CA1213283A - Process for production of encainide - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

An improved process for the preparation of 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide has been developed. This compound is also known as encainide. The process comprises essentially three steps starting with methyl anthranilate and 2-picoline and features a novel low-pressure hydrogenation sequence.

Description

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This invention describes an improved, more economical process for synthesis of encainide (I) .

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which is suitable for large scale manufacture. Encainide, chemically, 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]
j benzanilide, is a member of a series of antiarrhythmic it 2-phenethylpiperidines bearing aside su~stituents in the 1 ortho-position of the phenol ring. Encainide hydra-¦ 15 chloride is also referred to in the literature as MY 9067-1 SUSAN and the US Dictionary of Drug Names, Jo 1980, p. 122, United states Pharmacopeal Convention, Inc., ¦ 12601 Twin brook Parkway, Rockville, My., 20852, Library of Congress Catalog Card No. 72-88571) Currently, encainide is undergoing clinical evaluation as an effect live antiarrhythmic agent.
Previous synthesis of encainide and closely no-fated compounds is described in the following references.

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Dexter, SO et at., J. Med. Chum., 16, 1015-1020 (1973).
So Dexter and JO Manuel, USE Patent No.
3,931,195 patented Jan. 6, 1967; US. Patent No. 4,000/143 patented Dec. 28, 1978; US.
Patent No. 4,064,254 patented Dec. 20, 1977.
Byrne, JOE., et at., J. Pharmacolo~ and Experimental Therapeutics, 200, 147-154 (1977).
The process, as disclosed in the above cited references, which has been used for preparation of encainide is shown in Scheme 1.
Scheme 1 Step 1 2 (1) (2) (3) Step 2 X21Pd 20~H--~3 3 4 SHOP
( 3 2 4 CH3O~COGl ~H42~

(5) Step 4 UP
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(I) .

: ~3L3~3 i Thy first step of the process outlined in Scheme 1 involves starting with ortho-nitrobenzaldehyde (1), a i' relatively expensive material, and one objective of the instant invention was to devise a process starting with ,, 5 a more readily available, less expensive, starting :
,¦ material. Work up of the reaction mixture of step 3 of "¦~ Scheme 1 gives a red oil which is dissolved in asset-,.~
nitrite and treated with dimethylsulfate tub), a toxic alkylating agent, yielding 2 [2-[2-(4-methoxybenzamido) phenyl~ethyl]-l-methylpyridinium methyl sulfate I Step 4 is the hydrogenation of an alcoholic solution of I
using a platinum catalyst.
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The prior ax method represented by Scheme 1 is thus a multiple step process using expensive and hazer 1 15 duos raw materials. In contrast, the process of the Jo instant invention uses a less expensive commercially ¦ available starting material; requires less labor; avoids toxic alkylating agents; and, in total, provides high ¦ quality encainide at lower cost.
¦ 20 The following references relate to component steps of the instant process described herein.
1. H. Stephen and G. Wedge! J. Chum. So., 4420 (owe This reference describes methyl N-~-anisoyl anthrax ; Pilate, an intermediate produced in the instant process.
Jo pa. JO Wolfe, DYE. Port lock and DO Furbish, Journal of Organic Chemistry, 39, 2006-2010 (1974).
2b. R. Levine and S. Reynolds, J. Organic Chemistry, 25, 530-537 (1960).
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.' - ~2~L3;;~133 2c. N. Goldberg and R. Levine, Journal American Chemical , 74, 5217-5219 (1952).
Ed. N. Goldberg, L. Barley and R. Levine, Journal American Chemical Soviet 73 4301-4303 (1951~.
Y , These references describe the acylation of mutilated methyl heteroaromatics with non enolizable esters; address sing the scope, mechanism, and application of the react lion. The acylation of mutilated 2-picoline in the ; instant process is one specific application of this reacting type.
This invention relates to an improved synthetic process which can be adapted for large-scale preparation of the antiarrhythmic agent encainide, chemically, 4-` methoxy-2'-~2-(1-methyl-2-piperidyl)ethyl]benzaniltide.
The instant process, which starts from methyl anthrani-late, an inexpensive chemical of commerce features a novel low-pressure hydrogenation sequence which converts a readily prepared precursor directly to encainide. The subject process comprises essentially three steps and offers advantages in economies of starting raw material and labor costs as well as increased suitability for use with standard larger-scale chemical process equipment.
Thus in certain aspects the present specification discloses a process for preparing 4-methoxy-2'-[2-(1-methyl-2-piper~dyl)ethyl]benzanilide (I), which comprises:

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', 5 a) reacting methyl N-_ anisoylanthranilate (III) I

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(III) (II) ; with 2-picolyllithium to give 2-(2~pyridylacetyl)-p-anisanilide (II);
j 15 b) forming an acid addition salt of IT and reacting ; said salt with hydrogen in the presence of platinum and palladium catalysts and excess formaldehyde.
Thus the present invention provide a process for preparing 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-benzanilide II), which comprises: a forming an acid addition salt of 2~(2-pyridylacetyl)-~-anisanilide (II) and b) reacting said salt with hydrogen in the presence of platinum catalyst and then palladium catalyst, and then excess formaldehyde.
In another aspect the present invention provides a process for preparing 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide (I) which comprises: a) reacting methyl N-~-anisoylanthranilate (III) with .

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2-picolyllithium to give 2-(2-pyridylacetyl)-p-anisanilide (II); b) forming an acid addition salt of (II) and no-acting said salt with hydrogen in the presence of platinum and palladium catalysts and excess formaldehyde.
The present invention also provides a process for preparing encainide by:
a) hydrogenating an acid addition salt of 2-t2-pyridylacetyl)-~- anisanilide in glacial acetic acid in Jo the presence of a platinum catalyst until hydrogen 1 10 uptake reaches 3 equivalents;
¦ b) replacing the platinum catalyst with palladium-on-carbon catalyst and continuing hydrogenation until two more equivalents of hydrogen are absorbed; and c) adding excess ~ormalin (e.g. 37%) and continuing 15 hydrogenation until hydrogen absorption ceases.
The formaldehyde or formal in will normally be in I, the form of 37% formal in.
In one aspect the invention provides a process for preparing the compound 2-(2-pyridylacetyl~-p-anisanilide c 20 (II) ; 25 so I
SHEA
30 (I) which comprises reactions methyl N-_-anisoylanthranilate (III) Jo .
lo Jo 35 'or 'I:

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; OUCH
NH

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with 2-picolyllithium, as well as the compound (II) when prepared by that process.
The following flow chart, scheme 2, illustrates the preparation of encainide from readily available starting materials utilizing the instant process. Step

3 depicts the novel hydrogenation sequence.
- Scheme 2 ' 15 CDCL OUCH

OUCH H2~'CH2C12 ) OUCH
(III) 2-pic~line n-LuLi i Step 2 :`
:
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S t e p 3 5 1) PtlH
2) Pd/H2 0 I
Jo 3) Pd/H2, SHEA OUCH
(II) Jo 10 Step 1 of the scheme outlined above involves the ; reaction of methyl anthranilate (V) and ~-anisoyl chloride (IV) to give the intermediate compound methyl N-p-anisoyl anthranilate (III). The starting materials for Step 1 are commercially available. Step 2 is accomplished by treating (III) with 2-picolyl lithium (prepared from 2-picoline, diisopropylamine, and n-butyl lithium) thereby yielding 2-(2-pyridyl acetyl)-~-anisanilide (II).
A conversion of the intermediate compound (II) to encainide (I) via Step 3 represents a novel hydrogenation sequence allowing the direct reduction of IT to (I) without isolating any intermediate. This sequence con-sits of stirring the hydrochloride salt of IT with Tao under Ho in glacial acetic acid at about room temperature until at least three equivalents of Ho have been absorbed. The platinum catalyst is removed and replaced with added dry Pd/C catalyst and the resultant , mixture stirred under Ho with heating until two add-Jo tonal equivalents of Ho have been absorbed. The mixture is then cooled to approximately room temperature, excess 37~ formal in is added and the mixture is stirred until all Ho absorption stops. Work up of the reaction mixture allows direct isolation of encainide hydrochloride.
This hydrogenation sequence makes operable the instant r`` process which produces encainide in good yield using readily available inexpensive starting materials.
Additionally, this process is well suited for scaling Jo I:`

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up Jo large size chemical process equipment. The lesser ; requirement for handling of intermediates of the instant process compared to the older process reduces labor costs.
¦ 5 The entire synthesis of encainide as representedin the subject process is preferably carried out as a }I series of three steps going from the simplest startingmaterials (methyl anthranilate, p anisoyl chloride, and 2-picoline) to encainide hydrochloride. The steps come 1 10 prosing the process are as follows:
I` (1) adding pencil chloride to a stirred chilled solution of methyl anthranilate and 50~ sodium ¦ hydroxide in ethylene chloride-water. The stirred reaction mixture is allowed to warm to room temperature to give methyl N-~-anisoyl anthranilate (III) in approximately 95% yield.
Jo (2) adding (III) to a stirred cold solution of 2-i` picolyl lithium (preformed from n-butyl lithium, diisopropylamine, and 2-picoline) in a reaction ' 20 inert solvent such as tetrahydrofuran. The stirred reaction mixture is allowed to warm Jo ! room temperature to give 2-(2-pyridylacetyl)-p-¦ anisanilide (II).
j (3) hydrogenating (II) in glacial acetic acid in the presence of a platinum catalyst, e.g. Tao or carbon-support Pi, until hydrogen uptake reaches three equivalents, replacing the Pi catalyst with palladium~on-carbon catalyst and continuing I hydrogenation until two more equivalents of hydrogen are absorbed; and then adding excess 37% formal in to the reaction mixture and continue in hydrogenation until all hydrogen absorption ceases. The catalyst is removed and the product (I) is isolated directly in approximately 75 I` 35 yield.

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Description of Specific Embodiments The process of this invention is illustrated in greater detail by the following examples directed to preferred embodiments of the hereinabove described process steps. These examples, however, should not be construed as limiting the scope of the present invention on any way.

Methyl N-p-Anisoylanthranilate (III~
A solution of 529.8 g (3.505 mole) methyl anthrax Pilate and 294.4 g 50 weight percent Noah (3.68 mole) in 3.6 L SCHICK and 1.8 L HO was stirred in an ice-bath as 627.8 g (3.680 mole) pencil chloride was added at such rate that the temperature did not exceed 10C (time required was 1.25 ho). The mixture was allowed to warm to 23C. Acetic acid (50 my) was added to adjust the pi to 5. The layers were separated and the organic layer was washed with 10~ aqueous Nikko (1 x 0.8 L) and brine (1 x 0.8 L). The solvent was removed in vacua.
The residual white solid was recrystallized from 7.0 L
boiling methanol. The product (III) was dried in vacua at 70C for 24 ho to yield 959.7 g (96.0~) white crystalline solid, mop. 122.5-124.5C~

2-(2~Pyridylacetyl)-p-anisanilide (II) A dry, nitrogen purged flask was charged with 1,875 my 1~6 N (3.0 mole) n-butyl lithium in hexane.
The solution was stirred under nitrogen and chilled to -45 to -40C, and 1.5 L THY (dried over molecular sieve 30 4 A) was added slowly. Diisopropylamine (303.5 g; 3.0 mole) was added at such a rate that the temperature did not exceed -30C. Then 307.3 g (3.3 mole) 2-picoline was added with stirring, keeping the temperature below -30C. The cooling was interrupted, and the mixture was slowly warmed to 10C by which time the conversion ~L3~l~3 ' to anion was complete and all the 2-picolyl lithium had redissolved. The solution was retooled to -45 to -40C
(the orange solid reprecipitated), and a solution of 285.3 g (1.0 mole) methyl N-p-anisoylanthranilate (III) I, 5 in 1.9 L dry THY was added at a rate so the temperature did not exceed -kiwi After the addition, the mixture was slowly warmed to 25C. The solution was adjusted to pi 6 with 500 my acetic acid; 5.0 L HO was added with stirring. Then the organic solvents were distilled in vacua and the residual yellow semi-solid product was extracted with SCHICK (1 x 2.5 L). The extract was j washed with HO (1 x 1.0 L) and stripped to dryness in vacua. The residue was dissolved in 6.7 L boiling is-propanol. the solution was chilled with stirring to 5 5C, and the resulting yellow solid was collected on a filter, rinsed with isopropanol and dried in vacua at 80C for six hours. The filtrate was concentrated and i.` chilled to yield a second crop of product. Both crops of intensely yellow material exhibited single spots in the TLC ~7.5 cm silica gel with indicator, 9 SCHICK
¦ methanol, W). The total yield was 306.7 g (88.5%) of I material, mop. 145-148.5C.
Jo , I; EXAMPLE 3 ¦ Large Scale Preparation of (II) Charge a dry, nitrogen purged, 100 gallon stain-less steel reactor with tetrahydrofuran (47 kg). Cool the HO to 5C or less. Slowly add 15% n-butyl lithium in hexane (37 kg x 0.152 = 5.62 kg of n bottle lithium;
I`. 87.6 mole) to the THY at a rate that will keep the reaction temperature below 5C. Slowly add diisopropyl-amine (8.9 kg; 37.9 mole) to the mixture at a rate that will keep the reaction temperature below 5. Slowly ¦ add 2-picoline (8.3 kg; 89.1 mole) to the reaction soul-lion at a rate that maintains the reaction tempera-Jo 35 lure at less than 5C. In a separate reactor, dissolve Jo .

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I, ~L3Z83 the N-p-anisoyl anthranilate (7.7 kg; 27 mole) in warm (approximately 30C) THY (47 kg). Slowly add this solution to the 2-picolyl lithium mixture at a raze that will keep the reaction temperature below 10C. After the addition is completed, the mixture is warmed to approximately 20C and stirred for 15 minutes. Charge a 500 gal. glass-lined reactor with HO (135 kg) and acetic acid (13.5 go 224.6 mole). Cool the mixture to about 0C and add the THY solution to this chilled mixture.
The HO layer (bottom) is separated and washed with ethylene chloride (2 x 58 kg). The organic layers are combined and concentrated in vacua. Isopropanol (143 kg) -is added, and the mixture is heated to reflex. The mixture is concentrated in vacua to one-half volume and cooled to about 0C. The solid is collected and washed with isopropanol (2 x 6 kg). The solid is dried at about 40C under vacuum to yield 8.25 kg (89%) of product (II).

2-(2-Pyridylacetyl)-~-anisanilide hydrochloride (II Hydrochloride) 2-(2-Pyridylace~yl)-~-anisanilide (II) (25.0 g, 0.0722 mole) was dissolved with gentle warming in 500 ml THY. The bright yellow solution was chilled in an ice bath, and 6.5 ml (0.078 mole) 12 N Hal was added. The yellow color disappeared and a white precipitate formed immediately. The solid was collected on a filter; rinsed with THY and air-dried to give 27.4 g white solid (99.3%), mop. 190.5-191.5 (doe.).

4-Methoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide (I), Encainide A mixture of 53.5 ~0.1397 mole) 2-(2-pyridylacetyl)-p-anisanilide hydrochloride, 1.0 g platinum catalyst (2.5-5~ Pt/C or Tao) and 1.0 L glacial acetic acid was stirred vigorously under a 5-1 tight positive pressure of ~2~3~33 Ho at 23-25C for 20 ho, by which time 0.43 mole (3.08 equivalents) of Ho had been absorbed. The catalyst was removed by filtration through a elite bed. The filtrate was returned to the flask, and 10.0 g 10% Pd/C
was added under nitrogen. The mixture was stirred vigorously under Ho as it was heaved to 60 + 3C. After an additional 6.5 ho the total Ho uptake equaled 0.71 mole (5.08 equivalents, 101.6% of theory). The mixture was cooled to 25C, and 22.7 g formal in (37 weight percent formaldehyde, 8.4 g, 0.28 mole) was injected into the reaction mixture. The mixture was stirred vigorously under Ho at 23 25C for 20 ho; during that time 0.1452 mole (1.04 equivalents) Ho was absorbed. The catalyst was removed by filtration, and the filtrate concentrated in vacua to a thick oil. Twice the oil was mixed with 200 my isopropanol and stripped in awoke at 90C to a thick oil. The oil was dissolved in 200 my boiling is-propanol. The solution was stirred, seeded with (I), and chilled to 10C for 1 hr. The solid was collected on a litter, rinsed with cold isopropanol (2 x 2.0 I
to give 36.6 g (67.4%) product, mop. 181.5-184.5C.
Additiorlal product was obtained from isopropanol filtrate to give a total yield of 76.1~ encainide.

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Claims (2)

1. A process for preparing the compound 2-(2-pyridyl-acetyl)-p-anisanilide (II), (II) which comprises reacting methy N-p-anisoylanthranilate (III) (III) with 2-picolyllithium.

2. The compound 2-(2-pyridylacetyl)-p-anisanilide (II) whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.