GB2185983A - Intermediates in process for production of 1,2,4-triazolones - Google Patents

Abstract

In a novel process for the preparation of 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazolone (used in the synthesis of antidepressant 1,2,4-triazolones typified by 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl- 4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one, also known as nefazodone), novel intermediate acid addition salts of formula <IMAGE> and processes for their preparation are disclosed.y

Description

1 GB 2 185 983 A 1

SPECIFICATION

Intermediates in process for production of 1,2,4-triazolones Reference is made to co-pending U.K. Patent Application No. 8430275 which discloses and claims an 5 improved, more economical process forthe synthesis of a valuable chemical intermediate (1) 0'1--1 0 - H 10 6 V M 0 15 15 used in the manufacture of the antidepressant agent 2-[3-[4-(3-chlorophenyl)-l -piperazinyl]propyl]-5-ethyl-4-(2phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one which is also known as nefazodone.

20 ci 20 N -1 25 \-/ -C5 25 nefazodone The above compound of formula I is also known as MJ 14814.

30 The improved process disclosed in the above co-pending application offers advantages in economies of 30 both material and labor costs byvirtue of being shorter in length, involving fewer intermediate isolations, and providing a higheryield of product.

Thefollowing flow chart, Scheme 5, illustratesthe preparation of MJ 14814from readily available starting materials utilizing the process of GB 8430275.

0 0 OH + 175 a N Step 1- NH (V) (IV) Amide activation Step 2 (SOX 2; Me 2 so 4; Pocl 3; cocl 2; etc.) 1.

NNHCO 2 R Y 00 H 2 NNHCO 2 R -, 0 Hx Step 3 ao,--. -kx II E) CH, heat III -i Sep t 4 (1; MJ 14814) 40-55% yield 2 GB 2 185 983 A 2 In Scheme 5, R is C1-4alkyl; X is Cl, Br, or S04; Y'sCl, Br, or OR; and amide activation is formation of a reactive imidoyl halide or ester by treatment of the am ide with a suitable activating reagent such aSSOC12, SOBr2, POCI.3, dimethyl sulfate, phosgene, etc.

Step 1 of the scheme outlined above involves the reaction of phenol (1) and 2-ethyl-2-oxazoline (V) to give the intermediate compound N-(2-phenoxyethyl)propionamide (IV). The starting materials forstep 1 are 5 commercially available. Step 2, activation of the amide (IV), is accomplished by treatment of IV with an amide-activating reagent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, dimethyl sulfate, and the like, to give an imidoyl halide or ester intermediate (111). The preferred agents are phosgene or phosphorus oxychloride. Intermediate III need not be isolated but can be allowed to reactwith 10 an alkyl carbazate of formula H2NNHCO2R, R = methyl is preferred, instep 3 to give the novel triazolone 10 precursor(H). Instep 4the hydrazinecarboxylate acid addition salt (11) is converted to its base form and cyclized to the desired triazolone product (1) by heating.

This four-step improved process involves isolation of only two intermediate products (IV and 11) in addition It tothetarget 15 The synthesis of MJ 14814 as represented in the above process is preferably carried out as a series of four 15 steps going from the simplest starting materials (phenol, 2- ethyloxazoline) to MJ 14814. The steps comprising the process are as follows:

(1) Adding 2-ethyl-2-oxazolineto hot (150') phenol and maintaining heating at about 175'for 16 additional hours. The oil is then quenched in water to give N-(2- phenoxyethyl)propionamide (IV) in 20 approximately 90% yield. 20 (2) Adding phosgene or phosphorus oxychloride to a solution of IV containing a catalytic amount of imidazole in methylene chloride to give a solution of the intermediate imidoyl chloride hydrochloride (111).

(3) Treating the solution of III with a solution of an alkyl carbazate to give alkyl [1 -[(2-phenoxyethyl)amino]propylidene]-hydrazine carboxylate hydrochloride (11) is about 75% yield.

25 (4) The free base form of 11, resulting from the treatment of 11 with a basifying agent, is heated in solution 25 for several hours to yield I in about 75%.

The present invention is directed to the intermediates of formula III and in one aspect provides an imidoyl halide or ester of formula 30 'Y 30 0 -EX 35 35 wherein Y is a halogen oralkoxy moiety and X is an anion.

In another aspect the invention provides a process forthe production of a compound of formula III wherein 40 Y is a halogen oralkoxy moiety and X is an anion comprising:

a) reacting phenol with 2-ethyl-2-oxazoline (V) 45 " 10 45 U, 50 CV) 50 to give N-(2-phenoxyethyl)propionamide (IV) 0 55 /--f 55 h"d a 0 --' 60 ( 1AV) 60 b) activating the amide functional group of compound IV by reacting compound IV with an amide-activating agent so as to produce an imidoyl halide or ester intermediate of formula III; 3 GB 2 185 983 A 3 1 0 5 0."" - HX 3 5 10 said am ide activating agent containi ng precu rsors of X and Y wherei n Y is a ha logen or a Ikoxy moiety and 10 wherein X is an anion which results from the reaction between said amide- activating agent and compound Preferably said a mide-activating agent is th ionyl ch loride, th ionyl bromide, phosphorous oxychloride, 15 phosgeneordimethyl sulphate. 15 The process involving the intermediates of this invention and their synthesis is illustrated in greater detail bythe following non-limiting examples. In examples which follow, used to illustrate thefore-going processes, temperatures are expressed, as in the foregoing in degrees centigrade('). Melting points are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics referto chemical shifts (8) 20 expressed as parts per million (ppm) versuestetramethylsilane (TMS) as reference standard. The relative 20 area reported forthe various shifts in the H NMR spectral data corresponds to the number of hydrogen atoms of a particularfunctional type in the molecule. The nature of the shifts asto multiplicity is reported as broad singlet (bs), singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m). Abbreviations employed are DMSO-d6 (deuterodimethylsulfoxide), CDC13 (deuterochloroform), and are otherwise conventional. The 25 infrared (M) spectral descriptions include only absorption wave numbers (cm-') having functional group 25 identification value. The IR determinations were employed using potassium bromide (KBr) as diluent.The elemental analyses are reported as percent byweight.

Example 1

30 Methylcarbazate 30 An alternate name for this commercially available chemical is methyl hydrazinocarboxylate. Methyl carbazate may also be synthesized by adding 85% hydrazine hydrate (58.5 9, 1.00 mole) with stirring to dimethyl carbonate (90.0 g, 1.00 mole) over a 10 min period. The mixture quickly warmed to 64'and became clear. The solution was stirred for another 15 min and the volatile materials were stripped in vacuo at70'.

35 Upon cooling, the residue solidified. It was collected on a filter and after drying in air gave 69.3 g (76.9%) of 35 white solid, m.p. 69.5-71.5'.

Example2

N-(2-Phenoxyethyl)proplonamide (N) 40 Phenol (13.1 moles) was heated to 1500 and stirred under N2 as 2-ethyl- 2-oxazoline (12.2 moles) was added 40 over 'I hr. The mixture was heated to 175 30. After heating 16hr the oil was cooled to about 1400, and then it was poured into water (12 L) 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 su pernatantwas decanted. The residual solid was stirred with 17 L of hot (85') water. The mixture was cooled to 25', seeded 45 with the amide product, and the mixtu re ref rigerated. The resulting granular solid was collected on a filter, 45 rinsed with several portions of water and left to air dry. This gave a 92% yield of material, m.p. 61.5-64'.

Example 3

A.Methyl[l-[(2-Phenoxyethyllaminolpropylidene hydrazinecarboxylate hydrochloride (11) 50 Phosgene (57.4 g, 0.58 mole) was added to a solution of W(2- phenoxyethyl)propionamide (IV, 112.0 9,0.58 50 mole) and imidazole (0.4 g, 0.006 mole) in 450 mL methylene chloride over 1 hr employing cooling so thatthe temperature did not exceed 25'. The reaction solution was then stirred at 250for an additional 2.5 hr. A solution of methyl carbazate (52.5 g, 0.58 mole) in 500 mi- methylene chloride was stirred over 25 9 of a molecular sieve for 15 m in and then the solution was filtered. The filtrate was added under N2 over a 0.5 hr 55 period to the amide/phosgene solution while employing cooling 15-200. Avoluminous precipitate formed 55 and the mixture was left to stir at 25' under N2. After stirring fora total of 16 hrs, the mixture was filtered to isolate a solid. The solid was stirred in 750 mi- methylene chloride for 15 min, refiltered, and then dried in vacuo at 65'for 2 hrs to give 135 g (77%) while solid, m.p. 150-154. Recrystallization of the productfrom isopropanol gives analytically pure material, m.p. 157-159'.

60 Anal. Caled. for C131-119N303.1---ICI:C, 51.74; H, 6.68; N, 13.92; Cl, 11.75. Found: C, 51.73; H, 6.76; N, 13.94; Cl, 60 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).

[R (KBr); 695,755,1250,1270,1500,1585,1600,1670,1745, and 2900 cm-1.

65 By appropriate modification of the above procedure (A), thionyl chloride, thionyl bromide, dimethyl sulfate 65 4 GB 2 185 983 A 4 or other amide-activating agents maybe employed in place of phosgene. A slightly different procedure (B) may also be used.

B.Methyl[l-[(2-Phenoxyethyllaminolpropylidene hydrazinecarboxylate (11 Base Form) 5 Phosphorus oxychloride (53.0 g, 0.346 mole) was slowly added to a solution of 5 W(2-phenoxyethyl)propionamide (IV, 100.0 g, 0.518 mole) in 200 m L ethylene chloride while being stirred under nitrogen. This solution was stirred for 4 h rs at which time a solution (dried over moecuiar sieve 4A) of methyl carbazate (46.4 g, 0.518 mole) in 600 mL methylene chloride was added to the stirring solution overa 0.5 hr period. The resulting mixture was stirred and heated at gentle ref lux under nitrogen for 18 hr. The m,xture was then stirred with 1.0 L ice-water. The layers were separated and the aqueous layers extracted 10 with an additional 200 mi- methylene chloride. The aqueous layer was made basic (pH 12) with aqueous sodium hydroxide. This resulted in precipitation of the free base form of H which was collected byfiltration, rinsed with water and dried in air to give 65.8 g of product, m.p.97-99'. 1; Anal. Calcd. for C13H1gl\1303: C, 58.85; H, 7.22; N, 15.84. Found: C, 59. 02; H, 7.24; N,15.92.

15 When this free base form of 11 is employed forthe conversion to], the preliminary basification step outlined 15 in Example 4 (which follows) is skipped. The base form of 11 is cyclized directly by gently refluxing in xylene according to the procedure of Example 4.

Example4

20 5-ethyl-4-(2phenoxyethyl)-2H-1,2,4triazol-3(4H)-one(l) 20 Methyl [1 -[(2-p h enoxyethyl)a m i no]pro pyl i dene]hyd razine ca rboxyl ate hyd roch i oride (11, 655.3 g, 2.17 mole) was stirred vigorously with 4.0 L methylene chloride, 2.4 L water and 179.4 g 50% NaOH (2.24 moles).

The layers were separated and the organic layer was dried (K2C03) and concentrated in vacuo. The residue was stirred in 1.2 L xylene at gentle ref luxfor 2.5 hrs and then the solution was refrigerated. The solid was 25 collected on a filter, rinsed with toluene and leftto air dry. The white crystalline solid weighed 89.5 g (76.9%), 25 m.p. 134.5-1380.

Additional purification may be accomplished inthefollowing manner.A portion of 1 (171.2 9,033 mole) was dissolved in a boiling solution of 41.0 g (0.73 mole) KOH in 3.0 L water. The solution was treated with Celite (Registered Trade Mark) filter-aid and activated charcoal andfiltered. Thefiltratewas stirred in an ice 30 bath,and 37% HCI (61.0 mL, 0.73 mole) was added. The solid was collected on afilter, rinsed with water and 30 airdriedto give 166.0 g (97% recovery) of fine white crystalline product, m.p. 137.5-138'.

Claims (3)

1. 35 1. An imidoyl halide or ester of formula 35 1 1 [a o Hx 40 iii wherein Yis a halogen or alkoxy moiety and Xis an anion.

   45
2. 2. A compound of formula Ill substantially as hereinbefore described in Example 3. 45 3. A method for the production of a compound according to claim 1 comprising:

   a) reacting phenol with 2-ethyl-2-oxazoline (V) 50 0 50 U k 55 (V) 55 to give W(2-phenoxyethyl)propionamide (IV) 0 r--.

   NH 0 -- (1,11) 5 GB 2 185 983 A 5 b) activating the amide functional group of compound IV by reacting compound IV with an amicle-activating agent so as to produce an imidoyl halide or ester intermediate of formula 111; 5 5 O 0 RX I 10 111 10 said amide activating agent containing precursors of X and Y wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide- activating agent and compound IV.

   15 4. A method as cl aimed in claim 3 wherein said am ide-activati ng agent is thionyl chloride, thionyl 15 bromide, phosphorous oxychloricle, phosgene ordimethyl sulphate.

   5. A method forthe production of a compound according to claim 4 substantially as hereinbefore described ir Example 3.

   6. A compound of formula III when produced by a method according to either or claims 3 or4.

   20 20 Amendments to the claims have been filed, and have the following effect:

   (a) Claims 1 and 3 above have been deleted or textually amended.

   M New or textually amended claims have been filed as follows: - 25 1. An imidoyl halide or ester of formula 25 F Y ao I 1, 30 - t, - P] 30 35 35 wherein Y is a halogen or alkoxy moiety and X is an anion.
3. 3. A method forthe production of a compound according to claim 1 comprising:

   a) reacting phenol with 2-ethyl-2-oxazoline (V) 40 40 45 45 to give N-(2-phenoxyethyl)propionamide (IV) 50 0 50 C 0 55 55 (INI) b) activating the amide functional group of compound IV by reacting compound IV with an amide-activating agent so asto produce an imicloyl halide or ester intermediate of formula 111; 6 GB 2 185 983 A 6 1 1 5 re,) 1 M 1 5 p L I I L 10 10 said amide activating agent containing precursors of X and Y wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide- activating agent and compound [v.

   Pdritedfor Her Majesty's Stationery Office by Croydon Printing Company (UK) Ltd,6187, D8991685.

   Published byThe Patent Office, 25Southamptor, Buildings, London WC2A l AY, from which copies maybe obtained.