US2867623A - Pyridine compounds - Google Patents

Pyridine compounds Download PDF

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US2867623A
US2867623A US2867623DA US2867623A US 2867623 A US2867623 A US 2867623A US 2867623D A US2867623D A US 2867623DA US 2867623 A US2867623 A US 2867623A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals

Definitions

  • R and R in the above formula each represents an alkyl or alkenyl group.
  • the compounds of Formula I may be hydrogenated to obtain 3,3-disubstituted-2-amino-4-oxo3,4,5,6-tetrahydropyridine bases which may be represented by the following structural formula:
  • R and R in Formula II each represents an alkyl group.
  • the compounds of both Formula-I and Formula II form acid addition salts and, these salts. are also within the scope of the invention.
  • the compounds of this invention are useful as sedatives .and hypnotics. They may be administered orally or parenterally, preferably by in corporating therapeutic doses in tablets or in liquid preparations according to conventional procedures.
  • R and R in the above formulae represent alkyl or alkenyl groups such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, allyl, isobutenyl, etc.
  • R and R represent similar alkyl groups.
  • the groups represented by R and R or R and R in a given compound may be the same, that is, both substituents may be identical alkyl groups or identical alkenyl groups, or they may be mixed, that is, two dilferent alkyl groups or one alkyl group and one alkenyl group, as the case may be.
  • the alkyl and/or alkenyl groups'represented by R, and R or R and R together have a ate 'acetonitrile.
  • dialkyl groups For convenience the groups represented by R and R or R and R in the compounds of Formulae I and II above and the same substituents in the intermediates from which they are derived are sometimes hereinafter referred to as dialkyl groups, but this term is an abbreviated form intended to signify the alkyl and alkenyl groups defined in the preceding paragraph.
  • a monoalkylor monoalkenylacetoacetonitrile may be alkylated, for example with an alkyl halide or alkenyl halide, to obtain a,a-dialkyl-aceto-
  • the last named compound is treated with a formic acid ester, such as methyl formate, and with an alkaline condensation agent, such as sodium methylate, then with ammonia to obtain 1,1-dialkyl-l-cyano-2-oxo- 4-amino-3-butene.
  • the butene compound is cyclized with an alkali alcoholate, such as sodium methylate, preferably in methanol, to produce 2-amino-3,3-dialkyl-4-oxo- 3,4-dihydropyridine.
  • the last named compound is then catalytically hydrogenated to obtain 2-amino-3,3-dialkyl- 4-oxo-3,4,5,6-tetrahydropyridine.
  • a monoalkyl-acetoacetamide may be alkylated and the a,a-dialkyl-acetoacetamide thus obtained is dehydrated with thionyl chloride or phosphorus oxychloride to obtain a,a-dialkyl-acetoacetonitrile which is then further treated as described above.
  • the cyclization of the 1,l-dialkyl-1-cyano-2-oxo-4- amino-3-butene is preferably effected by the action of an alkali metal alcoholate in the presence of the corresponding alcohol at a slightly elevated temperature.
  • 1,l-dialkyl-l-cyano-2-oxo-4-amino-3-butene may be dissolved in methanol, treated with sodium methylate and then heated to boiling under reflux.
  • the 3,3-dialkyl- 2amino-4,-oxo-3,4-dihydropyridine thus formed may be obtained in crystalline form by partially distilling off the alcohol and adding water.
  • the 3,3 disubstituted 2 amino 4 oxo 3,4 dihydropyridine may, if desired, be reduced to the corresponding 3,3-disubstituted -2-amino-4-oxo-3,4,5,6-tetrahydropyridine.
  • This may be efiected, for example, by catalytically hydrogenating the base or its salt, preferably in the presence of a noble metal catalyst, e. g. finely divided palladium.
  • unsaturated substituents in the 3-position are hydrogenated to saturated groups.
  • the 3,3-disubstituted-2-amino-4-oxo-3,4,5,6- tetrahydropyridines produced in this manner may be isolated by separating the catalyst from the hydrogenation reaction mixture and evaporating the solvent.
  • the compounds are strongly basic substances and form acid addition salts with various organic and inorganic acids such as acetic acid, tartaric acid, salicylic acid, the hydrohalic acids, e. g. hydrochloric acid and hydrobromic acid, and other mineral acids such as sulfuric acid, phosphoric acid, etc.
  • Pharmaceutically acceptable acid addition salts constitute a preferred group.
  • the acid addition salts are produced by treating the base with the appropriate acid, preferably in a solvent, e. g. hydrochloric acid in alcohol.
  • the compounds may exist in other tautomeric forms which are also within the scope of the invention.
  • Other tautomeric forms of the compounds may, for example, be formulated as 3,3-disubstituted-2-imino-4-oxo-1,2,3,4-tetrahydropyridine and 3,3-disubstituted-Z-imino-4-oxopiperidine, respectively.
  • EXAMPLE 1 100 g. of diethyl-acetoacetami-de .were heatedwith-100 g. of thionyl chloride to boiling under reflux for mlnutes, then freed in --vacuo-from most of the thionyl chloride and poured into a mixtureof ice and soda solution. The mixture was extracted with ether and the ether solution, after drying over-sodium sulfate, was distilled. At first the ether'evaporated v.andthe the oc,adiethyl-acetoacetonitrile produced distilled over at 73- 76/ 13 mm.
  • EXAMPLE 2 100 g. of isopropyl-acetoacetamide were dissolved in i 100 g. of phosphorus oxychloride, quickly warmed to 100 and-pouredout ontoice and potassium carbonate solution. The reaction mixture was extracted with ether and the ether solution, after drying with sodium sulfate, was distilled under water vacuum. At first, the ether evaporated, then the isopropyl-acetoacetonitrile distilled over at 7880/10 mm.
  • hydrochloride of 2-amino-3-allyl-3-is0propyl-4- oxo-3,4-dihydropyridine, P. 178 was produced by treatingthe base with hydrochloric acid in alcohol as described in Examplel.
  • the hydrochloride of 2-amino-3-isopropyl-3-n-propyl- 4-oxo-3,4-dihydropyridine was produced by the method .described above, M. P. 179.
  • a compound having the formula 1 A member of the group consisting of bases having the formula 0 0 alkenyl ⁇ alkenyl-O on Rr-O CH HgN- H HsN-( H and wherein the two alkenyl groups together have a total of O 2 to 10 carbon atoms. 4. A compound having the formula Rs C R
  • R and R each represents a member of the group HIN- H: consisting of alkyl and alkenyl, and R and R each represents alkyl, said groups represented by R and R and by R and R having together a total of 2 to 10 carbon atoms in a given compound, wherein the two alkyl groups together have a total of 2 to 10 carbon atoms. and pharmaceutically acceptable acid addition salts of 5. 2 amino 3,3 diethyl 4 oxo 3,4,5,6 tetrahysaid bases. dropyridine.
  • alkyl I5 7. 2 amino 3,3 diallyl 4 oxo 3,4 dihydropyridine.

Description

States PYRIDINE COMPOUNDS August Hans Lutz and Otto Schnider, Basel, Switzerland, assignors to Holfrnann-La Roche Inc., Nutley, N. 5., a corporation of New Jersey No Drawing. Application October 28, 1957 Serial No. 692,526
Claims priority, application Switzerland November 28, 1956 8 Claims. (Cl. 260-296) R and R in the above formula each represents an alkyl or alkenyl group.
The compounds of Formula I may be hydrogenated to obtain 3,3-disubstituted-2-amino-4-oxo3,4,5,6-tetrahydropyridine bases which may be represented by the following structural formula:
(II) R and R in Formula II each represents an alkyl group.
The compounds of both Formula-I and Formula II form acid addition salts and, these salts. are also within the scope of the invention. The compounds of this invention are useful as sedatives .and hypnotics. They may be administered orally or parenterally, preferably by in corporating therapeutic doses in tablets or in liquid preparations according to conventional procedures.
R and R in the above formulae represent alkyl or alkenyl groups such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, allyl, isobutenyl, etc. R and R represent similar alkyl groups. The groups represented by R and R or R and R in a given compound may be the same, that is, both substituents may be identical alkyl groups or identical alkenyl groups, or they may be mixed, that is, two dilferent alkyl groups or one alkyl group and one alkenyl group, as the case may be. According to a preferred modification, the alkyl and/or alkenyl groups'represented by R, and R or R and R together have a ate 'acetonitrile.
total of 2 to 10 carbon atoms. Most preferred are lower alkyl or lower alkenyl groups.
For convenience the groups represented by R and R or R and R in the compounds of Formulae I and II above and the same substituents in the intermediates from which they are derived are sometimes hereinafter referred to as dialkyl groups, but this term is an abbreviated form intended to signify the alkyl and alkenyl groups defined in the preceding paragraph.
The compounds of this invention may be produced in the following manner. A monoalkylor monoalkenylacetoacetonitrile may be alkylated, for example with an alkyl halide or alkenyl halide, to obtain a,a-dialkyl-aceto- The last named compound is treated with a formic acid ester, such as methyl formate, and with an alkaline condensation agent, such as sodium methylate, then with ammonia to obtain 1,1-dialkyl-l-cyano-2-oxo- 4-amino-3-butene. The butene compound is cyclized with an alkali alcoholate, such as sodium methylate, preferably in methanol, to produce 2-amino-3,3-dialkyl-4-oxo- 3,4-dihydropyridine. The last named compound is then catalytically hydrogenated to obtain 2-amino-3,3-dialkyl- 4-oxo-3,4,5,6-tetrahydropyridine.
Alternatively, a monoalkyl-acetoacetamide may be alkylated and the a,a-dialkyl-acetoacetamide thus obtained is dehydrated with thionyl chloride or phosphorus oxychloride to obtain a,a-dialkyl-acetoacetonitrile which is then further treated as described above.
The cyclization of the 1,l-dialkyl-1-cyano-2-oxo-4- amino-3-butene is preferably effected by the action of an alkali metal alcoholate in the presence of the corresponding alcohol at a slightly elevated temperature. For example, 1,l-dialkyl-l-cyano-2-oxo-4-amino-3-butene may be dissolved in methanol, treated with sodium methylate and then heated to boiling under reflux. The 3,3-dialkyl- 2amino-4,-oxo-3,4-dihydropyridine thus formed may be obtained in crystalline form by partially distilling off the alcohol and adding water.
The 3,3 disubstituted 2 amino 4 oxo 3,4 dihydropyridine may, if desired, be reduced to the corresponding 3,3-disubstituted -2-amino-4-oxo-3,4,5,6-tetrahydropyridine. This may be efiected, for example, by catalytically hydrogenating the base or its salt, preferably in the presence of a noble metal catalyst, e. g. finely divided palladium. By this procedure unsaturated substituents in the 3-position are hydrogenated to saturated groups. The 3,3-disubstituted-2-amino-4-oxo-3,4,5,6- tetrahydropyridines produced in this manner may be isolated by separating the catalyst from the hydrogenation reaction mixture and evaporating the solvent.
The compounds are strongly basic substances and form acid addition salts with various organic and inorganic acids such as acetic acid, tartaric acid, salicylic acid, the hydrohalic acids, e. g. hydrochloric acid and hydrobromic acid, and other mineral acids such as sulfuric acid, phosphoric acid, etc. Pharmaceutically acceptable acid addition salts constitute a preferred group. The acid addition salts are produced by treating the base with the appropriate acid, preferably in a solvent, e. g. hydrochloric acid in alcohol.
Although the foregoing discussion speaks in terms of only one tautomeric form of the intermediates and final 'methylate.
products represented by the above formulae, the compounds may exist in other tautomeric forms which are also within the scope of the invention. Other tautomeric forms of the compounds may, for example, be formulated as 3,3-disubstituted-2-imino-4-oxo-1,2,3,4-tetrahydropyridine and 3,3-disubstituted-Z-imino-4-oxopiperidine, respectively.
The following examples are illustrative of the invention. All temperatures are in degrees centigrade.
EXAMPLE 1 100 g. of diethyl-acetoacetami-de .were heatedwith-100 g. of thionyl chloride to boiling under reflux for mlnutes, then freed in --vacuo-from most of the thionyl chloride and poured into a mixtureof ice and soda solution. The mixture was extracted with ether and the ether solution, after drying over-sodium sulfate, was distilled. At first the ether'evaporated v.andthe the oc,adiethyl-acetoacetonitrile produced distilled over at 73- 76/ 13 mm.
770 .g. of can:-diethyl-acetoacetonitrile and 500 g. of formic acid methyl ester were dissolved in 2,000-cc.'of toluene and treated portionwise with 316-g.-of sodium The reaction mixture was cooled as required so thatthetemperaturedid notexceed 27. At-the-end of the reaction, ice water was added, the organic phase was separated and extracted with three 100 cc. portions of 3 N sodiumhydroxide. The combined aqueous extracts were treated with 390 g. of ammonium chloride, 70 cc. of aqueous ammonia and 1,000 cc. of benzene and warmed for 75 minutes at 6070 withvigorous stirring. After cooling, thebenzene layer was separated and the aqueous phase was extracted twice with -150-cc. portions of benzene. After evaporating the solventthere remained an oil-which quickly solidified. The -1,l-diethyl- 1-cyano-2-oxo-4-amino-3-butene obtained-in this manner boiled-at 137-145 -/O.1 mm. After dissolving-and crystallizing from petroleum ether, the light yellow crystals melted at 67.
835 g. of 1,1-diethyl-1-cyano-2-oxo-.4-amino-3-butene were dissolved in 700 cc. of-warm methanol and treated with 270 g. of sodium methylate with occasional cooling. The dark red colored solution was'heated to. reflux for 10 minutes and then concentratedto about its volume. The concentrate was cooled with ice water and treated with 1,500 cc. of ice water while stirring vigorously. The 2-amino-3,3-diethyl-4-oxo-3,4-dihydropyridine 'crystallized in yellow crystals which were difiicultly soluble in water. To complete the crystallization, an additional portion of methanol was evaporatedfrom the cold soluhydrogen, the hydrogenation came to an end. The catalyst was separated from the solution which was then concentrated and treated with dry ether. The colorless crystalline hydrochloride of 2 amino 3,3 diethyl 4 oxo- 3,4,5,6-tetrahydropyridine melted at 263-264.
EXAMPLE 2 100 g. of isopropyl-acetoacetamide were dissolved in i 100 g. of phosphorus oxychloride, quickly warmed to 100 and-pouredout ontoice and potassium carbonate solution. The reaction mixture was extracted with ether and the ether solution, after drying with sodium sulfate, was distilled under water vacuum. At first, the ether evaporated, then the isopropyl-acetoacetonitrile distilled over at 7880/10 mm.
300 cc. of boiling diethyl carbonate was treated first with 43 g. of sodium methylate and then with g. of isopropyl-acetoacetonitrile. Approximately 50 cc. of the mixture was then distilled off. To the suspension of the sodium salt thus formed, g. of allyl bromide were added. The reaction mixture was refluxed with stirring for a short time, cooled, treated with ice water, separated from the aqueous phase and distilled under water vacuum. The a-allyl-a-isopropyl-acetoacetonitrile thus produced boiled at 87-89/1l mm.
A mixture of 112g. of a-allyl-a-isopropyl-acetoacetonitrile, 61 g. of formic acid methyl ester and 200 cc. of benzene were poured into a suspension of 16.3 g. of finely divided sodium in 200 cc. of benzene and stirred for 16 hours. By means-of occasional cooling the temperature within the flask was maintained below 28. The sodium salt of 1-allyl-.l-cyano-1-isopropyl-2-oxo-4-hydroxy-3- butene thus formed and water were brought into solution and the phases were separated from each other. The organic phase was washed with approximately 30 cc. of
.3 N sodium hydroxide, the combined aqueous extracts were treated with 300 cc. of benzene, 75 g. of ammonium chloride and 20cc. of concentrated ammonia and the mixture was intensively stirred for 1% hours at 70. The benzene solution, containing l-allyl-l-cyano-l-isopropyl- 2-oxo-4-amino-3-butene, was separated, dried and concentrated. After the evaporation the residue spontaneously solidified, M. P. 73-74.
.100 g. of l-allyl-lrcyano-1:isopropyl-2-oxo-4-amino-3- butene were introducedinto a solution of 18 g. of sodium and 250 cc. of methanol with stirring. The mixture was refluxed for hour. Then approximately 100 cc. of methanol were permitted to distill off under reduced pressure, the dark colored solution was cooled and treated with 400 cc. of ice water whereupon 2-amino-3-allyl-3- isopropyl-4-oxo-3,4-dihydropyridine precipitated as yellow colored crystals. The melting point of the base, recrystallized from methanol, was 162163.
The hydrochloride of 2-amino-3-allyl-3-is0propyl-4- oxo-3,4-dihydropyridine, P. 178, was produced by treatingthe base with hydrochloric acid in alcohol as described in Examplel.
2 amino 3 allyl 3 isopropyl 4 0x0 3,4 dihydropyridine was dissolved in methanol, treated with 5% palladium charcoal and agitated at room temperature with hydrogen. After one mol of hydrogen was ab sorbed, the hydrogenation was stopped, the catalyst was filtered off and the methanol solution was concentrated.
The residue, 2-amino-3-isopropyl-3-n-propyl-4-oxo-3,4-di- V hydropyridine, melted at l90191 after recrystallization from methanol. 7
The hydrochloride of 2-amino-3-isopropyl-3-n-propyl- 4-oxo-3,4-dihydropyridine was produced by the method .described above, M. P. 179.
amino 3 isopropyl 3 n propyl 4- 0X0 3,45,6-
tetrahydropyridine crystallized in colorless needles, M. P. 182.
Additional compounds represented by Formulae-I and II above and salts thereof were synthesized according to the method of Example 2. The melting point or boiling point of the intermediates and final products obtained are wherein the two alkyl groups together have a total of 2 set forth in the following table. to 10 carbon atoms.
Table R1 R: A B
Base, H01, Base, H01, M P M. P. M. P. M
B. B. P44 161-172- 149 B. B. P.o.o5 152 140 B. 011 143 B. B. P. 0.05 150 116 B. M. P. 74-75"- 212 B. M. P. 114.- 225 Is butenyL-" B. 011 175 yl Ally] B. on 146 IsopropyL-.. n-Propyl B. P. 89-91" 191 A MR -a-R7-8.(!Bt08.09t0111tti18. B l-Ri-l-R -1-cyano-2-oxo-4-amino-3 butene. C=3-R -3-Rn-2-a1nino-4-oxo-3,4-dihydropyridine. D=3-R -3-R -2-amino-4-oxo-3,4,5,6-tetrahydropyridine. We claim: 3. A compound having the formula 1. A member of the group consisting of bases having the formula 0 0 alkenyl\ alkenyl-O on Rr-O CH HgN- H HsN-( H and wherein the two alkenyl groups together have a total of O 2 to 10 carbon atoms. 4. A compound having the formula Rs C R| O/ \ZH! E HgN- Hg alkyl alky1 G om wherein R and R each represents a member of the group HIN- H: consisting of alkyl and alkenyl, and R and R each represents alkyl, said groups represented by R and R and by R and R having together a total of 2 to 10 carbon atoms in a given compound, wherein the two alkyl groups together have a total of 2 to 10 carbon atoms. and pharmaceutically acceptable acid addition salts of 5. 2 amino 3,3 diethyl 4 oxo 3,4,5,6 tetrahysaid bases. dropyridine.
2. A compound having the formula 6. 2 amino 3,3 di n propyl 4 0x0 3,4 di.
0 hydropyridine. alkyl I5 7. 2 amino 3,3 diallyl 4 oxo 3,4 dihydropyridine. alkyl-C CH 8. 2 amino 3,3 di n propyl 4 oxo 3,4,5,6- H tetrahydropyridine.
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1. A MEMBER OF THE GROUP CONSISTING OF BASES HAVING THE FORMULA
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