DK171451B1 - Alkyl [1 - [(2-phenoxyethyl) amine] propylidene] hydrazinecarboxylate acid addition salts and process for their preparation - Google Patents

Description

in DK 171451 B1

The present invention relates to the alkyl [1 - [(2-phenoxyethyl) amine] propylidene] hydrazine carboxylate acid addition salts thereof of formula (II) 5 m ™ C ° 2'hx (II) wherein R is (Cx-C4), and X is Cl, Br or SO4 as well as a process for their preparation.

The compounds of formula (II) can be used as intermediates in the preparation of the valuable chemical intermediate (I) 20

ISLAND

(I) used to prepare the antidepressant 2- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-ethyl -4- (2-phenoxyethyl) -2H-1,2 , 4-triazole-3 (4H) -one, also known as nefazodone.

0 -

The respective intermediate 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone of formula (I) is also known as MJ 14814 and its present synthesis described in U.S. Patent No. 4,338,317 as Example 5, is shown in Scheme 1. A total yield of 33% for Scheme 1 is predicted based on dividend calculations of the individual steps of Example 5 in the current application.

2 DK 171451 B1 SCHEME 1 O "OH + 'Mf T ^ = i O-0 ^ \ Et (1) (2) (3) 0 Step 2 i + Η2ΝΝΗ2 · Η20 i) h2nnh2 (5) 2) HC1 4 o

Step 3 Al? 0 · »H

\ <4> -HC1 (6)

Step 4a ^ 'Γο ~ · ~ "] in."

L (8) J L (7) J

'0 0 (9) H2O0OH Step 6 •' (I; MJ 14814) 3 DK 171451 B1

As shown in Scheme 1, the preparation of MJ 14814 is started with phenol and ethyl acrylate, an unpleasant high vapor pressure substance. This process has been successfully upgraded and repeatedly used to form MJ 14814 from phenol in a total yield of 25-30%.

5 MJ 14814 is converted to the antidepressant nefazodone (MJ

13754) as described in the aforementioned U.S. Patent. This conversion results in the reaction of MJ 14814 with 1- (3-chlorophenyl) -4- (3-chlorophenyl) piperazine hydrochloride (10)

Cl - / - HCl (10) 15

Preparation of MJ 14814 via Scheme 1 involves six steps and four isolated intermediates, the two of which are liquids which require purification by vacuum distillation.

In contrast, preparation of MJ 14814 via the compound of formula II, described below, comprises four steps involving only three isolated intermediates, all of which are solids, with a total yield of MJ 14814 of 40-55%. from phenol. In comparison, the known method is represented by Scheme 1, a longer approach that requires more work and yields MJ 14814 in much lower yield.

The following references relate to steps involved in the preparation of MJ 14814 via the compound of formula II.

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

2. W. Reid and A. Czack, Ann. 676, pp. 121-129 (1964). This reference describes the reaction of imidoyl ethers with ethyl carbazate to form amidrazones which then terminate after further heating to 1,2,4-triazoles as outlined in Scheme 2 below.

4 DK 171451 B1

Scheme 2 * + HjMsbcOjR · '- * »' '' SramctMt" "T ^ 5

ISLAND

R ”ethyl

However, there is no mention of the use of N-substituted imidoyl ethers which would be required to obtain a desired N-10 substituted triazolone via a compound of formula II.

3. M. Pesson, et al., Bull. Soc. Chem., Fr., pp. 1367-71 (1962).

This reference describes a very low-performance synthesis (0.3%) of a triazolone with the desired substitution pattern via the method shown below in Scheme 3.

15 Scheme 3 N-Ph Δ Θ0Η ΗΘ Ύ— Α »*>” “·” - π * * 20 Ο 0.3% yield

The authors state that imidoyl ethers of secondary amides are difficult to prepare (p. 1364, bottom, 2nd column). Pesson, et al disclose the preparation of a triazolone having the desired substitution pattern, but via a synthesis, shown as Scheme 4, which is different from the synthesis to produce MJ 14814 via the compound of formula II. The reference synthesis begins with an imidoyl ether of a primary amide to form an intermediate, carbethoxyhydrazone, which is then reacted with a primary amine.

Schedule 4 ___. NNHCO ^ Et «inn ^« i P 10 · JT 2 * ”” 2 „- * j 35 * oEt v · 00» * * 0Et Δ

R II

o 5 DK 171451 B1

Note that the carbazate displaces the imine function of Scheme 4, which represents another feature whereby this synthesis differs from the method of preparing MJ 14814 via the compound of formula II.

Pesson, et al., Also disclose that thioamides are more reactive than 5 amides, forming N-substituted amidrazones after reaction with carbazate. However, no reaction with ethyl carbazate was observed when the N-substituent is all alkyl, as required in the process of preparing MJ 14814 via the compound of formula II. Finally, Pesson, et al., Report activation of thiobenzamide with dimethyl sulfate 10 followed by reaction with carbazate to form the triazolone product. Also not mentioned herein involves the activation of alkyl-carboxylic acid ethamides, a structural prerequisite for the process of preparing MJ 14814 via the compound of formula II.

In summary, references 2 and 3 describe essentially conversions of certain amide derivatives with carbazate esters which finally yield triazolone products, but with distinct structural deviations from the process of preparing MJ 14814 via the compound of formula II.

The present application relates to an improved synthesis process 20 for the preparation of the compound of formula (II), which is characterized in that it comprises: a) reacting phenol with 2-ethyl-2-oxazoline (V) ^ Γ \ 25 Ks> ( V) to form N- (2-phenoxyethyl) propionamide (IV) (35) (b) activating the amide functional group of compound (IV) by reacting compound (IV) with an amide activating agent such as f. eg. thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene or dimethyl sulphate to form an imidoyl halide or ester intermediate of formula (III)

OuCX · 10 (III) wherein y is preferably a halogen or an alkoxy group and X is as defined above, and c) reacting the product of step b without isolating the compound (III) with a carbazate ester of formula H2NNHCO2R to give a alkyl [1 * [(2-phenoxyethyl) amine] propylidene] -hydrazinecarboxylate acid addition salt (II) [(II) wherein R is (C 1 -C 4) alkyl and X is Cl, Br or SO 2.

The useful chemical intermediate 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone can be prepared via the compound of formula II on a large scale. The process for preparing MJ 14814 via the compound of formula 30 II is based on phenol and 2-ethyl-2-oxazoline, raw materials that are cheap and readily available. The improved process for preparing MJ 14814 via the compound of Formula II offers economic benefits, both in terms of material and labor costs, due to the shorter run, involves fewer intermediate insulations and provides a greater yield of the product.

The following flow chart Scheme 5 shows the preparation of MJ 14814 from readily available starting materials via the compound of formula II.

7 DK 171451 B1

Scheme 5 o or · i (V) (V) (IV)

Anid activation

Step 2 (SOX2 * Me ^ O ^; POC13; COC12; etc.) 10 ojx: ^ feux 15 11 \ Θ in v. OH, heat Step Os.

(I; KJ 14814) 2Q 40-55% yield In Scheme 5, R is Cjj4 alkyl, X is Cl, Br or SO4, Y is Cl, Br or OR, and amide activation is the formation of a reactive imidoyl halide or a reactive ester. by treating the amide with a suitable activating reagent such as SOC12, SOBr2, POC13, dimethyl sulphate, phosgene etc.

Step 1 of the above scheme involves the reaction of phenol (1) and 2-ethyl-2-oxazoline (V) to form the intermediate compound N- (2-phenoxyethyl) propionamide (IV). The starting materials for step 1 are commercially available. Step 2, activation of the amide (IV) is carried out by treating (IV) with an amide activating reagent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, dimethyl sulfate and the like to form an imidoyl halide or ester intermediate (III). The preferred agents are phosgene or phosphorus oxychloride. The intermediate (III) is not isolated but reacted with an alkyl carbazate of the formula H2NNHCO2 R, R 'methyl is preferred, in step 35 3 to form the novel triazolone precursor (II). In step 4, the hydrazine carboxylate acid addition salt (II) of the invention is converted to its base form and is cyclized to the triazolone product (1) by heating.

8 DK 171451 B1

This improved four-step process results in the isolation of only two intermediates (IV and II) in addition to the target compound (I).

In comparison, the present process involves six steps and isolation of four intermediates, two of which are liquid and require 5 purification by vacuum distillation. The reduced processing of intermediates by the present process significantly reduces the labor cost of manufacture.

The synthesis of MJ 14814 is preferably carried out as a four-step series ranging from the simplest starting materials (phenol, 2-ethyloxazoline) to 10 MJ 14814. The process steps are as follows: (1) Addition of 2-ethyl-2-oxazoline to hot ( 150 *) phenol and maintaining heating to approx. 175 * for another 16 hours. The oil is then quenched in water to give N- (2-phenoxyethyl) propionamide (IV) for approx. 90% yield.

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

(3) Treatment of the solution of (III) with a solution of the alkyl carbazate to form [1 - [(2-phenoxyethyl) amino] propylidene] - hydrazine carboxylate, hydrochloride (II) for approx. 75% yield.

(4) The free base form of (II) which results from treatment of (II) with a basifying agent is heated in solution for several hours to form (I) for approx. 75% yield.

The process for preparing MJ 14814 via the compound of formula II is described in more detail by the following examples which are directed to preferred embodiments of the process steps described hereinafter. In the following examples to illustrate the foregoing methods, temperatures are expressed in degrees Celcius (*) as in the previous. Melting points are not corrected. Nuclear magnetic resonance spectral characteristics (NMR) refer to chemical shifts (6) expressed as parts per million (ppm) to tetramethylsilane (TMS) as a reference standard. The relative range reported for the different shifts in 1 H NMR spectral data corresponds to the number of 35 special functional type hydrogen atoms in the molecule. The nature of multiplicity shifts is referred to as broad singlet (bs), singlet (s), doublet (d), triplet (t), quartet (q) or multiplet (m). Abbreviations used are DMSO-d6 (deuterodimethylsulfoxide), CDC13 (deutero-chloroform), and are otherwise conventional. The infrared spectral descriptions (IR) include only absorption wave numbers (cm *) having a functional group identification value. The IR determinations used potassium bromide (KBr) as a diluent. The elemental analyzes are reported as weight percent.

Example 1 Methyl carbazate

An alternative term for this commercially available chemical is methylhydrazine carboxylate. Methyl carbazate can also be synthesized by adding 85% hydrazine hydrate (58.5 g, 1.00 mol) to dimethyl carbonate (90.0 g, 1.00 mol) with stirring over a period of 10 minutes. The mixture was rapidly warmed to 64e and became clear. The solution was stirred for another 15 minutes and the volatiles were evaporated in 15 vacuum at 70 °. After cooling, the residue solidified. It was collected on a filter and, after air drying, yielded 69.3 g (76.9%) of a white solid, m.p. 69.5 - 71.5 *.

N- (2-phenoxyethyl) propionamide (IV) Phenol (13.1 mol) was heated to 150 ° and stirred under N 2 while 2-ethyl-2-oxazoline (12.2 mol) was added over 1 hour. After heating for 16 hours, the oil was cooled to about 140 * and then poured into water (12 liters) with vigorous stirring, the mixture was stirred and cooled, and at about 25 * the mixture was seeded with crystalline amide product. The material solidified and the supernatant was decanted off The remaining solid was stirred with 17 liters of warm water (85 '), the mixture was cooled to 25', inoculated with the amide product and cooled. The resulting granular solid was collected on a filter, rinsed with several parts of water and added 30 to air dry to give a material yield of 92%, mp 61.5 - 64 *.

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

Phosgene (57.4 g, 0.58 mol) was added to a solution of N- (2-phenoxyoxy) propionamide (IV, 112.0 g, 0.58 mol) and imidazole (0.4 g, 0.006 mol) in 450 ml of methylene chloride over 1 hour with cooling so that the temperature did not exceed 25 *. The reaction solution was then stirred at 25 ° for an additional 2 hours. A solution of methyl carbazate (52.5 g, 10 mL, 0.58 mol) in 500 mL of methylene chloride was stirred over 25 g of a molecular sieve for 15 minutes, after which the solution was filtered. The filtrate was added under N 2 to the amide / phosgene solution over 1 h with cooling to 15-20 °. A bulky precipitate formed and the mixture was stirred at 25 ° under N 2. After stirring for 15 hours altogether, the mixture was filtered to isolate a solid. The solid was stirred in 750 ml of methylene chloride for 15 minutes, filtered again and then dried in vacuo at 65 ° for 2 hours to give 135 g (77%) of white solid, m.p. 150-154 *. Recrystallization of the product from isopropanol 10 gives analytically pure substance, m.p. 157-159 *.

Analysis

Calcd for C 13 H 19 N 3 O 3 · HCl: 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, 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); 10.90 (3, bs); 11.72 (3, bs) IR (KBr): 695, 755, 1250, 1500, 1585, 1600, 1670, 1745 .1 and 2900 cm.

By appropriate modification of the above process (A), thionyl chloride, thionyl bromide, dimethyl sulphate or other amide activating agents may be used in place of phosgene. A slightly varying method (B) can also be used.

B. Methyl [1 - [(2-phenoxyethyl] amino] propylidene hydrazine carboxylate (II

(Phosphorus oxychloride (53.0 g, 0.346 mol) was slowly added to a solution of N- (2-phenoxyethyl) propionamide (IV, 100.0 g, 0.518 mol) in 200 ml. This solution was stirred for 4 hours at which time a solution (dried over molecular sieve 4A) of methylcarbazate (46.4 g, 0.518 mol) in 600 ml of methylene chloride was added to the stirred solution in a period of one ¼ hour.

The resulting mixture was stirred and heated at gentle reflux under nitrogen for 18 hours. The mixture was then stirred with 1.0 L of ice water. The layers were separated and the aqueous layers were extracted with additional DK 171451 B1 n 200 ml methylene chloride. The aqueous layer was made basic (pH 12) with aqueous sodium hydroxide. This resulted in precipitation of the free base form of (II) which was collected by filtration, rinsed with water and air dried to give 65.8 g of product, m.p. 97-99 *.

Analysis

Calcd for C 13 H 19 N 3 O 3: C, 58.85; H, 722; N, 15.84

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

When this free base form of (II) is used for the conversion to (I), the initial basification step of Example 4 (which follows 10 below) is omitted. The base form of (II) is cyclized directly by mild reflux in xylene according to the procedure of Example 4.

Example 2

Preparation of 5-ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazole-3 (4H) -one (15) from a compound of formula II

Methyl - [1 - [(2-phenoxyethyl) aminopropylene] hydrazinecarboxylate, hydrochloride (II, 665.3 g, 2.17 mol) was stirred vigorously with 4.0 liters of methylene chloride, 2.4 liters of water and 179.4 g 50% NaOH (2.24 mol). The layers were separated and the organic layer was dried (K 2 CO 3) and concentrated in vacuo. The residue was stirred in 1.2 L of xylene at gentle reflux for 1 hour and then the solution was cooled. The solid was collected on a filter, rinsed with toluene and added to air drying. The white crystalline solid weighed 89.5 g (76.9%), m.p. 134-138 *.

Further purification can be performed as follows. A portion of (I) 25 (171.2 g, 0.73 mol) was 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 charcoal and filtered. The filtrate was stirred in an ice bath and 37% HCl (61.0 ml, 0.73 mol) was added. The solid was collected on a filter, rinsed with water and air dried to give 166.0 g (97% recovery) of a fine white crystalline product, m.p. 137.5 to 138 °.

35

Claims (4)

12 DK 171451 B1 1. Alkyl [1 - [(2-phenoxyethyl) amino] propylidene] hydrazine carboxylate acid addition salt of formula (II) niwcOjR O-o / Ν ^ ΝΗ · (II) wherein R is (C ) alkyl, and X is Cl, Br or SO 2. 2. A compound of formula (II), CHARACTERIZED in that it is methyl - [1 - [(2-phenoxyethyl) amino] propyl in den] hydrazinecarboxylate, hydrochloride. A process for preparing a compound of formula 20 (II), characterized in that it comprises: a) reacting phenol with 2-ethyl-2-oxazoline (V) (V) to give N- (2-phenoxyethyl) ) propionamide (IV) QCcS. (IV) b) activating the amide functional group of Compound (IV) by reacting Compound (IV) with an amide activating agent such as e.g. thionyl chloride, thionyl bromide, phosphorous, oxychloride, phosgene or dimethyl sulfate, to form an imidoyl halide or ester intermediate of formula (III) (III) 10 wherein y is preferably a halogen or an alkoxy group and X is as defined in claim 1, and c) reacting the product of step b without isolating the compound (III) with a carbazate ester of the formula 15 H 2 NNHCO II) K> eco 2 R 20 -hx (Π) wherein R is lower (C 1 -C 4) alkyl and X is Cl, Br or SO 2. 4. A process according to claim 3, characterized in that the compound of formula (II) prepared is: (1) methyl - (1- (2-phenoxyethyl) amino) propyl in the) hydrazinecarboxylate acid addition salt or (2) ) methyl - (1- (2-phenoxyethyl) amino) propylidene) hydrazine carboxylate, hydrochloride.