DE3443820C2 - Process for the preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3- (4H) -one, intermediate and process for the preparation thereof - Google Patents

Description

The invention relates to an improved and economical Licher process for the synthesis of the valuable chemical Intermediate (I)

which is effective in producing the anti-depressive Using 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5- ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one, which is also called Nefazodon

referred to, is used.

The present intermediate, namely 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone of formula (I) is also known as MJ 14814, and its synthesis is in DE-A- 34 23 898.0 described in Example 5. This synthesis  path is shown in scheme 1 below. The Yield calculations for the individual stages of the game 5 gives one Overall yield of 33%.

Scheme 1

As can be seen in Scheme 1, the production goes the compound MJ 14814 from phenol and ethyl acrylate, which is a very uncomfortable material with high vapor pressure is. This way of working has been successful on larger ones Scale and applied repeatedly, based on the phenol, the compound MJ 14814 in one 25 to 30% overall yield was obtained.

Compound MJ 14814 is described in the above patent message described in the anti-depressant agent Convicted to Nefazodon (MJ 13754). This transfer includes the reaction of the compound MJ 14814 with 1- (3-chlorophenyl) - 4- (3-chloropropyl) piperazine hydrochloride (10)

The preparation of compound MJ 14814 via Scheme 1 comprises 6 stages and 4 isolated intermediates, from which are 2 liquids which are cleaned by Require vacuum distillation.

In contrast, the Ver described here includes drive four steps, which are only three isolated intermediate include products that are always festive body acts. Here you get an overall yield of compound MJ 14814 from 40-55%, based on phenol.  

In comparison, the method of earlier application according to scheme 1 to a longer Ver drive, which requires more work and the connection MJ 14814 delivers in much lower yield.

The following publications relate to the individual Levels of the procedure described here.

• 1. Dow Technical Bulletin "Developmental 2-Ethyl-2- Oxazaline XAS-1454 Ethyloxazoline: An Intermediate for Aminoethylation ". This publication describes the synthesis of N- (2-phenoxyethyl) propionamide, an intermediate used in the present process connection.
• 2. W. Reid and A. Czack, Ann. 676, pages 121-129 (1964). This publication concerns the reaction of Imidoyl ethers with ethyl carbazate, taking amidrazone receives, which is then heated to 1,2,4- Cyclize triazoles as shown in Scheme 2 below is shown.

Scheme 2

However, the document does not disclose the use of N-substituted imidoyl ethers that would be required to obtain an N-substituted triazolone.

• 3. M. Pesson et al, Bull. Soc. Chim. FR. Pages 1367-71 (1982).
  This publication reports a synthesis with a very low yield (0.3%) of a triazolone with the desired substitution scheme via the process shown in Scheme 3 below

Scheme 3

The authors state that imidoyl ether of secondary amines are difficult to produce (Page 1364, bottom, 2nd column). Pesson et al however, requires the production of a triazolone with the desired substitution pattern, but via a synthesis shown in Scheme 4 and which differ from the present working method is. The synthesis of the publication begins with one Imidoyl ether of a primary amide and leads to one Carbethoxyhydrazone intermediate, which then with a primary amine is implemented.  

Scheme 4

It should be noted that the carbazate in Scheme 4 is the Imine functions replaced which is another characteristic which the inventive method from the prior art Technology makes a difference.

Pesson et al also discloses that thioamides are more reactive are as amides, and in the reaction with carbazate too Lead N-substituted amidrazone. However, if it is the N substituent is alkyl, as is the case with inventive method is required no reaction with the ethyl carbazate observed. Finally, Pesson et al teaches the activation of one Thiobenzamids with dimethyl sulfate, followed by the Reaction with carbazate to give the triazolone product. Again, there is no revelation regarding this the activation of alkyl carboxylic acid thioamides, which is a Prerequisite for the work according to the invention is wise.  

The invention relates to a method for producing 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone, which in large Scale can be done. It is known by it draws that in successive stages:

• a) phenol with 2-ethyl-2-oxazoline (V) to N- (2-phenoxyethyl) propionamide (IV) implements
• b) the compound (IV) with a halogenating or alkylating agent to give an imidoyl halide or ester intermediate of the formula (III), implements
  in which Y represents a halogen atom or an alkoxy group and in which X ^{Θ represents} an anion which results from the reaction of compound (IV) with the halogenating or alkylating agent,
• c) the compound III without isolating it with a carbazate ester of the formula H₂NNHCO₂R, where R is (C₁-C₄) alkyl,
  to an alkyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate acid addition salt (II) where R and X have the meanings given above,
  implements, and
• d) compound (II) converted into compound (I) appropriate heat treatment in the form of their free Base.

The present process is based on phenol and 2-ethyl-2-oxazoline, i.e. H. Raw materials, which are cheap and are easily accessible. The procedure is in economic in terms of material and labor costs advantageous as it takes less time, less intermediate Insulations and a higher product yield delivers.

The following flow chart, Scheme 5, explains the Making the connection MJ 14814 from the easily he available raw materials using the Operation according to the invention.  

Scheme 5

In Scheme 5, R is C _1-4 alkyl, X is Cl, Br, or SO₄, Y is Cl, Br, or OR, and "amide activation" is accomplished by forming a reactive imido yl halide or ester by treating that Amides with a suitable halogenating or alkylating agent, for example SOCl₂, SOBr₂, POCl₃, dimethyl sulfate or phosgene.

Level 1 of the scheme shown above includes Reaction of phenol (1) with 2-ethyl-2-oxazoline (V) to the intermediate compound N- (2-phenoxyethyl) propionamide (IV) to surrender. The starting materials are level 1 available in the stores. In stage 2 the amide (IV) with a halogenating or alkylating agent, for example thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or Treated dimethyl sulfate, imidolyhalide or an ester intermediate (III) is obtained. The before drawn agents are phosgene or phosphorus oxychloride. The Intermediate (III) is not isolated, it is left however in step 3 with an alkyl carbazate of the formula H₂NNHCO₂R, where R is preferably methyl, react, to form the new triazolone precursor (II). In the  Step 4 becomes the hydrazine carboxylate acid addition salt (II) converted to its base form and by heating converted to the desired triazolone product (I).

This improved four-step process includes the Isolation of only two intermediates (IV and II) in addition to the target compound (I). In comparison The working method currently used comprises 6 levels and the isolation of four intermediates, one of which are two liquids and vacuum cleaning require distillation. The lower workload at Handling the intermediates in the invention Process results in a substantial reduction in Manufacturing costs.

The synthesis of the compound MJ 14814 according to the improved Operation is preferred as a series of four stages, starting from the one most specialized raw materials (phenol, 2-ethyloxazoline) to the product MJ 14814. The stages of the process are as follows:

• (1) Add 2-ethyl-2-oxazoline to hot (150 ° C) Phenol and further heating to about 175 ° C for another 16 hours. Then the oil quenched in water to yield approximately 90% the N- (2-phenoxyethyl) propionamide (IV).
• (2) Add phosgene or phosphorus oxychloride to one Solution of compound (IV), which is a catalytic Amount of imidazole in methylene chloride contains one  Solution of the intermediate product imidoyl chloride To give hydrochloride (III).
• (3) Treating the solution of compound (III) with a solution of an alkyl carbazate to be in a Yield of approximately 75% of the [1 - [(2-phenoxy ethyl) amino] propylidene] -hydrazinecarboxylate- To give hydrochloride (II).
• (4) heating the free base form of compound (II), which of the treatment of compound (II) with one basic agent comes from several For hours in solution, the compound (I) in a Yield of approximately 75% is obtained.

Description of specific embodiments

The process according to the invention is explained in more detail by the examples below, which represent preferred embodiments of the process stages described below. However, these examples should not be interpreted as limiting the scope of the present invention. In the examples below, which serve to explain the above procedures, the temperatures are - as before - expressed in ° C. The melting points are not corrected. The characteristics of the nuclear magnetic resonance spectra (NMR) relate to chemical shifts (δ), expressed as parts per million (ppm) against tetramethylsilane (TMS) as standard. The relative areas listed for the various shifts in the H NMR spectral data correspond to the number of hydrogen atoms of a special functional type in the molecule. The type of shifts in terms of multiplicity is expressed as a broad singlet (bs), doublet (d), triplet (t), quartet (q) or multiplet (m). The abbreviations used mean DMSO-d₆ (deuterodimethyl sulfoxide), CDCl₃ (deuterochloroform) and are also common abbreviations. The infrared (IR) spectral data only comprise absorption wave numbers (cm ^-1 ), which have a value for identifying functional groups. The IR determinations were carried out using potassium bromide (KBr) as a diluent. The elementary analyzes are given in% by weight.

example 1 Methyl carbazate

An alternative name for this in trade he Chemical available is methylhydrazine carboxylate. Methyl carbazate can also be synthesized by 85% hydrazine hydrate (58.5 g, 1.00 mol) under Stir to dimethyl carbonate (90.0 g, 1.00 mol) in Ver add 10 minutes. The mixture warms up quickly reaches 64 ° C and becomes clear. You stir it Solution another 15 minutes and removes volatile Materials at 70 ° C in a vacuum. Consolidates when cooling yourself the backlog. You collect it on a filter  and after drying in the air receives 69.3 g (76.9%) white solid with melting point 69.5-71.5 ° C.

Example 2 N- (2-phenoxyethyl) propionamide (IV)

Phenol (13.1 mol) is heated to 150 ° C. and stirred below N₂ while over 1 hour Add 2-ethyl-2-oxazoline (12.2 moles). The mixture is heated to 175 ± 3 ° C. After 16 hours of heating the oil is cooled to approximately 140 ° C. and poured then with vigorous stirring in water (12 l). The Mixture is stirred and cooled and at approximately Inoculated 25 ° C with crystalline amide product. The Material solidifies and the excess liquid decanting. The remaining solid is stirred with 17 l of hot (85 ° C.) water. You cool the mixture to 25 ° C, inoculates with the amide product and cools the mixture. The grainy feast obtained fabric is collected on a filter, with several Share water rinsed and air to dry leave. In this way you get a 22% Yield of material with melting point 61.5-64 ° C.  

Example 3 A. Methyl- [1-1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate hydrochloride (II)

One gives with cooling in the course of 1 hour, so that the temperature does not rise above 25 ° C, Phosgene (57.4 g, 0.58 mol) to a solution of N- (2-phenoxyethyl) propionamide (IV, 112.0 g, 0.58 mol) and imidazole (0.4 g, 0.006 mol) in 450 ml of methylene chloride. The reaction solution then becomes more Stirred at 25 ° C for 2.5 hours. A solution is stirred of methyl carbazate (52.5 g, 0.58 mol) in 500 ml Methylene chloride over 25 g molecular for 15 minutes sieve and then filter the solution. The hydrate will over 0.5 hours under N₂ to the amide / phosgene Solution added while cooling to 15 to 20 ° C. A voluminous precipitate forms, and the Mixture is stirred under N₂ at 25 ° C. After a The total stirring time of 16 hours is filtered Mixture to isolate a solid. The feast Cloth is in 750 ml methylene chloride for 15 minutes stirred, filtered again and then in vacuo Dried at 65 ° C for 2 hours to white 135 g (77%) To give solid with melting point 150 to 154 ° C. Recrystallization of the product from isopropanol results analytically pure material with melting point 157 bis 159 ° C.

Analysis for C₁₃H₁₉N₃O₃ · HCl:
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-d₆): 1.15 (3, t [7.5 Hz]), 1.28 (3, t [7.5 Hz]), 2.74 (2, m), 3.66 ( 3.5), 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), 10.90 (3, bs), 11.72 (3, bs).
IR (KBr): 695, 755, 1250, 1270, 1500, 1585, 1600, 1670, 1745 and 2900 cm ^-1 .

With appropriate modification of the above procedure (A) one can use thionyl chloride, thionyl bromide, dimethyl sulfate or other amide activators instead of Use phosgene. You can also do something a little different Use method (B).

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

It is slowly added with stirring and under nitrogen Phosphorus oxychloride (53.0 g, 0.346 mol) to a solution of N- (2-phenoxyethyl) propionamide (IV, 100.0 g, 0.518 mol) in 200 ml of methylene chloride. This solution will last 4 hours long and then a solution (via molecular sieve 4A) dried) of methyl carbazate (46.4 g, 0.518: Mol) in 600 ml of methylene chloride to the stirred solution added over the course of 0.5 hours. The received Mixture is stirred and under nitrogen for 18 hours allowed to boil gently at reflux. Then you stir it Mix with 1.0 l ice water. The layers are ge  separates and the aqueous layers are too extracted an additional 200 ml of methylene chloride. Man makes the aqueous layer with aqueous sodium hydroxide basic (pH 12). This leads to the precipitation of the free ones Base form of the compound (II), which by filtration collected, washed with water and air is dried, giving 65.8 g of product with enamel point 97-99 ° C.

Analysis for C₁₃H₁₉N₃0₃:
calculated: C 58.85, H 7.22, N 15.84;
found: C 59.02, H 7.24, N 15.92.

If this free base form of compound (II) for the Conversion to compound (I) is used one described in Example 4 below, preliminary basification step. The base shape of compound (II) is cyclized directly by following the procedure of Example 4 in xylene boils at reflux.

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

Methyl [1 - [(2-phenoxyethyl) amino] propylidene] is stirred hydrazine carboxylate hydrochloride (II, 655.3 g, 2.17 mol) violently with 4.0 l of methylene chloride, 2.4 l of water and 179 g 50% NaOH (2.24 mol). You separate the layers  and dries the organic layer (K₂CO₃) and then concentrated in vacuo. The residue is stirred in gentle reflux in 1.2 l of xylene and cool then the solution. The solid is on a filter collected, rinsed with toluene and air dried. The white crystalline solid weighs 89.5 g (76.9%) and has a melting point of 134.5 to 138 ° C.

Further cleaning can be done in the following way be achieved. Part of compound (I) (171.2 g, 0.73 mol) is in a boiling solution of 41.0 g (0.73 Mol) KOH dissolved in 3.0 l of water. You treat them Solution with Celite filter aid and activated carbon and filtered. The filtrate is stirred in an ice bath and added 37% HCl (61.0 ml, 0.73 mol) too. The solid will collected on a filter, rinsed with water and turned on dried in air, giving 166.0 g (recovery 97%) fine, white, crystalline product with enamel point 137.5 to 138 ° C.

Claims (10)

1. Process for the preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one (I): characterized in that in successive stages:

• a) phenol with 2-ethyl-2-oxazoline (V) to N- (2-phenoxyethyl) propionamide (IV) implements
• b) the compound (IV) with a halogenating or alkylating agent to give an imidoyl halide or ester intermediate of the formula (III), implements
  in which Y represents a halogen atom or an alkoxy group and in which X ^{Θ represents} an anion which results from the reaction of compound (IV) with the halogenating or alkylating agent,
• c) the compound III without isolating it with a carbazate ester of the formula H₂NNHCO₂R, where R is (C₁-C₄) alkyl,
  to an alkyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate acid addition salt (II) where R and X have the meanings given above,
  implements, and
• d) Compound (II) is converted into compound (I) by suitable heat treatment in the form of its free base.

2. The method according to claim 1, characterized in that that in stage b) thionyl as halogenating agent chloride, thionyl bromide, phosphorus oxychloride or phosgene and used as the alkylating agent dimethyl sulfate. 3. The method according to claim 1, characterized in that in the heat treatment of stage d) free base of compound (II) in a suitable, inert organic solvents under reflux heated. 4. Compounds of formula (II) wherein R is (C₁-C₄) alkyl and their acid addition salts. 5. Methyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate and its acid addition salts. 6. Methyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate hydrochloride. 7. A process for the preparation of the compounds according to claims 4 to 6, characterized in that in successive stages:

• a) phenol with 2-ethyl-2-oxazoline (V) to N- (2-phenoxyethyl) propionamide (IV) implements
• b) the compound (IV) with a halogenating or alkylating agent to give an imidoyl halide or ester intermediate of the formula (III), in which Y represents a halogen atom or an alkoxy group and in which X⊖ represents an anion which results from the reaction of compound (IV) with the halogenating or alkylating agent,
• c) the compound III without isolating it with a carbazate ester of the formula H₂NNHCO₂R, where R is (C₁-C₄) alkyl,
  to an alkyl- [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate acid addition salt (II).

8. Compounds of the general formula (III) wherein Y represents a halogen atom or an alkoxy group and wherein X⊖ represents an anion derived from a halogenating or alkylating agent. 9. A process for the preparation of the compounds according to claim 8, characterized in that the compound of formula (IV) which is optionally obtained by reacting 2-ethyl-2-oxazoline (V) with phenol, reacted with a halogenating or alkylating agent and, if appropriate, isolates the compound of the general formula (III) obtained in a customary manner. 10. The method according to claim 9, characterized in that thionyl chloride as halogenating agent, Thionyl bromide, phosphorus oxychloride or phosgene and used as the alkylating agent dimethyl sulfate.