JPH0516424B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4-(2-phenoxyethyl)-1,
Regarding the 2,4-triazolone method.

The present invention relates to Nefazodone: Also known as depression treatment 2-[3-[4]
-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl) -2H -1,2,4-triazol-3( 4H )
- Valuable chemical intermediates used in the production of on (): Concerning a more economical and improved synthesis method for. The subject intermediate, 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazolone, also has the formula
Known as MJ14814, its recent synthesis is described as Example 5 of pending patent application SN 06/509266 and is shown in Scheme 1. The overall yield of 33% in Scheme 1 is expected from the yield calculations for each step in Example 5 above.

As shown in Scheme 1, the production of MJ14814 starts from phenol and ethyl acrylate, an unpleasant substance, under vapor pressure. This method is conveniently scaled up and used iteratively to obtain an overall yield of 25-30% from phenols.
% gives MJ 14814.

MJ14814 is converted into the depression treatment drug nefazodone (MJ 13754) as described in the above patent application. This conversion combines MJ 14814 and 1-[3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride (10): It reacts.

From Scheme 1, the preparation of MJ 14814 requires six steps and four separate intermediates, two of which are liquids that require purification by vacuum distillation.

In contrast, the improved process described later consists of four steps involving only three intermediates and involves the production of phenols from phenols.
The overall yield of MJ 14814 is 40-55% and all intermediates are fixed. Comparing the conventional method shown in Diagram 1, it takes a long time and requires more labor.
MJ 14814 yield is small.

The following documents relate to each step of the process herein: 1 Dow Technical Bulletin, "Development of 2-ethyl-2-oxazoline XAS-1454 Ethyloxazoline: Intermediate for Aminoethylation Reactions." This document describes the synthesis of the intermediate compound N-(2-phenoxyethyl)propionamide of the present process.

2 W. Reid and A. Czack, Ann. 676, 121-129
(1964). This document discloses that imidoyl ether and ethyl carbazate are reacted to obtain amidrazone, which is further heated and cyclized to produce 1,2,
4-triazole is taught.

However, there is no mention here of the use of N-substituted imidoyl ethers, which may be necessary to obtain the desired N-substituted triazolones.

3 M. Pesson et al., Bull.Soc.Chim., Fr., 1367−
71 (1962). This document reports a very low yield (0.3%) synthesis of triazolone according to the desired substitution scheme as shown in Scheme 3 below.

The author states that imidoyl ethers of secondary amides are difficult to make. (page 1364, bottom 2nd column). Pesson et. The synthesis method in the literature starts with the imidoyl ether of a primary amide to form the intermediate carbetoxyhydrazone, which is then reacted with a primary amine.

It should be noted that the carbazate replaces the imine functionality of Scheme 4 and exhibits other features that distinguish the process of the invention.

Pesson et al. have also shown that thioamides are more reactive than amides and react with carbazates to form N-substituted amidrazones. However, no reaction with ethyl carbazate was observed when the N-substituent was alkyl, as required in the process of the present invention. Finally, Pesson et al. teach activation of thiobenzamide with dimethyl sulfate followed by reaction with carbazate to yield the triazolone product. However, there is no description of the activation of alkylcarboxylic acid thioamide, which is structurally necessary for the method of the present invention.

Taken together, references 2 and 3 essentially describe the reaction of certain amide derivatives with carbazate esters to ultimately obtain triazolone products, whereas the products produced by the method of the present invention This is a structurally notable variation.

The present invention provides a convenient chemical intermediate 5-ethyl-4-
This invention relates to an improved synthetic method suitable for large-scale production of (2-phenoxyethyl)-1,2,4-triazolone.
This method uses inexpensive and easily available raw materials, phenol and 2-
Starting from ethyl-2-oxazoline. This improved process provides economic benefits in terms of both materials and labor due to short time, minority intermediate separation, and high yield production.

Scheme 5 below illustrates the preparation of MJ 14814 from readily available starting materials using the process of the present invention.

In scheme 5, R is C _1-4 alkyl and X is
Cl, Br or SO ₄ , Y is Cl, Br or OR, and amide activation converts the amide into SOCl ₂ ,
Formation of reactive imidoyl halides or esters by treatment with appropriate activating reagents such as SOBr ₂ , POCl ₃ , dimethyl sulfate, phosgene, and the like.

The above schematic process 1 is phenol (1) and 2-ethyl-
This is the formation of the intermediate compound N-(2-phenoxyethyl)propionamide () by the reaction of 2-oxazoline (). Starting materials for Step 1 are commercially available. Activation of the amide () in step 2 can be achieved by treating the amide () with an amide activating reagent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, dimethyl sulfate, etc. to form an imidoyl halide or ester intermediate. () can be obtained. Preferred reagents are phosgene or phosphorus oxychloride. The intermediate is not separated, but in step 3 it has the formula H ₂ NNHCO ₂
Reaction with an alkyl carbazate containing R (where R is preferably methyl) provides a novel triazolone precursor ( ). In step 4, the hydrazine carboxylate acid addition salt () is converted to its base form and cyclized by heating to give the desired triazolone product ().

This four-step improved process involves separation of only two intermediate products in addition to the target compound. In contrast, the conventional method involves six steps and separation of four intermediates, two of which are liquids and require purification by vacuum distillation. The reduction in intermediate handling of the process of the invention results in a significant reduction in manufacturing labor costs.

The MJ 14814 synthesis method presented in the improved method is successfully carried out as a series of four steps leading to MJ 14814 from the simplest materials (phenol and 2-ethyloxazoline). This method consists of the following steps: (1) Adding 2-ethyl-2- to hot phenol (150°C)
Add oxazoline and continue heating at approximately 175°C for 16 hours. The oil is then cooled in water to give N-(2-phenoxyethyl)propionamide () in about 90% yield.

(2) Adding phosgene or phosphorus oxychloride to a solution containing a contact amount of imidazole in methylene chloride to form the intermediate imidoyl chloride hydrochloride ().

The solution of (3) is treated with an alkyl carbazate solution to produce alkyl[1-[(2-phenoxyethyl)amino]propylidene]hydrazinecarboxylate hydrochloride () in about 75% yield.

The free base obtained by treating (4) with a basifying agent is heated in solution for several hours to obtain a yield of about 75%.

The method of the invention is illustrated in detail by the following examples which describe preferred embodiments of the steps of the method. However, these examples should not be considered as limiting the scope of the invention. In the examples used to illustrate the method, temperatures are expressed in degrees Celsius (° C.) and are uncorrected for melting point. Nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in ppm relative to tetramethylsilane (TMS) as a comparison standard. The area ratios reported for various shifts in the H NMR spectral data correspond to the number of specific functional hydrogen atoms in the molecule. The nature of the shift with respect to multiplicity is reported as broad singlet (bs), singlet (s), doublet (b), triplet (t), quartet (q) or multiplet (m). ing. The symbols used are
DMSO−d ₆ (deuterodimethylsulfoxide),
CDCl ₃ (deuterochloroform) and the rest are normal. The infrared (IR) spectrum description is only the number of absorption wavelengths (cm ^-1 ) with functional group identification values. IR measurements with potassium bromide (KBr) as diluent
This was done using Elemental analysis is reported in weight percent.

Example 1 Methyl Carbazate Another name for this commercially available drug is methyl hydrazinocarboxylate. Methyl carbazate can also be synthesized by adding 58.5 g (1.00 mole) of 85% hydrazine hydrate to 90.0 g (1.00 mole) of dimethyl carbonate over 10 minutes with stirring. The mixture became clear when quickly heated to 64°C. The solution was stirred for an additional 15 minutes and the volatile components were removed in vacuo at 70°C. The residue solidified upon cooling. Collect the solid through filtration and air dry to obtain 69.3g (76.9%) of white solid.
I got it. Melting point 69.5-71.5℃.

Example 2 N-(2-Phenoxyethyl)propionamide () Phenol (13.1 mol) was heated to 150° C. and 2-ethyl-2oxazoline (12.2 mol) was added over 1 hour with stirring under _N2 atmosphere. Ta.
After heating the mixture at 175±3℃ for 16 hours, the oil was heated to about 140℃.
Cool to 12 ml and pour into 12 ml of water with vigorous stirring. The mixture was stirred, cooled and seeded with crystalline amide product at about 25°C. The material crystallized and the supernatant was decanted. Heat the remaining solids (85°C) with water 17
The mixture was cooled to 25° C., seeded with the amide product, and the mixture was refrigerated. The resulting granular solid was filtered, washed with water several times, and air-dried to obtain the product in a yield of 92%. melting point
61.5−64℃.

Example 3 A Methyl[1-[(2-phenoxyethyl)amino]propylidenehydrazinecarboxylate hydrochloride () N-(2-phenoxyethyl)propionamide (, 112.0 g, 0.58 mol) in 450 ml of methylene chloride
A solution of 0.4 g (0.006 mol) of imidazole and
57.4g of phosgene while cooling to avoid
(0.58 mol) was added over 1 hour. The reaction solution was stirred for an additional 2.5 hours at 25°C. Methyl carbazate 52.5 g (0.58 mol) methylene chloride
The solution in 500 ml was filtered over 25 g of molecular sieves after stirring for 15 minutes. This liquid was added to the above amide-phosgene solution cooled to 15-20° C. under N ₂ over 30 minutes. A bulky precipitate forms and the mixture
After stirring at 25° C. under N ₂ for 16 hours, the mixture was filtered to separate the solids. The solid was stirred in 750 ml of methylene chloride for 15 minutes, filtered, and then vacuum dried at 65° C. for 2 hours to yield 135 g (77%) of a white solid. Melting point 150−
154℃. The product was recrystallized from isopropanol to obtain analytically pure material. Melting point 157-159℃.

Analysis value for C ₁₃ H ₁₉ N ₃ O ₃・HCl: Calculated value: C, 51.74: H, 6.68: N: 13.92: Cl,
11.75.

Measured value: C, 51.73: H, 6.76: N: 13.94: Cl,
11.78.

NMR (DMSO- _d6 ): 1.15 (3,t [7.5Hz]): 1.28
(3, t [7.5Hz]): 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
[6.8Hz]): 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 .

Method A above may be suitably modified to replace phosgene with thionyl chloride, thionyl bromide, dimethyl sulfate, or other amide activators. A slightly different method B can also be used.

B Methyl[1-[(2-phenoxyethyl)amino]propylidenehydrazinecarboxylate (base form) A solution of N-(2-phenoxyethyl)propionamide (, 100.0 g, 0.518 mol) in 200 ml of methylene chloride was heated under nitrogen. While stirring, 53.0 g (0.346 mol) of phosphorus oxychloride was slowly added. After stirring this solution for 4 hours, methylene chloride 600
Methylcarbazate 46.4g (0.518mol) in ml
(dried over 4A molecular sieves) was added with stirring over 30 minutes. The resulting mixture was stirred for 18 hours under N ₂ with gentle reflux. The mixture was stirred with 1.0 ml of ice water, the layers were separated, and the aqueous layer was extracted with 200 ml of methylene chloride. The aqueous layer was made alkaline (PH12) with sodium hydroxide. The precipitated free base was filtered, washed with water and air dried to yield 65.8 g of product. Melting point 97-99℃.

Analytical values _{for C13H19N3O3} : Calculated values _: C, 58.85:H, 7.22:N _: 15.84.

Measured value: C, 59.02: H, 7.24: N: 15.92.

When the free base of this is used for conversion to,
The prebasification step shown in Example 4 (below) is omitted. The base form of is directly cyclized by the method of Example 4 by gentle reflux in xylene.

Example 4 5-ethyl-4-(2-phenoxyethyl)-2H
-1,2,4-triazol-3(4H)-one () Methyl[1-[(2-phenoxyethyl)amino]propylidene]hydrazinecarboxylate hydrochloride (,655.3g, 2.17mol) in methylene chloride 4.0, water 2.4 and 50% NaOH solution 179.4
g (2.24 mol). The layers were separated and the organic layer was dried with K ₂ CO ₃ and concentrated in vacuo. After 2.5 hours of gently refluxing the residue with 1.2 xylene,
The liquid was refrigerated. The solid was collected by excess, washed with toluene, and air-dried to yield 89.5 g (76.9%) of a white crystalline solid. Melting point 134.5-138℃.

It can be further purified as follows. 1 part 171.2g
(0.73 mol) in water 3.0 KOH41.0g (0.73 mol)
It was dissolved in boiling liquid. The liquid was treated with Celite super-aid and activated carbon. The solution was stirred in an ice bath and 61.0 ml (0.73 mol) of 37% HCl was added. The solid is collected by excess, washed with water and air-dried to produce a white microcrystalline product.
166.0g (recovery rate 97%) was obtained. Melting point 137.5−138
℃.

Claims (1)

[Claims] 1 (a) Phenol as 2-ethyl-2-oxazoline (): N-(2-phenoxyethyl)propionamide () by reacting with: (b) reacting compound () with an amide activator to produce an imidoyl halide or ester intermediate; (c) converting the product of step b without separation to the formula
By reacting with a carbazate ester having H ₂ NNHCO ₂ R, the formula (): (In the formula, R represents lower (C ₁ - _{C 4} ) alkyl and X represents an anion)
- [(2-phenoxyethyl)amino]propylidene]hydrazinecarboxylate acid addition salt, and (d) heat-treating compound () in the free base form to form the formula (): 5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazole-3 having the above formula (), characterized by comprising a continuous process of converting it into a compound represented by
(4H)-one production method. 2. The method according to claim 1, wherein the amide activator in step b is thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or dimethyl sulfate. 3. The method of claim 1, wherein the amide activator in step b is phosgene. 4. The method according to claim 1, wherein the amide activator in step b is phosphorus oxychloride. 5. The method of claim 1, wherein the heat treatment of step d comprises refluxing the free base form of the compound in an inert organic solvent.