Preparation of sulfonamide herbicide process intermediates

Abstract

Provided are improved methods for preparing chemical precursors of sulfonyl chlorides III, which are important intermediates in the preparation of formosan herbicides. Specifically, these precursors are compounds of formula VII and / or VIII and IX, wherein R is C1-C6 alkyl, R1 is C1-C6 alkyl, X is Cl or OH, and Y is halogen, OH or OR 2 , and R 2 It is a C1-C6 alkyl group.

Description

Background Art

[0001] This application claims priority to U.S. Provisional Application Serial No. 62 / 785,343, filed on December 27, 2018, U.S. Provisional Application Serial No. 62 / 806,176, filed on February 15, 2019, and U.S. Provisional Application Serial No. 62 / 835,689, filed on April 18, 2019, the entire disclosures of each of which are hereby expressly incorporated by reference.

[0002] Fensulfuron (I), a member of the triazolopyrimidinesulfonamide family of herbicides, disclosed in WO 2002036595, is a commercially available herbicide that provides control of many broadleaf weeds and grass weeds in cereal crops. The preparation of Fensulfuron has been described in various literatures, such as described in U.S. Patent Application Publication No. 2005 / 0215570, the disclosure of which is incorporated herein by reference.

[0003]

[0004] The final step in the preparation of formosulam (I) involves coupling an amine having formula II with a sulfonyl chloride having formula III:

[0005]

[0006] The sulfonyl chloride III is prepared by converting 2-oxo-pyridine IIIa to 2-methoxypyridine IIIc via 2-chloropyridine IIIb. The sulfonyl chloride III is then prepared by metalation / thiolation of IIIc with a mixture of lithium diisopropylamide (LDA) and elemental sulfur followed by chloroxidation of the resulting lithium thiolate with chlorine / HCl to provide III.

[0007]

[0008] However, such conventional methods can be expensive, reduce profits, and in some cases may adversely affect the ability to use the produced formosulam in some markets.

[0009] Therefore, there is a need to reduce the production costs of formosulam in an efficient and economical manner. Furthermore, there is a need to be able to prepare formosulam in a manner that allows formosulam to be sold in currently restricted markets. Summary of the invention

[0010] This article describes an improved process for preparing chemical precursors of sulfonyl chlorides III, which are important intermediates in the preparation of formosan herbicides. Specifically, these precursors are compounds of formula VII and / or VIII and IX, wherein R is a C1-C6 alkyl group, R 1is C1-C6 alkyl, X is Cl or OH, Y is halogen, OH or OR 2 , and R 2 It is a C1-C6 alkyl group.

[0011]

[0012] Another aspect of the present disclosure is the novel intermediate produced by the described process, namely, the following compound:

[0013]

[0014] Where R is a C1-C6 alkyl group, R 1 is C1-C8 alkyl, and X is Cl or OH; and

[0015]

[0016] Where R is a C1-C6 alkyl group, R 1 is C1-C8 alkyl, and X is Cl or OH; and

[0017]

[0018] Wherein X is Cl or OH. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The above and other features and objects of the present disclosure and the manner in which they are obtained will become more apparent and the present disclosure itself will be better understood by referring to the following description of exemplary aspects of the present disclosure in conjunction with the accompanying drawings, in which:

[0020] Figure 1 is a schematic diagram of an exemplary continuous flow reactor for synthesizing (E)-5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile according to various aspects;

[0021] Figure 2 are pictures of experimental continuous flow reactors according to various aspects; and

[0022] Figure 3 is a picture of a continuously stirred tank with a water quencher having a pilot continuous flow reactor according to different aspects.

[0023] Throughout the several views, corresponding reference symbols indicate corresponding parts. Although these figures represent various aspects of the present disclosure, these figures are not necessarily to scale and certain features may be enlarged to better illustrate and explain the present disclosure. The examples set forth herein illustrate exemplary aspects of the present disclosure in various forms, and such examples should not be construed as limiting the scope of the present disclosure in any way. DETAILED DESCRIPTION

[0024] Methods for preparing precursors of sulfonyl chlorides III are described, which can be important intermediates in the preparation of formosan herbicides. In particular, these precursors are compounds of formula VII and / or VIII and IX, wherein R is C1-C6 alkyl, R 1 is C1-C8 alkyl, X is Cl or OH, Y is halogen, OH or OR 2 , and R 2 It is a C1-C6 alkyl group.

[0025]

[0026] As shown in Schemes 1 and 2 described herein, these methods may include the following chemical process steps: (1) converting compounds of Formula IV, and V or VI to nitriles of Formula VII and / or VIII, and (2) converting VII and / or VIII to compounds of Formula IX (wherein Y is halogen, OH or OR) by using reactants A, B, C, D or E. 2 , and R 2 is a C1-C6 alkyl), and the reactants include acids (reactant A), alcohols (reactant B), water (reactant C), alkoxides (reactant D), or dehydrating halogenating agents (reactant E), and combinations thereof.

[0027] Scenario 1:

[0028]

[0029] Where R is a C1-C6 alkyl group, R 1 is C1-C8 alkyl and X is Cl or OH;

[0030] Scenario 2:

[0031]

[0032] Where R is C1-C6 alkyl, Y is halogen, OH or OR 2 , and R 2 It is a C1-C6 alkyl group.

[0033] I. Definitions

[0034] As used herein, the term "halo" or "halogen" may be understood to include one or more of F, Cl, Br, and I.

[0035] As used herein, the term "aryl" and derivative terms such as aryloxy are understood to include groups that include monovalent aromatic carbocyclic groups containing 6 to 14 carbon atoms. Aryl groups may include a single ring or multiple condensed or fused rings. In some aspects, aryl groups include C6-C10 Aryl.

[0036] Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl and indanyl. In some respects, aryl can be phenyl, indanyl or naphthyl. The term "heteroaryl" and derived terms such as "heteroaryloxy" can be understood to include 5 or 6 aromatic rings containing one or more heteroatoms (e.g., N, O or S). In some respects, these heteroaromatic rings can be fused with other aromatic systems. In some respects, heteroaryl can be pyridyl, pyrimidyl or triazine. Aryl or heteroaryl substituents can be unsubstituted or substituted by one or more chemical moieties. Examples of suitable substituents include, for example, amino, halo, hydroxy, nitro, cyano, formyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 acyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl ... 10 Alkoxycarbonyl, C1-C6 carbamoyl, hydroxycarbonyl, C1-C6 alkylcarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 dialkylaminocarbonyl, provided that these substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. Preferred substituents include halogen, C1-C4 alkyl, C1-C 10 Alkoxycarbonyl and C1-C4 haloalkyl.

[0037] II. Preparation of Nitrile VII (and / or Aldehyde VIII)

[0038] In some aspects, the first step of the method for preparing a compound of formula IX (wherein Y is halogen, OH or OCH3) may include converting a compound of formula V or VI to a nitrile of formula VII and / or VIII by reacting V or VI with a metal anion of an alkylthioacetonitrile IV (M is Li, Na or K), as prepared as illustrated in Scheme 3. The base used for this reaction step may include, but is not limited to, an organolithium reagent such as n-butyllithium, sec-butyllithium, lithium diisopropylamide (LDA), and lithium hexamethyldisilazane or sodium hexamethyldisilazane (LHMDS or NaHMDS). Other bases such as sodium tert-butoxide and potassium tert-butoxide (Na-tBuO and K-tBuO), and sodium tert-amylate and potassium tert-amylate may also be used. The reaction of V with lithium acetonitrile has been disclosed in US8,063,226, the disclosure of which is included herein by reference, while the preparation of VII (X=Cl or OH) using V or VI has not been previously disclosed. The reaction is quenched with an acid. Acids used in this reaction step include, but are not limited to, inorganic acids such as hydrochloric acid (HCl), phosphoric acid (H PO 4 ) or sulfuric acid (H SO 4 ), or organic acids such as acetic acid. In some aspects, a buffer system can be used, for example, the formation of a compound with Formula VII can be achieved in a buffer system. Exemplary buffers can be phosphate buffer, Tris buffer, sodium acetate buffer, ammonium acetate buffer, tartrate buffer, citrate buffer or a combination thereof.

[0039] Solution 3 :

[0040]

[0041] Where R is a C1-C6 alkyl group, R 1 is C1-C8 alkyl and X is Cl or OH;

[0042] Compound VI can be prepared by the following method as described in WO 2002053518, the disclosure of which is incorporated herein by reference.

[0043]

[0044] The process steps for preparing VII (and / or VIII) can be carried out in solvents such as, but not limited to, ether solvents like THF (tetrahydrofuran), DME (1,2-dimethoxyethane), 2-methyl-THF, diethyl ether, cyclopentyl methyl ether (CPME), or dioxane, and mixtures thereof, and mixtures of ether solvents with hydrocarbon solvents (such as pentane, hexane, cyclohexane, toluene, etc.), or using hydrocarbon solvents alone. This process step can be carried out at a temperature ranging from as low as about -80°C, -75°C, -70°C, -60°C, -50°C or -45°C, or at a temperature as high as about -30°C, -25°C, -20°C, -10°C, 0°C, 10°C or 25°C, or any range defined between any two of the above values, such as about -80°C to about 25°C, about -80°C to about 0°C, about -70°C to about -30°C, about -50°C to about -25°C, about -75°C to about -25°C.

[0045] Moreover, in different aspects, the reaction can be carried out for different time periods, such as, for example, as short as about 15 minutes, 30 minutes, 45 minutes, 1 hour, or as long as about 2 hours, 24 hours, 36 hours, or 72 hours, or any range defined between any of the above values, such as about 15 minutes to about 72 hours, about 30 minutes to about 36 hours, about 45 minutes to about 24 hours, about 1 hour to about 24 hours, or about 15 minutes to about 2 hours.

[0046] In some aspects, excess molar amount can be used to make one of reagents react completely. In some aspects, the ratio of the molar equivalent of reagent can be, for example, as low as about 1, 1.01, 1.05, 1.07, 1.1, up to about 1.15, 1.2, 1.3 or 1.5 ratio, or be limited to any scope between any pair of above-mentioned values; As the molar equivalent of alkali can be used for preparing the process of VII (and / or VIII) with a ratio of about 1 to about 1.5, about 1.01 to about 1.15, about 1.1 to about 1.15, about 1.05 to about 1.3 or about 1.1 to about 1.5.

[0047] The process steps for preparing VII (and / or VIII) (as shown in Scheme 3) can be carried out in a batch process mode (e.g., preparing a single batch of product), semi-batch mode, semi-continuous mode, or continuous process mode (e.g., flow process).

[0048] In the continuous process mode, the reactants 2-(propylthio)acetonitrile and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one are premixed in solvent 1 to form solution 1, which is then connected to pump 1 (P1). The base is dissolved in solvent 1 to form solution 2, which is connected to pump 2 (P2). The acid is dissolved in THF or CPME to form solution 3, which is connected to pump 3 (P3). Solution 1 (containing the reactants) and solution 2 (containing the base) are precooled and mixed together through a tee joint into the static mixer in reactor 1 (R1). After the mixture is suspended in R1 for the desired residence time, it is then mixed together with the precooled acid quench solution (solution 3) through a tee joint at the eye of the static mixer in reactor 2 (R2). The outlet of R2 is connected to a product collection tank. At the completion of the continuous flow process operation, the organic solution in the product collection tank is further processed by using standard separation and purification techniques so that the desired product can be obtained. Bases for the continuous flow process include tert-amylate, sodium tert-butoxide, potassium tert-butoxide, or NaHMDS (same base as the batch process), and solvents may include THF, CPME, or toluene.

[0049] In another aspect of the continuous process mode setup, reactants 2-(propylthio)acetonitrile and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one are separate solutions in solvent 1 to form solutions 1 and 2, with solution 1 then connected to pump 1 (P1). (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one is dissolved in solvent 1 to prepare solution 2, which is connected to pump. Base is dissolved in solvent 1 to form solution 3, which is connected to pump 2 (P2). Acid is dissolved in THF or CPME to form solution 4, which is connected to pump 4 (P4). Solution 1 (containing 2-(propylthio)acetonitrile) and solution 3 (containing base) are pre-cooled and mixed together through a tee fitting into a static mixer in reactor 1 (R1). After the mixture is suspended in R1 for the required residence time, it is then mixed with a pre-cooled solution 2 containing (E)-4-ethoxy-1,1,1-trifluorobut-3-ene-2-one through a three-way joint at the eye of the static mixer in reactor 2 (R2). After the mixture is suspended in R2 for a residence time (t), it is then mixed with a pre-cooled acid quenching solution (solution 4) through a three-way joint at the eye of the static mixer in reactor 3 (R3). The outlet of R3 is connected to a product collection tank. When the continuous flow process operation is completed, the organic solution in the product collection tank is further processed by using standard separation and purification techniques so that the desired product can be obtained. The base used for the continuous flow process includes tert-amyl alcohol salt, sodium tert-butoxide, potassium tert-butoxide, or NaHMDS (the same base as the batch process), and the solvent can include THF, CPME, or toluene.

[0050] III. Preparation of Substituted Pyridines IX

[0051] The next step of the process for preparing the compound of formula IX comprises treating a compound of formula VII (wherein R is C1-C6 alkyl, R 1 is C1-C6 alkyl and X is Cl or OH) is converted to a substituted pyridine having formula VIII (Scheme 4). The reactant or reactant combination used must include a reactant that promotes the cyclization of the nitrile VII to the pyridine VIII.

[0052] Solution 4 :

[0053]

[0054] wherein R is C1-C6 alkyl, Y is halogen, OH or OR2, and R2 is C1-C6 alkyl;

[0055] Table 1 lists many exemplary reactants that may be used for the transformation shown in Scheme 4. Reactant A (acid) or E (dehydrating halogenating agent) easily promotes the cyclization of VII (and / or VIII) to IX, however, in some aspects, reactant B, C or D, alone or in combination, may not easily promote the cyclization of VII (and / or VIII) to IX. However, in different aspects, when reactant B, C or D is used in combination with reactant A or B, in a simultaneous manner (mixed together before being added to VII and / or VIII) or in a sequential manner (added separately to VII and / or VIII), the cyclization of nitrile VII and / or VIII to pyridine IX can then occur.

[0056] Table 1: Description of reactants AE

[0057]

[0058]

[0059] In some aspects of the process being carried out simultaneously, a mixture containing an acid and an alcohol is combined with compound VII and / or VIII to provide compound IX (wherein X is Cl or OH, R is C1-C6 alkyl, R 1 is C1-C6 alkyl, and R2 is C1-C6 alkyl). This can be demonstrated by the following reaction:

[0060]

[0061] In a different aspect in a somewhat similar manner, a mixture containing an acid and water is combined with compound VII and / or VIII to provide compound IX (wherein X is Cl or OH, R is C1-C6 alkyl, and R1 These aspects are demonstrated by the following reaction:

[0062]

[0063] In some aspects of proceeding in a sequential manner, anhydrous acid HY (Y is Cl or Br) can be combined with compound VII and / or VIII to provide compound IX, wherein R is C1-C6 alkyl, and Y is Cl or Br, which can then react with alkoxide MOR 2 (M is Na or K) to provide compound IX (wherein R is C1-C6 alkyl and R 2 This can be demonstrated by the following exemplary reaction:

[0064]

[0065] In some aspects of proceeding in a sequential manner, a dehydrating halogenating agent (SOY2, POY3, PY3, PY5 or oxalyl chloride) can be combined with compound VII and / or VIII to provide compound IX, wherein R is C1-C6 alkyl and Y is Cl or Br, which can then react with an alkoxide MOR 2 (M is Na or K) is further combined to provide compound IX (wherein R is C1-C6 alkyl and R 2 is a C1-C6 alkyl group). This can be exemplified or demonstrated by the following reaction:

[0066]

[0067] Solvents that may be suitable for preparing substituted pyridines of Formula IX from compounds of Formula VII and / or VIII include, but are not limited to, acetonitrile (ACN), N,N-dimethylformamide (DMF), dichloromethane (DCM), 1,2-dichloroethane (DCE), tetrahydrofuran (THF), 2-methyl-THF, dioxane, cyclopentyl methyl ether (CPME), toluene, one or more xylenes, methanol, or ethanol, and mixtures thereof.

[0068] In some aspects, one or more of the reactants may also serve as a solvent in the preparation of the substituted pyridine having Formula IX.

[0069] The preparation of the compound of formula IX from the compound of formula VII and / or VIII can be carried out at a temperature of at least about 0° C., at least about 10° C., at least about 20° C., at least about 25° C., at least about 30° C., at least about 40° C., at least about 50° C., at least about 60° C., at least about 70° C., at least about 80° C., at least about 90° C., or at least about 100° C. In some aspects, the preparation of the compound of formula IX from the compound of formula VII and / or VIII can be carried out at a temperature of about 0° C. to about 50° C., about 10° C. to about 50° C., about 25° C. to about 50° C., about 25° C. to about 60° C., about 25° C. to about 70° C., about 25° C. to about 80° C., about 25° C. to about 90° C., about 25° C. to about 100° C., about 25° C. to about 125° C., or about 25° C. to about 150° C.

[0070] IV. Preparation of 2-alkoxy-4-(trifluoromethyl)pyridine-3-sulfonyl halide

[0071] Using previously disclosed methods, a compound of formula IX (wherein R is C1-C6 alkyl and R 2 is C1-C6 alkyl) to a compound having formula IIId. This transformation is shown in Scheme 5 and comprises treating compound IX with a hydrohalic acid HY, a halogen Y2 and water (wherein Y is Cl or Br) to provide a compound having formula IIId (wherein Y is Cl or Br, and R 2 is a C1-C6 alkyl group).

[0072] Solution 5 :

[0073]

[0074] Where R is a C1-C6 alkyl group, R 2 is C1-C6, and Y is Cl or Br.

[0075] In one aspect of the method for preparing a compound of formula III, Y 2 is Cl2 (chlorine), the hydrohalic acid HY is HCl, and R 2 It is CH3.

[0076] In another aspect of the method for preparing a compound of formula IIId, a water-immiscible co-solvent is included. The co-solvent may be selected from dichloromethane, 1,2-dichloroethane, chlorobenzene, 1,2-dichlorobenzene, chloroform, trichlorobenzene, or α,α,α-trifluorotoluene, and mixtures thereof.

[0077] In another aspect of the method for preparing the compound of formula III, a phase transfer catalyst may be included. Suitable phase transfer catalysts included are tetraalkylammonium halides and tetraalkylammonium sulfates, such as, for example, methyltributylammonium chloride, tetrabutylammonium halide (chloride or bromide) or tetrabutylammonium sulfate.

[0078] In another aspect of the method for preparing the compound of formula III, a sodium chloride solution (eg, a saturated solution) can be used as the aqueous phase of the reaction.

[0079] In yet another aspect of the method for preparing the compound of formula III, a catalytic acid such as trifluoroacetic acid can be used to promote the reaction.

[0080] The preparation of the compound of formula III from the compound of formula IX can be carried out at a temperature of about -5°C to about 40°C, about 0°C to about 40°C, about 0°C to about 30°C, about 0°C to about 20°C, about 0°C to about 15°C, about 0°C to about 10°C, or about 0°C to about 5°C.

[0081] V. Isolation / Purification

[0082] After preparing the compounds of formula III, VII and / or VIII, and IX by the methods described herein, the products can be isolated by using standard separation and purification techniques. For example, the crude product can be isolated using standard methods as described herein and purified by crystallization using a single solvent or a mixture of two or more solvents. In addition, the crude product can be purified by washing it with a single, two or three component solvent mixture or stirring it in a single, two or three component solvent mixture. In one aspect, the crude product can be purified by stirring it in an aqueous alcohol solvent mixture.

[0083] The crude product may also be purified by dissolving it in one solvent to form a solution, and then adding a second solvent to the solution to cause the product to crystallize out from the mixture of the two solvents.

[0084] The crude product can also be purified by any known separation means, such as by distillation, for example under vacuum.

[0085] The following examples are presented to illustrate the methods and compositions described herein.

[0086] Examples

[0087] Example 1a. Preparation of 2-(propylthio)acetonitrile

[0088]

[0089] A 250 mL three-necked round bottom flask (with hot well) was charged with dichloromethane (DCM; 200 ml) and the mixture was cooled with a water / ice bath. The flask was then charged with propane-1-thiol (29.3 ml, 315 mmol) and the flask was briefly filled with nitrogen using a glass bubbler with an outlet to a bleach (5% v / v in water) scrubber. The clear solution was allowed to stir until the internal temperature stabilized (4 ° C), after which triethylamine (47.9 ml, 344 mmol) was added over 5 minutes using an addition funnel (the internal temperature increased to 6 ° C); the addition funnel was rinsed with about 5 mL of DCM. The mixture was allowed to stir until the internal temperature stabilized at 4 ° C, after which 2-chloroacetonitrile (21.62 g, 286 mmol) was slowly added over 10 min using an addition funnel. (Even though this funnel had been rinsed with DCM after being used to transfer triethylamine, a dark oil layer was still observed on top of the chloroacetonitrile (some smoke was briefly observed in the addition funnel)). The internal temperature slowly increased to 19°C during the addition. After the addition was complete, the reaction mixture slowly turned from clear (with a brown hue) to cloudy; the reaction mixture was stirred for about 30 min, after which time the temperature had dropped to 16°C and a white precipitate had formed (stirring was not hampered). The flask was removed from the ice bath and an aliquot (2 mL) was removed by syringe, washed with water, dried, concentrated (1.3 g clear oil) and analyzed by 1H NMR analysis, which showed about 10% conversion. Within 30 minutes of removing the flask from the ice bath, the reaction temperature slowly increased to 32°C, after which the reaction temperature dropped to room temperature (21°C) within 20 minutes. The reaction mixture was stirred at this temperature for an additional 2.5 h, after which an aliquot (0.3 mL) was removed, filtered, concentrated and analyzed by 1H NMR, which showed about 99% conversion of chloroacetonitrile to product. The reaction mixture was filtered using a disposable filter under gentle vacuum, and the filtrate (200 mL, slightly yellow-brown) was concentrated under reduced pressure and the resulting slurry (a small amount of solid had been lost) was distilled under vacuum using a short-path distillation apparatus with water cooling. Three distillates were collected (a total of 25 g, 75% yield, 98%-99% purity by 1H NMR). 1H NMR (400 MHz, chloroform-d) δ 3.30 (s, 2H), 2.79-2.65 (m, 2H), 1.69 (h, J = 7.3 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 116.67, 34.58, 21.99, 16.92, 13.20.

[0090] Example 1b. Preparation of PTAN

[0091]

[0092] A 2L jacketed glass reactor was connected to an overhead stirrer (set at 350 rpm) and loaded with NaOH (50% wt / wt in water, 612.0 g, 7.68 mol; Fisher), followed by deionized water (600.3 g, 33.35 mol) and catalytic tert-butylammonium bromide (TBAB, 50% wt / wt in water; 52.4 g, 0.08 mol; Sachem Inc.). The reactor contents were cooled to 20°C internal temperature before propanethiol (464.50 g, 6.10 mol, Sigma Aldrich) was added at a rate of approximately 10 g / min using a peristaltic pump (starting temperature 19.5°C; final temperature 20.7°C). The jacket temperature was set to 2°C and the reaction mixture was stirred for 1 h 45 min, after which chloroacetonitrile (456.70 g, 6.05 mol; Sigma-Aldrich) was added at a rate of about 3 g / min using a peristaltic pump. The starting temperature was 2.5°C and initially increased at about 0.3°C / min for the first about 50 g of PrSH; increased at about 0.2°C / min for the next 100 g of PrSH, and then increased at 0.05°C / min, with an end point temperature of 20.5°C. The reaction mixture was cooled to 2°C and stirred at this temperature overnight, after which stirring was stopped and the water layer was drained. Note: The reaction does not need to be stirred overnight. The reaction should be carried out in less than 11 h. The reaction was monitored by NMR. The resulting oil was washed with sodium bicarbonate solution (200 g) to give about 665 g of a clear oil of the crude product (about 96% yield, about 97% pure by NMR). This material was purified by distillation using a short-path distillation apparatus. The material was loaded into a still, placed under vacuum and heated slowly. The vacuum pump used for the distillation maintained a relatively constant vacuum normally at 1.0-3.0 torr. The distillation of PTAN at this pressure typically occurs at 85°C to 91°C. If enough water is left in the material by the reaction conditions, an azeotropic mixture is noted to be collected in a receiving flask at a temperature ranging from about 70°C to 85°C, which is distilled under vacuum to give 627 g (90% yield, about 99% pure by NMR). 1H NMR (400 MHz, CHLOROFORM-d) δ 3.30 (s, 2H), 2.79-2.65 (m, 2H), 1.69 (h, J = 7.3 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 116.67, 34.58, 21.99, 16.92, 13.20.

[0093] Example 1c. Preparation of 5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile by a batch process

[0094]

[0095] Load bis(trimethylsilyl)sodium amide (4.97g, 27.1mmol) and toluene (68ml) into a 250mL three-necked round-bottom flask containing a stirring bar and stir the mixture until the solid dissolves (slightly yellow clear solution). Fill the flask with nitrogen under stirring and then immerse it in a dry ice / isopropanol bath and cool until the internal temperature reaches -72°C. While maintaining the internal temperature below -65°C, add a solution of 2-(propylthio)acetonitrile (2.6g, 22.57mmol) in toluene (12mL) to this solution by a syringe in 20min. Add pure (E)-4-ethoxy-1,1,1-trifluorobut-3-ene-2-one (4.17g, 24.83mmol) to this solution by a syringe in 20min. Afterwards, quench the reaction mixture with phosphoric acid (5% v / v in water). The organic layer was dried over MgSO4 and purified by flash column chromatography (220 g "gold" column) using EtOAc / hexanes (0-50% v / v) as eluent to give 5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile (4.5 g, 15.88 mmol, 70.4% yield) as a mixture of two diastereomers (orange-yellow oil). 1H NMR: (400 MHz, CHLOROFORM-d) δ 6.88 ((d, J = 12.5 Hz) and 6.86 (d, J = 12.4 Hz), 1H), 4.92 ((d, J = 12.5 Hz) and 4.87 (d, J = 12.6 Hz), 1H), 3.31 ((s) and 3.28 (s), 1H), 2.88-2.68 (m, 2H), 1.81-1.56 (m, 2H), 1.32 (td, J = 7.0, 0.7 Hz, 3H), 1.04 (td, J = 7.4, 1.9 Hz, 3H). 13C NMR: (101 MHz, chloroform-d) δ 153.51, 152.74, 125.44, 125.39, 122.59, 122.55, 115.52, 115.47, 96.24, 95.58, 77.23, 76.12, 75.83, 75.54, 75.29, 75.00, 65.88, 65.80, 41.21, 40.62, 35.22, 35.12, 22.51, 22.24, 14.46, 14.43, 13.17. 19F NMR: (376 MHz, chloroform-d) δ -77.84, -78.95.

[0096] Example 1d. Preparation of 5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile by a continuous flow process

[0097]

[0098] Solutions of 2-(propylthio)acetonitrile and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one were premixed in solvent 1 to form solution 1, which was connected to pump 1 (P1). Base was dissolved in solvent 1 to form solution 2, which was connected to pump 2 (P2). Acid was dissolved in THF or CPME to form solution 3, which was connected to pump 3 (P3). All three pumps were LabAlliance dual-head HPLC pumps (piston type). Solution 1 (containing reactants) and solution 2 (containing base) were precooled through a heat exchanger and mixed together through a tee into the static mixer in reactor 1 (R1). After the mixture was suspended in R1 for the desired residence time, it was then mixed with a precooled acid quenching solution (solution 3) (delivered from the heat exchanger) through a tee at the eye of the static mixer in reactor 2 (R2). The outlet of R2 was connected to the product collection tank through a back pressure controller. At the completion of the continuous flow process operation, the organic solution in the product collection tank is analyzed by quantitative HPLC analysis to determine the yield of the product. Bases used in the continuous flow process include tert-amyl alkoxide, sodium tert-butoxide, potassium tert-butoxide, or NaHMDS, and solvents may include THF, CPME, or toluene, and mixtures thereof.

[0099] Example 1d. Preparation of Additional 5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile

[0100] A 1 L jacketed reactor (Reactor 1) with an overhead mechanical stirrer that was dried and inerted with nitrogen was charged with 29.03 grams of solid sodium tert-butoxide (292.99 mmol, 1.35 eq., finely granulated white powder, 97 wt% purity). The reactor was re-inerted with nitrogen and charged with 597.3 g of CPME using a peristaltic pump. A 4.63 wt% solution of sodium tert-butoxide was frozen to approximately -71.0°C. Using a peristaltic pump, 25.0 g of pure PTAN (217 mmol, limiting reagent) was added to Reactor 1 over approximately 15 min to provide a PTAN anion solution. The rate of addition was such that the reaction temperature of the reactor was maintained below -69°C. A 37 wt% solution of ETFBO (48.9 g, 282.14 mmol, 1.3 eq., 97 wt% purity) in CPME was prepared in a separate container. This solution was continuously added to Reactor 1 over approximately 40 minutes using a peristaltic pump to provide an alkoxide solution. The path was rinsed with 65 g of CPME. The addition rate was such that the reaction temperature of the reactor was maintained below -66°C. The reaction product (alkoxide) was immediately transferred by gravity to a 2L jacketed reactor with an overhead mechanical stirrer containing a pre-cooled 1.62 equivalents of potassium dihydrogen phosphate aqueous solution (1 weight molar concentration, pH = 4.5) at an internal temperature of 0°C. The contents of the 2L jacketed reactor were warmed to 25°C. The aqueous phase was decanted and the organic phase was analyzed by LC and NMR. The organic phase was used as a crude solution in the next step.

[0101] Example 2a. Synthesis of 2-chloro-3-(propylthio)-4-(trifluoromethyl)pyridine

[0102] To a 50 mL one-necked round bottom flask equipped with a stir bar was added (E)-5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile (1 g, 3.53 mmol, nitrogen atmosphere). While stirring, anhydrous hydrochloric acid (20.00 ml, 60.0 mmol, 17.0 equivalents of HCl) in cyclopentyl methyl ether (CPME, 3M) was added and the reaction was stirred at room temperature for three days. TLC analysis (20% ethyl acetate in hexanes) indicated complete conversion. The reaction mixture was worked up by careful addition to 100 mL of stirred, concentrated aqueous sodium bicarbonate solution. Additional bicarbonate solution was added until gas evolution was no longer observed and the aqueous phase tested slightly basic. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, concentrated on a rotary evaporator and further dried under high vacuum until constant weight was obtained. The residue was analyzed by 1H NMR without further processing. Crude 2-chloro-3-(propylthio)-4-(trifluoromethyl)pyridine was received in approximately 88% purity as a yellow oil (0.9057 g, 3.12 mmol, 88% yield, corrected for NMR purity).

[0103] An analytically pure sample was obtained by stirring 50 mg (176 μmol) of the starting material with HCl (3 M, 1 mL, 3 mmol, 17 eq. HCl) in CPME for two days followed by heating to 70 °C for two hours in a 4 mL screw cap vial. The extractive bicarbonate / ethyl acetate workup was performed as described above. No further purification was required. The chromatogram and spectrum of the crude material thus received are shown below. 1H NMR (400 MHz, CDCl3) δ 8.49 (dq, J = 5.0, 0.8 Hz, 1H), 7.54 (d, J = 5.0 Hz, 1H), 2.95 (t, J = 7.3 Hz, 2H), 1.63 (h, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ159.10, 149.24, 144.77 (q, J = 30.8 Hz), 130.62, 121.95 (q, J = 275.0 Hz), 119.56 (q, J = 5.1 Hz), 37.89, 22.92, 13.34. 19F NMR (376 MHz, CDCl3) δ-61.66; low resolution ESI (+), for [C9H 10 ClF3NS]+ expected: m / z = 256.0 (35Cl) and 258.0 (37Cl), found: m / z: 255.8, 257.9, 296.8 (MeCN adduct), 298.8 (MeCN adduct).

[0104] Example 2b. Preparation of 2-chloro-3-(propylthio)-4-(trifluoromethyl)pyridine

[0105]

[0106] Method 1: Under nitrogen atmosphere, 5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile (50 mg, 0.176 mmol) and dry toluene (0.5 mL) were added to a 4 mL vial followed by thionyl chloride (38.6 μl, 0.529 mmol). The mixture was stirred for 1 h before ethanol (30 μL) was added. The reaction was stirred for two days.

[0107] For HPLC analysis, a 400 μL aliquot of the reaction mixture was removed and diluted to a total volume of 3 mL with a 1:2 mixture of water and acetonitrile. From this diluted mixture, a 240 μL aliquot (approximately 0.4 mg) was transferred to a self-filtering HPLC filter vial and diluted with 150 μL acetonitrile and 10 μL acetic acid / triethylamine 1:1: buffer. Low-resolution ESI (+) was used for [C9H 10 ClF3NS]+ expected: m / z = 256.0 (35Cl) and 258.0 (37Cl), found: m / z: 255.8, 257.9, 296.8 (MeCN adduct), 298.8 (MeCN adduct).

[0108] Method 2: To a 4 mL vial under nitrogen atmosphere was added 5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile (50 mg, 0.176 mmol) followed by thionyl chloride (502 μl, 6.88 mmol). The reaction was stirred for two days. The reaction was worked up by dropwise addition into saturated sodium bicarbonate solution (1 mL) to which sodium hydroxide (50% w / w) was added dropwise until the mixture became basic. The mixture was extracted with ethyl acetate. A sample from the ethyl acetate layer was diluted to a concentration of approximately 1 mg / mL (based on starting material) in 400 μL acetonitrile and 10 μL acetic acid / triethylamine buffer, microfiltered and analyzed by LC / MS. Low resolution ESI (+) for [C9H 10 ClF3NS]+ expected: m / z = 256.0 (35Cl) and 258.0 (37Cl), found: m / z: 255.8, 257.9, 296.8 (MeCN adduct), 298.8 (MeCN adduct).

[0109] Example 2c. Preparation of 2-ethoxy-3-(propylthio)-4-(trifluoromethyl)pyridine

[0110]

[0111] 5-Ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile (50 mg, 0.176 mmol) was added to a 4 mL vial with a stir bar followed by ethanol (30 μL) and concentrated sulfuric acid (198 μL, 3.71 mmol). The reaction was stirred at room temperature overnight and then heated to 80° C. for 4 hours. The contents of the vial were processed dropwise into concentrated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated, concentrated, and dried under high vacuum. The product 2-ethoxy-3-(propylthio)-4-(trifluoromethyl)pyridine was isolated as a dark residue: 30 mg, 0.113 mmol, (64%); 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 4.7 Hz, 1H), 6.49 (d, 4.7 Hz, 1H), 4.74-4.39 (m, 2H), 3.35-3.07 (m, 2H), 1.77-1.56 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H), 1.07 (td, J = 7.4, 3H); 19F NMR (376MHz, CDCl3) δ-59.6; 13CNMR (101MHz, CDCl3) δ170.0, 158.4, 144.3 (t, J = 31.3HZ), 122.2 (q, J = 275.2), 104.2 (q, J=4.65), 85.2, 40.2, 33.1, 18.7, 12.8, 9.9; MS (ESI-) m / z=235.9 (M-H+); MS (ESI+) m / z=237.9 (M+H+).

[0112] Example 2d. Preparation of 2-methoxy-3-(propylthio)-4-(trifluoromethyl)pyridine

[0113]

[0114] 5-Ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile (50 mg, 0.176 mmol) was added to a 4 mL vial with a stir bar, followed by methanol (30 μL) and concentrated sulfuric acid (198 μL, 3.71 mmol), and then heated at 60° C. overnight. The contents of the vial were worked up by dropwise addition into concentrated sodium bicarbonate solution and extraction with dichloromethane. The organic phase was separated, concentrated, and dried under high vacuum. The dark residue (approximately 32 mg) was received, which contained the desired product 2-methoxy-3-(propylthio)-4-(trifluoromethyl)pyridine [MS (ESI+) m / z = 251.9 (M+H+)], which was a mixture with 3-(propylthio)-4-(trifluoromethyl)pyridin-2(1H)-one [MS (ESI-) m / z = 235.9 (M-H+), MS (ESI+) m / z = 237.9 (M+H+)] and additional unidentified impurities.

[0115] Example 3a. Preparation of 2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonyl chloride

[0116]

[0117] A 125 mL flat bottom three neck jacket reactor (propylene glycol / water bath fluid) was equipped with mechanical stirring (PTFE half moon stirring paddle). The jacket temperature was set to 0°C and 2-methoxy-3-(propylthio)-4-(trifluoromethyl)pyridine (13.93 mmol) dissolved in 66.3 g of dichloromethane was loaded, followed by a solution of methyltributylammonium chloride (0.641 mmol) in water (25 g). Stirring (330 rpm) was started and when the reaction mixture reached the desired temperature, chlorine was added. Chlorine (125.9 mmol) was added over 125 minutes. After adding approximately 0.3 g of chlorine, a white slurry was formed, which gradually faded as the addition proceeded, and the color gradually turned yellow. At the end of the chlorine addition, all solids had dissolved. During the entire addition process, the reaction temperature was maintained below 2.5°C. HPLC analysis at the end of the chlorine addition showed 73.8 area % of the desired product. The reaction was sampled after 1, 2, and 3 hours, with a maximum of 75.5 area % of the desired product at the 1 hour sampling. Excess chlorine was quenched with 4.62 g of 40% aqueous sodium bisulfite. The reaction mixture was transferred to a separatory funnel. The organic phase was cut and concentrated by rotary evaporation to give 4.28 g of a colorless oil, 76.0 area % of the desired product by HPLC analysis.

[0118] As previously described, in various aspects, the synthesis of (E)-5-ethoxy-3-hydroxy-2-(propylthio)-3-(trifluoromethyl)pent-4-enenitrile can be performed, for example, as shown in Scheme A below.

[0119] I. Plan A

[0120] PTAN deprotonation:

[0121]

[0122] Formation of alkoxides:

[0123]

[0124] Quenching of alkoxides:

[0125]

[0126] In various aspects, the various synthetic methods can be performed in batch, semi-continuous, or continuous reactors. Figure 1 , showing an exemplary semi-batch reactor flow Figure 1 . Figure 2 and Figure 3 An exemplary pilot semi-batch reactor 100 is shown according to various aspects. Figure 1 In the exemplary aspect shown in , deprotonation of 2(propylthio)acetonitrile (PTAN) is performed in the first tubular reactor 21 using 1.5 equivalents of base. This is followed by salt alcohol formation in the second tubular reactor 23 using 1.3 equivalents of ETFBO. The alkoxide is then quenched with a proton source in a jacketed stirred tank reactor 30. Both tubular reactors 21 and 23 are operated at -20°C and the stirred tank reactor 30 is operated at 0°C. The residence times of the deprotonation and alkoxide reactors 21 and 23 are 0.5 minutes and 0.33 minutes, respectively. The stirred tank reactor 30 is operated in semi-batch to allow a predetermined amount of product for downstream testing. The alkoxide can also be quenched at 0 to 20°C using a proton source in a third tubular reactor (not shown).

[0127] The reaction sequence in scheme A was previously shown in batch mode at -78 ℃, wherein with 2-4 gram scale productive rate is about 83%. In various aspects, using continuous flow system, reaction can be carried out at higher temperature such as -20 ℃, wherein productive rate is up to 90%-92%. In various aspects, short residence time can help realize smaller reactor volume, and this can be conducive to chemical inventory, imprint and potential capital expenditure. When this type of reaction may be amplified to larger amount, some aspects can explain low temperature maintenance, which may cause longer reaction time (slower reagent addition), local hot spot and / or deeper cryogenic condition. In some aspects, longer reaction time may cause increased impurity formation and productive rate reduction. In some aspects, the use of cryogenic condition also increases the cost of production technology and is not that many CRO and 3PM are equipped to handle cryogenic condition.

[0128] like Figure 2 and Figure 3 The reactor is assembled as shown in . Pump 1 (P1) 4 is connected to the PTAN bottle, Pump 2 is connected to the base solution bottle and Pump 3 is connected to the ETFBO. All three pumps are double acting piston pumps. The P1 and P2 outlets are pre-cooled to the reactor temperature, mixed through a 'tee' connection (not shown) and immediately enter a spiral type static mixer (3 / 16" OD, 12 elements) 27. The downstream of this static mixer is connected to a coiled reactor (1 / 8" OD, 16' long tube coiled to give a 2" OD). The Reactor 1 outlet is combined with the pre-cooled ETFBO stream from P3 through a similar 'tee' / static mixer assembly 27 and enters Reactor 2 (23). Reactor 2 (23) has the same temperature as Reactor 1 (21). Same geometry. A K-type thermocouple was installed at the outlet of Reactor 2 (23) to measure the reactor outlet temperature. The choice of the outlet of Reactor 2 (23) was directed to either waste / sample collection or product collection. Product collection was performed by running the flow reactor for a specified amount of time in a 1 liter jacketed stirred tank (R3) (30) with a known amount of quench solution. The flow reactor outlet exited the -20°C bath and entered the stirred tank through a dip tube. The dip tube was positioned in such a way that the alkoxide solution entered the aqueous phase and bubbled through the aqueous phase to the organic phase. Figure 1 The reactor and precooler 22, 24 and 26 are as follows Figure 2 The jacketed reactor was connected to a circulating bath.

[0129] Prior to the reaction, THF was pumped through the reactor to flush the system. Once the temperature reached the desired level while the solvent was pumped, the flow was diverted to the reaction reagents from the bottle. The flow rates were: P1 = 13.2 mL / min for PTAN solution, P2 = 13.2 mL / min for base solution, and P3 = 13.2 mL / min for EtFBO solution. Reactors R1 and R2 and the precooler loop were maintained at -20°C. The stirred tank was maintained at 0°C. For the above reactor configuration and flow rates, the residence time in R1 was 0.5 minutes and the residence time in R2 was 0.33 minutes. Samples were collected at different time points indicated in Table 2 below and analyzed by 19F NMR and HPLC to determine the conversion to the desired product. Once the samples showed that the reactor had reached a steady state, the reactor effluent was diverted to the stirred tank, where the quench solution was maintained at 0°C under stirring.

[0130] Table 2:

[0131] Examples# RT1 RT2 T NaOtBu equivalent EtFBO equivalent Yield A1 0.25 0.17 -35℃ 1.5 1.3 89.6％ A5 0.5 0.34 -35℃ 1.5 1.3 87.7％ A6 1 0.67 -35℃ 1.5 1.3 85.7％ B1 0.5 0.33 -20℃ 1.5 1.3 90.6％ C1 0.5 0.33 -25℃ 1.5 1.3 92.0％

[0132] The compositions and methods of the claims are not limited by the scope of the specific compositions and methods described herein (which are intended as illustrations of several aspects of the claims), and any compositions and methods that are functionally equivalent are intended to fall within the scope of the present claims. Various modifications to these compositions and methods, in addition to those shown and described herein, are also intended to fall within the scope of the appended claims. Further, although only certain representative composition materials and method steps disclosed herein are specifically described, other combinations of these composition materials and method steps are intended to fall within the scope of the appended claims even if not specifically described. Therefore, a combination of steps, elements, components or elements may be explicitly mentioned herein; however, other combinations of steps, elements, components and elements are included even if not explicitly stated. As used herein, the term "comprising" and its variations are used synonymously with the term "including" and its variations, and are open, non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various aspects, the terms "consisting essentially of" and "consisting of" may also be used instead of "comprising" and "including" to provide more specific aspects of the present invention and are also disclosed.

Claims

1. A method comprising: reacting a compound having formula IV, a first base, and a compound having formula V, To form a compound of formula VII, a compound of formula VIII, or a mixture thereof, Where R is a C1-C6 alkyl group, R 1 is C1-C6 alkyl, and X is OH.

2. The method of claim 1, further comprising preparing the compound of formula IV by a process by reacting an alkylthiol RSH, a halogenated acetonitrile Y-CH2CN, and a second base, wherein R is a C1-C6 alkyl group and Y is a halogen.

3. The method of claim 1, further comprising: allowing the compound of formula VII or formula VIII or a mixture thereof - wherein R is a C1-C6 alkyl group, R 1 is C1-C6 alkyl, and X is OH - reacted with an acid or a dehydrating halogenating agent, or a combination thereof, wherein the acid is HCl, HBr or HI, and the dehydrating halogenating agent is SOCl2, SOBr2, POCl3, POBr3, PCl3, PBr3, PCl5, PBr5, or oxalyl chloride, or a combination thereof, to form a compound having Formula IX wherein R is C1-C6 alkyl, and Y is halogen.

4. The method of claim 3, wherein: The acid is HCl or HBr.

5. The method of claim 3, wherein: The dehydrating halogenating agent is SOCl2, SOBr2, POCl3, PCl3, or oxalyl chloride, or a combination thereof.

6. The method according to claim 3 or 4, wherein: In the case where the acid is selected, the method further comprises reacting one or more of an alcohol and water with the reactant of claim 3 simultaneously, wherein the alcohol is a C1-C6 alcohol, to form a compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is a C1-C6 alkyl group.

7. The method of claim 6, wherein: The alcohol is methanol to form a compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is CH3.

8. The method according to claim 3 or 4, wherein: In the case where the acid is selected, the method further comprises: reacting the alkoxide with the compound of formula IX of claim 3 sequentially to form a compound having the formula Wherein R is C1-C6 alkyl, and R 2 is a C1-C6 alkyl group, The alkoxide is sodium C1-C6 alkoxide or potassium C1-C6 alkoxide.

9. The method of claim 8, wherein: The alkoxide is sodium methoxide or potassium methoxide to form a compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is CH3.

10. The method according to claim 3 or 5, wherein: In the case where the dehydrating halogenating agent is selected, the method further comprises: reacting the alkoxide with the compound of formula IX of claim 3 sequentially to form a compound having the formula Wherein R is C1-C6 alkyl, and R 2 is a C1-C6 alkyl group, The alkoxide is sodium C1-C6 alkoxide or potassium C1-C6 alkoxide.

11. The method according to claim 3 or 5, wherein: The dehydrohalogenating agent is thionyl chloride to form the compound of formula IX, wherein R is C1-C6 alkyl and Y is Cl.

12. The method of claim 10, wherein: The alkoxide is sodium methoxide or potassium methoxide to form the compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is CH3.

13. The method of any one of claims 7, 9 and 12, further comprising making a compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is CH3, Reaction with chlorine and water to form a compound having formula III 14. The method of claim 1, wherein: The first base is selected from: n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, potassium tert-amylate, or a mixture thereof.

15. The method of claim 1 or 14, further comprising a solvent selected from the group consisting of tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, dioxane, pentane, hexane, cyclohexane, toluene, or a mixture thereof.

16. The method of claim 1 or 14, wherein: The reaction is carried out at -80°C to 25°C.

17. The method of claim 1 or 14, wherein: The method is carried out as a batch process.

18. The method of claim 1 or 14, wherein: The method is carried out as a continuous process.

19. The method of any one of claims 7, 9 and 12, further comprising making a compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is CH3, Reaction with chlorine gas and sodium chloride solution to form a compound having formula III 20. The method of claim 19, wherein: The sodium chloride solution is saturated.

21. The method of any one of claims 7, 9 and 12, further comprising making a compound having the formula Wherein R is C1-C6 alkyl, and R 2 It is CH3, Reaction with chlorine, water and trifluoroacetic acid to promote the reaction to form a compound having formula III 22. A compound having the following structure: Where R is a C1-C6 alkyl group, R 1 is C1-C6 alkyl, and X is OH.

23. A compound having the following structure: wherein R is C1-C6 alkyl and X is OH.

24. A compound having the following structure: wherein X is OH.

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