CA2286646A1 - Process and intermediates for preparing nicotinamide derivatives - Google Patents
Process and intermediates for preparing nicotinamide derivatives Download PDFInfo
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- CA2286646A1 CA2286646A1 CA002286646A CA2286646A CA2286646A1 CA 2286646 A1 CA2286646 A1 CA 2286646A1 CA 002286646 A CA002286646 A CA 002286646A CA 2286646 A CA2286646 A CA 2286646A CA 2286646 A1 CA2286646 A1 CA 2286646A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for preparing a compound of the formula comprising reacting a compound of the formula IV with a carbonate base in an alcohol solvent. The compound of the formula IV is prepared by reacting a compound of the formula III with a methyl grignard reagent in an inert solvent. The compound of formula III is prepared by reacting a compound of formula II with an acetic anhydride and and amine base in a chlorinated solvent. The compound of Formula II is prepared by reacting a compound of forumula I with an alcohol in acid media to form an ester group. The invention also includes novel compounds of the formula wherein R is (C1-C6)alkyl and
Description
' CA 02286646 1999-10-19 Process and Intermediates for Preparing Nicotinamide Derivatives Background of the Invention This invention relates to the process and intermediates for preparing nicotinamide derivatives. The nicotinamide derivatives that are prepared in accord with the present invention are disclosed in United States Patent No. 4,861, 891 filed August 31, 1988 entitled "Antidepressant-N-substituted Nicotinamide Compounds" and PCT Application No.
PCT/IB9800315 filed March 10, 1998 and entitled "Nacotinamide Derivatives".
The compounds and processes of the present invention are useful in the preparation of N-substituted nicotinamide derivatives that are selective inhibitors of calcium-independent phosphodiesterase and are useful as antidepressants. Such nicotinamide derivatives are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF).
Summary of the Invention The present invention relates to a process for preparing a compound of the formula:
H_N
V
which comprises reacting a compound of the formula _2_ H
I I
O
IV
C
H3C/ I \CH3 OH
with a base in an alcoholic solvent.
In a further aspect of the present invention, the compound of Formula IV is prepared by reacting a compound of formula H
N C
I I
O III
wherein R is (C,-C6)alkyl with an alkyl Grignard reactant in an inert solvent.
In a further aspect of the present invention, the compound of Formula III is prepared by reacting a compound of the formula:
I I
COZR
wherein R is (C,-C6)alkyl with trifluoroacetic anhydride in the presence of an amine base in a chlorinated solvent.
In a further aspect of the present invention, the compound of formula II is prepared by reacting a compound of the formula I
with an alcohol in acidic media to form an ester In the process for preparing compound I, excess Grignard reagent is preferably used.
Examples of suitable Grignard reagents are methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide. The Grignard reagent is preferably methyl magnesium chloride. The solvent is inert under the reaction conditions and is preferably tetrahydrofuran. The base is a carbonate preferably potassium carbonate in a methyl alcohol solvent. The esterifying reagent is an acetic anhydride and an amine, preferably trifluoroacetic anhydride and trimethyl amine in dichloroethylene. The ester forming group is methyl alcohol in hydrochloric acid.
The invention also relates to a novel compound of the formula H
I I
O III
wherein R is (C,-Cs)alkyl The invention also relates to a novel compound of the formula:
H
N C~
I I
O
IV
C
H3C/ I \CH3 OH
These novel compound are used in the preparation of intermediates for N-substituted nicotinamide derivatives useful as selective inhibitors of calcium independent phjosphodiesterase and intermediates for nicotinamide derivatives useful as selective inhibitors phosphodiesterase type 4 (PDE4) and the production of tumor necrosis factor (TNF).
Detailed Description of the Invention The new process synthesis is shown in the Reaction Scheme 1 below NN H
I I
O
HzN Hs s C
H3C/ I \CH3 V OH
IV
I
H
I I
O
\
III
Aminomethyl benzoic acid compound I is treated with an alcohol in acidic media to transform its acid functionality group to an ester compound II. Using acetamide group to protect the free amine of compound II gives the trifluoroacetamide ester compound III.
Treating the trifluoroacetamide ester compound III with methyl Grignard in an inert solvent gives the desired tertiary alcohol Compound IV. Reacting the acetamide compound IV with a carbonate base in an alcoholic solvent deprotects the tritluoroacetamide to give the desired amino alcohol compound V.
The previous synthesis of compound V relied on selective methyl Grignard addition to 4-cyanobenzoic acid methyl ester (PCT/IB9800315). This methyl G,rignard addition gives complex reaction mixtures and the need for chromatographic purification. The present process prepares large quantities of the desired amino alcohol without the need for tedious purification.
Compound V can be used as an intermediate with a 2-aryloxy-nicotinic acid compound as disclosed in United States Patent No. 4,861,891 to form nicotinamide derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosis factor (TNF).
These useful inhibitors of PDE4 and TNF can be administered in a wide variety of dosage forms.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0.1 to 1000 mg daily, in single or divided doses, for an average adult patient (70 kg). The active compounds can be administered in single or divided doses. Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1 % (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously.
For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic.
Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.
Example I
4~(2,2,2-Trifluoro-acetylamino)-methyl]-benzoic acid methyl ester Into a 100 mL three-necked flask equipped with a NZ inlet, mechanical stirrer, and addition funnel was charged 4-aminomethyl-benzoic acid methyl ester hydrochloride( 5.00 gm, 24.8 mmoles) in 50 mL CHzCl2. Triethylamine (7.3 ml, 52.1 mmoles) was added via syringe, and the reaction mixture was cooled to 0°C in an acetonelice bath. The trifluoroacetic anhydride (3.7 mL, 26.0 mmoles) was charged to the addition funnel and added to the reaction dropwise over 30 minutes. An exotherm to 3.1 °C
occurred. The ice bath was removed after the addition of the trifluoroacetic anhydride and the reaction was complete as indicated by HPLC (Waters Symmetry C-8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm). The reaction was partitioned with 50 mL H20 and then the layers were separated. The aqueous layer was extracted 2x 50mL CHzCl2. The organic layers were combined, washed 1x 100 ml brine, dried (NazS04), filtered and concentrated to afford a white solid (5.43 gm, 84%).
1 H , NMR (CDCI3, 400 MHz) d 8.01 (2H, br d, CH), 7.28 (2H, br d,CH), 4.58 (2H, br d, CHZ), 3.90 (3H, s, CH3); 13C NMR (CDCI3, 100 MHz) d 166.5, 140.8, 130.3, 130.1, 127.7, 52.2, 43.4; IR (KBr, cm-1 ) 3290, 1723, 1702, 1559, 1438; EA Theory: C 50.58 H 3.86 N 5.36 F
21.82 Actual: m.p. 70.6 °C-74.4°C.
Example II
PCT/IB9800315 filed March 10, 1998 and entitled "Nacotinamide Derivatives".
The compounds and processes of the present invention are useful in the preparation of N-substituted nicotinamide derivatives that are selective inhibitors of calcium-independent phosphodiesterase and are useful as antidepressants. Such nicotinamide derivatives are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF).
Summary of the Invention The present invention relates to a process for preparing a compound of the formula:
H_N
V
which comprises reacting a compound of the formula _2_ H
I I
O
IV
C
H3C/ I \CH3 OH
with a base in an alcoholic solvent.
In a further aspect of the present invention, the compound of Formula IV is prepared by reacting a compound of formula H
N C
I I
O III
wherein R is (C,-C6)alkyl with an alkyl Grignard reactant in an inert solvent.
In a further aspect of the present invention, the compound of Formula III is prepared by reacting a compound of the formula:
I I
COZR
wherein R is (C,-C6)alkyl with trifluoroacetic anhydride in the presence of an amine base in a chlorinated solvent.
In a further aspect of the present invention, the compound of formula II is prepared by reacting a compound of the formula I
with an alcohol in acidic media to form an ester In the process for preparing compound I, excess Grignard reagent is preferably used.
Examples of suitable Grignard reagents are methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide. The Grignard reagent is preferably methyl magnesium chloride. The solvent is inert under the reaction conditions and is preferably tetrahydrofuran. The base is a carbonate preferably potassium carbonate in a methyl alcohol solvent. The esterifying reagent is an acetic anhydride and an amine, preferably trifluoroacetic anhydride and trimethyl amine in dichloroethylene. The ester forming group is methyl alcohol in hydrochloric acid.
The invention also relates to a novel compound of the formula H
I I
O III
wherein R is (C,-Cs)alkyl The invention also relates to a novel compound of the formula:
H
N C~
I I
O
IV
C
H3C/ I \CH3 OH
These novel compound are used in the preparation of intermediates for N-substituted nicotinamide derivatives useful as selective inhibitors of calcium independent phjosphodiesterase and intermediates for nicotinamide derivatives useful as selective inhibitors phosphodiesterase type 4 (PDE4) and the production of tumor necrosis factor (TNF).
Detailed Description of the Invention The new process synthesis is shown in the Reaction Scheme 1 below NN H
I I
O
HzN Hs s C
H3C/ I \CH3 V OH
IV
I
H
I I
O
\
III
Aminomethyl benzoic acid compound I is treated with an alcohol in acidic media to transform its acid functionality group to an ester compound II. Using acetamide group to protect the free amine of compound II gives the trifluoroacetamide ester compound III.
Treating the trifluoroacetamide ester compound III with methyl Grignard in an inert solvent gives the desired tertiary alcohol Compound IV. Reacting the acetamide compound IV with a carbonate base in an alcoholic solvent deprotects the tritluoroacetamide to give the desired amino alcohol compound V.
The previous synthesis of compound V relied on selective methyl Grignard addition to 4-cyanobenzoic acid methyl ester (PCT/IB9800315). This methyl G,rignard addition gives complex reaction mixtures and the need for chromatographic purification. The present process prepares large quantities of the desired amino alcohol without the need for tedious purification.
Compound V can be used as an intermediate with a 2-aryloxy-nicotinic acid compound as disclosed in United States Patent No. 4,861,891 to form nicotinamide derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosis factor (TNF).
These useful inhibitors of PDE4 and TNF can be administered in a wide variety of dosage forms.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0.1 to 1000 mg daily, in single or divided doses, for an average adult patient (70 kg). The active compounds can be administered in single or divided doses. Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1 % (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously.
For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic.
Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.
Example I
4~(2,2,2-Trifluoro-acetylamino)-methyl]-benzoic acid methyl ester Into a 100 mL three-necked flask equipped with a NZ inlet, mechanical stirrer, and addition funnel was charged 4-aminomethyl-benzoic acid methyl ester hydrochloride( 5.00 gm, 24.8 mmoles) in 50 mL CHzCl2. Triethylamine (7.3 ml, 52.1 mmoles) was added via syringe, and the reaction mixture was cooled to 0°C in an acetonelice bath. The trifluoroacetic anhydride (3.7 mL, 26.0 mmoles) was charged to the addition funnel and added to the reaction dropwise over 30 minutes. An exotherm to 3.1 °C
occurred. The ice bath was removed after the addition of the trifluoroacetic anhydride and the reaction was complete as indicated by HPLC (Waters Symmetry C-8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm). The reaction was partitioned with 50 mL H20 and then the layers were separated. The aqueous layer was extracted 2x 50mL CHzCl2. The organic layers were combined, washed 1x 100 ml brine, dried (NazS04), filtered and concentrated to afford a white solid (5.43 gm, 84%).
1 H , NMR (CDCI3, 400 MHz) d 8.01 (2H, br d, CH), 7.28 (2H, br d,CH), 4.58 (2H, br d, CHZ), 3.90 (3H, s, CH3); 13C NMR (CDCI3, 100 MHz) d 166.5, 140.8, 130.3, 130.1, 127.7, 52.2, 43.4; IR (KBr, cm-1 ) 3290, 1723, 1702, 1559, 1438; EA Theory: C 50.58 H 3.86 N 5.36 F
21.82 Actual: m.p. 70.6 °C-74.4°C.
Example II
2,2,2-Trifluoro-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-acetam ide Into a flame dried 200 mL three-necked flask equipped with a NZ inlet, mechanical stirrer, and addition funnel was charged 4-[(2,2,2-trifluoro-acetylamino)-methyl]-benzoic acid Trade-mark _g_ methyl ester (3.37 gm, 12.9 mmoles) in 135 mL THF. This was cooled to 0°C in an acetone/ice bath. Methyl magnesium chloride (21.5 mL of 3M sol'n in THF, 64.5 mmoles) was charged to the addition funnel and introduced to the reaction dropwise over 15 minutes. The reaction exothermed to 7.4°C. The reaction was allowed to warm to room temperature after addition of the grignard reagent. The reaction was monitored by HPLC (Waters Symmetry C-8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm) and was complete after 3.5 hours.
The reaction was then slowly quenched with NH4CI (3.45 gm, 64.5 mmoles) in 130 mL H20.
The aqueous layer was extracted 2x 250 mL EtOAc. The combined organic layers were washed 1x 500 mL brine, dried (Na2S04), filtered and concentrated to a pale oil (3.11 gm, 92.6%).1 H NMR (CDCI3, 400 MHz) b 7.50 (2H, br d, CH), 7.27 (2H, br d, CH), 4.50 (2H, br d, CH2), 1.57 (3H, s, CH3) 13C NMR (CDCI3, 100 MHz) d 149.4, 134.1, 127.9, 125.2, 112.4, 72.4, 43.6, 31.8; IR (neat, cm-1) 3300, 3092, 2977,1707, 1558, 1218; EA
Theory: C 55.17 H
The reaction was then slowly quenched with NH4CI (3.45 gm, 64.5 mmoles) in 130 mL H20.
The aqueous layer was extracted 2x 250 mL EtOAc. The combined organic layers were washed 1x 500 mL brine, dried (Na2S04), filtered and concentrated to a pale oil (3.11 gm, 92.6%).1 H NMR (CDCI3, 400 MHz) b 7.50 (2H, br d, CH), 7.27 (2H, br d, CH), 4.50 (2H, br d, CH2), 1.57 (3H, s, CH3) 13C NMR (CDCI3, 100 MHz) d 149.4, 134.1, 127.9, 125.2, 112.4, 72.4, 43.6, 31.8; IR (neat, cm-1) 3300, 3092, 2977,1707, 1558, 1218; EA
Theory: C 55.17 H
5.40 F 21.82 N 5.36 Example III
2-(4-Aminomethyl-phenyl)-propan-2-of Into a 100 mL one neck flask equipped with stir bar was charged 2,2,2-trifluoro-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-acetamide (3.11 gm, 11.9 mmoles) in 31 mL
MeOH. To this was added KZC03 (4.11 gm, 29.75 mmoles in 9.6 mL H20. The reaction was allowed to stir at room temperature. The reaction was monitored by HPLC (Waters Symmetry C-8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm) and was complete after 24 hrs. The reaction was worked up by adding 150 mL CHCI3 and 150 mL brine. The layers were separated and the aqueous layer was extracted 3x 150 mL 10% MeOH/CH2C12. The layers were dried (Na2S04), filtered and concentrated to afford a waxy yellow solid (1.18 gm, 60%).
Example IV
4-(1-Hydroxy-1-methyl-ethyl)-benzyl-ammonium; benzoate To a 25 mL round bottom flask equipped with a stir bar was charged 2-(4-aminomethyl-phenyl)-propan-2-of (184 mg, 1,12 mmoles) in 2.7 mL isopropyl alcohol.
Benzoic acid (136 mg, 1.12 mmoles) was added and the reaction allowed to stir at room temperature. Solids began to precipitate immediately. After 1 hr., the mixture was filtered and the solids were washed with additional isopropyll alcohol. White solids (141 mg, 44% yield) were isolated. The filtrate was allowed to stir overnight at room temperature.
A second crop (32 mg, 10% yield) was isolated.
Trade-mark
2-(4-Aminomethyl-phenyl)-propan-2-of Into a 100 mL one neck flask equipped with stir bar was charged 2,2,2-trifluoro-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-acetamide (3.11 gm, 11.9 mmoles) in 31 mL
MeOH. To this was added KZC03 (4.11 gm, 29.75 mmoles in 9.6 mL H20. The reaction was allowed to stir at room temperature. The reaction was monitored by HPLC (Waters Symmetry C-8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm) and was complete after 24 hrs. The reaction was worked up by adding 150 mL CHCI3 and 150 mL brine. The layers were separated and the aqueous layer was extracted 3x 150 mL 10% MeOH/CH2C12. The layers were dried (Na2S04), filtered and concentrated to afford a waxy yellow solid (1.18 gm, 60%).
Example IV
4-(1-Hydroxy-1-methyl-ethyl)-benzyl-ammonium; benzoate To a 25 mL round bottom flask equipped with a stir bar was charged 2-(4-aminomethyl-phenyl)-propan-2-of (184 mg, 1,12 mmoles) in 2.7 mL isopropyl alcohol.
Benzoic acid (136 mg, 1.12 mmoles) was added and the reaction allowed to stir at room temperature. Solids began to precipitate immediately. After 1 hr., the mixture was filtered and the solids were washed with additional isopropyll alcohol. White solids (141 mg, 44% yield) were isolated. The filtrate was allowed to stir overnight at room temperature.
A second crop (32 mg, 10% yield) was isolated.
Trade-mark
Claims (15)
1. A process for preparing a compound of formula:
comprising reacting a compound of the formula:
with a carbonate base in an alcohol solvent.
comprising reacting a compound of the formula:
with a carbonate base in an alcohol solvent.
2. The process according to Claim 1 wherein the carbonate is potassium carbonate.
3. The process according to claim 1 wherein the solvent is methyl alcohol.
4. The process of Claim 1 wherein said compound of formula IV is prepared by reacting a compound of formula:
wherein R is (C1-C6)alkyl with a methyl Grignard reagent in a reaction inert solvent
wherein R is (C1-C6)alkyl with a methyl Grignard reagent in a reaction inert solvent
5. The process of Claim 4 wherein greater than about 5 equivalents of the Grignard reagent are used.
6. The process according to claim 4 wherein the Grignard reagent is methyl magnesium chloride.
7. The process according to Claim 4 wherein the solvent is tetrahydrofuran.
8. The process according to Claim 4 wherein said compound of formula III is prepared by reacting a compound of the formula:
wherein R is (C1-C6)alkyl with an acetic anhydride and an amine base in a chlorinated solvent.
wherein R is (C1-C6)alkyl with an acetic anhydride and an amine base in a chlorinated solvent.
9. The process according to Claim 8 wherein the acetic anhydride is trifluoroacetic anhydride.
10. The process according to Claim 8 wherein the amine is triethylamine.
11. The process according to Claim 8 wherein the solvent is dichloroethylene.
12. The process according to Claim 8 wherein said compound of formula II is prepared by reacting a compound of formula I:
with an alcohol in acidic media to form the ester group.
with an alcohol in acidic media to form the ester group.
13. The process according to Claim 12 wherein the ester forming group is methyl alcohol in hydrochloric acid.
14. A compound of the formula:
wherein R is (C1-C6)alkyl.
wherein R is (C1-C6)alkyl.
15. A compound of the formula:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10512098P | 1998-10-21 | 1998-10-21 | |
| US60/105,120 | 1998-10-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2286646A1 true CA2286646A1 (en) | 2000-04-21 |
Family
ID=22304138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002286646A Abandoned CA2286646A1 (en) | 1998-10-21 | 1999-10-19 | Process and intermediates for preparing nicotinamide derivatives |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JP2000128835A (en) |
| KR (1) | KR20000029190A (en) |
| AR (1) | AR020919A1 (en) |
| AU (1) | AU5595399A (en) |
| BR (1) | BR9904696A (en) |
| CA (1) | CA2286646A1 (en) |
| HU (1) | HU9903736D0 (en) |
| IL (1) | IL132405A0 (en) |
| PL (1) | PL336111A1 (en) |
| ZA (1) | ZA996624B (en) |
-
1999
- 1999-10-14 IL IL13240599A patent/IL132405A0/en unknown
- 1999-10-19 AU AU55953/99A patent/AU5595399A/en not_active Abandoned
- 1999-10-19 CA CA002286646A patent/CA2286646A1/en not_active Abandoned
- 1999-10-20 ZA ZA9906624A patent/ZA996624B/en unknown
- 1999-10-20 AR ARP990105300A patent/AR020919A1/en unknown
- 1999-10-20 KR KR1019990045464A patent/KR20000029190A/en not_active Application Discontinuation
- 1999-10-20 HU HU9903736A patent/HU9903736D0/en unknown
- 1999-10-20 PL PL99336111A patent/PL336111A1/en not_active Application Discontinuation
- 1999-10-20 JP JP11298121A patent/JP2000128835A/en active Pending
- 1999-10-20 BR BR9904696-2A patent/BR9904696A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BR9904696A (en) | 2000-08-08 |
| ZA996624B (en) | 2001-04-20 |
| HU9903736D0 (en) | 1999-12-28 |
| KR20000029190A (en) | 2000-05-25 |
| JP2000128835A (en) | 2000-05-09 |
| PL336111A1 (en) | 2000-04-25 |
| AR020919A1 (en) | 2002-06-05 |
| AU5595399A (en) | 2000-05-04 |
| IL132405A0 (en) | 2001-03-19 |
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