KR890000990B1 - 4-(2-phenoxyethyl)-1.2.4-triazolone and process for preparing there of - Google Patents

Abstract

Title compd. [I was prepd.. Thus, 2.17 mole methyl [1-[(2phenoxyethyl)amino propylene hydrazine carboxylate.HCl was vigorously mixed with 4 liter methylene chloride, 2.4 liter H2O, and 2.24 mol NaOH. Organic layer was dried and concd.. The resulting residue was refluxed with 2.5 liter xylene and freezedried. The solid material was washed with toluene, treated with boiled KOH and charcoal, filtered, treated with 37% HCl to give 5-ethyl-4-(2- phenoxy-ethyl)-2-1,2,4-triazol-3(4H)-one.

Description

4- (2-phenoxyethyl) -1,2,4-triazolone and its preparation

The present invention relates to 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl-4- (2-phenoxyethyl, an anti-inhibitor known as nefazodone. An economical and improved process for the synthesis of valuable chemical intermediates (I) used in the preparation of) -2H-1,2,4-triazol-3 (4H) -one.

In addition, 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone of general formula (I), an intermediate of the present invention, is known as MJ 14814 and its synthesis method is currently pending. It is described in Example 5 of Application 06 / 509,266 and this synthesis method is shown in Reactor Mechanism 1 below. The 33% total yield for reactor 1 can be predicted by calculating the yield of each of the steps described in Example 5 of the pending application.

As can be seen from the reactor 1, the preparation of MJ 14814 starts with phenol and ethyl acrylate, an unpleasant substance with high vapor pressure. This method was successfully scaled and used repeatedly to yield MJ 14814 having a total yield of 25-30% from phenol. MJ 14814 is converted to nepazodone, an anti-inhibitor, as described in the aforementioned pending application. This conversion involves reacting MJ 14814 with 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazinehydrochloride (10).

The preparation of MJ 14814 via reactor 1 comprises six steps and four separate intermediates, two of which are liquids that need to be purified by vacuum distillation. In contrast, the improved process described below consists of four steps comprising only three separate intermediates, all of which are solid and the total yield of MJ 14814 from phenol is between 40 and 55%. In comparison, the conventional method, represented by Organization 1, requires more labor and provides a much lower yield of MJ 14814.

The following references relate to the construction steps of the process described in the text.

1. [Dow Technical Bulletin, “Developmental 2-Ethyl-2-Oxazoline XA S-1454Ethyloxazoline: An Interme-diate for Aminoethylation.”] The above references refer to N- (2-phenoxyethyl) propion as an intermediate compound of the method. It describes a method for synthesizing amides.

2. W. Reid and A. Crack, Ann . 676, pp. 121-119 (1964).] The reference is as outlined in Reaction Scheme 2 below to react imidoyl ether with ethyl carbazate to produce amidazone, which is then heated and cyclized to 1,2,4 It describes the reaction to produce triazoline.

However, the use of N-substituted imidoyl ethers necessary to obtain the desired N-substituted triazolones is not described.

3. M. Pesson, et al ., Bull . Soc . Chim ., Fr., PP. 1367-71 (1962). The document describes very low yields (0.3%) of triazolone synthesis by the desired substitution mode via the method of Reactor III.

The authors explain that it is difficult to produce imidoyl ethers of secondary amides. (P. 1364, lower column 2) Many of the pensons are produced by different synthesis from the process of the present invention as shown in Reactor 4 The preparation method of triazolone is described by the desired substitution form. The method of synthesis in this document starts with the imidoyl ether of the primary amide, yields the carbetoxy hydrazone and reacts it with the primary amine.

In instrument 4, carbazate substitutes an imine group, which is different from the method of the present invention. Peson et al. Also describe that thioamides are more reactive than amides and result in N-substituted amidrazone by reaction with carbazate. However, no reaction with ethyl carbazate was observed when the N-substituent is alkyl as required by the process of the invention. Finally, Peson et al. Described a method of activating thiobenzide with dimethylsulfate and then reacting with carbazate to yield the thiazolone product. The activity of alkyl carboxylic thioamides, which are structural requirements of the process of the present invention, is not described.

In summary, references 2 and 3 describe a method of substantially reacting a specific amide derivative with a carbazate ester to yield a thiazolone product, but the structure with the product produced by the method of the present invention. Have variables that are distinguished from one another in relation to each other.

The present invention relates to an improved method of synthesis that can be applied to large scale production of useful chemical intermediates 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone. The process of the present invention starts with phenol and 2-ethyl-2-oxazoline and the raw materials are inexpensive and readily available. The improved process of the present invention is intermittent and offers both economical advantages in material and labor costs in that it provides less intermediate separation and higher yield of product.

The following flow diagram, reactor 5, describes a method of making MJ 148 14 from starting materials using the method of the present invention.

In reactor 5, R is C _1-4 alkyl; X is C1, Br, or SO ₄ ; Y is C1, Br or OR; And amide activation produces reactive imidoyl halides or esters by treating the amide with a suitable activator such as SOC1 ₂ , SOBr ₂ , POCL ₃ , dimethyl sulfate, phosgene and the like.

Step 1 outlined above includes a method of reacting phenol (1) with 2-ethyl-2-oxazoline (V) to yield the intermediate compound N- (2-phenoxyethyl) propionamide (IV). . The starting material of step 1 is commercially available.

Step 2 of amide activation (IV) is carried out by treating compound (IV) with an amide activator such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, dimethyl sulfate to yield imidoyl halide or ester intermediate (III) Is performed. Preferred active agents are phosgene or phosphorus oxychloride. Intermediate (III) is not isolated but is reacted with alkylcarbazate of formula H ₂ NNHCO ₂ R (where R is methyl) in step 3 to yield a novel triazolone precursor (II). In step 4 the hydrazine carboxylate acid addition salt (II) is converted to its base form and cyclized to the desired thiazolone product (I) by heating.

The four step improvement process involves the separation of only two intermediate products (IV and II) in addition to the desired compound (I). As a comparison, current methods include six steps and four intermediate separations, two of which are liquid and must also be vacuum distilled. Reduction of intermediate treatment in the method of the present invention significantly reduced labor cost during manufacturing. As indicated in the improved process, the synthesis of MJ 14814 is preferably carried out in a series of four steps from the simplest starting material (phenol, 2-ethyloxazoline) to MJ 14814. The steps involving the process are as follows. (1) 2-ethyl-2-oxazoline is added to hot (150 ° C.) phenol and then heated at about 175 ° C. for 16 hours. The oil is then quenched in water to yield N- (2-phenoxyethyl) propionamide (IV) in about 90% yield. (2) To a solution of intermediate (IV) containing a catalytic amount of imidazole in methylene chloride, phosgene or phosphorus oxychloride is added to yield a solution of intermediate imidoyl chloride hydrochloride (III). (3) Treating the intermediate (III) solution with an alkyl carbazate solution to yield approximately 75% yield of alkyl [1-[(2-phenoxyethyl) amino] propylledene] -hydrazine carboxylate hydrochloride (II) Calculate (4) The free base form (II) obtained by treating general formula (II) with a basicizing agent is heated in a solution for several hours to yield compound (I) having a yield of 75%.

The method of the invention is explained in more detail by the following examples which are preferred specific examples of process steps. However, these examples should not be construed as limiting the scope of the invention. In the embodiment for explaining the above-described method, the temperature is in degrees Celsius (° C.) as described above, and the melting point is not accurate. The properties of the nuclear magnetic resonance (NMR) spectrum refer to chemical shifts (δ) in ppm relative to the standard tetramethylsilane (TMS).

The relative area recorded in the various shifts in the H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional form in the I molecule. Shift characteristics for doubling are recorded as broad single (bs), single (s), double (d), triple (t), quadruple (q) or multiple (m). Abbreviations used are DMSO-d ₆ (deutero dimethyl sulfoxide), CDC1 ₃ (deutero chloroform) and others are conventional ones. The infrared (IR) spectrum includes only the absorption wavelength number (cm ⁻¹ ) having a functional group identification. IR measurement was performed using potassium bromide (KBr) as a diluent. Elemental analysis is expressed in weight percent.

Example 1

Methyl carbazate

Another commercially available name for the title compound is methyl hydrazino carboxylate. Methyl carbazate can also be synthesized by adding 85% hydrazine hydrate (58.5 g, 1.00 mole) to dimethyl carbonate (90.0 g, 1.00 mole) with stirring over 10 minutes. The mixture quickly warms to 64 ° C. and becomes clear. The solution is stirred again for 15 minutes and the volatiles are removed in vacuo at 70 ° C. Upon cooling, the residue solidified. This was collected by a filter and dried in air to yield 69.3 g (76.9%) of white solid. (M.p. 69.5-71.5 ° C.)

Example 2

N- (2-phenoxyethyl) propionamide (IV)

Phenol (13.1 mol) was heated to 150 and 2-ethyl-2-oxazoline (12.2 mol) was added over 1 hour under nitrogen (N ₂ ) atmosphere. The mixture is heated to 175 ± 30 ° C. After heating for 16 hours, the oil was cooled to 140 ° C. and poured water (12 L) with vigorous stirring. After the mixture was stirred and cooled, the mixture was seeded with crystalline amide product at 25 ° C. The residue solid is stirred with 171 hot water (85 °). The mixture is cooled to 25 °, seeded with amide product and the mixture is frozen. The solid particles produced here are collected by filtration, rinsed several times with water and dried in air. This method yielded the title compound with a yield of 92%. Melting point61.5-64 ℃

Example 3

A. Methyl [1-[(2-phenoxyethyl) amino] propylidene hydrazine carboxylate hydrochloride (II)

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 methylene chloride over 1 hour, phosgene (57.4 g, 0.58 mole) ), And allow the temperature to not exceed 25 °. The reaction solution is stirred again at 25 ° C. for 2.5 hours. The solution was filtered by stirring a solution of methyl carbazate (52.5 g, 0.58 mole) in 500 ml methylene chloride over 25 g of molecular sieve for 15 minutes. The filtrate is kept at 15-20 [deg.] C. while being added to the amide / phosgene solution over 0.5 h under N ₂ atmosphere. If a lot of precipitate is formed, the mixture is stirred at 25 ° C. under N ₂ atmosphere.

After stirring for a total of 16 hours, the mixture is filtered to separate the solids. The solid was stirred in 750 ml of methylene chloride for 15 minutes, then filtered and dried under vacuum at 65 ° C. for 2 hours to yield 135 g (77%) of white solid. m.p. The product was recrystallized from 150-154 ° C. isopropanol to yield an analytically pure material (melting point 157-159 °).

Analysis of C ₁₃ H ₁₉ N ₃ O ₃ .HCl

Calculated Value: C; -51.74, H; -6.68, N; -13.92, CL; -11.75

Found value; C; -51.73, H; -6.76, N; -13.94, Cl; -11.78

NMR (DMSOd ₆ ): 1.15 (3, t [7.5 HZ]); 1.28 (2.3 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); 10.40 (3, bs); 10.90 (3, bs); 11.72 (3, bs)

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

Appropriate modifications to the above method (A) may be used instead of phosgene with thionyl chloride, thionyl bromamide, dimethyl sulfate or other amide activators. In addition, a slightly different method (B) can be used.

B. Methyl [1-[(2-phenoxyethyl] amino] propylidenehydrazine carboxylate (II base form)

To a solution of N- (2-phenoxyethyl) propionamide (IV, 100 .0 g, 0.158 mole) in 200 ml methylene chloride is added phosphorus oxychloride (53.0 g, 346 mole) slowly with stirring under nitrogen. While stirring this solution for 4 hours, a solution of methyl carbazate (46.4 g, 0.518 mole) in 600 ml methylene colorado (dried on molecular sieve 4A) is added to the stirring solution over 0.5 hours. The resulting mixture is stirred and then slowly heated to reflux under nitrogen for 18 hours. The mixture is stirred with 1.01 ice water. The layers are separated and the aqueous layer is extracted with 200 ml methylene chloride.

The aqueous layer is basified (pH 12) with sodium hydroxide solution. In this process, compound (II) in the form of free base precipitates, which is collected by filtration, rinsed with water, and dried in air to yield 65.8 g of a product (melting point 97-99 ° C.).

Analysis of C ₁₃ H ₁₉ N ₃ O ₃

Calculated Value: C; -58.85, H; -7.22, N; -15.84

Found: C; -59.02, H; -7.24, N; -15.92

When the compound (II) in free base form is converted to compound (I), the preliminary basicization step outlined in Example 4 (described below) is skipped. Compound (II) in base form is directly cyclized by gentle reflux in xylene according to the method of Example 4).

Example 4

5-ethyl-4- (2-phenoxyethyl) -2-1,2,4-triazol-3 (4H) -one (I)

Methyl [1-[(2-phenoxyethyl) amino] propylene] hydrazine carboxylate hydrochloride (II, 655.3 g, 2.17 mole) was added to 4.01 methylene chloride, 2.41 water and 179.4 g of 50% NaOH (2.24 mole) Stir vigorously with excess. The layers are separated, the organic layer is dried (K ₂ CO ₃ ) and concentrated in vacuo. The residue is stirred gently under reflux for 2.5 hours in 1.21 xylenes and the solution is frozen. The solid is collected by filtration, then rinsed with toluene and air dried. A white crystalline solid weighed 89.5 g (76.9%) and a melting point of 134.5-138 ° C.

Further purification is carried out according to the following method. A portion (171.2 g, 0.73 mole) of Compound (I) is dissolved in 41.0 g of a boiling solution of (0.73 mole) KOH in 3.01 water. The solution is treated with Celite filter aid and activated carbon followed by filtration. The filtrate is stirred in an ice bath and then 37% HCl (61.0 ml, 0.73 mole) is added. The filtered solid was washed with water and air dried to yield 166.0 g (97% recovery) of fine white crystals (melting point 137.5-138 ° C).

Claims (10)

a) reacting phenol with 2-ethyl-2-oxazoline (V) to produce N- (2-phenoxyethyl) propionamide (IV); b) thionyl chloride, thionyl bromide, phosphorus oxychloride; Reacting with an amide activator selected from the group consisting of phosgene or dimethyl sulfate to activate the amide functional group of the above compound (IV) to produce an imidoyl halide or ester intermediate of the following general formula (III); c) without separating compound (III), the product of step b) is reacted with a carbazate ester of formula H ₂ NHCO ₂ R (where R is as defined below) to give alkyl [1- [ To produce (2-phenoxyethyl) amine] propylidene] -hydrazine carboxylate addition salt (II); d) 5-ethyl-4- (2-phenoxy) comprising the steps of appropriately heat treating a compound of formula (II) in freebase form to a compound of formula (II) to produce a compound of formula (I) the method of one (I) - ethyl) -2 H -1,2,4- triazol -3 (4 H).

Wherein R is lower (C ₁ -C ₄ ) alkyl, X is an anion resulting from the reaction of an amide activator with compound (IV), and Y is a halogen or alkoxy moiety. The process according to claim 1, wherein the amide activator used in step b) is a phosgene. The process according to claim 1, wherein the amide activator used in step b) is phosphorus oxychloride. The process according to claim 1, wherein the heat treatment step of step d) comprises refluxing the free base of compound (II) in a suitable inert organic solvent. a) reacting phenol with 2-ethyl-2-oxazoline (V) to produce N- (2-phenoxyethyl) propion amide (IV); b) reacting the compound (IV) with an amide activator selected from the group consisting of thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or dimethyl sulfate to activate the amide functional group of the compound (IV) To generate the imidoyl halide or ester intermediate of III); c) reacting the compound of step b) with a carbazate ester of formula H ₂ NHCO ₂ R, wherein R is as defined below, without isolating said compound (III). A process for preparing a compound of formula (II) comprising the step of producing (2-phenoxyethyl) amine] propylledene] -hydrazine carboxylate addition salt (II).

Wherein R is lower (C ₁ -C ₄ ) alkyl, X is an anion resulting from the reaction of the amide activator with compound (IV), and Y is a halogen or alkoxy residue. Methyl (1- (2-phenoxyethyl) amino) propylidene) hydrazine carboxylate or acid addition salts thereof or methyl (1- (2-phenoxyethyl) amino) propylidene) hydrazine carboxylate hydrochloride A method for producing a compound of formula (II) comprising the. The compound of formula (II) or acid addition salt thereof which is methyl [1-[(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate. The compound of formula (II) which is methyl [1-[(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate hydrochloride. 5-ethyl-4 of the formula (I) (2- phenoxy (ethyl) -2 H -1,2,4- triazol -3- (4 H) - one.

A compound of formula (II) prepared by the method of claim 5.