US3856795A - Process for preparation of secondary amines from tertiary amines - Google Patents

Process for preparation of secondary amines from tertiary amines Download PDF

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US3856795A
US3856795A US24743872A US3856795A US 3856795 A US3856795 A US 3856795A US 24743872 A US24743872 A US 24743872A US 3856795 A US3856795 A US 3856795A
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023Preparation; Separation; Stabilisation; Use of additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/64Preparation of compounds containing amino groups bound to a carbon skeleton by disproportionation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C07D215/60N-oxides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22Bridged ring systems
    • C07D221/26Benzomorphans
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D455/00Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

A process of converting tertiary amines to secondary amines is described comprising reacting the tertiary amine with a peracid to form the N-oxide which is converted to the secondary amine in the presence of an alkali metal and liquid ammonia.

Description

ilnited States Patent [191 [111 3,856,795 Yardley Dec. 24, 1974 PROCESS FOR PREPARATION OF [56] References Cited SECONDARY AMINES FROM TERTIARY OTHER PUBLICATIONS 1 AMINES Smith, Open Chain Nitrogen Compounds, Vol. 2, (W. [7 Inventor: J P- ard y, K ng of Prus a, A. Benjamin, Inc, New York, 1966), pages 15, 23-24,

Pa. 27, QD412N156. [73] Assignee: American Hom P du t Herbs! et al., J. Med. Chem, Vol, 9, pages 864-868 Corporation, New York, NY. (1969) R515- [22] Filed: 1972 Primary ExaminerAlton D. Rollins [21] App]. No.: 247,438

[57] ABSTRACT [52] US. CL. 260/283 SY, 260/239 B, 260/239 BB, A process of converting tertiary amines to secondary 260/247, 260/268 SY, 260/283 SY, 260/286 amines is described comprising reacting the tertiary R, 260/288 R, 260/288 E, 260/293.51, amine with a peracid to form the N-oxide which is 260/293.53, 260/293.54, 260/326.5 B, converted to the secondary amine in the presence of g 1 260/326.8, 260/326.81 an alkali metal and liquid ammonia. [51] lint. Cl...... C07b 1/00, 'C07b 3/00, C07d 41/08 [58] Field of Search.... 260/239 BB, 239 BE, 239 B,

260/286 R, 288 R, 288 E, 340.5, 326.5 B, 326.8, 326.81, 287 E, 283 SY, 247, 293.51, 293.53, 293.54, 293.62, 583 R, 583 D, 583

H, 563 R, 563 C, 584 R, 584 C, 570.8 R, 570.9, 574, 576, 577, 268 SY, 618 C 10 Claims, N0 Drawings PROCESS FOR PREPARATION OF SECONDARY AMINES FROM TERTIARY AMINES This invention relates to a novel process for producing secondary amines from tertiary amines.

One aspect of the present invention relates to a novel process for the protection and preparation of secondary amines from tertiary amines through the preparation of an intermediate N-oxide which is converted to the secondary amine.

A further aspect of the present invention is to convert tertiary amines wherein the nitrogen is substituted with a benzyl, allyl or propargyl group to the corresponding secondary amine by the cleavage of such group.

Yet another aspect of the present invention relates to an improved process for scission of a benzylic type bridgehead carbon-nitrogen bond in a ring system to convert the tertiary nitrogen to a secondary amine.

An additional aspect of the present invention relates to converting compounds containing ring systems, such as appropriate benzquinolizines (including emetines), benzindolizines, indolquinolizines and indolindolizines to secondary amines at the carbon-nitrogen bridgehead, in yields higher than heretofore obtainable with prior art processes.

These and other aspects of the present invention will be apparent from the following description.

In its broadest aspect, the process of the present invention comprises reacting a tertiary amine with an oxidizing agent such as a peracid to form the N-oxide of the selected tertiary amine and then reacting the N- oxide with an alkali metal in the presence of liquid ammonia to form the secondary amine.

The tertiary amines that are particularly useful in the process of the present invention are those having either (a) a substituent linked directly to the N-atom selected from the class consisting of allyl, dimetyl allyl, propargyl, benzyl or substituted benzyl or (b) a benzylic type bridgehead carbon-nitrogen structure. The preferred secondary amines obtained by the process of the present invention have the following structural formula:

wherein R and R are selected from the class consisting of an aliphatic radical and an alicyclic radical, which radicals are not subject to cleavage from the nitrogen to which it is linked under the process conditions of the present invention and which radicals do not undergo any change in chemical structure under the process conditions for converting the tertiary amine to a secondary amine and/or obtaining a substituted aralkyl compound; R plus R may be joined to form with the N atom a non-aromatic type heterocyclic moiety having up to nine carbom atoms in the ring which may optionally include one additional hetero atom in the ring selected from the class consisting of oxygen and nitrogen. The hetero ring is either saturated or it may contain a non-allylic double bond; n is a whole number which is l or 2; A represents a fused benzene nucleus or fused indole nucleus attached through its 2-3 position to the nitrogen containing ring; X represents one or more substitutents selected from the group consisting of hydrogen, (lower)alkyl, lower alkoxy, methylene radical are piperidino, pyrrolidino, piperazino, morpholino, hexamethylenimino, decahydroquinoline, benzazocine, 2,3,6,7-tetrahydro-lH-azepine, etc. lllustrative of aliphatic radicals defined by R and R are straight or branch chain alkyl groups havingl to 12 carbon atoms, an non-allylic alkenyl group having 4 to 12 carbon atoms (e.g. S-pentenyl) or a non-allylic, nonconjugated alkadienyl group having 6 to 12 carbon atoms (e.g. 3,6-decadienyl). lllustrative of alicyclic radicals are cycloalkyl groups having four through ten ring carbon atoms (e.g. cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl), non-allylic cycloalkenyl groups having seven through ten ring carbon atoms (e.g. 4- cycloheptenyl), an aryl radical having from six to ten ring carbon atoms (e.g. phenyl, naphthyl), an aryl(lower)alkyl radical (e.g. ,B-phenylethyl, a-phenylpropyl). The foregoing radicals may contain one or more substituents such as hydroxy, (lower)alkoxy.

The process of the present invention is carried out by treating compound [II with a peracid at a temperature between +32 and 40C. to produce the corresponding N-oxide which is then treated with an alkali metal in liquid ammonialto produce the secondary amine as shown in the following equations:

wherein R is selected from the group consisting of allyl, dimethyl allyl, propargyl and unsubstituted or substituted benzyl. The treatment of Illa is preferably carried out in the presence of a proton donor. The formation ofl is via N-OH intermediate. In the absence of a proton donor (i.e. an alcohol) the reaction of Illa with the alkali metal in liquid ammonia leads to the formation of a mixture of Illb and I.

In the same manner the secondary amines defined by formula II are prepared by starting with a bridgehead nitrogen compound shown in the following formula:

(2 llquldmnmoniii l (1 alkali metal Formula 11 (T EXAMPLE 1 1,3,4,6,7,11b-Hexahydro-9,l0-Dimethoxy-2H- Benzo[a]Quinalizine -Oxide Hydrochloride The compound 1,3,4,6,7,1 1b-hexahydro-9,l0- dimethoxy-2H-benzo[alquinolizine (R. Child and F. Lee Pyman, JCS 36 [1931]) (5 g. 2.07 X moles) in MeOH (40 ml) is treated, dropwise, at l0C. with ethereal monoperphthalic acid solution (38 ml., 0.65 molar, 2.47 X 10 moles) and the resultant solution is stored at 0C. overnight. Excess 10% NaOH solution is added which results in formation of two layers. The upper ethereal layer is washed with water and discarded. The aqueous layer is extracted with CHCl three times. The extracts are washed with brine, dried K CO and stripped. The residue, a pale green oil is treated in tetrahydrofuran with a slight excess of isopropanolic hydrogen chloride to give a crystalline precipitate of the product. Recrystallization from chloroform-acetone provides 4.5 g. of the titled product, m.p. 205-212C. decomposition.

Analysis: Calculated for C H NO HCl: C, 60.09;

H, 7.40;N, 4.67; Cl, 11.83 Found: C, 59.84; H, 7.26; N, 4.65; Cl, 11.82

EXAMPLE 2 l ,2,3,5,6,10b-Hexahydro-8,9-Dimethoxypyrrolo[2,la] lsoquinoline-4-Oxide, Hydrochloride Using the method of Example 1, l,2,3,5,6,10bhexahydro-8,9-dimethoxypyrrolol2,1-a]isoquinoline [R. Child and F. Lee Pyman, JCS 36 (1931)] is converted to the title compound, m.p. l88.5-192C. decomposition.

Analysis: Calculated for C H NO HCl'. C, 58.84;

H, 7.05; N, 4.90; Cl, 12.41 Found: C, 58.93; H, 7.07; N, 5.14; CI, 12.45

EXAMPLE 3 1,2,3,4,5,6,7,8-Octahydro-l0,1l-Dimethoxy-3- Benzazecine Hydrochloride The compound prepared in Example 1 (2 g., 7.6 X 10 moles) in THF (20 ml.) is added toa stirred solution of NH (500 ml.) containing 1-methoxy-2- propanol (3 ml., 3 X 10 moles) Lithium (260 mg.. 3.7 X 10 moles) is added portionwise and the deep blue solution vigorously during a further 6 minutes after completion of the addition. Excess lithium is decomposed by water and the reaction mixture diluted cautiously with warm water. The product isolated by CHCl extraction is purified by filtration in ether through a short column of Woelm A1 0 Grade 1 basic. The hydrochloride is obtained by addition of isopropanolic hydrogen chloride to the eluate and recrystallized from acetonehexane to give 1.2 g. of the title compound, m.p. -126C. identical with an authentic sample [J. P. Yardley, R. W. Rees and H. Smith, J. Med. Chem., 10, 1088 (1967)].

EXAMPLE 4 Using the compound of Example 1 as a starting material, Example 3 was repeated except that the 1- methoxy-Z-propanol was omitted and the reaction time is reduced from 6 minutes to 2 h minutes. There is obtained after dilution with warm water and CHCl extraction a crystalline residue, m.p. -143C. shown by glc. to be a mixture of two major components. Column silicone (Floro) QF-l linear program l80-250, 5 minutes at then at 8lmin. 59% mixture retention time after 4.6 minutes and 14 minutes 36% mixture (N-OH compound). Mass spectograph indicates a mixture with molecular ions at 249 (title compound of Example 3) and 265 (/NOH compound of Example 3 EXAMPLE 5 2,3,4,5,6,7-Hexahydro-9,l0-Dimethoxy-1H-3- Benzazonine Hydrochloride Using the method of Example 3, 1,2,3,5,6,10bhexahydro-8,9-dimethoxypyrrolo[2,1-a]isoquinoline- 3-oxide is converted to the title compound. Identity is established by comparison with an authentic sample [1. P. Yardley et al. J. Med. Chem, 10, 1088 (1967)]. The starting N-oxide was prepared in accordance with the procedure of Example 1.

EXAMPLE 6 1,2-Secoemetine Benzyloxycarbonylemetine [J. P. Yardley et al. J. Med. Chem., 10, 1088 (1967)] 14.3 g. (2.32 X 10'2 moles) in methanol (60 ml.) is treated, dropwise, at 10C. with 58.5 ml. ethereal monoperphthalic acid (0.585 molar 3.5 X 10 moles) and the mixture is kept at 05C. overnight. This mixture is basified strongly with 10% aqueous NaOH solution and extracted with CHCl (five times). The CHCl extracts are washed with brine, dried (K Co and evaporated to give the crude oily N-oxide (12 g.). The oily N-oxide (5 g., 7.7 X 10* moles) is placed in tetrahydrofuran (25 ml.) and added to NH (1.5 L) containing 1-methoxy-2- propanol (4.8 ml., 419 X 10 moles). Lithium (260 mg., 3.7 X 10' moles) is added portionwise to a permanent blue coloration. Acetic acid (2.22 g., 2.1 ml.

3.5 X moles) is added and the solution again titrated to a permanent blue coloration. 200 mg. of lithium is added, after 6 minutes the reaction mixture is diluted with hot water and extracted with CHCl The chloroform extracts are washed with brine, dried (Na S0 and the stripped residuein ether is charcoaled (Norite) and treated with an excess of isopropanolic hydrogen chloride. The precipitate crystallizes from acetone to give 3 g. l',2'secoemetinehydrochloride, m.p. 234-237C.

Conversion ofa portion to the bis hydroiodide [cf. J. P. Yardley et al., J. Med Chem, 10, 1088 (1967)] confirmed its identity.

EXAMPLE 7 N-Allyl trans Decahydroquinoline Hydrochloride Trans decahydroquinoline g., 1.44 X 10 moles), allyl chloride (16 ml., 1.96 X 10 moles), triethylamine (18 ml., 1.96 X 10 moles) and acetonitrile (200 ml.) are stirred at room temperature under nitro- 7 gen overnight. The reaction mixture is evaporated in vacuo and the residue distributed between ether and saturated NaHCO- solution. The ether layer is washed with water (twice), brine, and dried (Na SO The product is filtered in ether through a Woelm A1 0 (Grade 1 basic) column and eluted with the same solvent. Treatment of the eluate with an excess of isopropanolic hydrogen chloride and recrystallization of the precipitate from acetone-hexane gives 14 g. of the title compound m.p. l33l35C.

Analysis: Calculated for C H NClz C, 66.79; H,

10.28; N, 6.49; Cl, 16.43

Found: C, 66.71; H, 10.16; N, 6.45; Cl, 16.15

The free base (clear oil) is regenerated from 8 g. of the hydrochloride by treatment with aqueous K CO solution extraction into ether, washing with brine and drying (Na SO NMR (CDCl shows a complex vinylic resonance (3H) in the range 4.9-6.35 ppm.

The N-allyl trans decahydroquinoline (5.0 g., 2.8 X 10' moles) is placed in methanol ml.) and is treated, dropwise at 20C. during 1 hour with 94 ml.

0.65N monoperphthalic acid solution in ether (3.05 X 10 moles). After one further hour during which the reaction mixture is allowed to warm to room temperature, excess aqueous 10% NaOH is added. The ether layer is separated, washed with water, and discarded. The combined aqueous layers are extracted (three times) with CHCl washed with brine, dried (Na SO and stripped at 20C. to give N-allyl trans dodecahydroquinoline N-oxide, a solid crystalline product (4.5 g.). The NMR shows a complex vinylic resonance (3H) in the range 5.2-6.5 ppm.

EXAMPLE 8 N-allyl decahydroquinoline N-oxide (2.0 g., 1 X 10' moles) prepared in accordance with the procedure of Example 7 is placed in NH (1 L) containing 1- methoxy-2-propanol, 4 ml. (4 X 10 moles), is treated with lithium (360 mg, 5.2 X 10" moles) following by a further 6 ml. (6 X 10 moles) of the alcohol. This mixture is stirred until white (ca. 20 minutes), then diluted with hot water and extracted with CHCl (twice), washed with brine, dried (Na SO.,) and stripped; the residue is filtered in ether through Woelm A1 0 l 0 g.) and eluted with ether to give trans decahydroquinoline (l g.), m.p. -47C. (70% yield) identical with an authentic sample.

EXAMPLE 9 l,2,3,4,5,6-Hexahydro-6a,8,l l-Trimethyl-2,6- Methano-3-Benzazocine Dl-l ,2,3,4,5,6-Hexahydro-cis-6,l l-dimethyl-3-(3- methyl-2-butenyl)-2,6-methnano-3benzazocine-8- methanol (700 mg, 2.34 X 10' moles) is placed in methanol (7 ml.) and stirred at 20C. during the dropwise addition of ethereal monoperphthalic acid (6 ml.,

0.46 molar, 2.76 X 10' moles). The mixture is stirred for a further 3 hours during which time the reaction mixture is allowed to attain room temperature. The mixture is then basified with 10% NaOH solution, washed with ether and the ether layer, after a water backwash, discarded. The aqueous layers are extracted (thrice), the organic layers washed with brine, filtered to clarify thesolution and stripped to give a residue of the crude N-oxide (600 mg).

The crude product (500 mg.) in THF (30 ml.) is added to a freshly distilled NH (180 ml.), treated with l-methoxy-Z-propanol, followed by an excess of lithium. After 8 minutes the mixture is diluted with hot water and extracted with CHCI (twice). The organic layer is washed with brine, stripped and filtered in ether through a column of Woelm A1 0 Elution with ether afforded 200 mg. colorless oil homogeneous by thin layer chromatography (tlc) (SiO system CHCl saturated NH;,) and R, identical with that of 1,2,3,4,5,- 6-hexahydro-6a,8,1 ltrimethyl-2,6-methano-3- benzazocine prepared by an alternative route. The crystalline hydrochlorine m.p. 23 l-232C. was identical with an authentic sample by mixed m.p., IR, Mass spectograph and NMR.

EXAMPLE l0 Trans-2Benzylcyclohexanol from Trans-2-[a-(4- Methyl-l-Piperazinyl) Benzyl]Cyclohexanol Trans-2-[a-(4-methyl-l-piperazinyl)benzl]cyclohexarol (4.0g, 1.39 X 10 moles) in THF (60 ml.) is added at 0-5C to a solution ofmonochloroperbenzoic acid 5.7 g., 2.8 X 10' moles) during 10 minutes and the solution stored at 5C. overnight. The reaction mixture is filtered througha Woelm basic A1203 column (Grade 1) built in CHCl and eluted with chloroformmethanol (3:1) to give 45 g. of white solid (mass spectrum shows an M 1 ion at 321 for a bis N-oxide), 4.4 g of the above product as a vigorously stirred suspen sion in THF"(4'O'riil.)liquid"ammonia (filter) is treated with excess lithium (230 mg., 3.3 X 10 moles). The mixture is quenched with acetone 30 seconds after the appearance of a uniform blue color. Solvent is removed on the steam bath and the residue acidified with an ice-hydrochloric acid mixture. A crystalline solid separates at this stage and is extracted into ether. The ether phase is washed with water, brine and dried (Na SO The residue crystallizes from pentane to give 2.0 g. trans 2-benzylcyclohexanol, m.p. 77C. (lit. 77, P. B. Russell, J. Chem. $06., 1771, [1951]).

Found C, 81.67; H, 9.76. C H O requires: C, 82.06;

EXAMPLE 1 1 l,2,4,5,6,7,8,9-Octahydro-3H-Azecino [5,4-b]lndole Using the methods of Examples 1 and 3, l,2,3,4,6,7,--

l2,12b-octahydroindolo-(2,3-a) quinolizine was converted to the title product.

EXAMPLE 12 When the following tertiary amines are employed in the process of the present invention in Examples 1 and 3;

. dimethyl allyl amine dihydroxyethyl allylamine dimethyl benzyl amine N-allyl piperidine N-propargyl morpholine diphenyl allyl amine dipropyl benzyl amine N-benzyl-2,3,6,7-tetrahydro-lH-azepine N-methyLN-[3-pentenyl]-benzylamine 10. N-benzyLN-methyl-3,6-decadienylamine the following corresponding secondary amines are produced:

. dimethyl amine dihydroxyethyl amine dimethyl amine piperidine morpholine diphenyl amine dipropyl amine 2,3,6,7-tetrahydro-lH-azepine N-methyl-3-pentenylamine lv N-methyl-3,6-decadienylamine The secondary'amines of the present invention are useful intermediates in the preparation of pharmacologically active compounds, such as tertiary amines. For example, the compound of Example 6 has been reported to have amebicidal activity [.I. P. Yardley, R. W. Rees and H. Smith, J. Med. Chem., 10, 1088 (1967)]. The benzazocines and benzazonines described herein belong to a class of compounds that exhibit diuretic activity and central nervous system depressant activity.

One of the advantages of the process of the present invention is that it affords a simple and convenient method of cleavage of allylic tertiary amines. The previous claim in the literature by Clemo et al. J. Chem.

$00., 1661 (1948) for allyl amine cleavage in strychnine and strychnidine has been disproved by R. Rees et al. J. Med. Chem., 10, 624 (1967), while E. M. Perry Dissertation Abstracts 16, 1587-1588 (1956), (CA. 51, 2532g) reports The best catalytic method of cleaving allylic amines is with a platinum catalyst in methyl alcohol solution. Nevertheless, the extent of cleavage even by this catalytic method is small since hydrogenation of the double bond competes with the cleavage reaction; the saturated amine is resistant to cleavage by this method."

What is claimed is: 1. A process of converting a tertiary amine of the formula:

R1 wherein R and R are each a radical selected from the class consisting of an alkyl group of 1 through 12 carbon atoms, a cycloalkyl group having 4 through ring carbon atoms, phenyl, naphthyl and phenyl(lower)alkyl; R and R when joined together form with the N- atom a member selected from the class consisting of piperidino, pyrrolidino, piperazino, morpholino, hexamethylenimino, decahydroquinolino, and 1.2.3.456- hexahydro-6,1 l-dimethyl-2,6-methano-3-benzazocino- 8-methanol, said groups defined by R and R being optionally substituted with a member selected from the class consisting of hydroxy and (lower)-alkoxy; and R is a member selected from the group consisting of allyl, dimethyl allyl, propargyl and benzyl; to a secondary amine of the formula:

NII R! which comprises reacting said tertiary amine with an organic peracid to form the N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in the presence of liquid ammonia to form the corresponding secondary amine by cleavage of said R group from said tertiary amine, the reaction of said tertiary amine with said organic peracid being carried out at a temperature between about 40C. and about +32C. l5 2. A process according to claim 1 wherein said reaction of said N-oxide with said alkali metal in liquid ammonia is carried out in the presence of a proton donor.

3. A process according to claim 1 wherein R and R are joined together to form decahydroquinolyl.

4. A process according to claim 1 wherein said tertiary amine is l,2,3,4,5,6-hexahydro-6,l l-dimethyl-3- (3-methyl-2-butenyl)-2,6-methano-3-benzazocine-8- methanol.

5. Aprocess according to claim 1 wherein said tertiary amine is'N-allyl dodecahydroquinoline.

6. A process of converting a tertiary amine of the formula:

wherein:

A represents a fused benzene nucleus or fused indolc nucleus attached through its 2-3 position to the nitrogen containing ring; X represents one or more 0 substituents selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, hydroxy (lower)alkyl, lower alkoxyisoquinolinylmethyl, 2-(lower)alkyl-isoquinolinylmethyl; Z or Z are se- 5 lected from the class consisting of hydrogen and (lower)alkyl; n is a number selected from 1 to 2; to a secondary amine of the formula:

q 6 5 iii- (011.1.

which comprises reacting said tertiary amine with an organic peracid to form the corresponding N-oxide of said tertiary amine, said reaction being carried out be- 0 tween -40C. and about 0C., and reacting said N- oxide with an alkali metal in the presence of liquid ammonia to form said secondary amine.

7. A process according to claim 6 wherein said reaction of said N-oxide with said alkali metal is carried out in the presence ofa proton donor.

8. A process according to claim 7 wherein said proton donor is l-methoxy-Z-propanol.

9. A process according to claim 6 wherein said tertiary amine is benzyloxycarbonylemetine and the secondary amine obtained is l,2,2' -secoemetine.

Z-acetylisoquinolinylmethyl,

10.Apr0cess which comprises reacting trans-Z-[athe presence of liquid ammonia to cleave off (4-methyl-l-piperazinyl)benzyl]cycl0hexanol with an trans-2-benzylcycl0hexan0l.

organic peracid to form an N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in gig UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION p t N 3,856,795 Dated December 24, 1974 Invenmfl John P. Yardley It is certified that error appears in the above-identified patent; and that said Letters Patent are hereby corrected as shown below:

Column 3, change formula IVb from Column 8 line |-6, change "1 b0 2" to ----1 and 2--.

Signed and sealed this 8th day of April 1975.

SEAL) Attest:

C. Z-IARSHALL DANN RUTH C. MASON I Commissioher of Pat n nttestlng Officer 7 and Trademarks ts

Claims (10)

1. A PROCESS OF CONVERTING A TERTIARY AMINE OF THE FORMULA:
2. A process according to claim 1 wherein said reaction of said N-oxide with said alkali metal in liquid ammonia is carried out in the presence of a proton donor.
3. A process according to claim 1 wherein R1 and R2 are joined together to form decahydroquinolyl.
4. A process according to claim 1 wherein said tertiary amine is 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3 -benzazocine-8-methanol.
5. A PROCESS ACCORDING TO CLAIM I WHEREIN SAID TERTIARY AMINE IS N-ALLYL DODECAHYDROQUINOLINE.
6. A process of converting a tertiary amine of the formula:
7. A process according to claim 6 wherein said reaction of said N-oxide with said alkali metal is carried out in the presence of a proton donor.
8. A process according to claim 7 wherein said proton donor is 1-methoxy-2-propanol.
9. A PROCESS ACCORDING TO CLAIM 6 WHEREIN SAID TERTIARY AMINE IS BENZYLOXYCARBONYLEMETINE AND THE SECONDARY AMINE OBTAINED IS 1'',2'',2'' -SECOEMETINE.
10. A process which comprises reacting trans-2-( Alpha -(4-methyl-1-piperazinyl)benzyl)cyclohexanol with an organic peracid to form an N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in the presence of liquid ammonia to cleave off trans-2-benzylcyclohexanol.
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4115389A (en) * 1977-05-02 1978-09-19 Bristol-Myers Company Process of N-demethylating (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
US4264776A (en) * 1976-01-02 1981-04-28 Monsanto Company Production of secondary amines
US4492803A (en) * 1983-09-26 1985-01-08 Toyo Soda Manufacturing Co., Ltd. Method for producing bis[β-(N,N-dimethylamino)alkyl]-ether
US20090048447A1 (en) * 2000-10-31 2009-02-19 Rensselaer Polytechnic Institute Method for decreasing opioid metabolism
US20100240691A1 (en) * 2009-03-19 2010-09-23 Alkermes, Inc. Morphinan derivatives with high oral bioavailability
JP2011503150A (en) * 2007-11-16 2011-01-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Aryl benzomorphan and related skeletal - and heteroarylcarbonyl derivatives, using pharmaceutical and these containing such compounds
US20110028445A1 (en) * 2008-02-12 2011-02-03 Boehringer Ingelheim International Gmbh Urea derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
US20110136848A1 (en) * 2009-12-04 2011-06-09 Alkermes, Inc. Morphinan derivatives for the treatment of drug overdose
US20110230511A1 (en) * 2010-03-22 2011-09-22 Rensselaer Polytechnic Institute Carboxamide bioisosteres of opiates
US8735585B2 (en) 2011-08-17 2014-05-27 Boehringer Ingelheim International Gmbh Indenopyridine derivatives
US20140148377A1 (en) * 2011-05-20 2014-05-29 Oladapo Bakare Emetine Derivatives, Prodrugs Containing Same, And Methods Of Treating Conditions Using Same
US8765780B2 (en) 2008-05-13 2014-07-01 Boehringer Ingelheim International Gmbh Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
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US8822488B2 (en) 2011-12-15 2014-09-02 Alkermes Pharma Ireland Limited Compositions of buprenorphine and μ antagonists
US8962646B2 (en) 2011-06-29 2015-02-24 Alkermes, Inc. Peripherally acting opioid compounds
US9029543B2 (en) 2011-04-05 2015-05-12 Alkermes, Inc. Process for the synthesis of quaternary amine compounds
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Herbst et al., J. Med. Chem., Vol. 9, pages 864 868 (1969) RS1J5. *
Smith, Open Chain Nitrogen Compounds, Vol. 2, (W. A. Benjamin, Inc., New York, 1966), pages 15, 23 24, 27, QD412N156. *

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US4492803A (en) * 1983-09-26 1985-01-08 Toyo Soda Manufacturing Co., Ltd. Method for producing bis[β-(N,N-dimethylamino)alkyl]-ether
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US8859580B2 (en) 2007-11-16 2014-10-14 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
US20110190262A1 (en) * 2007-11-16 2011-08-04 Boehringer Ingelheim International Gmbh Aryl-and Heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
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JP2015199770A (en) * 2007-11-16 2015-11-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Aryl-and heteroarylcarbonyl derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
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