BR102017003941A2 - METHOD FOR THE PREPARATION OF 4-ALCOXY-3-HYDROXYPICOLINIC ACIDS - Google Patents

Description

Patent Descriptive Report for "PROCESS FOR PREPARING 4-ALCOHYL-3-HYDROXYPICOLINIC ACIDS".

FIELD

The present description relates to a process for the preparation of 4-alkoxy-3-hydroxypicolinic acids. More particularly, the present disclosure relates to a process for the preparation of 4-alkoxy-3-hydroxypicolinic acids from furfural. BACKGROUND

US Patent No. 6,521,622 B1 and US Serial Nos. 61 / 747,723 and 14 / 142,183, the disclosures of which are incorporated herein by reference in their entirety, describe inter alia certain heterocyclic aromatic amide compounds of Formula [ 003] and its use as fungicides.

These descriptions also describe the preparation of 4-alkoxy-3-hydroxypicolinic acids as essential intermediates in the preparation of these heterocyclic aromatic amide compounds. It would be useful to have an efficient and scalable process pathway for 4-alkoxy-3-hydroxypicolinic acids from cheap raw materials. SUMMARY

The present disclosure relates to processes for the preparation of 4-alkoxy-3-hydroxypicolinic acids of Formula A

Wherein R1 is a C1-C3 alkyl;

[007] from the compound of Formula B

The compound of Formula A may be prepared in a multistep process comprising the following steps: a) creating a first mixture by combining the compound of Formula B together with a chlorinating agent to form a first mix;

B) isolating a compound of Formula C from the first mixture;

Wherein R is H or Cl.

C) create a second mixture containing an alkali metal alkoxide of Formula D MOR1 D

Wherein M is Na or K, and R1 is a C1-C3 alkyl;

[0014] and the compound of Formula C;

E) isolating a compound of Formula E from the second mixture wherein R is H or Cl, and R 1 is a C 1 -C 3 alkyl;

F) creating a third mixture containing the compound of Formula E, water, and one of a mineral acid and a strong base;

G) heating the third mixture;

H) isolating a compound of Formula F from the third mixture wherein R is H or Cl and R 1 is a C 1 -C 3 alkyl;

I) creating a fourth mixture containing the compound of Formula F and a reducing agent; and j) isolating the compound of Formula A from the fourth mixture.

The present disclosure also relates to a process for the preparation of trichloro-3-hydroxypicolinonitrile of Formula C

Wherein R is Cl;

From the compound of Formula B

In a process comprising the following steps: a) creating a mixture by combining one another with the compound of Formula B and sulfuryl chloride to form a mixture;

B) heating the mixture; and c) isolating the compound of Formula C from the heated mixture, wherein R is Cl.

Another aspect of the present disclosure is the novel intermediates produced in the present process, namely compounds selected from the group consisting of: wherein R1 is a C1 -C6 alkyl; d) wherein R1 is a C1 -C3 alkyl; e) wherein R1 is a C1 -C6 alkyl; f) wherein R1 is a C1 -C6 alkyl. DETAILED DESCRIPTION

The terms "isolating", "isolating" or "isolating" as used herein mean the partial or complete removal of the desired product from the other components of a finished chemical process mixture using standard methods such as, but not limited to these. , filtration, extraction, distillation, crystallization, centrifugation, trituration, liquid-liquid phase separation or other methods known to those skilled in the art. The isolated product may have a purity ranging from <50% to> 50%, and may be purified to a higher purity level using standard purification methods. The isolated product may also be used in a subsequent process step with or without purification.

In the processes described herein, the 4-alkoxy-3-hydroxypicolinic acids of Formula A are prepared from 3-hydroxypolinolinitrile (B) in a series of chemical steps involving chlorination, substitution of a chlorine group with a group. alkoxide, nitrile hydrolysis and halogen reduction. Some of the individual steps can be performed in different order sequences. 3-Hydroxypicolinonitrile of Formula B is readily prepared from furfural as disclosed in U.S. Application Serial Number 14/794430.

A. Preparation of the Formula C Compound

In the process depicted in Scheme I, chlorination of 3-hydroxypolinolinonitrile B may provide a mixture of mono-, di- and tri-chloro-3-hydroxypicolinonitrile depending on the chlorination reagent used. The use of chlorine gas provides a low yield of a mixture of di- and trichloropicolinonitriles C (R = H, Cl), while chlorination of B with 1,3-dichloro-5,5-dimethylidantoin produces mainly the monochlorination product. B1 and smaller quantities Scheme I

Of the di- and trichloropicolinonitrile C (R = H, Cl), chlorination of B with sulfuryl chloride, however, provides predominantly trichloropicolinonitrile of Formula C (R = Cl) in very good yield. Reaction solvents for the chlorination reaction may be selected from the group including water, acetonitrile, sulfolane, DMF, DMSO and mixtures thereof.

B. Preparation of the Formula A Compound

The chemical steps used to convert compound C (R = H, Cl) to the 4-alkoxy-3-hydroxypicolinic acid of Formula A are shown in Scheme II. In the substitution reaction to replace the 4-chloro group of the compound of Formula C with an alkoxy group (Step a), the use of an alkali metal alkoxide of formula MOR1 (M is an alkali metal, R1 is a C1 -C3 alkyl ) yields the 4-alkoxypicolinonitrile of Formula D (R = H, Cl). At least 2 equivalents, and preferably from 2 to 5 equivalents, of alkali metal alkoxide are used in this reaction. Typical alkali metal alkoxides useful in this reaction include sodium or potassium methoxide, ethoxide, 1-propoxide or 2-propoxide. The reaction may be carried out in a protic solvent or reaction medium such as methanol (for methoxide), ethanol (for ethoxide), 1-propanol (for 1-propoxide) or 2-propanol (for 2-propoxide), or mixtures. methanol, ethanol, 1-propanol or 2-propanol with a polar aprotic co-solvent such as DMSO, DMF, sulfolane or NMP. The reaction may also be conducted with an alkali metal alkoxide in one or more of the aprotic polar solvents in the absence of an alcohol co-solvent. The temperature at which the reaction is conducted is between about 20 ° C and about 150 ° C, preferably between about 40 ° C and about 100 ° C. The substitution reaction generally requires from about 1 to about Scheme II.

48 hours to proceed to completion and may be conducted under pressure in a sealed container to prevent loss of volatile solvents. After the reaction is complete, the desired product is recovered by employing standard isolation and purification techniques.

In some embodiments, the preparation of the compound of Formula D (R = H, Cl) from the compound / of Formula C may be conducted by employing solvent mixtures including at least one of a protic solvent and a solvent. polar aprotic, whereby the ratio of percent by volume (vol%) of the protic solvent to the polar aprotic solvent in the total solvent mixture ranges from about 100: 0 to about 0: 100. In some embodiments, the ratio of volume percent (vol%) of the protic solvent to the polar aprotic solvent in the total solvent mixture is from 80 to 100 vol% of the protic solvent to 0 to 20 vol% of the polar aprotic solvent. from 60 to 80% by volume of protic solvent to 20 to 40% by volume of polar aprotic solvent, from 40 to 60% by volume of protic solvent to 40 to 60% by volume of polar aprotic solvent from 20 to 40% by volume of protic solvent to 60 to 80% by volume of polar aprotic solvent, or from 0 to 20% by volume of protic solvent to 80 to 100% by volume of polar aprotic solvent. Preferred volume-to-volume ratios (% by volume) of the protic solvent to the polar aprotic solvent are about 0.01 to 10% by volume of protic solvent to around 90 to 99.99% by volume of aprotic solvent. polar. In some embodiments the solvent mixtures used to prepare the compound of Formula D (R1 = CH3) from the compound of Formula C are methanol and DMSO, methanol and DMF, methanol and sulfolane or methanol and NMP.

In the hydrolysis reaction of the 4-alkoxy-3-hydroxypolinolinonitrile nitrile group of Formulas D and F to produce the 4-alkoxy-3-hydroxypicolinic acids of Formulas E and A, respectively (Steps b in Scheme II), The starting picolinonitriles are typically suspended in a strong aqueous mineral acid reaction medium and heated over a period of time at elevated temperature with a good mixture. Strong mineral acids useful in the hydrolysis reaction include sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid. Preferred strong mineral acid reaction media include aqueous sulfuric acid mixtures such as around 25%, around 30%, around 35%, around 40%, around 45%, around 50%, around 55%, around 60%, around 65%, around 70%, around 75% or around 80% sulfuric acid in water on a weight basis. More preferably, from about 25% to about 70% sulfuric acid in water may be used. The temperature at which the hydrolysis reaction may be conducted is generally between about 75 ° C and about 150 ° C, and preferably between about 80 ° C and about 120 ° C. The hydrolysis reaction generally requires from about 8 to about 48 hours, preferably from about 8 to about 36 hours, to reach completion. After the reaction is complete, the desired product is recovered by cooling and slowly pouring the reaction mixture into cold water and employing standard isolation and purification techniques.

In some embodiments, the hydrolysis reaction of the 4-alkoxy-3-hydroxypicolinonitrile nitrile group of Formulas D and F to produce the 4-alkoxy-3-hydroxypicolinic acids of Formulas E and A, respectively (Steps b in Scheme II), the starting picolinonitriles are suspended in an aqueous reaction medium containing a strong base, such as alkali or alkaline earth metal hydroxide, and heated for a period of time at elevated temperature with a good mixture. Strong bases for use in picolinonitrile hydrolysis include sodium hydroxide and potassium hydroxide. The concentration of the strong base used in picolinonitrile hydrolysis may range from about 10 to about 40 weight percent (% by weight), from about 15 to about 40 weight percent, from about 20 to about 40 weight percent. wt.%, from about 30 to about 40 wt.%, or from about 15 to about 25 wt.%. The ratio of strong base molar equivalent to nitrile starting material to hydrolysis reaction may range from about 3: 1 to about 10: 1, preferably from about 4: 1 to about 7: 1. . The temperature at which the strong base hydrolysis reaction may be conducted is generally between about 75 ° C and about 150 ° C, and preferably between about 80 ° C and about 120 ° C. The strong base hydrolysis reaction generally requires from about 8 to about 48 hours, preferably from about 8 to about 36 hours, to reach completion. After the hydrolysis reaction is complete, the desired product can be isolated by acidifying the reaction mixture and employing standard isolation and purification techniques.

Removal of chlorine groups from positions 5 and 6 of the compound of Formula E to produce the reduced Formula A product can be accomplished by catalytic reduction using a hydrogen source and a transition metal catalyst.

In hydrogen catalytic reduction, suitable hydrogen sources include hydrogen gas or hydrogen transfer reagents such as ammonium, potassium or sodium formate. Suitable transition metal catalysts include, but are not limited to, palladium on carbon (Pd / C) and Raney nickel (Ra / Ni). These catalysts may be used at levels of from about 0.01% to about 10% on a weight basis of the metal for the chloropyridine substrate. Exemplary solvents for use in this reaction include methanol, ethanol, isopropanol, ethyl acetate and acetic acid. A soluble base such as, for example, triethylamine is commonly used for catalytic reduction with hydrogen. From about 2 to about 4 molar equivalents of the soluble base are commonly used. When hydrogen gas is used as the hydrogen source, the reduction reaction may be conducted under an atmospheric hydrogen gas pressure, or at high hydrogen gas pressures such as 69, 138, 276, 414, 552, 689. , 1379, 2068, 2758, 3447, 4137, 4826, 5516, 6205, 6895 kPa or more (10, 20, 40, 60, 80, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 pounds or more per square inch (psi) above atmospheric pressure, or hydrogen gas increase pressures between these values. After the catalytic reduction reaction is complete, the desired product is recovered by employing standard isolation and purification techniques.

In some embodiments, removal of the chlorine groups from positions 5 and 6 of the Formula D compound to produce the reduced Formula F product may be accomplished by catalytic reduction using a hydrogen source and a transition metal catalyst.

The products obtained by any of these processes may be recovered by conventional means such as evaporation, filtration or extraction, and may be purified by standard procedures such as by recrystallization or chromatography.

The following examples are given to illustrate the description.

EXAMPLES

Example 1a. 4,6-Dichloro-3-hydroxypicolinitrile and 4,5,6-trichloro-3-hydroxypicolinitrile [0051] 3-Hydroxypicolinitrile (2.4 g, 20 mmol) and sodium acetate (2.5 g, 30 mmol ) were dissolved in acetonitrile (120 mL) and water (30 mL). The mixture was cooled to -15 to -20 ° C and treated with a slow stream of chlorine until 1.7 g of chlorine was dispensed. The mixture was heated to -2 to -4 O, another 9.0 g of chlorine was dispensed into the mixture and stirring continued for 90 minutes. Excess chlorine was destroyed by the addition of sodium bisulfite solution and two phases were formed. The phases were separated and the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were washed with 20 ml of sat. NaCl, dried (Na 2 SO 4) and evaporated under vacuum. The crude material was purified by RP-HPLC using a YMC-AQ column eluting with 50% aqueous ace-tonitrile containing 0.20% v / v H3PO4 to afford 550 mg of 4,6-dichloro-3-hydroxypicolinitrile and 660 mg 4,5,6-trichloro-3-hydroxypicolinitrile as white solids which decompose when heated to determine melting point. 4,6-Dichloro-3-hydroxypicolinitrile: 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6) δ 154.26, 140.14, 135.24, 129.48, 121.14, 114.58; ESIMS m / z 187 [(Μ - H) -]. 4,5,6-trichloro-3-hydroxypicolinitrile: 13 C NMR (101 MHz, DMSO-d 6) δ 155.16, 137.98, 134.29, 133.17, 118.63, 114.49. ESIMS m / z 221 [(Μ - H) -].

Example 1b. 6-Chloro-3-hydroxypicolinitrile. 4,6-Dichloro-3-hydroxypolinolinitrile and 4,5,6-trichloro-3-hydroxypolinolinitrile [5002] 3-Hydroxypolinolinitrile (500 mg, 4.2 mmol) was combined with 1,3-dichloro-5,5-dimethylidantoin (900 mg, 4.6 mmol) in 2.5 mL of dry acetonitrile and heated at 50 ° C for 20 h. After cooling, the mixture was stirred with 30 mL of ethyl acetate and 10 mL of 20% sodium bisulfite solution. The organic phase was washed with 10 ml of water and 10 ml of sat. NaCl, dried (Na 2 SO 4) and evaporated. The residue was chromatographed by RP-HPLC using a YMC-AQ column eluting with 50% aqueous acetonitrile containing 0.20% v / v H3PO4 to provide 300 mg of 6-chloro-3-hydroxypicolinitrile, 84 mg of 4, 6-dichlorohydroxypicolinitrile and 214 mg of 4,5,6-trichlorohydroxypicolinitrile.

Example 1c. 4.5.6-trichloro-3-hydroxypolinolinitrile To a 100 ml 3-necked flask equipped with a thermal probe and a condenser was added 3-hydroxypolinolinonitrile (2.00 g, 1.67 mmol) and sulfone (15 mL). ). The reaction mixture was heated to 62 ° and 4.2 ml of sulfuryl chloride was slowly added. After 3 h stirring at 62 ° C, the reaction mixture was tested and analyzed by LC-MS, which showed about 75% formation of the desired trichlorinated product. To the mixture was added another 1.0 ml of sulfuryl chloride. The reaction mixture was stirred overnight at 62 ° C, after which LC-MS showed> 90% conversion to the desired product. The reaction mixture was cooled to room temperature and water (25 mL) was added. The organics were extracted with ethyl acetate (150 ml), dried over MgSO4, and volatiles removed by vacuum to reveal an orange oil. The crude product was purified by flash chromatography (hexane-ethyl acetate gradient) to afford 4,5,6-trichloro-3-hydroxypicolinonitrile as a yellow solid (2.30 g, 62%): 13 C NMR (101 MHz, DMSO) δ 155.4, 137.7, 134.3, 133.1, 118.6. 114.6. HRMS ESI (m / z) [M] δ for C 6 HCl 3 N 2 O, 221.9154; measured 220.9087.

Example 1d. 5,6-Dichloro-3-hydroxy-4-methoxypolinolinonitrile To a magnetically stirred solution of 4,5,6-trichloro-3-hydroxypolinolinonitrile (867 mg, 3.88 mmol) in DMSO (8 mL) was added 30% sodium methoxide (3.494 g, 19.40 mmol) in MeOH solution at room temperature. The reaction mixture was heated at 50 ° C for 2 h. The reaction mixture was cooled to 15 to 20 ° C and quenched with 1.5 N HCl. The aqueous layer (pH 1) was extracted twice with MTBE. The combined organic layers were concentrated and the concentrate purified by normal phase chromatography (CH 2 Cl 2 -MeOH) to provide 5,6-dichloro-3-hydroxy-4-methoxypolinolinonitrile (700 mg, 3.20 mmol, 82% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.96 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6) δ 154.55, 152.59, 139.02, 127.59, 118.53, 114.57, 61.31; HRMS-ESI (m / z) [M] + calcd for C 7 H 4 Cl 2 N 2 O 2, 217.965; found 217.9654.

Example 1e. 6-Chloro-3-hydroxy-4-methoxypolinolinonitrile To a magnetically stirred solution of 4,6-dichloro-3-hydroxypolinolinonitrile (150 mg, 0.794 mmol) in DMSO (3 mL) was added 30% sodium methoxide. (715 mg, 3.97 mmol) in MeOH solution at room temperature. The reaction mixture was heated at 50 ° C for 18 h. The reaction mixture was cooled to 15 to 20 Ό and quenched with 1.5 N HCl. The aqueous layer (pH ~ 1) was extracted twice with MTBE. The combined organic layers were concentrated and the concentrate purified by normal phase chromatography (CH 2 Cl 2 -MeOH) to afford 6-chloro-3-hydroxy-4-methoxypolinolinonitrile (110 mg, 0.596 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.40 (s, 1H), 3.98 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6) δ 156.96, 148.97, 141.41, 117.68, 114.98, 111.22, 57.23; HRMS-ESI (m / z) [M] + calcd for C 7 H 5 ClN 2 O 2, 184.0041; found 184.0040. Example 1f. 5,6-Dichloro-3-hydroxy-4-methoxypolyolinic acid To the solid of 5,6-dichloro-3-hydroxy-4-methoxypolyolinonitrile (153 mg, 0.7 mmol) was added 30% KOH (4 ml) at room temperature, and the mixture was stirred overnight at 90 to 95 Ό. After the reaction was complete, the reaction mixture was cooled to rt and the pH adjusted to 2 to 3 with 3 N HCl. The precipitated solid was collected, washed with water and dried to provide 5,6-dichloro-3-acid. hydroxy-4-methoxypolyolinic (165 mg, 0.693 mmol, 99% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 4.03 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6) δ 168.70, 154.37, 153.49, 134.62, 131.82, 124.09, 60.23; HRMS-ESI (m / z) [M] + calcd for C 7 H 5 Cl 2 NO 4, 236.9596; found, 236.9591.

Example 1q. 6-Chloro-3-hydroxy-4-methoxypicolinic acid A mixture of 6-chloro-3-hydroxy-4-methoxypolyolinonitrile (80 mg, 0.433 mmol) in 30% KOH (5 mL) was stirred at 90 Ό for 20 h. The reaction mixture was cooled to room temperature, followed by the addition of 6N HCl slowly to precipitate the product. The solid was filtered and washed with water to afford 6-chloro-3-hydroxy-4-methoxypicolinic acid (60 mg, 0.295 mmol, 68.0% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6 δ 7.29 (s, 1H), 3.92 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6) δ 170.16, 156.99, 148.72, 139.90, 129.31, 111.03, 56.80; HRMS-ESI (m / z) [M] + calcd for C 7 H 6 ClNO 4, 202.9985; found 202.9990.

Example 1 i. 3-Hydroxy-4-methoxypolycinic acid To 3-hydroxy-6-bromo-4-methoxypolyolinic acid (60 mg) and MeOH (5 ml) in a pressure tube (50 ml) was added triethylamine (51 mg) . Then, under a nitrogen atmosphere, 10% Pd / C (20 mg) was added to the tube. The reaction slurry was placed under 500 psi (3447 kPa) hydrogen gas and stirred at 50 ° C. After 20 h, the hydrogen gas was removed. The reaction slurry was filtered through a pad of celite and the pad of celite was washed with fresh methanol. The methanolic filtrate was concentrated to afford a solid. The solid was diluted with 0.2 N HCl (10 mL) to adjust the pH to about 1 to 2 and the resulting suspension was collected by filtration, washed with water and dried outdoors for several hours and then in an oven. vacuum at 50 ° C to provide 3-hydroxy-4-methoxypolycinic acid (20 mg) as a white solid in 45% yield: 1H NMR (400 MHz, DMSO-d6 δ 8.04 (d, J = 6, 4 Hz, 1H), 7.39 (d, J = 6.5 Hz, 1H), 4.04 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6) δ 164.16, 162.03, 152.52, 132.32, 126.57, 109.13, 57.35 HRMS-ESI (m / z) calcd for C 7 H 7 NO 4, 169.0379, found 169.0375.

Claims (10)

A process for the preparation of the compound of Formula A wherein R1 is a C1 -C3 alkyl; from the compound of Formula B characterized in that it comprises the following steps: a) creating a first mixture by combining the compound of Formula B and a chlorinating agent; b) isolating a compound of Formula C from the first mixture; wherein R is H or Cl; c) creating a second mixture containing an alkali metal alkoxide of Formula D MOR1 D wherein M is Na or K, and R1 is a C1 -C3 alkyl; and the compound of Formula C; d) isolating a compound of Formula E from the second mixture wherein R is H or Cl and R1 is a C1 -C4 alkyl; e) creating a third mixture containing the compound of Formula E, water, and one of a mineral acid and a strong base; f) heating the third mixture; g) isolating a compound of Formula F from the third mixture wherein R is H or Cl and R 1 is a C 1 -C 3 alkyl; h) creating a fourth mixture containing the compound of Formula F and a reducing agent; and i) isolating the compound of Formula A from the fifth mixture; wherein R1 is a C1-C3 alkyl. Process according to Claim 1, characterized in that the solvent for the first mixture is selected from the group including water, acetonitrile, sulfolane, DMSO and xylene. Process according to Claim 1, characterized in that the chlorinating agent is selected from the group including chlorine, sulfuryl chloride and 1,3-dichloro-5,5-dimethylidantoin. Process according to Claim 1, characterized in that R1 is CH3. Process according to Claim 1, characterized in that the mineral acid is sulfuric acid. Process according to Claim 1, characterized in that the strong base is sodium hydroxide or potassium hydroxide. Process according to Claim 1, characterized in that the reducing agent comprises hydrogen and a transition metal catalyst. Process according to claim 7, characterized in that hydrogen is hydrogen gas and the transition metal catalyst is comprised of palladium on carbon. A process for preparing the compound of Formula C wherein R is Cl; from the compound of Formula B characterized in that it comprises the following steps: a) creating a mixture by combining the compound of Formula B and sulfuryl chloride; b) heat the mixture; and c) isolating the compound of Formula C from the mixture. Compound, characterized in that it is selected from the group consisting of: a) wherein R1 is an alkyl d) wherein R1 is a C1 -C3 alkyl; e) wherein R1 is a C1 -C3 alkyl; and f) wherein R1 is a C1 -C3 alkyl.