TWI733749B - Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids - Google Patents

Abstract

4-Alkoxy-3-hydroxypicolinic acids may be conveniently prepared from 4,6-dibromo-3-hydroxypicolinonitrile in a series of chemical steps selected from bromo substitution, nitrile hydrolysis and halogen reduction that are conducted as a single pot process. 4,6-Dibromo-3-hydroxypicolinonitrile may be prepared from furfural in a series of chemical steps selected from cyano-amination, amine salt formation and bromination-rearrangement.

Description

Method for preparing 4-alkoxy-3-hydroxypicolinic acid

Field This disclosure relates to methods for preparing 4-alkoxy-3-hydroxypicolinic acid. More specifically, this disclosure relates to a method for preparing 4-alkoxy-3-hydroxypicolinic acid from furfural.

及其等作為殺真菌劑之用途。Background U.S. Patent No. 6,521,622 B1 and U.S. Application Serial No. 61/747,723 specifically describe heterocyclic aromatic amide compounds with the following general formula

And its use as a fungicide.

These disclosures also describe the preparation of 4-alkoxy-3-hydroxypicolinic acid and its derivatives, which are used as key intermediates for the preparation of these heterocyclic aromatic amide compounds. It would be useful to have an efficient and scalable process path for preparing 4-alkoxy-3-hydroxypicolinic acid from inexpensive raw materials.

其中，R¹ 係一C₁ -C₃ 烷基。Summary This disclosure relates to a method for preparing 4-alkoxy-3-hydroxypicolinic acid of chemical formula A from a compound of chemical formula B.

Wherein, R ¹ is a C ₁ -C ₃ alkyl group.

其中，M係Na或K，且R¹ 係一C₁ -C₃ 烷基； 及具有化學式B之化合物，及加熱此第一混合物； b)藉由使水、一強鹼，及鋅金屬添加至第一混合物產生一第二混合物； c)加熱此第二混合物；及 d)隔離具有化學式A之化合物。The compound of formula A can be prepared in a one-pot method, which comprises the following steps: a) A first mixture is produced, which contains an alkali metal alkoxide of formula C

Wherein, M is Na or K, and R ¹ is a C ₁ -C ₃ alkyl group; and a compound of formula B, and heating the first mixture; b) by adding water, a strong base, and zinc metal Until the first mixture produces a second mixture; c) heating the second mixture; and d) isolating the compound of formula A.

。This disclosure also relates to a method for preparing a compound of chemical formula B from a compound of chemical formula D,

.

c)使一礦物酸之一水溶液添加至第二混合物形成一第三混合物； 其中，礦物酸係HCl、HBr、H₂ SO₄ 、HNO₃ ，或H₃ PO₄ ； d)自第三混合物分離一第四混合物，其係含有具有化學式F之一化合物的一水性混合物；

其中，X係Cl、Br、HSO₄ 、NO₃ ，或H₂ PO₄ ； e)使選自包括下列之組群的一溴化劑： i)溴及具有一氧化劑之一溴化物化合物；及 ii)具有一氧化劑之一溴化物化合物， 添加至第四混合物形成一第五混合物；及 f)自第五混合物隔離具有化學式B之化合物。The compound of formula B can be prepared by one of the following steps: a) by mixing a two-phase water-organic solvent system, an ammonia source, a cyanide source, and a compound of formula D together to produce a A first mixture; b) separating a second mixture from the first mixture, which contains a compound of formula E, which is a solution in an organic solvent;

c) Add an aqueous solution of a mineral acid to the second mixture to form a third mixture; wherein the mineral acid is HCl, HBr, H ₂ SO ₄ , HNO ₃ , or H ₃ PO ₄ ; d) separate from the third mixture A fourth mixture, which is an aqueous mixture containing a compound of formula F;

Wherein, X is Cl, Br, HSO ₄ , NO ₃ , or H ₂ PO ₄ ; e) using a brominating agent selected from the group consisting of: i) bromine and a bromide compound having an oxidizing agent; and ii) A bromide compound with an oxidant is added to the fourth mixture to form a fifth mixture; and f) the compound of formula B is isolated from the fifth mixture.

。This disclosure also relates to a method for preparing a compound of chemical formula G from a compound of chemical formula D

.

c)使一礦物酸之一水溶液添加至第二混合物形成一第三混合物； 其中，礦物酸係HCl、HBr、H₂ SO₄ 、HNO₃ ，或H₃ PO₄ ； d)自第三混合物分離一第四混合物，其係含有具有化學式F之化合物的一水性混合物；

其中，X係Cl、Br、HSO₄ 、NO₃ ，或H₂ PO₄ ； e)使一溴化劑添加至第四混合物形成一第五混合物，此溴化劑係具有一氧化劑之一溴化物化合物；及 f)自第五混合物隔離具有化學式G之化合物。The compound of formula G can be prepared by one of the following steps: a) A first mixture is produced by mixing water, an organic solvent, an ammonia source, a source of cyanide, and a compound of formula D together; b ) Separating a second mixture from the first mixture, which contains a compound of formula E, which is a solution in an organic solvent;

c) Add an aqueous solution of a mineral acid to the second mixture to form a third mixture; wherein the mineral acid is HCl, HBr, H ₂ SO ₄ , HNO ₃ , or H ₃ PO ₄ ; d) separate from the third mixture A fourth mixture, which is an aqueous mixture containing a compound of formula F;

Wherein, X is Cl, Br, HSO ₄ , NO ₃ , or H ₂ PO ₄ ; e) adding a brominating agent to the fourth mixture to form a fifth mixture, this brominating agent has an oxidizing agent and a bromide Compound; and f) isolating the compound of formula G from the fifth mixture.

Detailed description The term "isolation" as used herein means the use of unlimited methods such as filtration, extraction, distillation, crystallization, centrifugation, grinding, liquid-liquid phase separation, or other methods known to those skilled in the art The standard method allows the desired product to be partially or completely removed or separated from the other components of a complete chemical method mixture. The isolated product can have a purity ranging from <50% to >50%, and can be purified to higher purity using standard purification methods. The isolated product can also be used in a subsequent processing step with or without purification.

In the method described here, 4-alkoxy-3-hydroxypicolinic acid is derived from 4,6-dibromo-3-hydroxypicolinonitrile, in a series of chemistry involving bromine substitution, nitrile hydrolysis, and halogen reduction Steps to prepare. This disclosure describes an improved method for preparing 4-alkoxy-3-hydroxypicolinic acid from 4,6-dibromo-3-hydroxypicolinonitrile using a more efficient "one-pot" method.

An improved method for preparing 4,6-dibromo-3-hydroxypyridinecarbonitrile from furfural is also described here. This method uses one of the bromide/oxidant to partially or completely replace the bromine in the reagent to generate bromine in situ. This method is improved to reduce the need for the treatment of elemental bromine and to improve the utilization efficiency of bromine atoms.

The production of bromine in situ in the preparation of 4,6-dibromo-3-hydroxypicolinonitrile from furfural described here is equivalent to the use of elemental bromine, and surprisingly, the presence of oxidants will not negatively impact Strecker or rearrangement reaction. In addition, it is also surprising that the oxidizing agent will not cause degradation or oxidation of the pyridine ring or nitrile group of 4,6-dibromo-3-hydroxypyridinecarbonitrile. A. Preparation of compounds of formula A

An improvement for the preparation of 4-alkoxy-3-hydroxypicolinic acid of formula A from 4,6-dibromo-3-hydroxypyridinecarbonitrile (compound B) using a more efficient "one-pot" method The method is described. This method involves first treating a compound of formula B with sodium monoalkoxide, then treating with zinc metal (a strong aqueous base), and optionally adding another strong aqueous base, and finally acidifying the final reaction mixture with a strong aqueous acid to produce a chemical formula Compound of A (wherein, R ¹ is a C ₁ -C ₃ alkyl group).

以從約1至約3莫耳當量之鋅金屬(即，具有＜ 10 µm顆粒尺寸之Zn粉塵，具有＜ 150 µm之顆粒尺寸的Zn粉塵，或另外高表面積之Zn固體)處理，及於從約20 °C至約70 °C攪拌至完成6-溴基基團還原為止。然後，可添加另外之強水性鹼(2-3莫耳當量)，且形成之混合物於從約80 °C至約95 °C加熱從約4至約24小時。具有化學式A之合意化合物(其中，R¹ 係甲基)可藉由酸化反應混合物及使用標準隔離及純化技術而隔離。In an embodiment of this method, the reaction of a compound of formula B with sodium methoxide can be carried out in a bipolar aprotic solvent (such as DMSO or cyclobutane), optionally with added methanol, or as a solvent Carried out in methanol. Use at least 2 molar equivalents of sodium methoxide, preferably 2.5-3 molar equivalents, and ^{heat from about 50 to about 80 o} C for about 1 hour to about 24 hours to complete the replacement of 4-bromo group with methoxide Group. Then, the formed reaction mixture can be diluted with water and a strong aqueous base (such as potassium hydroxide or sodium hydroxide) (2-3 molar equivalents), process I

Treated with from about 1 to about 3 molar equivalents of zinc metal (ie, Zn dust with a particle size of <10 µm, Zn dust with a particle size of <150 µm, or another high surface area Zn solid), and Stir at about 20 °C to about 70 °C until the reduction of the 6-bromo group is complete. Then, another strong aqueous base (2-3 molar equivalents) can be added, and the resulting mixture is heated from about 80°C to about 95°C for about 4 to about 24 hours. Desirable compounds of formula A (wherein R ¹ is a methyl group) can be isolated by acidifying the reaction mixture and using standard isolation and purification techniques.

In another embodiment of this method, after the reaction of the compound of formula B with sodium methoxide is completed, the resulting reaction mixture can be diluted with water, a strong aqueous base (4-6 molar equivalent), and zinc metal, and then, Maintain a temperature ranging from about 20 °C to about 95 °C for from about 2 to about 48 hours. After the zinc reduction and alkaline hydrolysis reactions are complete, the desired product can be isolated by acidifying the reaction mixture and using standard isolation and purification techniques.

In another embodiment of the present invention, after the reaction of the compound of formula B with sodium methoxide is completed, the resulting reaction mixture can be diluted with water and a strong aqueous base (4-6 molar equivalents), and the resulting mixture can be from about The hydrolysis of the nitrile group is completed by heating at 80°C to about 95°C for about 4 to about 24 hours. The resulting mixture can then be treated with zinc metal and then maintained at a temperature ranging from about 20°C to about 70°C until the reduction of the 6-bromo group is complete. After the zinc reduction and alkaline hydrolysis reactions are complete, the desired product can be isolated by acidifying the reaction mixture and using standard isolation and purification techniques.

In another embodiment of this method, after the reaction of the compound of formula B with sodium methoxide is completed, the hydrolysis of the nitrile group and the reduction of the 6-bromo group can be achieved by making water, a strong aqueous base, and zinc metal ( Add to the reaction vessel in one portion or over a period of time) and heat from about 80°C to about 95°C for the time required for the hydrolysis of the nitrile group and the reduction of the 6-bromo group And at the same time. B. Preparation of compounds of formula B

具有化學式F之氰基(呋喃-2-基)四甲基鹵化銨鹽係以一二相方法(有機-水性，2相溶劑系統)而製備，其係先使糠醛(化學式D)與至少1當量之一氨源及一氰化物源之每一者於此項技藝者稱為α-胺基腈之Strecker合成的反應中反應(步驟a)，此反應係描述於Organic Syntheses， Coll. Vol. I，第21頁及Coll. Vol. III，第84及88頁，

而提供具有化學式E之胺基(呋喃-2-基)乙腈。適合之氨源包括：銨鹽，不受限地諸如，乙酸銨、溴化銨、氯化銨、甲酸銨、硫酸銨，及氰化銨；溶於一有機溶劑中之氨，諸如，於甲醇中之氨、於乙醇中之氨，及於二

烷中之氨；於水中之氨(即，氫氧化銨)；及液體水性氨或氣體氨。適合之氰化物源包括：氰化物鹽，不受限地諸如，氰化鈉、氰化鉀，及氰化銨；及氰化氫，其可以一連續添加方式與氨添加至糠醛。反應(步驟a)係於一2相溶劑系統中實行，其係由水及選自下述之一水不互溶之溶劑所組成：醚類，諸如，乙醚、甲基第三丁基醚(MTBE)、四氫呋喃(THF)，及2-甲基四氫呋喃(2-MeTHF)；酯類，諸如，乙酸乙酯，及乙酸異丙酯；烷類，諸如，己烷、庚烷，及辛烷；芳族化合物，諸如，苯甲醚、甲苯，及二甲苯，或二甲苯之混合物，及此等之混合物。此一反應已描述於WO申請案第2000049008號案，第55頁。本反應典型上係以攪拌足以維持基本上均勻之反應物混合物而進行。此一反應可於約15°C與約30°C之間進行約1至約50小時。As shown in Scheme II, furfural (chemical formula D) can be converted into 4,6-dibromo-3-hydroxypicolinonitrile (chemical formula B) using one of chemical steps a, b, and c. Process II

The cyano (furan-2-yl) tetramethylammonium halide salt of chemical formula F is prepared by a one-two phase method (organic-aqueous, two-phase solvent system), which is firstly made of furfural (chemical formula D) and at least 1 Each of an equivalent source of ammonia and a source of cyanide reacts in a reaction of the Strecker synthesis of α-aminonitrile called by the artisan (step a), and this reaction is described in Organic Syntheses, Coll. Vol. I, page 21 and Coll. Vol. III, pages 84 and 88,

And provide the amino (furan-2-yl) acetonitrile with the chemical formula E. Suitable ammonia sources include: ammonium salts, such as, without limitation, ammonium acetate, ammonium bromide, ammonium chloride, ammonium formate, ammonium sulfate, and ammonium cyanide; ammonia dissolved in an organic solvent, such as methanol Ammonia in Ammonia, Ammonia in Ethanol, and Ammonia in Two

Ammonia in alkanes; ammonia in water (ie, ammonium hydroxide); and liquid aqueous ammonia or gaseous ammonia. Suitable cyanide sources include: cyanide salts, such as, without limitation, sodium cyanide, potassium cyanide, and ammonium cyanide; and hydrogen cyanide, which can be added to furfural with ammonia in a continuous addition. The reaction (step a) is carried out in a two-phase solvent system, which is composed of water and one of the following water-immiscible solvents: ethers, such as diethyl ether, methyl tertiary butyl ether (MTBE) ), tetrahydrofuran (THF), and 2-methyltetrahydrofuran (2-MeTHF); esters, such as ethyl acetate, and isopropyl acetate; alkanes, such as hexane, heptane, and octane; aromatic Group compounds, such as anisole, toluene, and xylene, or mixtures of xylenes, and mixtures of these. This reaction has been described in WO Application No. 2000049008, page 55. The reaction is typically carried out with stirring sufficient to maintain a substantially homogeneous mixture of reactants. This reaction can be carried out between about 15°C and about 30°C for about 1 to about 50 hours.

After the reaction to prepare the amino (furan-2-yl)acetonitrile of formula E is completed, the organic phase of the two-phase solvent system containing the compound of formula E is easily separated from the aqueous phase by standard phase separation and extraction methods. Then, the compound of formula E in a solution in the organic phase is converted into a salt of formula F by treatment with an aqueous mineral acid solution. Suitable mineral acids include, without limitation, hydrobromic acid (HBr), hydrochloric acid (HCl), nitric acid (HNO ₃ ), sulfuric acid (H ₂ SO ₄ ), and phosphoric acid (H ₃ PO ₄ ). This reaction can be carried out from about 0°C to about 25°C. After the organic phase containing the compound of chemical formula E and the aqueous mineral acid solution are suitably mixed, the aqueous acid solution containing the cyano(furan-2-yl)tetramethylammonium halide salt of chemical formula F is separated and extracted by standard phase The method is separated from the organic phase and is ready for the final bromination/rearrangement reaction (Scheme II, step c) to prepare the compound of formula B.

具有化學式F之起始材料，其中，X係Br、Cl、NO₃ 、HSO₄ ，或H₂ PO₄ ，可以一適合溴化劑處理。從約3至約6莫耳當量之溴可被使用。此反應較佳係使用約3-5莫耳當量之溴及具有化學式F(X=Br)之化合物的溴化物鹽進行。通當常方便地係使用過量之溴化劑，諸如，5%、10%，或15%莫耳過量，以確保此反應進行完全。此反應較佳係於一質子性溶劑或反應介質中實行，諸如，水，或水與一水可溶之有機溶劑(諸如，甲醇、乙醇、四氫呋喃、二

烷，或乙腈)的混合物。此反應進行之溫度一般係於約10°C與約25°C之間。於添加溴完成時，可使反應混合物緩慢加溫至室溫，並且攪拌10-48小時，或此反應可於約30-40^o C加熱使反應完成。選擇性地，反應時間可藉由添加一鹼(諸如，2-4莫耳當量之乙酸鈉)至此反應而縮短。於反應完全後，合意之產物係藉由使用標準隔離及純化技術回收。In the bromination/rearrangement reaction step of this method, the cyano(furan-2-yl)tetramethylammonium salt of formula F is treated with a brominating agent such as bromine to provide a product of formula B.

The starting material with the chemical formula F, where X is Br, Cl, NO ₃ , HSO ₄ , or H ₂ PO ₄ , can be treated with a suitable brominating agent. From about 3 to about 6 molar equivalents of bromine can be used. This reaction is preferably carried out using about 3-5 molar equivalents of bromine and the bromide salt of the compound of formula F (X=Br). It is often convenient to use an excess of brominating agent, such as 5%, 10%, or 15% molar excess, to ensure that the reaction proceeds to completion. This reaction is preferably carried out in a protic solvent or reaction medium, such as water, or a water-soluble organic solvent (such as methanol, ethanol, tetrahydrofuran, two

Alkane, or acetonitrile). The temperature at which this reaction proceeds is generally between about 10°C and about 25°C. When the addition of bromine is complete, the reaction mixture can be slowly warmed to room temperature and stirred for 10-48 hours, or the reaction can be ^{heated at about 30-40 o} C to complete the reaction. Alternatively, the reaction time can be shortened by adding a base (such as 2-4 molar equivalents of sodium acetate) to this reaction. After the reaction is complete, the desired product is recovered by using standard isolation and purification techniques.

In certain embodiments of the present disclosure, the bromination/rearrangement of compounds of formula F may involve the use of one or polybromination agents selected from: (1) bromine, and (2) paired with an oxidant A bromide compound. It is known in the literature that when mixed with an oxidizing agent such as hydrogen peroxide, potassium peroxymonosulfate (ie, Oxone®), DMSO or tertiary butyl peroxide under appropriate reaction conditions, such as HBr, KBr, and The bromide compound of NaBr produces bromine (which is referred to herein as bromine in situ). The use of a bromide compound as a salt (such as NaBr or KBr) for bromine generation in situ also requires the use of an acid for bromine formation. The acid may be selected from the group including HBr, HCl, H ₂ SO ₄ , HNO ₃ , H ₃ PO ₄ , acetic acid, and mixtures thereof. This approach involving the in-situ bromine generation provides the following advantages: limiting or eliminating the use of elemental bromine, improving the bromine atom efficiency of this method, and reducing the formation and disposal of bromide waste streams.

In certain embodiments of the present disclosure, in the method for preparing the compound of the chemical formula B from the compound of the chemical formula F (X = Br), a pair of an oxidizing agent such as hydrogen peroxide such as HBr, KBr, or NaBr is used One of the bromide compounds can be slowly added to the compound of formula F and bromide compound (ie, KBr or NaBr as the bromide compound) by slowly adding hydrogen peroxide (oxidant) due to the ambient temperature, which needs to be used for in-situ formation during one of bromo acid), and the addition the temperature was maintained at less than about 50 ^o C is performed. Relative to the compound of formula B, from about 3-5 molar equivalents of hydrogen peroxide can be used in this method in the presence of a sufficient amount of bromide compound (2-5 molar equivalents) and an acid.

Chemical literature describing bromination chemistry using bromide compounds and oxidants includes: a) "Simple and Practical Halogenation of Arenes, Alkenes, and Alkynes with Hydrohalic Acid/H2O2 (or TBHP)," Tetrahedron, 55, (1999) 1127- 1142, b) "Oxidative Halogenation with "Green" Oxidants: Oxygen and Hydrogen Peroxide," Angew. Chem. Int. Ed., 2009, 48, 8424, and its references. Patent cases describing the production of bromine from the reaction of bromide salt or HBr and hydrogen peroxide include U.S. 5,266,295, U.S. 4,029,732, and U.S. 2,772,302. C. Preparation of compounds of formula G

可進行過氧化氫添加之溫度係於約0°C與約50°C之間。於過氧化氫添加完成時，使反應混合物於室溫攪拌約1至約24小時。於反應完成後，合意產物藉由使用標準隔離及純化技術回收。 D.具有化學式H之化合物的製備Another embodiment of the present disclosure relates to a method for preparing a compound of formula G from furfural. In the first part of this method, the two-phase method described here is used to convert furfural into cyano(furan-2-yl)tetramethylammonium bromide salt of formula F (X-based Br). In the next step of this method, the bromide salt of formula F is mixed with other aqueous HBr (1.5 equivalents), and then, with from about 3 to about 4 molar equivalents of hydrogen peroxide (relative to the bromine of formula F) The reaction provides 3-hydroxy-picolinonitrile (chemical formula G).

The temperature at which hydrogen peroxide can be added is between about 0°C and about 50°C. When the addition of hydrogen peroxide is complete, the reaction mixture is allowed to stir at room temperature for about 1 to about 24 hours. After the reaction is complete, the desired product is recovered by using standard isolation and purification techniques. D. Preparation of compounds of formula H

The 4-alkoxy-3-hydroxypicolinic acid of chemical formula A can be converted into 3-acetoxy compound of chemical formula H by using one or more acetylating agents selected from the group consisting of acetic anhydride and acetyl chloride , Selected from pyridine, alkyl-substituted pyridine, and trialkylamine base, or use Schotten-Baumann reaction conditions to acetylate the compound of formula A.

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

The following examples are presented to illustrate this disclosure. Examples Example 1a. 3-Hydroxy-4-methoxypicolinic acid

A slurry of sodium methoxide (25 g, 0.45 mol) was prepared with 50 ml of anhydrous DMSO and 1 ml of MeOH. A solution of 4,6-dibromo-3-hydroxy-2-pyridinecarbonitrile (50 g, 0.181 mol) and about 50 ml of anhydrous DMSO was added to this slurry, which was added during 30 years. The reaction was maintained between 50-65ºC during the addition. After the addition was complete, the reaction was stirred at >50 ºC for another 1 hour. The reaction was judged to be complete ^{by 1 H NMR analysis.} The reaction was cooled to 35ºC, and then 100 ml of water, followed by 45% KOH (40 ml, 468 mmol) were added to the reaction solution. Then, zinc dust (15.4 g 234 millimoles; <10 micron particle size) was added in 5 g batches at 15 minute intervals, which caused the temperature to rise to about 45ºC. The reaction was allowed to stir overnight at ambient temperature. The reaction was not completed, so the reaction was heated to 50ºC, and then another Zn dust (4.8 g, 74 millimoles) was added. The reaction was completed after 3 hours. Additional KOH (45% aqueous, 40 mL, 468 mmol) was added to the reaction mixture. Then, the reaction was heated at 94ºC for 12 hours to complete the hydrolysis. The reaction was cooled to ambient temperature and then filtered to remove the solids. The solid was washed into the reaction solution with 100 ml of water. Then, the pH of the mixed filtrate and washing solution was adjusted to 0.4 with 12N HCl. The resulting mixture was stirred for about 1 hour to ensure a stable pH, and then the solid was collected by filtration. The off-white solid formed was washed with acetone. The material was dried in a vacuum oven at 50ºC to provide 4-methoxy-3-hydroxypicolinic acid as a very light yellow powder (19.22 g, 63.2% yield and 96% purity, which is equivalent to 60.7% yield). The organic purity was determined to be 99.75% by HPLC. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 6.4 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 4.04 (s, 3H). Example 1b. 3-Hydroxy-4-methoxypicolinic acid

Pure sodium methoxide (14.7 g, 271 millimoles) was added to 4,6-dibromo-3-hydroxypicolinonitrile (30.2 grams, 109 millimoles) and cyclobutane (120 grams) during 30 minutes. A solution, which causes the temperature to rise to 50ºC. Then, the reaction was heated at 60ºC for 18 hours. The reaction solution was cooled to ambient temperature, and then 150 mL of deionized water was added to the reaction, followed by 50 mL of 45% by weight KOH (5.4 equivalents, 586 millimoles). Add Zn dust (113 millimoles, 7.5 g), and then heat the reaction to 40ºC. After 2 hours, additional Zn dust (2.5 g, 38 millimoles) was added, and then the reaction was heated to 60ºC for another 2 hours. The reaction was allowed to stir overnight at ambient. ¹ H NMR analysis of the reaction mixture indicated that the debromination was complete. The reaction was filtered to remove solids, 45% KOH (50 mL, 596 mmol) was added to the filtrate, and then the resulting solution was heated to about 90ºC. The reaction was allowed to stir at about 90ºC for 5.5 hours, which resulted in nearly complete conversion. The reaction was allowed to stir overnight at about 90ºC. The reaction mixture was cooled to <30 º, and then the pH was adjusted to 0.8 with 40% sulfuric acid, which resulted in the formation of a solid. The solids are separated by filtration and then dried to produce solids with a yield of greater than 100%. This material was slurried in 0.5 pH hydrochloric acid overnight. Then, the material was separated by filtration and dried to provide 10.3 g of 4-methoxy-3-hydroxypicolinic acid as an off-white powder, which was determined to be 94% pure (53% yield) by HPLC. Example 1c. 3-hydroxy-4-methoxypicolinic acid

A 500 ml 3-neck flask was filled with sodium methoxide (25 g, 0.462 mol) and 25 ml of dimethyl sulfoxide. The sodium methoxide/DMSO mixture is placed under inert gas and mechanically stirred to produce a free-flowing slurry. A solution of 4,6-dibromo-3-hydroxypicolinonitrile (50.3 g, 0.181 mol, DBHP, 96.2 wt% purity) in about 25 ml of anhydrous DMSO was prepared in a separate container. The DBHP solution was added to the sodium methoxide/DMSO mixture via a syringe pump during 50 minutes. The temperature remained below 60ºC during this addition. After the addition was complete, the reaction was allowed to stir for another 1 hour. During this time, the reaction mixture solidified. 100 milliliters of water followed by 50% KOH (50 milliliters, 941 millimoles) were added to the solidified reaction mixture. The resulting mixture was stirred for about 1.5 hours to crush the solid into a thick slurry. Then, Zn dust (14.8 g, 226 millimoles) was added separately in about 5 g batches over 20 minutes, which caused the temperature to rise to about 40ºC. During the disintegration of Zn, the reaction dilutes into an easily mixed slurry. The reaction was allowed to stir overnight at ambient temperature. Then, the reaction was heated up to 95 ºC for 24 hours. The reaction was cooled to <20 ºC, and then the pH of the solution was adjusted to 0.6 with aqueous HCl (12 N), which caused the product to precipitate. The solid was separated by filtration, washed with about 50 ml of water, and then washed with about 25 ml of acetone. The yellowish powder formed was dried in an exhaust hood, which resulted in a product of 23.3 g. The product was determined to be 96% pure (relative to the internal standard) by 1H NMR. Based on the purity of the starting material and the final product, this was equal to the 76% yield of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 6.4 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 4.04 (s, 3H). Example 1d. Cyano(furan-2-yl)tetramethylammonium bromide

To a 500 ml flask equipped with a stir bar, 33.65 g of ammonium acetate (436 mmol), 150 ml of ethyl acetate, 30 ml of deionized water, and 10 g of KCN (154 mmol) were added. Then, furfural (14 grams, 145 millimoles) was added to the reactor via a syringe. The temperature in the reactor increased from approximately 15ºC to 24ºC. The reaction was allowed to stir at ambient overnight. ¹ H NMR analysis of the ethyl acetate phase showed that the conversion was> 95% complete. 75 ml of 20% aqueous sodium carbonate was added to the reactor and allowed to stir for 10 minutes. The sodium carbonate solution was removed, and then the reaction mixture was washed with 40 ml of saturated brine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (dd, J = 2.0, 1.0 Hz, 1H), 6.47 (dd, J = 3.4, 1.1 Hz, 1H), 6.42 (dd, J = 3.3, 1.7 Hz, 1H), 5.08 (s, 1H).

After removing the brine phase, 24.5 ml of aqueous 48% HBr (1 equivalent, 145 mmol) diluted in about 130 ml of deionized water was added to the reaction. The reaction was mixed for 15 minutes. The aqueous layer is removed and placed in a separate container. Then, the organic layer was washed with 2 x 25 ml of deionized water. Each wash is added to the storage container with the initial HBr extraction phase. A total of 210.5 grams of aqueous phase was obtained, which contained approximately 14.06% by weight of cyano(furan-2-yl)tetramethylammonium bromide. Example 1e. 4,6-Dibromo-3-hydroxypicolinonitrile

52.5 g of aqueous phase containing 7.38 g (36 millimoles) of cyano(furan-2-yl)tetramethylammonium bromide (14.06% by weight in water) was placed in the device and a stir bar in a 250 ml flask . Then, the flask was placed in an ice bath. After cooling to <10 ^o C, then, 5.8 g of bromine water (36 mmol) was added in a dropwise manner during the time was 15 min to the reaction, resulting in a solid form. After stirring for 1 hour, the reaction was allowed to warm to ambient temperature. Oxone® (27 g, 87.8 millimoles) was added to the reaction in batches, resulting in solid dissolution and a reddish-brown liquid phase, which slowly transformed into round pellets after stirring for 1 hour. The reaction is suppressed with saturated aqueous sodium bisulfite. Then, the solid was separated by filtration, washed with deionized water, and then dried overnight to produce 6.25 g of tan powder. ¹ H NMR analysis indicated that the product was composed of 4,6-dibromo-3-hydroxypicolinonitrile (96.6 mol%, 60.3% yield) and 6-bromo-3-hydroxypicolinonitrile (3.4 mol%, 2.2 % Yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1.00H), 7.75 (d, J = 8.9 Hz, 0.034H), 7.44 (d, J = 8.9 Hz, 0.034H). HRMS (m/z) positive ion mode [M+1], _{calculated 276.8612 for C 6} H ₃ Br ₂ N ₂ O; found 276.8611. Example 1f. 4,6-Dibromo-3-hydroxypicolinonitrile

52.5 grams of aqueous phase containing 7.38 grams (36 millimoles) of cyano(furan-2-yl)tetramethylammonium bromide (14.06% by weight in water) is placed in one of 250 milliliters equipped with a stirring rod In the flask. Then, the flask was placed in an ice bath. After cooling to <10 ^o C, and then 5.8 g of bromine (36 mmol) in a period of about 15 minutes was dropwise added to the reaction manner, resulting in a solid form. After stirring for 1 hour, 30% hydrogen peroxide (9.4 mL) was added to the reaction via a syringe during 20-30 minutes. This caused the solid to dissolve, and then, a fine powder precipitated out during 1-2 hours. The reaction is inhibited by saturated sodium bisulfite. Then, the solid was separated by filtration, washed with deionized water, and then dried overnight to produce 6.03 g of tan powder. ¹ H NMR analysis indicated that the product was composed of 4,6-dibromo-3-hydroxypicolinonitrile (94.5mol%, 57.3% yield) and 6-bromo-3-hydroxypicolinonitrile (5.5mol%, 3.2 % Yield) composition. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1.00H), 7.75 (d, J = 8.9 Hz, 0.075H), 7.44 (d, J = 8.9 Hz, 0.075H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 157.65, 141.95, 135.55, 128.76, 124.37, 120.34, 115.97. HRMS (m/z) positive ion mode [M+1], _{calculated for C 6} H ₃ Br ₂ N ₂ O ⁺ 276.8612; found 276.8609. Example 1g. 3-Hydroxypicolinonitrile

52.5 grams of aqueous phase containing 7.38 grams (36 millimoles) of cyano(furan-2-yl)tetramethylammonium bromide (14.06% by weight in water) is placed in one of 250 milliliters equipped with a stirring rod In the flask. 48% HBr (6.2 mL, 55 mmol) was added to the flask and stirred. Then, the flask was placed in an ice bath. After cooling to <5 ºC, approximately 7 ml of 30% hydrogen peroxide is added to the reaction via a syringe during 20-30 minutes. This causes very little heat generation. The reaction was warmed to ambient temperature, at which point the reaction began to heat up to about 50 ºC on its own. The reaction was cooled to 20ºC, and then 7 ml of 30% peroxide was added, which caused the formation of a precipitate. The reaction was allowed to stir for about 20 minutes, and then the reaction was inhibited by saturated sodium bisulfite, which caused the temperature to rise to about 40ºC. During the temperature rise, the solid dissolves. Then, the reaction was placed in an ice bath. After stirring for about 45 minutes, a solid developed. The solid was collected by filtration and washed with deionized water. 3-Hydroxypicolinonitrile (1.63 g) was isolated as a tan crystalline solid (37.3% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 8.19 (dd, J = 4.4, 1.3 Hz, 1H), 7.56 (dd, J = 8.6, 4.4 Hz, 1H), 7.47 ( dd, J = 8.7, 1.4 Hz, 1H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 157.67, 141.93, 135.56, 128.75, 125.99, 124.37, 120.34, 115.97. HRMS (m/z) negative ion mode [M-1] _{calculated 119.0246 for C 6} H ₄ N ₂ O; found 119.0240. Example 1h. 4,6-Dibromo-3-hydroxypicolinonitrile

53 grams of aqueous phase containing 7.45 grams (37 millimoles) of cyano(furan-2-yl)tetramethylammonium bromide (14.06% by weight in water) is placed in one of 250 milliliters equipped with a stirring rod In the flask. 48% HBr (8.2 mL, 73 mmol) was added to the flask and stirred. The flask was placed in an ice bath. After cooling to <5 ºC, 6 to 7 ml of 30% hydrogen peroxide is added to the reaction via a syringe during 20-30 minutes. This causes very little heat generation. The reaction was warmed to ambient temperature, at which point, the reaction began to heat to about 46-48ºC by itself, and the color became yellow-orange (uniform). The reaction was cooled to 20ºC, and then another 7 ml of 30% hydrogen peroxide was added via a syringe during 15-20 minutes, which caused the formation of a precipitate. The reaction was allowed to stir overnight. The reaction was inhibited by sodium bisulfite, resulting in a yellowish solution with solids. The peroxide test strip indicates no residual peroxide. The solid was collected by filtration, washed with water, and dried, yielding 6.22 g of slightly tan powder. ¹ H NMR analysis indicated that the product was composed of 4,6-dibromo-3-hydroxypicolinonitrile (58.1% yield) and 6-bromo-3-hydroxypicolinonitrile (3.8% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1.00H), 7.75 (d, J = 8.9 Hz, 0.064H), 7.44 (d, J = 8.9 Hz, 0.064H). Example 1i. 4,6-Dibromo-3-hydroxypicolinonitrile

A stock solution of cyano(furan-2-yl)tetramethylammonium chloride was prepared using 39.21 grams of furfural, 20 grams of sodium cyanide, and 96 grams of ammonium acetate in 300 ml of ethyl acetate and 260 ml of water. After the formation of α-amino nitrile, 75 ml of saturated sodium carbonate was added to the mixture and allowed to mix for 20-30 minutes. The aqueous phase was removed, and the organic phase was then washed with 2 x 50 ml of saturated brine. 34 mL of aqueous 12 N HCl (1 equivalent, 408 mmol) diluted in about 260 mL of deionized water was added to the organic phase. The resulting mixture was mixed (>500 rpm) for 15 minutes. After settling, the aqueous layer containing cyano(furan-2-yl)tetramethylammonium chloride is removed and placed in a plastic storage container to form a storage solution. Then, the organic layer was extracted with 44 ml of deionized water, and then with 46 ml of deionized water. Each aqueous extract is placed in a storage container, resulting in approximately 460 grams of aqueous phase. The aqueous phase was diluted to a total of 480 grams, which contained about 64.70 grams (13.5 wt%) of cyano(furan-2-yl)tetramethylammonium chloride.

A 60 g stock solution containing approximately 8.1 g (51 millimoles of cyano(furan-2-yl)tetramethylammonium chloride) was placed in a 250 ml round bottom flask with a stir bar. About 4.2 milliliters (50.4 millimoles) of 12N HCl and 10.4 grams (101 millimoles) of NaBr were added to the flask. 30% hydrogen peroxide (20 g, 176 millimoles) was added dropwise to the flask during 50 minutes. During the 25 minutes of the addition period (about 7.5 grams of peroxide has been added), the reaction heats up to 56 ºC by itself, at which point the reaction cools to about 36 ºC. After 40 minutes, solids began to form. The reaction was allowed to stir for another 6 hours. The solid was collected by filtration, washed with deionized water, and then dried. Obtained 6.28 grams of free-flowing light brown powder as 4,6-dibromo-3-hydroxypicolinonitrile (39.1% by weight yield), 6-bromo-3-hydroxypicolinonitrile (3.0% by weight yield) , A mixture of 6-chloro-3-hydroxy-picolinonitrile (6.23% by weight yield) and one of the isomers of 4/6-chloro/bromo-3-hydroxypicolinonitrile (0.4% by weight yield) , Which is ^{determined by 1} H NMR. An overall yield of 51% was observed. ¹ H NMR (400 MHz, DMSO-d ₆ ) of the desired product: δ 8.27 (s, 1.00H), δ 8.18 (s, 0.11H), δ 7.75 (d, J = 8.9 Hz, 0.64H), 7.65 ( d, J = 8.9 Hz, 0.01H), 7.53 (d, J = 8.9 Hz, 0.01H), 7.44 (d, J = 8.9 Hz, 0.064H). Example 1j. 4,6-Dibromo-3-hydroxypicolinonitrile

Add 36 grams of ammonium acetate (467 millimoles), 200 milliliters of ethyl acetate, and 7.5 grams of NaCN (153 millimoles) to one of a 500 milliliter flask with a stir bar. Use 75 ml of water to wash the residual sodium cyanide into the flask and from the funnel. Then, furfural (12.7 ml, 14.7 g, 153 millimoles) was quickly added to the reactor via a syringe. The temperature in the reactor increased from approximately 15ºC to 24ºC. The reaction was allowed to stir overnight at ambient temperature (18ºC). Turn off the stirring to separate the two liquid phases. Then, the organic phase was sampled for ¹ H NMR analysis, and the reaction was judged to be only about 80% complete. Then, the reaction was stirred at 25 ºC (using a water bath) for another 6 hours. The reaction was shown to be about 90% complete ^{by 1 H NMR.} 75 ml of 20% aqueous sodium carbonate was added to the reactor and allowed to stir for 30 minutes, and then the mixture was allowed to stand for 20-30 minutes without stirring. The aqueous phase was removed, and then the organic phase of α-aminonitrile containing furfural in ethyl acetate was washed with 2x50 ml of saturated brine.

10 N sulfuric acid (15 ml, 1 equivalent, 153 millimoles) was diluted in approximately 225 ml of deionized water. The ethyl acetate solution of α-aminonitrile containing furfural was extracted with a diluted sulfuric acid solution in about 1/3 batches. Each extract was placed in a 500 ml round bottom flask with a stir bar. The organic solution was extracted with another 5 ml of deionized water. To the mixed aqueous acid extract, add 47 grams of sodium bromide (459 millimoles), and then add hydrogen peroxide (30%, 360 millimoles) over a period of 2 hours, which caused the temperature to rise from 19ºC to about 50ºC . The reaction was allowed to stir overnight. ¹ H NMR analysis indicated that the reaction system was a 1:1 mixture of 6-bromo-3-hydroxypicolinonitrile and 4,6-dibromo-3-hydroxypicolinonitrile. Another 15 milliliters of 10 N sulfuric acid and 13.5 grams of 30% peroxide (107 millimoles) were added to the reaction solution, and the reaction was heated to 45 ºC. After 2 hours, ¹ H NMR analysis indicated that the reaction was complete. The solid was collected by filtration, washed with water, and dried, yielding 21.9 grams of light tan powder. ¹ H NMR analysis indicated that the powder was composed of 4,6-dibromo-3-hydroxypicolinonitrile (49.8% yield) and 6-bromo-3-hydroxypicolinonitrile (2.4% yield). Example 1k. 3-(Acetoxy)-4-methoxypicolinic acid

3-hydroxy-4-methoxypicolinic acid (5.0 g, 29.6 mmol) was slurried in 50 mL pyridine and 50 mL acetic anhydride at ambient temperature. After 1 hour, a yellow solution had formed, which was then stirred overnight. The solution was evaporated at 45°C (2 mm Hg), yielding 6.28 g of a tan solid (99% yield, mp=132-134°C). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.32 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 3.91 (s, 3H) , 2.27 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 167.95, 164.81, 158.34, 147.87, 142.77, 136.18, 110.87, 56.59, 20.27. HRMS (m/z) _{calculated 211.0478 for C 9} H ₉ NO ₅ and found 211.0481 ([M] ⁺ ).

Claims (11)

A method for preparing a compound of chemical formula A from a compound of chemical formula B,

Wherein R ¹ is a C ₁ -C ₃ alkyl group, the method includes the following steps: a) A first mixture is generated, which contains an alkali metal alkoxide having the chemical formula C

, Where M is Na or K, and R ¹ is a C ₁ -C ₃ alkyl group, and the compound of formula B, and heat the first mixture; b) by adding water, a strong base and zinc metal to The first mixture is used to produce a second mixture; c) the second mixture is heated; and d) the compound of formula A is isolated. Such as the method of claim 1, wherein M is Na and R ¹ is methyl. The method of claim 1, wherein the first mixture further comprises a solvent selected from the group consisting of mixtures of DMSO, methanol, cyclobutene, and the like. The method of claim 1, wherein the strong base is selected from sodium hydroxide or potassium hydroxide. The method of claim 1, further comprising a step of removing zinc salt or zinc metal from the second mixture before heating the second mixture. Such as the method of claim 1, wherein the compound of formula B

It is a compound of formula D

It is prepared in a method comprising the following steps: a) A first mixture is produced by combining a two-phase water-organic solvent system, an ammonia source, a cyanide source, and the compound of formula D; b; ) Separating a second mixture from the first mixture, the second mixture containing a compound of formula E

, Which is a solution in the organic solvent; c) adding an aqueous solution of a mineral acid to the second mixture to form a third mixture, wherein the mineral acid is HCl, HBr, H ₂ SO ₄ , HNO ₃ Or H ₃ PO ₄ ; d) separating a fourth mixture from the third mixture, the fourth mixture being an aqueous mixture containing the compound of formula F,

Wherein X is Cl, Br, HSO ₄ , NO ₃ or H ₂ PO ₄ ; e) adding a brominating agent to the fourth mixture to form a fifth mixture, the brominating agent includes bromine, a bromine with an oxidizing agent And f) separating the compound of formula B from the fifth mixture. The method of claim 6, wherein the organic solvent in the method for preparing the compound of formula B is selected from the group consisting of MTBE, ethyl acetate, isopropyl acetate, THF, 2-MeTHF, toluene, a xylene or two A mixture of toluenes, and a group of mixtures thereof. The method of claim 6, wherein the mineral acid is hydrobromic acid. Such as the method of claim 6, where X is Br. The method of claim 6, wherein the bromide compound is hydrobromic acid or a bromide salt selected from NaBr and KBr in combination with an acid. The method of claim 6, wherein the oxidizing agent is selected from hydrogen peroxide and potassium peroxymonosulfate (potassium peroxymonosulfate).