CA1158254A - Preparation of n-((1-naphthalenyl)carbonyl)-n-(lower alkyl)glycine derivatives - Google Patents
Preparation of n-((1-naphthalenyl)carbonyl)-n-(lower alkyl)glycine derivativesInfo
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- CA1158254A CA1158254A CA000374487A CA374487A CA1158254A CA 1158254 A CA1158254 A CA 1158254A CA 000374487 A CA000374487 A CA 000374487A CA 374487 A CA374487 A CA 374487A CA 1158254 A CA1158254 A CA 1158254A
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- lower alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
N-[(1-Naphthalenyl)carbonyl]-N-(lower alkyl)glycine derivatives, useful as intermediates for pharmacologically active compounds, are produced by reacting an organometallic derivative of a 1-halonaphthalene with a lower alkyl isocyanate and N-alkylating the naphthalenecarboxamide so formed.
N-[(1-Naphthalenyl)carbonyl]-N-(lower alkyl)glycine derivatives, useful as intermediates for pharmacologically active compounds, are produced by reacting an organometallic derivative of a 1-halonaphthalene with a lower alkyl isocyanate and N-alkylating the naphthalenecarboxamide so formed.
Description
_ ~YL)CARBONYL]-N-(LOWER ALKYL~
GLYCINE DERIVATIVES
. ~ _, -- .. . .
~9~atl~ ~ Related hereto is Canadian Patent Application Serial No.
374~469, filed April 2,1981 of G. Dionne et al.
This application relates to a process for preparing N-L(l-napllthalenyl)-carbonyl]-N-(lower alkyl)glycine derivatives, which are intermediates for the preparation of N-[(l-naphthalenyl)thioxomethyl]-N-(lower alkyl)glycine derivatives.
The process of this invention produces N-[(l-naphthalenyl)carbonyl~-10 N-(lower)glycine derivatives which are transformed readily into their corresponding N-[(l-naphthalenyl)thioxomethyl]-N-(lower alkyl)glycine derivatives. The latter compounds, thionaphthoylglycines, are useful for treating diabetic complications;
for example, neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis;
and the compounds, and another process for preparing them, are disclosed in 15 Canadian Patent Application Serial No. 372,119) filed March 2,1981 of K. Sestanj et al. According to that process, the thionaphthoylglycines are prepared by coupling a carboxyl acffvated derivative of an appropriate l-naphthalenecarboxylic acid with a glycine ester to obtain the corresponding N-~ naphthalenyl)carbonyl] glycine ester, the product of the process disclosed hereln. Thereafter, the latter compound 20 is reacted with phosphorus pentasul-fide to obtain the corresponding thionaphthoyl-glycine ester which, if desired, can be hydrolyzed to give the corresponding acid.
Optionally, the order of the last two steps can be reversed.
The present process provides an alternative proeess for obtaining the N-[(l-naphthalenyl)carbonyl]-N-(lower alkyl)glycine intermediate in an efficient, 25 inexpensive manner Irom readily available starting materials. A feature of the process is the reaction of a naphthalenyl Grignard reagent or lithium derivativewith an appropriate lower alkyl isocyanate to obtain the corresponding l-naphthalene-carboxamide derivative, which in turn is transformed readily by N-alkylation into the N-[(l-naphthalenyl)carbonyl]-N~(lower alkyl)glycine derivative. Although 30 benzanilide has been obtained by the reaction of phenyl magnesium bromide with phenyl isocyanate, see Ho Gilman and CoR~ Kinney, J. Am. Chem. Soc., 46, 493 (1924), the addition of a naphthalenyl magnesium halide or lithium derivative to ~ 1582~4
GLYCINE DERIVATIVES
. ~ _, -- .. . .
~9~atl~ ~ Related hereto is Canadian Patent Application Serial No.
374~469, filed April 2,1981 of G. Dionne et al.
This application relates to a process for preparing N-L(l-napllthalenyl)-carbonyl]-N-(lower alkyl)glycine derivatives, which are intermediates for the preparation of N-[(l-naphthalenyl)thioxomethyl]-N-(lower alkyl)glycine derivatives.
The process of this invention produces N-[(l-naphthalenyl)carbonyl~-10 N-(lower)glycine derivatives which are transformed readily into their corresponding N-[(l-naphthalenyl)thioxomethyl]-N-(lower alkyl)glycine derivatives. The latter compounds, thionaphthoylglycines, are useful for treating diabetic complications;
for example, neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis;
and the compounds, and another process for preparing them, are disclosed in 15 Canadian Patent Application Serial No. 372,119) filed March 2,1981 of K. Sestanj et al. According to that process, the thionaphthoylglycines are prepared by coupling a carboxyl acffvated derivative of an appropriate l-naphthalenecarboxylic acid with a glycine ester to obtain the corresponding N-~ naphthalenyl)carbonyl] glycine ester, the product of the process disclosed hereln. Thereafter, the latter compound 20 is reacted with phosphorus pentasul-fide to obtain the corresponding thionaphthoyl-glycine ester which, if desired, can be hydrolyzed to give the corresponding acid.
Optionally, the order of the last two steps can be reversed.
The present process provides an alternative proeess for obtaining the N-[(l-naphthalenyl)carbonyl]-N-(lower alkyl)glycine intermediate in an efficient, 25 inexpensive manner Irom readily available starting materials. A feature of the process is the reaction of a naphthalenyl Grignard reagent or lithium derivativewith an appropriate lower alkyl isocyanate to obtain the corresponding l-naphthalene-carboxamide derivative, which in turn is transformed readily by N-alkylation into the N-[(l-naphthalenyl)carbonyl]-N~(lower alkyl)glycine derivative. Although 30 benzanilide has been obtained by the reaction of phenyl magnesium bromide with phenyl isocyanate, see Ho Gilman and CoR~ Kinney, J. Am. Chem. Soc., 46, 493 (1924), the addition of a naphthalenyl magnesium halide or lithium derivative to ~ 1582~4
-2- AHP-7858 an alkyl isocyanate appears to be novel and allows the preparation of the objectcompounds of this invention ~y a simple, direct process which avoids the use of expensive or obnoxious chemicals or the need of protecting groups.
A process is provided ~or preparin~ a compound o~ formula I
O=C-N (R ) -c~l2cooR
4 ~
in which Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 ~nd R4 each separately is hydrogen, lower alkyl, lower alkoxy or trifluoromethyl, or R3 is halo and R4 is hydrogen; which comprises transforming the compound of formula II
~, R4 /~ (I I) in which R3 and R4 are as defined herein and X is bromo7 chloro or iodo into thecorresponding organometallic compound of formula 111 y R J~ (1~1) 30 in which R3 and R4 are as defined herein and Y is MgX wherein X is as defined herein or Y is Li;
reacting the organometallic compoun~ of formula III with a lower alkyl isocyanate of formula RlNCO in which Rl is lower alkvl to obtain the corresponding compoundof formula IV o=C-NHR
1 (IV) R ~~
. ~ R3 -~L 15~5~
A process is provided ~or preparin~ a compound o~ formula I
O=C-N (R ) -c~l2cooR
4 ~
in which Rl is lower alkyl; R2 is hydrogen or lower alkyl; R3 ~nd R4 each separately is hydrogen, lower alkyl, lower alkoxy or trifluoromethyl, or R3 is halo and R4 is hydrogen; which comprises transforming the compound of formula II
~, R4 /~ (I I) in which R3 and R4 are as defined herein and X is bromo7 chloro or iodo into thecorresponding organometallic compound of formula 111 y R J~ (1~1) 30 in which R3 and R4 are as defined herein and Y is MgX wherein X is as defined herein or Y is Li;
reacting the organometallic compoun~ of formula III with a lower alkyl isocyanate of formula RlNCO in which Rl is lower alkvl to obtain the corresponding compoundof formula IV o=C-NHR
1 (IV) R ~~
. ~ R3 -~L 15~5~
-3- AHP-7858 in which Rl, R3 and R are as defined herein9 and condensing the compound of formula IV with a haloacetic acid lower alkyl ester in the presence of a proton acceptor to obtain the corresponding compound 5 of formula I in which Rl, R3 and R4 are as defined herein and R2 is lower alkyl;
and when the compound of formula I in which Rl, R3 and R4 are as defined herein and R2 is hydrogen is required, hydrolyzing the compound of formula I in which Rl, R and R are defined herein and R2 is lower alkyl.
In a preferred embodiment of this process Rl is methyl, R2 is hydrogen 10 or methyl, R3 is bromo, chloro~ methyl, methoxy or trifluoromethyl, and R4 is hydrogen or methoxy.
Detailed Description of the Invention The term tqower alkyl" as used herein means a straight chain ~lk radical containing from one to four carbon atoms or a branched chain alkyl 15 radical containing three or four carbon atoms and includes methyl, ethyl, propyl, l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower alkyl radicals contain one to three carbon atoms.
The term "lower alkoxy" as used herein means a straight chain alkoxy radical containing from one to six carbon atoms, preferably one ts three carbon 20 atoms, or a br~nched chain alkoxy radical containing three or four carbon atoms, and includes methoxy, ethoxy, l-methylethoxy~ butoxy and hexanoxy.
The term "halo" as used herein me~ms a halo radical and includes, fluoro, chloro, bromo and iodo.
The term "inorganic proton acceptor" as used herein means the inorganic 25 bases, preferably the alkali metal hydrides, hydroxides and carbonates, for example, sodium hydride, sodium hydride-dimethylsulfoxide, potassium hydroxide, sodium carbonate, potassium carbonate and the likeO
The term "organic proton acceptor" as used herein means the organic bases or amines, for instance, triethylamine, pyridine, N-ethylmorpholine9 1,5-30 diazabicyclo[4.3.0~ non-5~ene and the like.
The term "proton acceptor" as used herein means a proton acceptor selected from an organic proton acceptor and inorganic proton acceptor, as defined hereinabove.
More specifically, with reference to the process, the compound 35 of formula Il, dissolved in an inert organic solvent for instance diethyl ether or tetrahydrofuran (THF), is reacted with magnesium according to the conditions 1 15~25~
-~- AHP-7858 of the Grignard reaction. A catalyst, for example 1,2-dibromoethane, can be used when forming the Grignurd reagent. Preferred conditions or this reaction include a temperature range from room temperature (20 - 22 C) to 100 C or 5 to the boiling point of the mixture, and fl reaction time of 30 minutes to four hours. In this manner, the organorlletallic compound of formula III in which R3 and R4 are as defined herein and Y is M~X in which X is bromo, chloro or iodo is obtained.
Alternatively, the compound of formula II is reacted with lithium 10 in an inert solvent employing the same techni~ue as that of the Grignard reagent formation to obtain the compound of formula III in which R3 and R4 are as defined herein and Y is Li.
The compounds of formula 11 are known or can be prepared by known methods (see, for example, "Elsevier's ~ncyclopaedia of Organic Chemistry", 15 F. Radt, Ed.~ Series III, vol 12B, Elsevier Publishing Co., Amsterdam, 1953, pp 264 - 321.
Thereafter, the organometallic compound of formula III in which R3 and R4 are as defined herein and Y is MgX in which X is halo or Y is Li is reacted with a lower alkyl isocyanate of formula RlCNO in which Rl is lower 20 alkyl in the presence of an inorganic proton acceptor to give the corresponding compounds of formula IV in which Rl, R3 and R4 are as defined herein.
Practical and convenient conditions for effecting this reaction with the lower alkyl isocyanate include brin~ing the two reactants in contact with each other in a non polar, inert solvent at temperatures ranging from 0 to 60 C25 from 3U minutes to six hours. Suitable solventi include diethyl ether, benzene or tetrahydrofuran.
In the next step, the compound of formula IV is subjected to N-alkyla-tion with a haloacetic acid lower alkyl ester in the presence of a suitable proton acceptor to give the corresponding compound of formula I in which Rl, R3 and 30 R4 are as defined herein and R2 is lower alkyl.
Practical and convenient conditions for effecting the N-alkylation include the use o sodium hydride, sodium hydride-dimethylsulfoxide, or an alkali metal hydroxide or carbonate, for example, sodium hydroxide or potassium carbonate, triethylamine or pyridine as the proton acceptor. Any solvent which 35 does not interfer with the reaction, can serve as the renction medium. Suitable ,, . ~
1 ~58254 solvents include dimethylsulfoxide, dimethylformamide, toluene, acetone and tetrahydrofuran. Preferred conditions for effecting the N-alkylation include the use of sodium hydride-dimethylsulfoxide as the proton acceptor and dimethyl 5 sulfoxide as the solvent. Although the optimum temperature and reaction time will vary depending on the reactants employed, the reaction is performed generally at 20 to 80 C for a period of 30 minutes to 48 hours~
If desired, the compound of formula I in which Rl, R3 and R4 are as defined herein and R is lower alkyl is hydrolyzed to the corresponding compound 10 of formula I in which R is hydrogen. The hydrolysis can be performed most conveniently by employing a base in the presence of sufficient water, followed by acidification of the reaction mixture to yield the desired acid. However, it should be ~mderstcod that the manner of hydrolysis for the process of this invention is not intended to be limited to basic hydrolysis since hydrolysis under 15 acidic conditions and other variations, for example, treatment with lithium iodide in collidine (see L.F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John Wiley ~nd Sons, Inc., New York, 1969, pp. 615-617), also are applicable.
Hydrolysis under acidic conditions is preferred for tert butyl esters.
For ~asic hydrolysis, a preferred embodiment involves subjecting 20 the ester to the action of a strong base, for example, sodium or potassium hy-droxide, in the presence of sufficient water to effect hydrolysis of the ester.
The hyclrolysis is performed using a suitable solvent, for example, methanol, ethanol or 2-methoxyethanol. The reaction mixture is maintained at a temperatureof from about 25 to lD0 C or at the reflux temperature o~ the solvent employed 25 until hydrolysis is complete. IJsually from 10 minutes to 6 hours is sufficient.
The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid or sulfuric acid, to release the free acid.
Subsequently, the compound of formula I, i.e. either the acid (R2 =
hydrogen) or the ester (R2 = lower alkyl), is converted into its corresponding 30 thionaphthoylglycine derivative, the pharmacologically active compo~u~d for which the product of the present process is an intermediute. This latter con-version is effected by reacting the compound of formula I with phosphorus pentasulfide. Convenient conditions for effecting this latter reaction include reacting the compound of formula I under anhydrous conditions with about two 35 to five molar equivalents of phosphorus pentasulfide in an inert solvent, e.g.
1 1582S~
xylene or toluene. ~his reaction cun be performed at temperatures ranging from 8Q to about 150~ C and at times ranging from 20 minutes to four hours.
This reaction also can be performed in the presence of an organic proton acceptor, 5 for instance, N-ethyl morpholine, triethylamine or pyridine. Note that in the instance where the compound of formula I in which R is hydrogen is reacted with phosphorus pentasulfide, the standard first step of the work up of the penta~
sulfide reaction mixture requires that the reaction mixture be decomposed in water. This action causes any corresponding thioacid, present in the reaction10 mixture as a result of the carboxyl group reacting with the phosphorus penta- sulfide, to be converted to the desired carboxylic acid.
The following examples further illustrate this reactioh.
5-Bromo-N-methyl-l~naphthalenecarboxamide (IV, Rl = CH3, R3 = Br and R4 = H) A solution of the starting material of formula II, 1,5-dibromonaphthalcne [1.20 g, 4.2 mmoles, described by H. El. Hodgson and J.S. Whitehurst, J. Chem.
Soc., 80 (1947)] and 1,2-dibromoethane (0.06 ml) in anhydrous freshly distilled THF (10 ml) was added over a period of 1 min to finely cut magnesium ribbon tll9 mg, 4.9 mmoles) under a nitrogen atmosphere. The exothermic reaction 20 was completed in 20 min. The reaction mixture was stirred for 0.5 hr. A solution of the lower alkyl isocyanate, methyl isocyanate (0~18 ml, 4.2 mmoles), in diethyl ether (5 ml) was added dropwise to the stirred reaction mixture at room tempera-ture (2Q-22 C). The mixture was stirred for an additional 1.5 hr at 20-22 C.
The mixture then was poured into water (125 ml). The aqueous mixture was 25 extracted with ethyl acetate. The extract was washed with water, dried (MgS04) and evaporated to give the crude product (818 mg). The crude product was purified by chromatography on silica gel (4S g) using 25% acetone in toluene as eluant.
The appropriQte fractions were pooled to yield 420 mg of the pure title compoundFor analysis, a sample was recrystallized from methylene chloride and hexane.
30 The recrystallized sample has mp 152-153 C; NMR (CDC13) ~ 3.03 ~d, J = 5Hz, 3H), 6.05 (broad, lE~), 7.B (m, 6H); IR (CHC13) 3450~ 3100,1655,1515 cm 1.
N-[(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine Methyl Ester (I, and R = CH3, R3 = ~3r and R4 = H) Sodium hydride (26 mg, 0.55 mmole, 5096 dispersion in oil) was added to dry dimethylsulfoxide (3 ml) at 55-60 CO The mixture was stirred ~Itil the efferves~ence ceased. 5-E~rom~N-methyl-l-naphthalenecarboxamide (132 mg, , 1 ~58254 0.5 mole, described in l~xample 1) was added to the rnixture and the resulting mixture was stirred at 55-60 C for 5 min. Methyl bromoacetate (0.045 ml, 0.55 mmole) was added to the reaction rnixture ~nd $he stirring was continued for 2 hr at 55- 60 C. After cooling, the reaction mixture was poured into 2N aqueous HCl (50 ml). The res~ting mixture was extracted with ethyl acetate (3 x). The extract was washed with water, dried (MgSO4) and evaporated to dryness to give 138 mg of a residue. The residue was subjected to chromatography on silica gel (9 g) using 20% acetone in toluene as the eluant. The appropriate fractions were pooled to give 50 mg of an oil which crystallized when triturated in diethyl ether. Re-crystallization of the solid material gave the title compoundt mp 90 - 92 C; NMR
(CDC13) ~ 2.8 & 3.25 (2s, 3H), 3.6 & 3.85 (2s, 3H), 4.35 (broad, 2H), 7.75 (m, 6H);
D~ (CHC13) 1745,1635 cm 1.
N-[(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine (Il Rl = CH3, R2 and R4 = HandR3=Br) N-[(5 Bromo-l-naphthalenyl)carbonyl]-N-methylglycine methyl ester (3.7 g, 11.0 mmoles, described in Example 2) was suspended in methanol (50 ml).
A solution of lN aqueous NaOH (13.2 ml) was added to the suspension. The mixturewas stirred at 20-22 C for 1.5 hr. The mixture was neutralized with aqueous HCl and concentrated under reduced pressure to remove the methanol. The residualsolution was made acidic with aqueous HCl and extracted with ethyl acetate.
The extract was dried (MgS04), filtered and evaporated to dryness. The residue was crystallized from ethanol-water to give 3.25 g of the title compound; mp 205 C; NMR (DMSO-d6) ~ 2.75 & 3.10 (2s, 3H), 3.75 & 4.25 (2s, 2H), 7.3 - 8.3 (m, 6EI); IR (Nujol*) 1745 with inflection at 1720,1580 cm 1; U~max (EtOH) 322 nm ( 680), 316 (1~000), 299 (6,510), 289 (9,055), 279 (7,150), 226 ~63,080); Anal Calcd:
C, 52.19% H, 3.76% N, 4u35%; Found: C, 52.09% H, 3.84% N, 4.48%.
By following serially examples 1, 2, 3, and optionally 4, and using the appropriate starting materials of formula II and the appropriate lower alkyl isocyanate, other compounds of formula I are obtained. For example, by replacing 1,5-dibromo-naphthalene with ~n equivalent amount of 5-bromo-1-methoxynaphthalene as the * Nujol is a brand name for a white mineral 3il ,.
1 1~8254 starting material of formula II, N-[(5-methoxy-1-naphthalenyl)thioxornethyl]-N-methylglycine; mp 120~ C, NMR (DMSO-d6) ~ 2.93 (s, 3H), 3.90 (S7 3H), 4.65 ~c 5.16 (2d, J = 17Hz, 2H), 6.95 (2d, Jl = 7Hz, J2 ~ 3Hz), 7.35 (m, 4H), 8.11 (2d, Jl =
5 8Hz, J2 = 2Hz, lH), is obtained; similarly, replacing 1,5-dibromonaphthalene with an equivalent amount of 1,5-dichloronaphthalene gives N-[(5-chlor~l-naphthalenyl)-thioxomethyl3 -N-methyl glycine; mp 153 -154 C, NMR (CDC13) 6 3.û3 (s, 3H),
and when the compound of formula I in which Rl, R3 and R4 are as defined herein and R2 is hydrogen is required, hydrolyzing the compound of formula I in which Rl, R and R are defined herein and R2 is lower alkyl.
In a preferred embodiment of this process Rl is methyl, R2 is hydrogen 10 or methyl, R3 is bromo, chloro~ methyl, methoxy or trifluoromethyl, and R4 is hydrogen or methoxy.
Detailed Description of the Invention The term tqower alkyl" as used herein means a straight chain ~lk radical containing from one to four carbon atoms or a branched chain alkyl 15 radical containing three or four carbon atoms and includes methyl, ethyl, propyl, l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower alkyl radicals contain one to three carbon atoms.
The term "lower alkoxy" as used herein means a straight chain alkoxy radical containing from one to six carbon atoms, preferably one ts three carbon 20 atoms, or a br~nched chain alkoxy radical containing three or four carbon atoms, and includes methoxy, ethoxy, l-methylethoxy~ butoxy and hexanoxy.
The term "halo" as used herein me~ms a halo radical and includes, fluoro, chloro, bromo and iodo.
The term "inorganic proton acceptor" as used herein means the inorganic 25 bases, preferably the alkali metal hydrides, hydroxides and carbonates, for example, sodium hydride, sodium hydride-dimethylsulfoxide, potassium hydroxide, sodium carbonate, potassium carbonate and the likeO
The term "organic proton acceptor" as used herein means the organic bases or amines, for instance, triethylamine, pyridine, N-ethylmorpholine9 1,5-30 diazabicyclo[4.3.0~ non-5~ene and the like.
The term "proton acceptor" as used herein means a proton acceptor selected from an organic proton acceptor and inorganic proton acceptor, as defined hereinabove.
More specifically, with reference to the process, the compound 35 of formula Il, dissolved in an inert organic solvent for instance diethyl ether or tetrahydrofuran (THF), is reacted with magnesium according to the conditions 1 15~25~
-~- AHP-7858 of the Grignard reaction. A catalyst, for example 1,2-dibromoethane, can be used when forming the Grignurd reagent. Preferred conditions or this reaction include a temperature range from room temperature (20 - 22 C) to 100 C or 5 to the boiling point of the mixture, and fl reaction time of 30 minutes to four hours. In this manner, the organorlletallic compound of formula III in which R3 and R4 are as defined herein and Y is M~X in which X is bromo, chloro or iodo is obtained.
Alternatively, the compound of formula II is reacted with lithium 10 in an inert solvent employing the same techni~ue as that of the Grignard reagent formation to obtain the compound of formula III in which R3 and R4 are as defined herein and Y is Li.
The compounds of formula 11 are known or can be prepared by known methods (see, for example, "Elsevier's ~ncyclopaedia of Organic Chemistry", 15 F. Radt, Ed.~ Series III, vol 12B, Elsevier Publishing Co., Amsterdam, 1953, pp 264 - 321.
Thereafter, the organometallic compound of formula III in which R3 and R4 are as defined herein and Y is MgX in which X is halo or Y is Li is reacted with a lower alkyl isocyanate of formula RlCNO in which Rl is lower 20 alkyl in the presence of an inorganic proton acceptor to give the corresponding compounds of formula IV in which Rl, R3 and R4 are as defined herein.
Practical and convenient conditions for effecting this reaction with the lower alkyl isocyanate include brin~ing the two reactants in contact with each other in a non polar, inert solvent at temperatures ranging from 0 to 60 C25 from 3U minutes to six hours. Suitable solventi include diethyl ether, benzene or tetrahydrofuran.
In the next step, the compound of formula IV is subjected to N-alkyla-tion with a haloacetic acid lower alkyl ester in the presence of a suitable proton acceptor to give the corresponding compound of formula I in which Rl, R3 and 30 R4 are as defined herein and R2 is lower alkyl.
Practical and convenient conditions for effecting the N-alkylation include the use o sodium hydride, sodium hydride-dimethylsulfoxide, or an alkali metal hydroxide or carbonate, for example, sodium hydroxide or potassium carbonate, triethylamine or pyridine as the proton acceptor. Any solvent which 35 does not interfer with the reaction, can serve as the renction medium. Suitable ,, . ~
1 ~58254 solvents include dimethylsulfoxide, dimethylformamide, toluene, acetone and tetrahydrofuran. Preferred conditions for effecting the N-alkylation include the use of sodium hydride-dimethylsulfoxide as the proton acceptor and dimethyl 5 sulfoxide as the solvent. Although the optimum temperature and reaction time will vary depending on the reactants employed, the reaction is performed generally at 20 to 80 C for a period of 30 minutes to 48 hours~
If desired, the compound of formula I in which Rl, R3 and R4 are as defined herein and R is lower alkyl is hydrolyzed to the corresponding compound 10 of formula I in which R is hydrogen. The hydrolysis can be performed most conveniently by employing a base in the presence of sufficient water, followed by acidification of the reaction mixture to yield the desired acid. However, it should be ~mderstcod that the manner of hydrolysis for the process of this invention is not intended to be limited to basic hydrolysis since hydrolysis under 15 acidic conditions and other variations, for example, treatment with lithium iodide in collidine (see L.F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John Wiley ~nd Sons, Inc., New York, 1969, pp. 615-617), also are applicable.
Hydrolysis under acidic conditions is preferred for tert butyl esters.
For ~asic hydrolysis, a preferred embodiment involves subjecting 20 the ester to the action of a strong base, for example, sodium or potassium hy-droxide, in the presence of sufficient water to effect hydrolysis of the ester.
The hyclrolysis is performed using a suitable solvent, for example, methanol, ethanol or 2-methoxyethanol. The reaction mixture is maintained at a temperatureof from about 25 to lD0 C or at the reflux temperature o~ the solvent employed 25 until hydrolysis is complete. IJsually from 10 minutes to 6 hours is sufficient.
The reaction mixture is then rendered acidic with an acid, for example, acetic acid, hydrochloric acid or sulfuric acid, to release the free acid.
Subsequently, the compound of formula I, i.e. either the acid (R2 =
hydrogen) or the ester (R2 = lower alkyl), is converted into its corresponding 30 thionaphthoylglycine derivative, the pharmacologically active compo~u~d for which the product of the present process is an intermediute. This latter con-version is effected by reacting the compound of formula I with phosphorus pentasulfide. Convenient conditions for effecting this latter reaction include reacting the compound of formula I under anhydrous conditions with about two 35 to five molar equivalents of phosphorus pentasulfide in an inert solvent, e.g.
1 1582S~
xylene or toluene. ~his reaction cun be performed at temperatures ranging from 8Q to about 150~ C and at times ranging from 20 minutes to four hours.
This reaction also can be performed in the presence of an organic proton acceptor, 5 for instance, N-ethyl morpholine, triethylamine or pyridine. Note that in the instance where the compound of formula I in which R is hydrogen is reacted with phosphorus pentasulfide, the standard first step of the work up of the penta~
sulfide reaction mixture requires that the reaction mixture be decomposed in water. This action causes any corresponding thioacid, present in the reaction10 mixture as a result of the carboxyl group reacting with the phosphorus penta- sulfide, to be converted to the desired carboxylic acid.
The following examples further illustrate this reactioh.
5-Bromo-N-methyl-l~naphthalenecarboxamide (IV, Rl = CH3, R3 = Br and R4 = H) A solution of the starting material of formula II, 1,5-dibromonaphthalcne [1.20 g, 4.2 mmoles, described by H. El. Hodgson and J.S. Whitehurst, J. Chem.
Soc., 80 (1947)] and 1,2-dibromoethane (0.06 ml) in anhydrous freshly distilled THF (10 ml) was added over a period of 1 min to finely cut magnesium ribbon tll9 mg, 4.9 mmoles) under a nitrogen atmosphere. The exothermic reaction 20 was completed in 20 min. The reaction mixture was stirred for 0.5 hr. A solution of the lower alkyl isocyanate, methyl isocyanate (0~18 ml, 4.2 mmoles), in diethyl ether (5 ml) was added dropwise to the stirred reaction mixture at room tempera-ture (2Q-22 C). The mixture was stirred for an additional 1.5 hr at 20-22 C.
The mixture then was poured into water (125 ml). The aqueous mixture was 25 extracted with ethyl acetate. The extract was washed with water, dried (MgS04) and evaporated to give the crude product (818 mg). The crude product was purified by chromatography on silica gel (4S g) using 25% acetone in toluene as eluant.
The appropriQte fractions were pooled to yield 420 mg of the pure title compoundFor analysis, a sample was recrystallized from methylene chloride and hexane.
30 The recrystallized sample has mp 152-153 C; NMR (CDC13) ~ 3.03 ~d, J = 5Hz, 3H), 6.05 (broad, lE~), 7.B (m, 6H); IR (CHC13) 3450~ 3100,1655,1515 cm 1.
N-[(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine Methyl Ester (I, and R = CH3, R3 = ~3r and R4 = H) Sodium hydride (26 mg, 0.55 mmole, 5096 dispersion in oil) was added to dry dimethylsulfoxide (3 ml) at 55-60 CO The mixture was stirred ~Itil the efferves~ence ceased. 5-E~rom~N-methyl-l-naphthalenecarboxamide (132 mg, , 1 ~58254 0.5 mole, described in l~xample 1) was added to the rnixture and the resulting mixture was stirred at 55-60 C for 5 min. Methyl bromoacetate (0.045 ml, 0.55 mmole) was added to the reaction rnixture ~nd $he stirring was continued for 2 hr at 55- 60 C. After cooling, the reaction mixture was poured into 2N aqueous HCl (50 ml). The res~ting mixture was extracted with ethyl acetate (3 x). The extract was washed with water, dried (MgSO4) and evaporated to dryness to give 138 mg of a residue. The residue was subjected to chromatography on silica gel (9 g) using 20% acetone in toluene as the eluant. The appropriate fractions were pooled to give 50 mg of an oil which crystallized when triturated in diethyl ether. Re-crystallization of the solid material gave the title compoundt mp 90 - 92 C; NMR
(CDC13) ~ 2.8 & 3.25 (2s, 3H), 3.6 & 3.85 (2s, 3H), 4.35 (broad, 2H), 7.75 (m, 6H);
D~ (CHC13) 1745,1635 cm 1.
N-[(5-Bromo-l-naphthalenyl)carbonyl]-N-methylglycine (Il Rl = CH3, R2 and R4 = HandR3=Br) N-[(5 Bromo-l-naphthalenyl)carbonyl]-N-methylglycine methyl ester (3.7 g, 11.0 mmoles, described in Example 2) was suspended in methanol (50 ml).
A solution of lN aqueous NaOH (13.2 ml) was added to the suspension. The mixturewas stirred at 20-22 C for 1.5 hr. The mixture was neutralized with aqueous HCl and concentrated under reduced pressure to remove the methanol. The residualsolution was made acidic with aqueous HCl and extracted with ethyl acetate.
The extract was dried (MgS04), filtered and evaporated to dryness. The residue was crystallized from ethanol-water to give 3.25 g of the title compound; mp 205 C; NMR (DMSO-d6) ~ 2.75 & 3.10 (2s, 3H), 3.75 & 4.25 (2s, 2H), 7.3 - 8.3 (m, 6EI); IR (Nujol*) 1745 with inflection at 1720,1580 cm 1; U~max (EtOH) 322 nm ( 680), 316 (1~000), 299 (6,510), 289 (9,055), 279 (7,150), 226 ~63,080); Anal Calcd:
C, 52.19% H, 3.76% N, 4u35%; Found: C, 52.09% H, 3.84% N, 4.48%.
By following serially examples 1, 2, 3, and optionally 4, and using the appropriate starting materials of formula II and the appropriate lower alkyl isocyanate, other compounds of formula I are obtained. For example, by replacing 1,5-dibromo-naphthalene with ~n equivalent amount of 5-bromo-1-methoxynaphthalene as the * Nujol is a brand name for a white mineral 3il ,.
1 1~8254 starting material of formula II, N-[(5-methoxy-1-naphthalenyl)thioxornethyl]-N-methylglycine; mp 120~ C, NMR (DMSO-d6) ~ 2.93 (s, 3H), 3.90 (S7 3H), 4.65 ~c 5.16 (2d, J = 17Hz, 2H), 6.95 (2d, Jl = 7Hz, J2 ~ 3Hz), 7.35 (m, 4H), 8.11 (2d, Jl =
5 8Hz, J2 = 2Hz, lH), is obtained; similarly, replacing 1,5-dibromonaphthalene with an equivalent amount of 1,5-dichloronaphthalene gives N-[(5-chlor~l-naphthalenyl)-thioxomethyl3 -N-methyl glycine; mp 153 -154 C, NMR (CDC13) 6 3.û3 (s, 3H),
4.67 & 5.33 (d, J = 17Hz, 2H); similarly, replacing 1,5-dibromonaphthE~lene withan equivalent amount of 5-brom~l-methylnaphthalerle gives N-[(5-methyl-1-naphtha-10 lenyl)thioxomethyll-N-methylglycine; mp 190 -191 C; NMR (CDC13) ~ 2.66 (s, 3H), 3.05 (s, 3M), 3.85 ~ 5.0 (m, 2H), 7.5 (m, 6H), 8.75 (broad, lH); sirnilarly, replacing 1,5-dibrornonaphthalene with l-~hlor~5-(tr if luoromsthyl)-6-methoxynaphthalene gives N-[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl] thioxomethyl]-N-methylgly-cine; mp 164 -165C; NMR (CDC13) ~ 3.05 (s, 3H), 3.95 (s, 3H), 4.55 ~ 5.4 (d, 15 J = 17Hz, 2H), 7.6 (m, 5iI), 9.8 (broad, lH).
An example of the subsequent conversion of a N-[(l-naphthalenyl)carbonyl]-N-~lower alkyl)glycine lower alkyl ester of formula I to its corresponding thi~
naphthoylglycine lower alkyl ester derivative, and subsequent hydrolysis of the 20 lalter compound into its corresponding acid, is EIS follows:
To a stirred solution of N-[(5-brom~-1 naphthalenyl)carbonyl]-N-meth~71-glycine methyl ester (35.5 g, 108 mmoles, described in Example 2) in dry pyridine (100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise.
The mixture was stirred and refluxed ~or 1.5 hr ~nd then poured into a liter of 25 water at 50 to 8QC (caution: evolution of copious quantities of H2S). The mixture was allowed to cool to 20 to 22C, filtered and the filtrate was extracted with ethyl acetate. The extract was washed with IN aqueous HCl solution, brine9 a saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethanol-water (4:1) 30 to give N-[t5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester;
mp 85 - 86~ C; NMR (CDC13) ~ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 ~ 5.37 (2d, J = 17,2H), 71- 8.3 (m, 6H); UV~max (EtOH) 281 nm (~ 14,480), 218 (149480~.
A lN aqueous NaOH solution (25 ml) was added to a suspension of N-~(5-bromo-1-naphthalenyl)thioxomethyl3-N-methylglycine rnethyl ester (7.3 g, 31 ~15~2~4 20.7 mmsles; describeà above) in methanol (75 ml). The mixture was stirred at 20 to 22 C for 21/2 hr, neutralized to pH 7 with aqueous HCl and concentrated under reduced pressure to remove methanol. The residual solution was rendered
An example of the subsequent conversion of a N-[(l-naphthalenyl)carbonyl]-N-~lower alkyl)glycine lower alkyl ester of formula I to its corresponding thi~
naphthoylglycine lower alkyl ester derivative, and subsequent hydrolysis of the 20 lalter compound into its corresponding acid, is EIS follows:
To a stirred solution of N-[(5-brom~-1 naphthalenyl)carbonyl]-N-meth~71-glycine methyl ester (35.5 g, 108 mmoles, described in Example 2) in dry pyridine (100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise.
The mixture was stirred and refluxed ~or 1.5 hr ~nd then poured into a liter of 25 water at 50 to 8QC (caution: evolution of copious quantities of H2S). The mixture was allowed to cool to 20 to 22C, filtered and the filtrate was extracted with ethyl acetate. The extract was washed with IN aqueous HCl solution, brine9 a saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethanol-water (4:1) 30 to give N-[t5-bromo-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester;
mp 85 - 86~ C; NMR (CDC13) ~ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 ~ 5.37 (2d, J = 17,2H), 71- 8.3 (m, 6H); UV~max (EtOH) 281 nm (~ 14,480), 218 (149480~.
A lN aqueous NaOH solution (25 ml) was added to a suspension of N-~(5-bromo-1-naphthalenyl)thioxomethyl3-N-methylglycine rnethyl ester (7.3 g, 31 ~15~2~4 20.7 mmsles; describeà above) in methanol (75 ml). The mixture was stirred at 20 to 22 C for 21/2 hr, neutralized to pH 7 with aqueous HCl and concentrated under reduced pressure to remove methanol. The residual solution was rendered
5 acidic (pH = 2) with the addition of aqueous HCl solution and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness. The residue was crystallized from ethyl acetate-hexane to give 5.3 g of N-[(5-bromo-1-naphtha-lenyl)thio~omethyl~-N-methylglycine; mp 181 C; NMR (DMSO-d6) ~ 2.95 (S7 3H)~
4.65 ~c 5.2 (2d, J = 16.8, 2H), 7.85 (m, 6H~; UY1~max (EtOH) 285 nm (~ 12,300), 280 ~12,400~, 221(42,600); IR (Nujol* ) 2900,1720 cm 1; Anal Calcd: C, 49.72% H, 3.58%
N, 4.1496; Found: C, 49.63% H, 3.63% N, 4.18%.
The aldose reductase inhibiting effects of the corresponding thiona-phthoylglycine derivatives3 for which the object compound of the present processlS are intermediates7 can be demonstrated by employing an in vitro testing procedure similar to that described by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240,877 (1965). In the present case the procedure of Hayman and Kinoshita is modified in that the final chromatography step is omitted in the preparation of the enzyme from bovine lens.
The following results were obtained when the foregoing listed thio-naphthoyl~lycine derivatives were evaluated in the above in vitro test.
*Nujol is a brand name for a white mineral oil ~ ~58~5~
% Inhibition at Different Molar Coneentrations (in vitro) Test Compound 10-5 1o~6 10-7 5 N-[(5-bromo-1-nQphthalenyl)thioxomethyl]-N-methylglycine 93 87 47 N-[(5-m ethoxy-l-naphthalenyl)thioxomethyl] -N-m ethylglycine 83 64 17 N-[~S-chloro-l-naphthalenyl)thioxomethyl] -N-methylglycine - 88 75 29 N-[(5-m ethyl-l-naphthalenyl)thioxomethyl] -15 N-methylglycine 89 74 26 N-[[~5-trifluoromethyl~6-m ethoxy-l naphthalenyl] thioxomethyl] -N-methylglycine ~8 94 65 The thionaphthoylglycine derivatives can be administered to mamm~ls, for example, man, cattle or rabbits, either alone or in dosage forms, i.e., capsules or tablets, combinPd with pharmacologically acceptable excipients, see below.
Advantageously, the thionaphthoylglycines are given orally. They may be admin-istered orally in solid form containing such excipients as stareh, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected psrenterally. For parenteral administration they may be used in the form of a sterile solution, preferably of pM 7.2 ~ 7.6, containing a pharmaceutically acceptable buffer.
The dosage of the thionaphthoylglycines will vary with the form of administration and the particular compound chosen. Furthermore, it will vary .
:.
1 ~L5~54 AHP-785~
wlth the particular host under treatment. Generally, treatment is initiated withsmall dosages substantially less than the optimal dose of the compound. There-after the dosage is increased by small increments until effic~cy is obtained. Ingeneral, the thionaphthoylglyeines are most desiraMy administered at a concen-tration level that will generaLly afford effective results without causing any harmful or deleterious side effects. For topical administration a 0.05 - 0.2% solution may be administered dropwise to the eye. The frequency of instillation varies with the subject under treatment from a drop every two or three days to once daily.
For oral or parenteral administration a preferred level of dosage ranges from about 0.1 mg to about 200 mg per kilo of body weight per day, although aforemen-tioned variations will occur. However, a dosage level that is in the range of from about O.S mg to about 30 mg per kilo of body weight per day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the like may contain from about 5.0 to about 250 mg of the thionaphthoylglycines, dependent on the type of unit dosage, preferably with a significant quantity of ~ pharma-ceutical carrier. Thus, for oral administration, capsules can contain from between about 5.0 to about 250 mg of the active ingredients with or without a pharma-ceutical diluent. Tablets, either effervescent or noneffervescent, can contain between about 5.0 to 250 mg of the active ingredients together with conventionalpharmaceutical carriers. Thus, tablets which may be coated and either effervescent or noneffervescent may be prepared according to the known art. Inert diluents or carriers, for example, magnesium carbonate or lactose, can be used together with conventional disintegrating agent~ for example, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared from water soluble salts, for example, sodium N-[[5-(trifluoromethyl)-6-methoxy-1-rlaphtha-lenyl3 thioxomethyll-N-methylglycinate, and may advantageously contain glycerol and ethyl alcohol as solvents or preservatives.
.,
4.65 ~c 5.2 (2d, J = 16.8, 2H), 7.85 (m, 6H~; UY1~max (EtOH) 285 nm (~ 12,300), 280 ~12,400~, 221(42,600); IR (Nujol* ) 2900,1720 cm 1; Anal Calcd: C, 49.72% H, 3.58%
N, 4.1496; Found: C, 49.63% H, 3.63% N, 4.18%.
The aldose reductase inhibiting effects of the corresponding thiona-phthoylglycine derivatives3 for which the object compound of the present processlS are intermediates7 can be demonstrated by employing an in vitro testing procedure similar to that described by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240,877 (1965). In the present case the procedure of Hayman and Kinoshita is modified in that the final chromatography step is omitted in the preparation of the enzyme from bovine lens.
The following results were obtained when the foregoing listed thio-naphthoyl~lycine derivatives were evaluated in the above in vitro test.
*Nujol is a brand name for a white mineral oil ~ ~58~5~
% Inhibition at Different Molar Coneentrations (in vitro) Test Compound 10-5 1o~6 10-7 5 N-[(5-bromo-1-nQphthalenyl)thioxomethyl]-N-methylglycine 93 87 47 N-[(5-m ethoxy-l-naphthalenyl)thioxomethyl] -N-m ethylglycine 83 64 17 N-[~S-chloro-l-naphthalenyl)thioxomethyl] -N-methylglycine - 88 75 29 N-[(5-m ethyl-l-naphthalenyl)thioxomethyl] -15 N-methylglycine 89 74 26 N-[[~5-trifluoromethyl~6-m ethoxy-l naphthalenyl] thioxomethyl] -N-methylglycine ~8 94 65 The thionaphthoylglycine derivatives can be administered to mamm~ls, for example, man, cattle or rabbits, either alone or in dosage forms, i.e., capsules or tablets, combinPd with pharmacologically acceptable excipients, see below.
Advantageously, the thionaphthoylglycines are given orally. They may be admin-istered orally in solid form containing such excipients as stareh, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected psrenterally. For parenteral administration they may be used in the form of a sterile solution, preferably of pM 7.2 ~ 7.6, containing a pharmaceutically acceptable buffer.
The dosage of the thionaphthoylglycines will vary with the form of administration and the particular compound chosen. Furthermore, it will vary .
:.
1 ~L5~54 AHP-785~
wlth the particular host under treatment. Generally, treatment is initiated withsmall dosages substantially less than the optimal dose of the compound. There-after the dosage is increased by small increments until effic~cy is obtained. Ingeneral, the thionaphthoylglyeines are most desiraMy administered at a concen-tration level that will generaLly afford effective results without causing any harmful or deleterious side effects. For topical administration a 0.05 - 0.2% solution may be administered dropwise to the eye. The frequency of instillation varies with the subject under treatment from a drop every two or three days to once daily.
For oral or parenteral administration a preferred level of dosage ranges from about 0.1 mg to about 200 mg per kilo of body weight per day, although aforemen-tioned variations will occur. However, a dosage level that is in the range of from about O.S mg to about 30 mg per kilo of body weight per day is most satisfactory.
Unit dosage forms such as capsules, tablets, pills and the like may contain from about 5.0 to about 250 mg of the thionaphthoylglycines, dependent on the type of unit dosage, preferably with a significant quantity of ~ pharma-ceutical carrier. Thus, for oral administration, capsules can contain from between about 5.0 to about 250 mg of the active ingredients with or without a pharma-ceutical diluent. Tablets, either effervescent or noneffervescent, can contain between about 5.0 to 250 mg of the active ingredients together with conventionalpharmaceutical carriers. Thus, tablets which may be coated and either effervescent or noneffervescent may be prepared according to the known art. Inert diluents or carriers, for example, magnesium carbonate or lactose, can be used together with conventional disintegrating agent~ for example, magnesium stearate.
Syrups or elixirs suitable for oral administration can be prepared from water soluble salts, for example, sodium N-[[5-(trifluoromethyl)-6-methoxy-1-rlaphtha-lenyl3 thioxomethyll-N-methylglycinate, and may advantageously contain glycerol and ethyl alcohol as solvents or preservatives.
.,
Claims (7)
1. A process for preparing a compound of formula I
(I) in which R1 is lower alkyl; R2 is hydrogen or lower alkyl; R3 and R4 each separately is hydrogen, lower alkyl, lower alkoxy or trifluoromethyl, or R3 is halo and R4 is hydrogen; which comprises:
transforming the compound of formula II
(II) in which R3 and R4 are as defined herein and X is bromo, chloro or iodo into thecorresponding organometallic compound of formula III
(III) in which R3 and R4 are as defined herein and Y is MgX wherein X is as defined herein or Y is Li;
reacting the organometallic compound of formula 111 with a lower alkyl isocyanate of formula R1NCO in which R1 is lower alkyl to obtain the corresponding compoundof formula IV
(IV) in which R1, R3 and R4 as e as defined herein; and condensing the compound of formula IV with a haloacetic acid lower alkyl ester in the presence of Q proton acceptor to obtain the corresponding compound of formula I in which R1, R3 and R4 are as defined herein and R2 is lower alkyl; and when the compound of formula I in which R1, R3 and R4 are as defined herein and R is hydrogen is required, hydrolyzing the compound of formula I in which R1, R3 and R4 are as defined herein and R2 is lower alkyl.
(I) in which R1 is lower alkyl; R2 is hydrogen or lower alkyl; R3 and R4 each separately is hydrogen, lower alkyl, lower alkoxy or trifluoromethyl, or R3 is halo and R4 is hydrogen; which comprises:
transforming the compound of formula II
(II) in which R3 and R4 are as defined herein and X is bromo, chloro or iodo into thecorresponding organometallic compound of formula III
(III) in which R3 and R4 are as defined herein and Y is MgX wherein X is as defined herein or Y is Li;
reacting the organometallic compound of formula 111 with a lower alkyl isocyanate of formula R1NCO in which R1 is lower alkyl to obtain the corresponding compoundof formula IV
(IV) in which R1, R3 and R4 as e as defined herein; and condensing the compound of formula IV with a haloacetic acid lower alkyl ester in the presence of Q proton acceptor to obtain the corresponding compound of formula I in which R1, R3 and R4 are as defined herein and R2 is lower alkyl; and when the compound of formula I in which R1, R3 and R4 are as defined herein and R is hydrogen is required, hydrolyzing the compound of formula I in which R1, R3 and R4 are as defined herein and R2 is lower alkyl.
2. The process of claim 1 in which R1 is methyl, R2 is hydrogen or methyl, R is bromo, chloro, methyl, methoxy or trifluoromethyl, and R4 is hydrogen or methoxy.
3. The process of claim 1 in which the proton acceptor is sodium hydride-dimethylsulfoxide.
4. The process of claim 1 in which Y is MgX wherein X is bromo, chloro or iodo.
5. The process of claim 1 in which Y is Li.
6. The process of claim I in which R1 is methyl, R2 is hydrogen or methyl, R3 is bromo or chloro and R4 is hydrogen.
7. The process of claim 1 in which R1 is methyl, R2 is hydrogen or methyl, and R3 and R4 each separately is hydrogen, methyl, methoxy or trifluoro-m ethyl.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000374487A CA1158254A (en) | 1981-04-02 | 1981-04-02 | Preparation of n-((1-naphthalenyl)carbonyl)-n-(lower alkyl)glycine derivatives |
| GR67622A GR75534B (en) | 1981-04-02 | 1982-03-17 | |
| DK150082A DK150082A (en) | 1981-04-02 | 1982-04-01 | METHOD FOR PREPARING N - ((1-NAPHTHALENYL) CARBONYL) -N- (LOWER ALKYL) GLYCINE DERIVATIVES |
| HU821019A HU187670B (en) | 1981-04-02 | 1982-04-02 | Process for producing n-square bracket-bracket-1-naphtyl-bracket closed-carbonyl-square bracket closed-n-bracket-lower-bracket closed-alkyl-glycine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000374487A CA1158254A (en) | 1981-04-02 | 1981-04-02 | Preparation of n-((1-naphthalenyl)carbonyl)-n-(lower alkyl)glycine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1158254A true CA1158254A (en) | 1983-12-06 |
Family
ID=4119616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000374487A Expired CA1158254A (en) | 1981-04-02 | 1981-04-02 | Preparation of n-((1-naphthalenyl)carbonyl)-n-(lower alkyl)glycine derivatives |
Country Status (4)
| Country | Link |
|---|---|
| CA (1) | CA1158254A (en) |
| DK (1) | DK150082A (en) |
| GR (1) | GR75534B (en) |
| HU (1) | HU187670B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0206546A3 (en) * | 1985-06-10 | 1987-09-02 | American Home Products Corporation | N-û(1-naphthalenyl)-thioxomethyl and carbonyl¨-n-methylglycinamide derivatives |
-
1981
- 1981-04-02 CA CA000374487A patent/CA1158254A/en not_active Expired
-
1982
- 1982-03-17 GR GR67622A patent/GR75534B/el unknown
- 1982-04-01 DK DK150082A patent/DK150082A/en not_active Application Discontinuation
- 1982-04-02 HU HU821019A patent/HU187670B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0206546A3 (en) * | 1985-06-10 | 1987-09-02 | American Home Products Corporation | N-û(1-naphthalenyl)-thioxomethyl and carbonyl¨-n-methylglycinamide derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| GR75534B (en) | 1984-07-27 |
| HU187670B (en) | 1986-02-28 |
| DK150082A (en) | 1982-10-03 |
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