DE3443820A1 - METHOD FOR PRODUCING 5-ETHYL-4- (2-PHENOXYETHYL) -2H-1,2,4-TRIAZOL-3- (4H) -ONE, INTERMEDIATE PRODUCT, AND METHOD FOR PRODUCING THE SAME - Google Patents

Description

PROF. DR. DR. J. REITSTÖTTER DR. WERNER KINZEBACH DR. ING. WOLFRAM BUNTE (,. ».- 1.7.)

- ο

REITSTÖTTER. KINZKBACH · FANTNBK PATENTANWÄLTE C 7 SO. DSOOO MÜNCHEN 43 APPROVED REPRESENTATIVES AT

EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

TELEPHONE: (Οββ) X 71 es 83 CABLE ·: PATMONDIAL MUNICH

TELEX: OB21S2O8 ISAR D TELEKOP: (Οββ) «71 βθ βϊ (ON. II + III) BAUERSTRABBE 22. D-BOOO MUNICH

Munich, November 30, 1984

OUR FILES:, - _ -

OURREF: M / 25 251

REFERENCE: RE

Bristol-Myers Company
Park Avenue
New York, NY 10154
United States

Process for the preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3- (4H) -one, intermediate and process for the same
Manufacturing

POSTAL ADDRESS: D-8OOO MUNICH 43. POST BOX 78Ο

3U3820

M / 25 251

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

(D

which in the production of the anti-depressant agent 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -δε thy1-4- (2-phenoxyethyl) -2H-1,2,4- triazol-3 (4H) -one, which is also called nefazodon

Nefazodone

is used.

The present intermediate, namely the 5-ethyl-4- (2-phenoxyethyl) -1 , 2 , 4-triazolone of formula (I) is also known as MJ 14814 and its synthesis, which is currently being carried out, is in German Patent application P 34 23 898.0 by the applicant, filed on June 28, 1984, corresponding to the applicant's ÜS patent application SN 06 / 509,266, described in example 5. This synthesis

M / 25

/ itr

way is shown in Scheme 1 below. From yield calculations for the individual stages in the example 5 of the pending patent application predicts an overall yield of 33% for Scheme 1

OH

⁺ XJ

Scheme

0 level

(D

(2)

(5)

OH +

step

(6)

NHNH.

step

N = OO

(8th)

Stage, "Δ

(9)

OH level

OEt

(3)

Level ₂ D 2

2) HCl

NHNH. (A) -HCl

Level ΔΑ

(7)

(I; MJ 1481 «)

Μ / 25 251

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

The compound MJ 14814 is, as in the above ¹ Pa ten tan message described, transferred to the anti-depressive agent nefazodone (MJ 13754). This conversion involves the reaction of the compound MJ 14814 with 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine hydrochloride (10)

• HC1

The preparation of the compound MJ 14814 via the scheme comprises 6 steps and 4 isolated intermediates, of which 2 are liquids that require cleaning by vacuum distillation.

In contrast to this, the method described here comprises four steps which only ^{include three isolated intermediates 1} , which are always solids. A total yield of compound MJ 14814 of 40 - 55% is achieved, based on phenol *

M / 25 251 / JQj

In comparison, the method of the earlier application according to Scheme 1 is a longer process, which requires more work and gives compound MJ 14814 in much lower yield.

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

1. Dow Technical Bulletin "Developmental 2-Ethyl-2-Oxazaline XAS-1454 Ethyloxazoline: An Intermediate for Aminoethylation ". This document describes the synthesis of N- (2-phenoxyethyl) propionamide, an intermediate used in the present process.

2. W. Reid and A. Czack, Ann. 676, pages 121 - 129 (1964) This publication relates to the reaction of imidoyl ethers with ethyl carbazate, whereby one amidrazones obtained, which then cyclize to 1,2,4-triazoles on further heating, as shown below in Scheme 2

25 is shown.

Scheme 2

R ' ^ OR ¹ ^ H ₂ NNHCO ₂ R "

R "= ethyl 35

M / 25 251

However, the document does not disclose the use of N-substituted imidoyl ethers that were required to get an N-substituted triazolone *

3. M. Pesson et al, Bull. Soc. Chim. FR. Pages 1367-71 (1982).

This publication reports a very low yield (0.3%) synthesis of a triazolone with the desired substitution scheme via the process shown in scheme 3 ^{according to 11}

Scheme 3

N-Ph 0

+ H ₉ NHCO ₀ Et - £ - * ~

OMe ^{2 2} A

ϊ ~ 1

0.3% from booty

² ^ The authors state that imidoyl ethers of secondary amines are difficult to prepare (page 1364, bottom, 2nd column). However, Pesson et al discloses the preparation of a triazolone with the desired substitution pattern, but via a synthesis which is shown as Scheme 4 and which is different from the present procedure. The synthesis of the reference begins with an imidoyl ether of a primary amide and leads to a carbethoxyhydrazone intermediate which is then reacted with a primary amine.

M / 25 251

Scheme 4

"""^ Ε 'K ¹ NH

2_ ^

.N ^ ^ N-H

It should be noted that the carbazate in Scheme 4 replaces the imine functions, which is another feature which distinguishes the method according to the invention from the prior art.

Pesson et al also discloses that thioamides are more reactive than amides, and when reacting with carbazate, too N-substituted amidrazones lead. However, when the N-substituent is alkyl, as is the case with If the method of the invention is required, no reaction with the ethyl carbazate was observed. Finally, Pesson et al teach the activation of a thiobenzamide with dimethyl sulfate followed by the Reaction with carbazate to give the triazolone product. Again, there is no disclosure regarding this the activation of Alkylcarbonsäurethioamiden, which is a structural requirement of the procedure according to the invention is.

According to all of this, publications 2 and 3 essentially describe reactions with certain amide derivatives Carbazate esters, to finally triazolone products too result, although there are differences to the structural relationships of the method of operation according to the invention manufactured product.

/ IS

3U3820

M / 25 251

The invention relates to an improved synthetic procedure which results in the preparation of the useful chemical intermediate compound 5-ethyl-4- (2-phenoxyethyl) "· 1,2,4-triazolon are transferred on a large scale to kahili The present process starts from phenol and 2-ethyl-2-oxazoline, i.e. raw materials which are inexpensive and are easily accessible. The present improved operation is economical in view on material and labor costs as it takes less time, fewer intermediate product isolations and provides a higher product yield.

The following flow sheet, Scheme 5, explains the preparation of the compound MJ 14814 from the readily available ones Starting materials using the procedure of the invention.

Scheme 5

OH +

175

step 1

(D

(V)

(IV)

Stage 2

Amide activation

(SOX ₂ ;

₂ ; COCl ₂ ; Etc.)

M / 25 251

NNHCO ₂ R

II

H ₂ NNHCO ₂ R
level 3

Stafe4

OH, heating

(I; MJ 14814) 40-55% yield

III

In Scheme 5, R stands for C _1-4 -AlCyI, X stands for Cl, Br, or SO ₄ , Y stands for Cl, Br or OR, and the amide activation takes place by forming a reactive imidoyl halide or ester by treating the amide with a suitable activating agents, for example SOC1 ", SOBr", POCl. ", dimethyl sulfate or phosgene.

■ 2 '

2 '

Step 1 of the scheme outlined above involves the reaction of phenol (1) with 2-ethyl-2-oxazoline (V) to give the intermediate N- (2-phenoxyethyl) propionamide (IV). Stage 1 starting materials are commercially available. In step 2, the activation of the amide (IV) is achieved by treating the compound (IV) with an amide activating agent, for example thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or dimethyl sulfate to give an imidoyl halide or an ester intermediate (III). The preferred agents are phosgene or phosphorus oxychloride. The intermediate (III) is not isolated, but is allowed to react in step 3 with an alkyl carbazate of the formula H ₂ NNHCO ₂ R * in which R is preferably methyl, in order to form the new triazolone precursor (II). In the

Stage 4 becomes the hydrazine carboxylate acid addition salt (II) converted into its base form and converted to the desired triazolone product (I) by heating.

This improved, four-step procedure comprises the isolation of only two intermediates (IV and II) in addition to the target compound (I). By comparison, the current procedure involves 6 steps and the isolation of four intermediates, two of which are liquids and require vacuum distillation purification. The lower amount of work involved in handling the intermediate products in the process according to the invention leads to a substantial reduction in laboratory costs during manufacture.

OQ The synthesis of the compound MJ 14814 according to the improved The procedure is preferably carried out as a series of four stages, which are based on the * - professional starting materials (phenol, 2-ethyloxazoline) for product MJ 14814 is running. The stages of the process

ge are as follows:

(1) Addition of 2-ethyl-2-oxazoline to hot (150 ⁰ C) of phenol and further heating to about 175 ° C for a further 16 hours. Then the oil

ο «quenched in water to yield in a yield of approximately 90% the N- (2-phenoxyethyl) propionamide (IV) to result.

(2) Addition of phosgene or phosphorus oxychloride to a solution of compound (IV), which is a catalytic Amount of imidazole in methylene chloride contains to one

M / 25 251

Solution of the intermediate product imidoyl chloride hydrochloride (III) to result.

(3) Treating the solution of the compound (III) with a solution of an alkyl carbazate to give in a Approximately 75% yield of the [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate hydrochloride (II) to result.

(4) heating the free base form of compound (II) resulting from treating compound (II) with

stems from a basifying agent, for several hours in solution, wherein the compound (I) in a Yield of about 75% is obtained.

Description of specific embodiments

The method according to the invention becomes more detailed illustrated by the examples below, which preferred embodiments of those described below Represent process stages. However, these examples should not fall within the scope of the present invention interpreted restrictively. In the following examples, which are intended to explain the The above working methods are the temperatures

on - as before - expressed in C. The melting points are not corrected. The characteristics of the nuclear magnetic resonance spectra (NMR) relate to chemical ones Displacements (£) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as the standard. the for the various shifts in the H NMR spectral

M / 25 251 / J (\

The relative areas listed in the data correspond to the number of hydrogen atoms of a particular functional type in the molecule. The type of Ver -schiebungen ⁴ with respect to multiplicity is expressed as broad singlet (bs), doublet (d), triplet (t), quartet (q) or multiplet (m). The abbreviations used mean DMSO-dg (Deuterodimethylsulfoxid), CDCl ₃ (Deuterochloroform) and are otherwise common abbreviations. The infrared (IR) spectral data

* -1 only include absorption wavenumbers (cm), which have value in identifying functional groups. The IR determinations were made using carried out by potassium bromide (KBr) as a diluent. The elemental analyzes are in% by weight specified.

example 1

Methyl carbazate
25th

An alternative name for this commercially available chemical is methyl hydrazine carboxylate. Methyl carbazate can also be synthesized by taking 85% hydrazine hydrate (58.5 g, 1.00 mole) under Stir to dimethyl carbonate (90.0 g, 1.00 mole) added over 10 minutes. The mixture heats up quickly to 64 ° C and becomes clear. The solution is stirred for a further 15 minutes and volatile substances are removed Materials at 70 ° C in a vacuum. The residue solidifies on cooling. You collect it on a filter

M / 25 251

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)

The phenol (13.1 mol) is heated to 150 ^° C. and stirred under NL while it is carried out in the course of 1 hour

Adds 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 about 140 ° C and poured then with vigorous stirring in water (12 l). The mixture is stirred and cooled and at about 25 C inoculated with crystalline amide product. The material solidifies and the supernatant liquid is decanted. The remaining solid is stirred with 17 l of hot (85 ° C.) water. One cools the mixture is reduced to 25 C, seeded with the amide product and the mixture is cooled. The granular solid obtained is collected on a filter, rinsed with several portions of water and allowed to air dry left. In this way, a 22% yield of material with a melting point of 61.5-64 ° C. is obtained.

M / 25 251 % A.

Example 3

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

¹ ^ Phosgene (57.4 g, 0.58 mol) is added 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 is then stirred at 25 ° C. for a further 2.5 hours. A solution of methyl carbazate (52.5 g, 0.58 mol) in 500 ml of methylene chloride is stirred over 25 g of molecular sieve for 15 minutes and the solution is then filtered. The hydrate is added to the amide / phosgene solution under nitrogen in the course of 0.5 hours, while cooling to 15 to 20 ° C. A voluminous precipitate forms and the mixture is stirred at 25 ° C. under N_. After a total of 16 hours of stirring, the mixture is filtered to isolate a solid. The solid is stirred in 750 ml of methylene chloride for 15 minutes, filtered again, and then dried in vacuo at 65 ° C for 2 hours to give 135 g (77%) of white solid, melting point 150-154 ° C.

Recrystallization of the product from isopropanol gives analytically pure material with a melting point of 157 bis 159 ° C.

Analysis for C ₁₃ H -N ₃ O ₃ * HCl

CH N Cl

calculated: 51.74 6.68 13.92 11.75 found: 51.73 6.76 13.94 11.78

M / 25

NMR (DMSO-d _c )

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 [6.8Hz]),

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 .

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

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

Phosphorus oxychloride (53.0 g, 0.346 mol) is slowly added to a solution with stirring and under nitrogen of N- (2-phenoxyethyl) propionamide (IV, 100.0 g, 0.518 mol) in 200 ml of methylene chloride. This solution will last 4 hours

stirred for a long time 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 0.5 hour. The resulting mixture is stirred and under nitrogen for 18 hours refluxed gently. The mixture is then stirred with 1.0 l of ice water. The layers are

> 5
M / 25 251

separate and the aqueous layers are extracted with an additional 200 ml of methylene chloride. Man make the aqueous layer basic (pH 12) with aqueous sodium hydroxide. That leads to the precipitation of the free The base form of the compound (II), which is collected by filtration, washed with water and left in the air is dried, 65.8 g of product having a melting point of 97-99 ° C. being obtained.

Analysis for C ₁ , HN, O .:
13 ig 3 3

calculated: found:

If this free base form of compound (II) for the Conversion into the compound (I) is used, one allows the described in Example 4 below, preliminary basic step. The base shape

the compound (II) is cyclized directly by 25th

following the procedure of Example 4 in xylene to the least

boils on reflux.
Example 4

C. 7th H N , 84 58 , 85 7th , 22 15th , 92 59 , 02 , 24 15th

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

Methyl [1 - [(2-phenoxyethyl) amino / propylidene] hydrazine carboxylate hydrochloride is stirred (II, 655.3 g, 2.17 mol) violently with 4.0 1 methylene chloride, 2.4 1 water and 179 g of 50% NaOH (2.24 moles). You separate the layers

M / 25 251

and dries the organic layer (K “CCL) and then concentrated in vacuo. The residue is stirred at gentle reflux for 2.5 hours in 1.2 liters of xylene and cooled then the solution off. The solid is collected on a filter, 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 purification can be achieved in the following manner. Part of the compound (I) (171.2 g,

jg 0.73 mol) is in a boiling solution of 41.0 g (0.73 Mol) KOH dissolved in 3.0 l of water. The solution is treated with Celite filter aid and activated charcoal and filtered. The filtrate is stirred in an ice bath and 37% HCl (61.0 ml, 0.73 mol) is added. The solid will

2Q collected on a filter, rinsed with water and turned on air dried to give 166.0 g (97% recovery) of fine, white, crystalline product with melting point Maintains 137.5 to 138 ° C.

Claims (10)

M / 25 251 Claims 1. Process for the preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazol-3 (4H) -one (I): (D characterized in that in successive stages: a) phenol with 2-ethyl-2-oxazoline (V) N. converts to N- (2-phenoxyethyl) propionamide (IV) (IV) to obtain; M / 25 b) the functional amide group of the compound (IV) activated by reacting the compound (IV) with an amide activating agent, in particular thionyl chloride, thionyl bromide, phosphorus oxychloride, Phosgene or dimethyl sulfate, converted to an imidoyl halide or ester intermediate to produce the formula (III), (III) wherein y preferably represents a halogen atom or an alkoxy group and wherein χ represents an anion stands- / "that results from the reaction between the amide activating agent and gives compound (IV); the product from stage b is reacted with a carbazate ester of _{the formula H 2 NNHCO 2} R without isolating the compound (III), wherein: R stands for lower (C ₁ -C ₄ ) alkyl and X represents an anion which in general corresponds to the anion of the amide activating agent of S £> ufe b, an alkyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate acid addition salt (II) M / 25 251 NNHCO ₂ R (H) NH-HX in which R and X have the meanings given immediately above, to obtain; and d) Compound (II) by appropriate heat treatment of Compound (II) in the form of its free Base converted into compound (I). 15th 2. The method according to claim 1, characterized in that the amide activating agent in step b) phosgene is. 3. The method according to claim 1, characterized in that the amide activating agent in step b) Is phosphorus oxychloride. 4. The method according to claim 1, characterized in that in the heat treatment of step d) the the free base of the compound (II) is refluxed in a suitable inert organic solvent. 5. Compounds of the formula (II)
30th NNHCO ₀ R ² (H) wherein R stands for lower (C ₁ -C ₄ J-AlkYl and their acid addition salts. 3U3820 M / 25 251 6. Methyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate and its acid addition salts. 7. Compound of the formula (II), methyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate hydrochloride. 8. Process for the preparation of the compounds according to Claims 5 to 7, characterized in that one in successive stages: a) phenol with 2-ethyl-2-oxazoline (V) converts to N- (2-phenoxyethyl) propionamide (IV) (IV) to obtain; 3Q b) the functional amide group of the compound (IV) activated by reacting the compound (IV) with an amide activating agent, in particular Thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, or dimethyl sulfate, gc is an imidoyl halide or ester intermediate of formula (III) M / 25 (III) to manufacture; and c) the product from stage b is reacted with a carbazate ester of _{the formula H 2 NNHCO 2} R without isolating the compound (III), wherein: R represents lower (CJ-C ₄ ) alkyl and X represents an anion which in general the anion of the amide activating agent of Corresponds to level b, to obtain the alkyl [1- [ (2-phenoxyethyl) antirio] propylidene] hydrazine carboxylate (acid addition salt) of the general formula (H): NNHCO ₂ R (II) (possibly -HX) in which R and X have the meanings given immediately above. M / 25 9. Compounds of the general formula (III) (III) wherein Y is a halogen atom or an alkoxy radical having in particular 1 to 6 carbon atoms, preferably 1 to Carbon atoms and most preferably with 1 carbon atom, and X stands for an anion, e.g. from the implementation between the amide activating agent mentioned in claim 1 and the aforementioned compound (IV) results. 10. Process for the preparation of the compounds according to claim 9, characterized in that the Compound of formula (IV) (IV) M / 25 which can optionally be obtained by reacting 2-ethyl-2-oxazoline (V) obtained with phenol, with an amide activator, in particular thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or dimethyl sulfate, converts to an imidoyl halide or ester product and the resulting compound of the general Formula (III), if desired, isolated in a customary manner.