heat is maintained at about 175 ° C for a further 16 hours. The oil is then cooled with water to give N- (2-phenoxyethyl) propionamide (IV) in about 90% yield.

2) Phosgene or phosphorus oxychloride is added to a solution of compound IV containing a catalytic amount of imidazole in methylene chloride to give a solution of imidoyl chloride hydrochloride intermediate (III).

3) Treat a solution of compound III with a solution of alkyl carbazate to give alkyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazinecarboxylate hydrochloride (II) in about 75% yield.

4) The free base form of Compound II obtained by treating Compound II with an alkalizing agent is heated in solution for several hours to give Compound I in about 75% yield.

The method according to the invention is illustrated in more detail by means of the following application examples. In these examples, temperatures are in degrees Celsius (° C). Melting points are uncorrected. Nuclear magnetic resonance (NMR) spectral values refer to chemical shift (6) expressed in parts per million (ppm) and using tetramethylsilane (TMS) as a reference standard. In the 1 H-NMR spectral values, the relative areas of the transitions correspond to the number of hydrogen atoms in a given functional group in the molecule. The multiplicity of transitions is expressed as broad singlet (bs), singlet (s), doublet 30 (d), triplet (t), quartet (q), or multiplet (m).

The abbreviations DMS0-d6 (deuterodimethylsulfoxide) and CDCl3 (deuterochloroform) are used, which have the usual meanings. Infrared (IR) spectral values include only absorption wave numbers (cm'1) that are relevant to the identification of the functional group. IR assays were performed using

II

Potassium bromide (KBr) as a diluent for 9,81785. Elemental analysis values are expressed as percentages by weight.

Example 1 Methyl Carbazate 5 An alternative name for this commercially available chemical is methyl hydrazinocarboxylate. Methyl carbazate can also be synthesized as follows. 58.5 g (1.00 mol) of 85% hydrazine hydrate were added over 10 minutes to 90.0 g (1.00 mol) of dimethyl carbon-10 carbonate with stirring. The mixture was rapidly heated to 64 ° C to form a clear solution. The solution was stirred for an additional 15 minutes and the volatiles were removed in vacuo at 70 ° C. During cooling, the residue solidified. It was collected by filtration and dried over air to give 69.3 g (76.9%) of a white solid; mp. 69.5 - 71.5 ° C.

Example 2 N- (2-Phenoxyethyl) propionamide (IV) 13.1 moles of phenol were heated at 150 ° C and stirred under nitrogen while 12.2 moles of 2-ethyl-2-oxazoline were added over one hour. The mixture was heated to 175 ± 3 ° C. Heating was continued for 16 hours, after which the oil was cooled to ca.

To 140 ° C and then poured with vigorous stirring into 25 liters of water. The mixture was stirred and cooled and at about 25 ° C the mixture was seeded with amide product crystals. The material solidified and the supernatant was removed by decantation. The remaining solid was stirred in 17 liters of hot (85 ° C) water. The mixture was cooled to 25 ° C, seeded with 30 amide products and cooled in a refrigerator. The granular solid formed was collected by filtration, rinsed with several portions of water and air dried. The yield of the substance thus obtained was 92% and m.p. 61.5-64 ° C.

10 81 785

Example 3 A.) Methyl {1 - [(2-phenoxyethyl) amino] propylidene} hydrazinecarboxylate hydrochloride (II) 57.4 g (0.58 mol) of phosgene were added to a solution of 112.0 g (0, 58 mol) of N- (2-phenoxyethyl) propionamide (IV) and 0.4 g (0.006 mol) of imidazole in 450 ml of methylene chloride, under cooling for 1 hour so that the temperature does not exceed 25 ° C. The reaction mixture was then stirred for an additional 2.5 hours at 25 ° C. A solution of 52.5 g (0.58 mol) of methyl carbazate in 500 ml of methylene chloride was stirred on 25 g of molecular sieve for 15 minutes and then the solution was filtered. The filtrate was added under a nitrogen atmosphere over a half hour amidifosgee-niliuokseen while cooling to 15-20 ° C. A large precipitate formed and the mixture was stirred at 25 ° C under nitrogen. After stirring for a total of 16 hours, the solid was isolated by filtration. The solid was stirred in 750 mL of methylene chloride for 15 minutes, re-filtered and then dried under vacuum at 65 ° C for 20 hours to give 135 g (77%) of a white solid; mp. 150-154 ° C. Recrystallization of the product from isopropanol gave analytically pure material; mp. 157-159 ° C.

Analysis for C13H19N3O3. HCl: 25 Calculated: C 51.74 H 6.68 N 13.92 Cl 11.75

Found: C 51.73 H 6.76 N 13.94 Cl 11.78 NMR (DMSO-d 6) δ: 1.15 (3, t) [7.5 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], 30.04 (3, bs), 10.40 (3, bs), 10.90 (3, bs) and 11.72 (3, bs).

IR (KBr): 695, 755, 1250, 1270, 1500, 1585, 1600, 1670, 1745 and 2900 cm-1.

Il 81 785 11

By appropriate modification of Method A.) described above, thionyl chloride, thionyl bromide, dimethyl sulfate or other activating agents can be used instead of phosgene. A slightly different method 5 can also be used.

B.) Methyl {1 - [(2-phenoxyethyl) amino] propylidene} hydrazinecarboxylate (II, base form) 53.0 g (0.346 mol) of phosphorus oxychloride were added to a solution of 100.0 g (0.518 mol) of N- (2-phenoxyethyl-10H) propionamide (IV) in 200 ml of methylene chloride while stirring under nitrogen. This solution was stirred for four hours and after this time the stirred solution was added over half an hour the solution (dried over molecular sieves-4A) containing 46.4 g (0.518 mol) of 15-metyylikar batsaattia 600 ml of methylene chloride. The resulting mixture was stirred and gently heated to reflux under nitrogen for 18 hours. The mixture was then stirred in 1.0 liter of ice water. The layers were separated and the aqueous layers were extracted with an additional 200 mL of methylene chloride. The aqueous layer was basified with aqueous sodium hydroxide solution (pH 12). The free base form of compound II precipitated and the precipitate was collected by filtration, rinsed with water and air dried to give 65.8 g of product; mp. 97-99 ° C.

25 Analysis for C3 3 9 N3 03:

Calculated: C 58.85 H 7.22 N 15.84

Found: C 59.02 H 7.24 N 15.92.

When this free base form of Compound II is converted to Compound I, the alkaloin-30 pathway described in Example 4 below is omitted. The base form of compound II is directly cyclized by gentle heating to reflux in xylene according to the method of Example 4.

i2 81 785

Example 4 5-Ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one (I) 655.3 g (2.17 mol) of methyl {1 - [( 2-Phenoxyethyl) -5-amino] propylidene} hydrazinecarboxylate hydrochloride (11) was added with vigorous stirring to a solution of 4.0 liters of methylene chloride, 2.4 liters of water and 179.4 g (2.24 mol) of 50% NaOH. solution. The layers were separated and the organic layer was dried over potassium carbonate-10a and concentrated in vacuo. The residue was stirred in 1.2 liters of xylene with gentle reflux for 2.5 hours, after which the solution was cooled in a refrigerator. The solid was isolated by filtration, rinsed with toluene and air dried. The weight of the white crystalline material was 89.5% (76.9%); mp. 134.5 - 138 ° C.

Further cleaning can be performed as follows.

171.2 g (0.73 mol) of compound I were dissolved in a boiling solution of 41.0 g (0.73 mol) of KOH in 3.0 liters of water. The solution was treated with Celite filter aid and activated carbon and filtered. The filtrate was stirred in an ice bath and 61.0 mL (0.73 mol) of 37% HCl was added. The solid was isolated by filtration, rinsed with water and air dried to give 166.0 g (97% yield) of a fine white crystalline product; mp. 137.5-138 ° C.

Il

Claims (3)

A process for the preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one (I) sequentially performs the following steps: a) Phenol is reacted with 2-ethyl-2-oxazoline (V) θ for obtaining N- (2-phenoxyethyl) propionamide (IV) b) the functional amyl group 1 of compound IV is activated by reacting the compound IV with an amide activating agent, such as, for example, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or dimethyl sulfate, to give an imidoyl halogenld or ester intermediate of formula III :: : Y is preferably a halogen or alkoxy group and X is an anion formed in the reaction between the amide activating agent and compound IV, c) the product of step b) is reacted without Isolation of Compound III with a carbazate ester of formula H2NNHCO2R for obtaining an alkyl {1 - [(2-phenoxyethyl) amine] propylidene} hydrazinecarboxylate acid diethyl on salt (II) Λ NNHCO-R f 10 () NH 11 · HX where R is lower alkyl of 1-4 carbon atoms and X is an anion which generally corresponds to the anion of the amide activating agent used in step b), and d) compound II is converted to compound I by suitable heat treatment of compound II in its free base form to form compound I. 2. A process according to claim 1, characterized in that the amide activating agent in step b) is phosgene or phosphorus oxychloride. 3. A process according to claim 1, characterized in that, during the heat treatment in step d), the free base of the compound II 25. is boiled a suitable inert organic solvent. Il