MXPA00007265A - Synthesis of 3-amino-2-chloro-4-methylpyridine from malononitrile and acetone - Google Patents

Abstract

A method for making 3-amino-2-chloro-4-methylpyridine from molononitrile, as depicted in reaction scheme (I).

Description

SYNTHESIS OF 3-A INO-2-CHLORINE-4-METHYL PYRIDINE FROM MALONONITRIL AND ACETONE Background of the Invention i. Field of the invention The present invention relates to a regioselective method for making • 3-amino-2-chloro-4-methylpyridine from malononitrile and acetone. 2. Description of the Referred Technique That Includes Information Described Under 37 CFR 1.97 and 1.98 As described in U.S. Patent Number. 5,336,972, the compound 3-amino-2-chloro-4-methylpyridine is useful as an intermediate material for the synthesis of ll-cyclopropyl-5,1, -di-idro-4-methyl-6H-dipyrido [3, 2-b: 2 ', 3' -e] [1,4] diazepin-6-one, an HIV reverse transcriptase inhibitor useful for the treatment of HIV-1, known as nevirapine.

There are several methods for the synthesis of 3-amino-2-chloro-4-methylpyridine. A close synthesis, which starts from 2-Chloro-4-methyl-3-nitropyridine, has been described by Chapman et al. (J. Chem. Soc. Perkin Trans. I, 2398-2404 (1980)).

Ref. 0121588 As reported by Grozinger et al. (J. Heterocyciic Chem. 32, 259 (1995)), the compound has been synthesized in small laboratory batches by nitrating the readily available 2-amino-picoline or 2-hydroxy-4-picoline. This procedure suffers from non-selective nitration in positions 3 and 5, as well as thermochemical risks and potential for "out of operation" when carried out on a large scale. The disadvantages of the nitration-based process lead to the development of two synthetic routes referred starting from ethylacetoacetone and cyanacetamide, as described in U.S. Patent Numbers. 5,668,287 and 5,200,522. Both of the last two synthetic routes require the dicloration of 2,6-dihydroxy-4-methyl-3-pyridinecarbonitrile intermediate, in positions 2 and 6, subsequent dechlorination and finally selective recloration in position 2. The dicloration and dehalogenation, as well as as the selective monochlorination in position 2 requires special manufacturing equipment that is expensive and which can not be easily available. Still another synthesis, comprising the steps of chlorination of ethyl cyanoacetate, addition of Michael with crotonaldehyde, cyclization, conversion to the amide and finally reduction to the amine has been described by Zhang et al.

(Tetrahedron 51 (48), 13177-13184 (1995)), who reported that while the desired product was obtained, the addition of Michael was slow and the performance cyclization low. Scheneider (U.S. Patent Number 5,686,618) has provided a aa ^ ^ -fe .. synthesis comprising the reduction of 2,6-dichloro-3-amino-4-methylpyridine and monochlorination at the 2-position using H202 in HCl, suitable for use on an industrial scale. A synthesis starting with 2-chloro-3-aminopyridine has been described by Nummy (U.S. Patent No. 5,654,429).

Brief Description of the Invention The present invention provides an improved method for making 3-amino-2-chloro-4-methylpyridine, which comprises the steps described below in the following reaction scheme. _ÉÍÍi__i__ According to the invention, and as shown in the above reaction scheme, the Knoevenagel reaction of acetone (2) with malononitrile (3) gives isopropylidenemalononitrile (4). This is condensed with triethyl orthoformate in acetic acid anhydride to give a mixture of the beta-gamma-unsaturated aldehyde equivalent (5) and the enol ether (6). The mixture of (5) and (6) is ring-sealed with anhydrous ammonia in ethanol to give 2-amino-4-methyl-pyridine-carbonitrile (7). The intermediate product (7) is converted with sodium nitrite to the diazonium salt, which is then treated in situ with water to produce 2-hydroxy-4-methyl-3-cyanopyridine (8). The derivative of 2-hydroxy-pyridine (8) is chlorinated with phosphorus oxychloride to produce 2-chloro-4-methyl-3-pyridinecarbonitrile (9). The nitrile (9) is hydrolysed in concentrated sulfuric acid to produce 2-chloro-4-methyl-3-carboxamide (10). Finally, the amide (10) is converted via the Hofmann amide degradation reaction (treatment with chlorine or bromine solution in excess sodium hydroxide by hypohalides), in a manner known per se, to the desired final product, 3- amino-2-chloro-4-methylpyridine (1).

Description of the Preferred Modality The following examples describe, in greater detail, the various steps of the process according to the invention and, in - ^ feS & g set, represent the presently preferred embodiment of the invention.

Example 1 Synthesis of 2- (1-methylethylidene) malononitrile (4).

The malononitrile (3) was heated at 50-60 ° C until the contents melted. In a 2000 mL three-necked round bottom flask containing 600 mL of MTBE (tert-butyl methyl ether), 200 g of the liquefied malononitrile was poured and equipped with a stirrer, reflux condenser and heating jacket. To the mixture was added 232 g of acetone (2), 40 mL of acetic acid and 2 g of beta-alanine. The reaction mixture was heated to reflux using a Dean Stark trap for two days. A total of 55 mL of water was collected. The reaction mixture was cooled and washed twice with 250 mL of water and once with 250 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to yield 283 g of an anhydrous amber oil. The oil was distilled using a Vigreaux distillation column at 0.05 to 0.02 mmHg at 56-60 ° C.

Yield 242.8g (84% theoretical) of 4. _. ~ -__- - > -.-- .., ___-__ * -_-_-- < - «» »_ Fj emplo 2 Synthesis = 2- (3-ethoxy-1-methyl- (E) -2-propenylidene) malononitrile [____) and: 2- (3,3-diethoxy-l-methylpropylidene) alononitrile (6) .

To a 1-liter three-necked flask equipped with a reflux condenser and a heating jacket was added 165g of isopropylidenemalononitrile (4), 280 mL of acetic anhydride and 253g of triethylorthoformate, followed by the addition of 19.2g of aluminum chloride at room temperature without cooling. The solution was heated to 115 ° C for 2 days, then 155 mL of low boiling material was distilled at 133-145 ° C at atmospheric pressure. After cooling to room temperature, additional 75 mL of maleic anhydride and 61.5 g of triethylorthoformate were added and the mixture was heated for an additional 24 hours at 150-155 ° C. The mixture was cooled to room temperature and poured into 300 mL of a saturated sodium carbonate solution, followed by extraction-with 250 mL of dichloromethane three times. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to give a dark oil, which was distilled at 0.05 mmHg, Fraction # 1, gave 65 g of a clear liquid, boiling temperature (pe) at 40-48 ° C, TLC (toluene / 5% ethanol): showed unreacted starting material. Fraction # 1 can be recycled in sequence batches. Fraction # 2 gave 97g of a colored oil - ______ ....... ^ a¿ ^^^ ______ tJ__ft? law ^^ m. -.tw? > «Yellow, boiling temperature (p.p.) at 130 to 145 ° C. The addition of petroleum ether gave 5. Melting temperature (m.p.): 53-56 ° C, NMR (CDC13), ppm: 1.34 (t, 3H); 6.3 (s, 3H); 4.1 (q, 2H).

No performance was calculated because Fraction # 2 is a mixture of (5) and (6).

Example 3 Synthesis of 2-amino-4-methylpyridine-3-carbonitrile (7) A mixture of (5) and (6) (97 g) obtained from the previous experiment (Fraction # 2) was added to 1 L of ethanol. Anhydrous ammonia was passed through the solution without cooling, using a fritted filter plug. After 15 minutes, the mixture was heated to reflux for two hours, then poured into 2L of water. The product was extracted with 300 mL of methylene chloride three times. The organic phase was dried over MgSO4, filtered and concentrated to dryness. The addition of ether gave 49g (39.0%) of (7) calculated for lOOg of Isopropylidenemalononitrile (4) (taking the recovered material into consideration). Melting point (m.p.): 148-151 ° C, NMR (CDC13), ppm: 2.4 (s, 3H); 5.4 (bs, 2H); 6.57 (d, 1H); 8.07 (d, 1H).

Example 4 Synthesis of 2-hydroxy-4-methylpyridine-3-carbonitrile ().

To a 2-liter three neck flask equipped with a stirrer, thermometer and dropping funnel was added 750 mL of water and 20 mL of sulfuric acid. To the solution was added 26.6g of (7). The suspension was heated to approximately 50 ° C, until everything was dissolved. The solution was cooled in an ice bath to 10 ° C, then the solution of 20.7 g of sodium nitrite in 100 mL of water was added dropwise slowly over a period of 5 hours, keeping the temperature below + 15 ° C. After the addition, the reaction mixture was stirred at room temperature overnight. The yellow crystalline material was filtered, dried under vacuum to give 12.8 g (47.8%) of (8). Melting temperature (m.p.): 238-240 ° C, NMR (DMSO); ppm: 2.4 (s, 3H); 3.5 (bs, 1H); 6.26 (m, 1H); 9.68 (m, 1H).

Analysis. Calculated: C, 62.68; H, 4.51; N, 20.88%.

Found: C, 62. 75; H, 4 79; N, 20 95% MS: (EI) m / z 134, 105 Example 9 Synthesis of 2-chloro-4-methylpyridine-3-carbonitrile (9).

To a 250 mL flask equipped with a magnetic stirrer was added lOg of 2-hydroxy-4-methyl-3-pyridinylcarbonitrile (8) and 60 mL of phosphorus oxychloride. The mixture was refluxed for one hour. Excess P0C13 was distilled under reduced pressure. The residue was poured into water. The crystalline material was filtered and dried to give 10.2g (89.2%) of (9). Melting point (m.p.): 109-110 ° C, NMR (DMSO); ppm: 2.56 (s, 3H); 7.6 (bs, 1H); 8.56 (, 1H). MS: (EI) m / z M + 152, 146.

Example LQ Synthesis ds 2-chloro-4-methylpyridin-3-carboxamide (3.0).

A solution of 6.33 g of 2-chloro-4-methyl-3-pyridinecarbonitrile (9) in 6 mL of concentrated H2SO4 was stirred at 100 ° C for 1 hour, ice water was added, made alkaline with ammonium hydroxide and it was extracted with ethyl acetate. The extract was dried and the solvent was removed to leave a crystalline residue. Recrystallization with ethyl acetate gave 4.9g (69%) of (10).

Melting temperature (m.p.): 178-180 ° C, NMR (DMSO); ppm: 2.3 (s, 3H); 7.3 (m, 1H); 7.75, 8.80 (NH2); 8.2 (m, 1H). gg ^^ Analysis. Calculated: C, 49.28; H, 4.14; Cl, 20.78; N, 16.42%. Found: C, 49.43; H, 4.23; Cl, 20.65; N, 16.52%. MS: (EI) m / z 170, 154, 126.

Example 11 Synthesis of 3-amino-2-chloro-4-methylpyridine (1).

A solution of 11.7 g (0.293 mol) of sodium hydroxide in 11 mL of water was stirred and cooled to 0 ° C. 14.2g (0.293 mol) of bromine was added dropwise maintaining the temperature at «0 ° C. To a pale yellow solution was added 13.2g (0.077 mole) of 2-Chloro-4-methylnicotinamide (10) in portions at 0-5 ° C. The ice bath was removed and the reaction mixture was heated to 75 ° C for one hour and maintained at 60-75 ° C for an additional 2 hours. The mixture was cooled all night and the crystalline product was collected by filtration to give lOg (90.6%) of the title compound [melting temperature (p.f.): 62-64 ° C]. NMR and MS were identical to the data reported by Hargrave, et al., J. Heterocyciic Chem., 34, 223 (1991).

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property. * - * - ~ - *. *

Claims (1)

1. A method for making 3-amino-2-chloro-4-methylpyridine, characterized in that it comprises the following steps: (a) reacting malononitrile with acetone to produce isoproyl-ylidenmalononitrile; (b) condensing the thus-produced isopropylidenemalononitrile with triethyl orthoformate in acetic anhydride to produce a mixture of 2- (3-ethoxy-1-methyl- (E) -2-propenylidene) ononitrile and 2- (3, 3) -dietoxy-l-methylpropylidene) malononitrile; (c) treating the mixture of 2- (3-ethoxy-1-methyl- (E) -2-propenylidene) malononitrile and 2- (3, 3-diethoxy-1-methylpropylidene) malononitrile thus produced with anhydrous ammonia in ethanol, to effect the ring closure, in this way 2-amino-4-methyl-pyridine-carbonitrile is produced; (d) reacting the 2-amino-4-methyl-pyridine-carbonitrile thus produced with sodium nitrite, to produce diazonium salt thereof, and then treating the diazonium salt in situ with water to produce 2-hydroxy-4- methyl-3-cyanopyridine; (e) reacting the 2-hydroxy-4-methyl-3-cyanopyridine thus produced with phosphorus oxychloride to produce 2-chloro-4-methyl-3-pyridinecarbonitrile, - (f) treating the 2-chloro-4-methyl -3-pyridinecarbonitrile thus produced with concentrated sulfuric acid, to effect hydrolysis, to produce 2-chloro-4-methyl-3-carboxamide; Y (g) converting the 2-chloro-4-methyl-3-carboxamide thus produced, via the Hofmann reaction (treatment with chlorine or bromine solution in excess sodium hydroxide), to 3-amino-2-chloro-4 -methylpyridine. SYNTHESIS OF 3-AMINO-2-CHLORO-4-METHYL PYRIDINE FROM MALONONITRILE AND ACETONE SUMMARY OF THE INVENTION A method for making 3-amino-2-chloro-4-methylpyridinone from malononitrile, as described in the following reaction scheme.