HK1088593B - Process for the preparation of n-substituted formamides - Google Patents

Description

Process for preparing N-substituted carboxamides

The invention relates to a method for producing N-aryl-or N-heteroaryl carboxamides from nitroarenes or nitroheteroarenes by reductive formylation.

N-aryl or N-heteroaryl carboxamides are useful intermediates in the synthesis of a number of compounds. For example, they can be dehydrated to form isonitriles (U.S. Pat. No. 3,3636036). Formyl groups may also serve as amino protecting groups, which are cleavable upon treatment with strong acids. Other uses of N-aryl-or N-heteroaryl carboxamides include their use as developers for thermal recording materials (JP-A-09-193553) or as assistants for polymerization catalysts (U.S. Pat. No. 3, 5153767).

Known processes for the production of N-aryl-or N-heteroaryl carboxamides are based on the reaction of the corresponding aryl and aromatic amines with formic acid. Common methods for producing aromatic amines include the reduction of the corresponding nitroarenes by hydrogenation or with iron as a reducing agent. WO-A-96/36597 discloses the hydrogenation of nitroarenes to aromatic amines with gaseous hydrogen in the presence of trace amounts of vanadium compounds using noble metal catalysts. In one embodiment, the aromatic amine is acetylated in situ when sodium acetate is present in the reaction mixture. The use of pressurized (up to 20bar) gaseous hydrogen and autoclaves is a drawback of this process.

It is an object of the present invention to provide a simple, one-step process for the production of N-aryl-or N-heteroaryl carboxamides from nitro compounds.

It is another object of the present invention to provide a one-step process for producing benzimidazoles from aromatic hydrocarbons containing nitroamino groups on adjacent ring carbon atoms. Substituted benzimidazoles are useful intermediates in the synthesis of compounds having pharmaceutical activity.

It has now been found that N-aryl or N-heteroaryl carboxamides can be produced by hydrogenating the corresponding nitroarenes or nitroheteroarenes with formic acid and/or ammonium formate as hydrogen donor and formylating agent in the presence of at least one noble metal-based hydrogenation catalyst and a vanadium or molybdenum compound as co-catalyst. One of the greatest advantages of this process is that the reaction can be carried out at ambient pressure without the use of gaseous hydrogen.

The terms "aromatic hydrocarbon" and "aryl" as used herein and below should be understood to mean all mono-, bi-and polycyclic aromatic hydrocarbons such as benzene, biphenyl, naphthalene, indane, anthracene, phenanthrene, fluorene, pyrene and perylene, respectively, and monovalent radicals derived from each of the above hydrocarbons (e.g., phenyl, biphenyl, naphthyl, etc.).

Correspondingly, the terms "heteroarene" and "heteroaryl" as used herein and below, respectively, are to be understood as meaning all mono-, bi-and polycyclic aromatic hydrocarbons containing at least one ring atom other than carbon, in particular nitrogen, oxygen or sulfur, and the monovalent radicals derived therefrom, examples of heteroarenes including pyridine, pyrimidine, pyrene-oxazine, pyridazine, pyrrole, pyrene-oxazole, imidazole, furan, thiophene, thiazole, indole, isoindole, indolizine, quinoline, isoquinoline, quinoxaline, quinazoline, o-naphthyridine, carbazole, azaanthracene and phenazine.

The term "noble metal" as used here and below is to be understood as meaning in particular the platinum group metals, i.e. rhodium, ruthenium, palladium, osmium, iridium and platinum.

In a preferred embodiment of the invention, the N-aryl or N-heteroaryl carboxamide has the following structural formula:

wherein, the substituent R¹And R⁵Independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radicalCyano, carboxyl, di (C)_1-6-alkyl) amino, C_1-6-alkoxycarbonyl and aryl;

R²to R⁴Independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxy, di (C)_1-6-alkyl) amino, C_1-6-alkoxycarbonyl, aryl and-NHCHO;

and/or R¹To R⁵Two or more of which together with the phenyl moiety form a bicyclic or polycyclic fused carbocyclic or heterocyclic ring system;

and the corresponding nitroarene or nitroheteroarene has the following structural formula:

wherein R is¹' to R⁵' Each has a substituent R corresponding to the formula (I)¹、R²、R³、R⁴And R⁵The same meaning, or-NO if the corresponding substituent is-NHCHO₂Or NH₂. Here and hereinafter, the term "C_1-6Alkyl "is understood to mean a linear or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl and the like. Thus, the term "C_1-6Alkoxy group "," C_1-6Alkoxycarbonyl and di (C)_1-6The meaning of-alkyl) amino "is understood to mean each of the radicals represented by C_1-6-an alkyl group and any moiety consisting of oxygen, carbonyloxy (-OC (═ O) -) or nitrogen.

Bicyclic or polycyclic fused carbocyclic or heterocyclic ring systems containing a phenyl moiety are, for example, naphthalene, indane, tetrahydronaphthalene, fluorene, anthracene, phenanthrene, acenaphthene, pyrene and perylene as carbocyclic rings and indole, benzimidazole, thiaindene, quinoline, quinoxaline, chroman, chromene, carbazole and azaanthracene as heterocyclic rings.

In another preferred embodiment of the invention, the N-aryl or N-heteroaryl carboxamides formed have an amino group on the carbon adjacent to the carbon atom bearing the nitro group which can react in situ with the carboxamide moiety to form an imidazole ring, thereby forming a benzimidazole system. If, for example, o-nitroaniline is used as a reactant, the product will be benzimidazole.

In a more preferred embodiment of the invention, the finally formed N-heteroaryl carboxamide is a benzimidazole having the following structural formula:

wherein, the substituent R¹、R⁴And R⁵As defined above, and the corresponding nitroarenes have the following structural formula:

wherein R is²' and R³One of' is-NO₂The other is-NH₂；

And R is¹、R⁴And R⁵As defined above for formula (Ia).

Particularly preferred nitroarenes (IIa) are those in which R is²' is-NO₂And R³' is-NH₂Especially those in which R¹Is methyl and R⁴Is cyano. The carboxamido group of the corresponding benzimidazole (IA) can be hydrolyzed to the corresponding amine, which is an intermediate in the synthesis of alphA-adrenoceptor agonists (WO-A-99/26942).

Benzimidazole (Ia) may exist in one of two tautomeric forms (forms 1H and 3H) or as a mixture of the two forms. For the sake of simplicity, only one of these forms will be described herein.

Preferably, the noble metal-based hydrogenation catalyst is platinum, especially platinum supported on a carrier such as activated carbon.

More preferably, the platinum is "poisoned", especially sulfided.

In order to obtain high yields of the desired formamide or benzimidazole with little formation of by-products or products which are not completely reduced, such as hydroxylamine or o-formylhydroxylamine, it is necessary to add auxiliary catalysts such as vanadium or molybdenum compounds. And the vanadium or molybdenum compound is preferably selected from vanadium (V) oxide₂O₅) Ammonium metavanadate (NH)₄VO₃) And such as sodium molybdate (Na)₂MoO₄) The molybdate of (1).

Preferably, the hydrogenation reaction is carried out at ambient pressure.

The present invention will be described in detail with reference to specific examples. It must be noted, however, that the invention is by no means limited thereto.

Example 1

Formanilide (N-phenylformamide)

Nitrobenzene (12.31g, 100mmol), formic acid (80%; 278mL, 328.0g), sulfided platinum catalyst (5% platinum on activated carbon support, Engelhard # 43045, lot # 08544; 1.55g dry weight), and vanadium oxide (57mg) were charged to a 0.3L double-walled stirred vessel with temperature control under argon. The argon flow was stopped and the slurry was warmed to 91-94 ℃ for 2 hours. HPLC analysis of the reaction mixture indicated: the carboxanilide yield was 79.9% with 18.3% aniline formation.

Example 2 (comparative example)

Formanilide (N-phenylformamide)

The procedure of example 1 was repeated, but without adding vanadium oxide. After 3 hours of reaction, the formamide yield was 55% with 30.6% formanilide and 10.2% aniline by-product.

Example 3

1-chloro-2, 4-bis (carboxamido) benzene

The procedure of example 1 was repeated using 1-chloro-2, 4-dinitrobenzene (100mmol, 20.26g) as a starting compound. The reaction temperature is 91-95 ℃, and the yield of the 1-chloro-2, 4-bis (formylamino) benzene is 77.0 percent. The yield of the partially reduced compound 1-chloro-2 (4) -formylamino-4 (2) -nitrobenzene was 20.5%.

Example 4

1-chloro-2, 4-bis (carboxamido) benzene

1-chloro-2, 4-dinitrobenzene (4mmol, 0.81g), aqueous formic acid (80%; 11mL, 13g), sulfided platinum catalyst (5% platinum on activated carbon support, Engelhard # 43045, lot # 08544; dry weight 62mg), and sodium molybdate dihydrate (2.3mg) were charged to a small stirred vessel under argon. The argon flow was stopped and the slurry was warmed to 90-95 ℃ for 2.5 hours. The yield of 1-chloro-2, 4-bis (formylamino) benzene was 76.1%, and the yield of the partially reduced compound 1-chloro-2 (4) -formylamino-4 (2) -nitrobenzene was 20.5%.

Example 5

1-chloro-2, 4-bis (carboxamido) benzene

The procedure of example 4 was repeated using ammonium metavanadate (2mg) instead of sodium molybdate dihydrate. After reacting at 90-95 ℃ for 2.5 hours, the yield of 1-chloro-2, 4-bis (formylamino) benzene was 77.2%, and the yield of the partially reduced compound 1-chloro-2 (4) -formylamino-4 (2) -nitrobenzene was 20.5%.

Example 6

1-chloro-2, 4-bis (carboxamido) benzene

1-chloro-2, 4-dinitrobenzene (4mmol, 0.81g), ammonium formate (about 40mmol, 2.6g), sulfided platinum catalyst (5% platinum on activated carbon support, Engelhard # 43045, lot # 08544; dry weight 62mg) and acetonitrile (11mL) were charged to a small stirred vessel under argon. The argon flow was stopped and the slurry was heated to 80 ℃ for 2.5 hours, giving a yield of 88.5% 1-chloro-2, 4-bis (carboxamido) benzene.

Example 7

1-chloro-2, 4-bis (carboxamido) benzene

The procedure of example 6 was repeated with the addition of vanadium oxide (2.3 mg). After reacting at 80 ℃ for 2.5 hours, the yield of 1-chloro-2, 4-bis (carboxamido) benzene was 95.7%.

Example 8

1-Formylamino-4-methylbenzene (p-formyltoluidine), the procedure of example 7 was repeated using p-nitrotoluene (4mmol, 0.55g) as a starting compound. The reaction temperature was 80 ℃ and the yield of 1-formylamino-4-methylbenzene was 87.9% after 2.5 hours, and 4-benzylamine (11.2%) was produced as a by-product.

Example 9

1, 3-bis (carboxamido) -2-methylbenzene

The procedure of example 4 was repeated using 2, 6-dinitrotoluene (4mmol, 0.81g) as a starting compound. The joint yield of 1, 3-bis (formylamino) -2-methylbenzene and 1-amino-3-formylamino-2-methylbenzene was 97.2%.

Example 10

1, 3-bis (carboxamido) -2-methylbenzene

The procedure of example 9 was repeated without adding sodium molybdate. The joint yield of 1, 3-bis (formylamino) -2-methylbenzene and 1-amino-3-formylamino-2-methylbenzene was 79.0%.

Example 11

1, 3-bis (carboxamido) -2-methylbenzene

The procedure of example 9 was repeated with the addition of vanadium oxide (2.3mg) in place of sodium molybdate dihydrate. The joint yield of 1, 3-bis (formylamino) -2-methylbenzene and 1-amino-3-formylamino-2-methylbenzene was 98.1%.

Example 12

2-amino-4-methyl-3, 5-dinitrobenzonitrile

A solution of 4-methyl-3, 5-dinitrobenzonitrile (10.5 kg; see for preparation U.S. Pat. No. 4H-3162675), 4-amino-4H-1, 2, 4-triazole (17.0kg) and dimethyl sulfoxide (68.6kg) was dosed into A mixture of lithium tert-butoxide (12.2kg) and dimethyl sulfoxide (106.6kg) over about 50 minutes, with the temperature of each solution being maintained at 20-25 ℃. After aging at 20-25 ℃ for 2 hours, acetic acid (8.9g) was dosed to the reaction mixture over about 10 minutes at 20 ℃. Water (158L) was dosed to the reaction mixture over a period of 1.5 hours at about 20 ℃ to crystallize the product. The product slurry was cooled to 10-15 ℃ and allowed to stand at this temperature for about 45 minutes. The resulting slurry was filtered and washed with water (106L). The resulting wet cake was placed in a vacuum tray dryer and dried at about 50 c under 30 torr vacuum with 2-amino-4-methyl-3, 5-dinitrobenzonitrile as an orange brown solid. The yield was 9.8kg (87%).

Example 13

5-formylamino-4-methyl-1H-benzimidazole-7-carbonitrile [ N- (7-cyano-4-methyl-1H-benzamidine-5-yl) -carboxamide](Ia，R¹＝Me，R⁴＝CN，R⁵＝H)

2-amino-4-methyl-3, 5-dinitrobenzonitrile (IIa, R) in an argon atmosphere¹＝Me，R²’＝NO₂’，R³’＝NH₂，R⁴＝CN，R⁵H,; 22.2g, 100mmol), formic acid (80% aqueous solution; 328.0g), sulfided platinum catalyst (5% platinum on activated carbon support, 57.8% moisture, Engelhard from italy, sample code 43045; 2.44g) and platinum/vanadium catalysisThe agent (5% platinum + 1% vanadium on activated carbon support, water 61.74%, Degussa CF 1082 XBA/W; 1.22g) was added to a 1L double-walled stirred vessel with temperature control. The argon flow was stopped and the slurry was warmed to 90 ℃ in 50 minutes, during which time carbon dioxide evolution began. The reaction mixture was kept at 90-93 ℃ for a further 2 hours under vigorous gassing, while monitoring by HPLC. After completion of the reaction, the mixture was cooled to 25 ℃ and the black suspension was filtered through a 1cm layer of Celite ®, followed by washing with 80% aqueous formic acid (50 g). The bright orange filtrate was concentrated to about 150g in a rotary evaporator at 45 ℃/30 mbar. Methanol (118.0g, 150mL) was added and after 15 minutes at 45 deg.C, the mixture was cooled to 0 deg.C over a half hour and stirred for an additional 1 hour. The precipitated product was filtered off and the product cake was washed with methanol (58.2g, 74 mL). The product thus obtained (21.7g) was dried at 45 ℃/25 mbar for 15 hours.

Yield: 15.3g (75.9%, determination (HPLC): 99.3%).

The melting point is > 310 ℃.

According to nmr data, the product is a mixture of conformers and/or tautomers. The chemical shifts of the main isomer (83%) are given only:

¹H NMR(DMSO-d₆)：δ＝13.2(br.s，1H)，9.87(br.s，1H)，8.47(s，1H)，8.35(d，J＝1.8Hz，1H)，7.91(s，1H)，2.48(s，2H)。

¹³C NMR(DMSO-d₆)：δ＝160.1，144.6，140.5，134.0，129.9，123.0，121.6，117.1，97.8，13.1。

example 14

5-amino-4-methyl-1H-benzamidine-7-carbonitrile

A mixture of 5- (carboxamido) -4-methyl-1H-benzimidazole-7-carbonitrile (4.8kg), water (46L), and concentrated hydrochloric acid (17.8kg) was stirred at about 80 deg.C for about 1.5 hours. After the mixture was cooled to 25 ℃, 50% aqueous sodium hydroxide (17.1kg) and water (64L) were added. The mixture was cooled to 25 ℃ over about 15 minutes. The mixture was then filtered and the product was washed with water (50L). The product was dried in a vacuum tray dryer at 45-50 deg.C and under about 40 torr vacuum.

Yield: 3.8kg (94%).

Example 15

1-Formylamino-2-methoxybenzene (o-formylmethoxyaniline (formoaniside)) the procedure of example 4 was repeated using o-nitrobenzylether (4mmol, 0.55g) as the starting material and vanadium oxide (2.3mg) instead of sodium molybdate dihydrate. After reacting for 2.5 hours at 90-95 ℃, the yield of o-formaniside is 24.8 percent, and the yield of o-anisidine is 62.8 percent as a main product.

Example 16

1-carboxamido naphthalenes

The procedure of example 4 was repeated using 1-nitronaphthalene (4mmol, 0.61g) as the starting material and vanadium oxide (2.3mg) in place of sodium molybdate dihydrate. After the reaction is carried out for 2.5 hours at the temperature of 90-95 ℃, the yield of the 1-formamidonaphthalene is 22.3 percent, and the yield of the alpha-naphthylamine is 60.8 percent.

Claims (10)

1. A process for preparing N-aryl-or N-heteroaryl carboxamides of the formula (I),

wherein, the substituent R¹And R⁵Independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxy, di (C)_1-6-alkyl) amino, C_1-6-alkoxycarbonyl groupAnd an aryl group;

R²to R⁴Independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxy, di (C)_1-6-alkyl) amino, C_1-6-alkoxycarbonyl, aryl and-NHCHO;

and/or R¹To R⁵Two or more of which form a bicyclic or polycyclic fused carbocyclic or heterocyclic ring system with the phenyl moiety;

the method comprises the hydrogenation of nitroarenes or nitroheteroarenes of the formula (II) with formic acid and/or ammonium formate as hydrogen donor and formylating agent in the presence of at least one hydrogenation catalyst based on noble metals selected from rhodium, ruthenium, palladium, osmium, iridium and platinum and a vanadium or molybdenum compound as co-catalyst

Wherein R is¹' to R⁵' each of which has the corresponding substituent R in the formula (I)¹、R²、R³、R⁴And R⁵or-NO if the corresponding substituent is-NHCHO₂Or NH₂。

2. The process of claim 1 wherein the N-aryl or N-heteroaryl carboxamide formed contains an amino group which is capable of reacting in situ with the carboxamide moiety to form an imidazole ring.

3. The method of claim 1 or 2, wherein the N-heteroaryl carboxamide has the following structural formula:

wherein, the substituent R¹、R⁴And R⁵As defined in claim 1, and said nitroarene has the following structural formula:

wherein: r²' and R³One of' is-NO₂The other is-NH₂；

And R is¹、R⁴And R⁵As defined above for formula (Ia).

4. The method of claim 3, wherein R is²' is-NO₂And R is³' is-NH₂。

5. The method of claim 4, wherein R is¹Is methyl and R⁴Is cyano.

6. The method of claim 1, wherein the noble metal is platinum.

7. The method according to claim 6, characterized in that the noble metal-based hydrogenation catalyst is platinum on an activated carbon support.

8. The method of claim 6 or 7, wherein the platinum is sulfided.

9. The method according to claim 1, wherein the vanadium or molybdenum compound is selected from the group consisting of vanadium oxide, ammonium metavanadate and sodium molybdate.

10. The process according to claim 1, characterized in that the hydrogenation reaction is carried out at ambient pressure.