DK159970B - METHOD FOR PREPARING 5-ETHYL-4- (2-PHENOXYETHYL) -2H-1,2,4-TRIAZOL-3 (4H) -ON - Google Patents

Description

in

DK 1 59970 B

The present invention relates to an improved, more economical method for the synthesis of the valuable chemical intermediate (I) 5 / Xr

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(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 and having the following formula o The process is characterized by the characterizing part of claim 1.

The respective intermediate 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone of formula (I) is also known under the designation MJ 14814, and the manner in which it is currently synthesized is described in U.S. Pat. .

No. 4,338,317 as Example 5 and illustrated in Scheme 1 below. An overall yield of 33% according to Scheme 1 can be determined from yield calculations of the individual steps of Example 5 of the US patent.

Scheme 1

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2 O - «* Μ" - 0- ~ Λ "m Oco®c (1) (2) 2 5 (3)

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In Step 9 0H + H Nnh H 0 222 D H, NNH0 (5) 2 2 2) HCl

Step 3 A1203 * 0 9 KHNH, (4), BC1 (o)

Step 4a »= Γο * ~ Η: ττ [o ~ \ 'L (8) J 3

(7) J

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0-020 (9) H2 ° Θ0Η Step 6 i '(I; MJ 14814)

3 DK 159970 B

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 prepare MJ 14814 from phenol in a total yield of 25-5 30%.

MJ 14814 is converted to the antidepressant nefazodone (MJ 13754) as described in the above U.S. application. This conversion results in reaction of MJ 14814 with 1- (3-chlorophenyl) -4- (3-chlorophenyl) piperazine, hydrochloride (10)

Preparation of MJ 14814 via Scheme 1 involves six steps and four 20 isolated intermediates, two of which are liquids which require purification by vacuum distillation.

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

The following references relate to steps included in the present process.

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 cyclize after further heating to 1,2,4-triazoles as outlined in Scheme 2 below.

Scheme 2 4 5 A Λ V-i R ^ OR '+ H.NNHCO R "-> R ^ NHNHCO R" ~> |

Z 2 HN. NH

ν 'R "- ethyl 0 10

However, there is no mention of the use of N-substituted imidoyl ethers which would be necessary to obtain a desired N-15 substituted triazolone.

3. M. Pesson et al., Bull. Soc. Chem., Fr., pp. 1367-71 (1962). This reference discloses a very low yield (0.3%) of a triazolone having the desired substitution pattern via the method shown below in Scheme 3.

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Scheme 3 l) '? H 4 ®0H H®' 1-! J

25 A + H-NHCO, Et -> -> - »I I

^ OMe 2 2 A / N ™

Ph V O

Yield of 0.3%

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 of the present process. The reference synthesis is based on an imidyl ether of a primary amide to form an intermediate, carbethoxyhydrazone, which is then reacted with a primary amine.

DK 159970B

5

Schedule 4 r

SNHCO £ t pVini - M

ψ 10 · X 2 R1% f = 1

5 / V, HCl + H KlfflCO Et R O «4 / R. M

R OEt R *

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Note that the carbazate displaces the imine function of Scheme 4, which represents another feature whereby this synthesis differs from the method of the present invention.

Pesson et al. also describe that thioamides are more reactive than amides, forming N-substituted amidrazones after reaction with carbazate. However, no reaction with ethyl carbazate was observed when the N-substituent is alkyl, as required by the present process. Finally, Pesson et al. activation of thiobenzamide with dimethyl sul fat followed by reaction with carbazate to form the triazolone product. Here, too, there is not mentioned anything involving the activation of all alkyl carboxyl acid ethamides, a structural assumption 20 of the present process.

In summary, references 2 and 3 describe essentially reactions of certain amide derivatives with carbazate esters which finally yield triazolone products but with distinct structural deviations from the product of the present process.

The present application relates to an improved synthetic process which can be adapted to produce the useful chemical intermediate 5-ethyl-4- (2-phenoxyethyl) -1,2,4-triazolone on a large scale. The present process is based on phenol and 2-ethyl-2-oxazoline, raw materials that are cheap and readily available. The improved method of the invention 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 diagram, Scheme 5, shows the preparation of MJ 14814 from readily available starting materials using the process of the invention.

Scheme 5

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6 or sh * OJ3 5 (i) (V) (IV)

Amide activation

Step 2 (SOXjj Ke2SO £; POC13; COC12; etc.) 10 i 0 / ^ ™ c ° 2r Γ Γ L HgNWHCO ^ R r- ^ | r · ΗΧ <Step 3 15 11 \ Θ ni

X. OH, heat Step iV

7n (I; KJ 14814) 40-55% yield In Scheme 5, R is Cj_4 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 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 intermediate compound compound sen- 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 sulphate 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 H 2 NNHCO 2 R, R = methyl is preferred, in step 3 to form the 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 triazolone product (1) by heating.

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This improved four-step process involves isolating 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 as shown by the improved process is preferably carried out as a four-step series starting from the simplest starting materials (phenol, 2-ethyloxazoline) to MJ 14814. The process steps are as follows: (1) 2-ethyl-2-oxazoline for 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 according to (III) with a solution of the alkyl carbazate to form [1 - [(2-phenoxyethyl) amino] propylidene] hydrozine carboxylate, hydrochloride (II) for approx. 75% yield.

(4) The free base form of (II), which is obtained by treatment of (II) with an all potassium agent, is heated in solution for several hours to form (I) for approx. 75% yield.

The process of the invention is described in more detail in the following examples. In these, as in the previous, temperatures are expressed in degrees Celcius (e). Melting points are uncorrected. Nuclear Magnetic Resonance Spectral Characteristics (NMR) refers to chemical shifts (6) expressed as parts per million (ppm) relative to tetramethylsilane (TMS) as a reference standard. The relative area reported for the different shifts in H NMR spectral data corresponds to the number of hydrogen atoms of particular functional type in the molecule. The nature of shifts in terms of multiplicity is referred to as broad singlet (bs), singlet (s), 35 doublet (d), triplet (t), quartet (q) or multiplet (m). Abbreviations used are DMSO-d6 (deuterodimethyl sul foxide), CDCl3 (deuterochloroform), and are otherwise conventional. The infrared spectral data (IR) includes only absorption wavelengths (cm ") having identification value

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8 for the functional group. 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 was also synthesized by adding 85% hydrazine hydrate (58.5 g, 1.00 mole) to dimethyl carbonate (90.0 g, 1.00 mole) with stirring over a period of 10 minutes. The mixture was rapidly heated to 64 ° and became clear. The solution was stirred for another 15 minutes and the volatiles were evaporated in vacuo 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 -15 71.5 °.

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

Phenol (13.1 mol) was heated to 150 ° and stirred under N 2, while 20 2-ethyl-2-oxazoline (12.2 mol) was added over 1 hour. The mixture was heated to 175 ± 3e. After heating for 16 hours, the oil was cooled to ca. 140 ° and then poured into water (12 liters) with vigorous stirring. The mixture was stirred and cooled, and at ca. At 25 °, the mixture was seeded with crystalline amide product. The material solidified and the supernatant was removed. The remaining solid was stirred with 17 liters of warm water (85 °). The mixture was cooled to 25 °, seeded with the amide product and the mixture was cooled. The resulting granular solid was collected on a filter, rinsed with several parts of water and added to air drying.

This yielded a material yield of 92%, m.p. 61.5 - 64 °.

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Example 3 A. Methyl-1-Γ (2-phenoxyethylaminaminopropyl idenhydrazine carboxylate hydrochloride (II) 35

Phosgene (57.4 g, 0.58 mol) was 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 over 1 hour while cooling, so that tem

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The temperature did not exceed 25 °. The reaction solution was then stirred at 25 ° for an additional 2 1/2 hours. A solution of methyl carbazate (52.5 g, 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 5 N 2 to the amide / phosgene solution over 1/2 hour with cooling to 15-20 *. A bulky precipitate formed and the mixture was stirred at 25 ° under N 2. After stirring for a total of 16 hours, 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 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, 1745-125 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 30 (B) may also be used.

B. Methyl fl-r (2-phenox, yethyllaminolpropylidene hydrazine carboxylate (II base form)) 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 of methylene chloride while stirring under nitrogen This solution was stirred for 4 hours at which time a solution (dried over molecular sieve)

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4A) of methylcarbazate (46.4 g, 0.518 mol) in 600 ml of methylene chloride was added to the stirred solution for a period of 1/2 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 extracted with an additional 200 ml of 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 °.

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Analysis.

Calcd for C 13 H 19 N 3 O 3: C, 58.85; H, 7.22; 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 (as follows) is omitted. The base form of (II) is cyclized directly by mild reflux 1 xylene according to the procedure of Example 4.

Example 4 5-Ethyl-4- (2-phenoxyethyl) -2H-1,2,4-triazole-3 (4H) -one (I)

Methyl - [1 - [(2-phenoxyethyl) amino] propyl in the] 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 of 50% NaOH (2.24 mol). The layers were separated and the organic layer dried (K 2 CO 3) and concentrated in vacuo. The residue was stirred in 1.2 L of xylene at gentle reflux for 2 1/2 hours 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) (171.2 g, 0.73 mol) was dissolved in a boiling solution of 41.0 g (0.73 mol) Κ0Η 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 °.

Claims (3)

5 DK 1 b9 9 7 O B A process for the preparation of 5-ethyl-4- (2-phenoxyethyl) ~ 2H-1,2,4-triazol-3 (4H) -one (I) 10 '> 0 characterized in that it sequentially comprises the following: Step: a) Reaction of phenol with 2-ethyl-2-oxazoline (V) 15 Γ \ (V) 20 to give N- (2-phenoxyethyl) propionamide (IV), Qu3. (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, thi onyl bromide, phosphorus oxychloride, phosgene or dimethyl sulphate to form an imidoyl halide or ester intermediate of formula (III) ~ QJX ·. III DK 159970 B wherein y is preferably a halogen or an alkoxy group and X is an anion derived from the reaction between the amide activating agent and compound (IV), c) reacting the product of step b) without isolating the compound (III) ) with a carbazate ester of the formula H2NNHCO2R to form an alkyl (1- [(2-phenoxyethyl) amine] propylidene] -hydrazinecarboxylate acid addition salt (II) 15 (R) lower (C1- C4) alkyl, and X is an anion usually similar to the anion of the amide activating agent used in step b), and d) converting compound (II) to compound (I) by appropriate thermal treatment of compound (II) at its free base form so that compound (I) is formed. 2. A process according to claim 1, characterized in that the amide activating agent in step b is phosgene or phosphorus oxychloride. 30 3. A process as claimed in claim 1, characterized in that the thermal treatment of step d) includes refluxing the free base of compound (II) in a suitable inert organic solvent. 35