WO2021076681A1 - Procédé de synthèse de picolinamides - Google Patents

Procédé de synthèse de picolinamides Download PDF

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Publication number
WO2021076681A1
WO2021076681A1 PCT/US2020/055658 US2020055658W WO2021076681A1 WO 2021076681 A1 WO2021076681 A1 WO 2021076681A1 US 2020055658 W US2020055658 W US 2020055658W WO 2021076681 A1 WO2021076681 A1 WO 2021076681A1
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Prior art keywords
formula
mixture
mmol
compound
added
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PCT/US2020/055658
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English (en)
Inventor
Nicholas R Babij
Elizabeth O MCCUSKER
Gregory T Whiteker
Neeraj Sane
Siyu TU
Xianoyong LI
Daniel W KLOSOWSKI
Patrick T MCGOUGH
Meng Guo
Matthew Robinson
Jeffrey Scott Nissen
Tyler Davis
Yan Hao
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Dow Agrosciences Llc
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Application filed by Dow Agrosciences Llc filed Critical Dow Agrosciences Llc
Priority to US17/754,977 priority Critical patent/US20220411375A1/en
Priority to EP20877148.5A priority patent/EP4044811A4/fr
Priority to CN202080072411.5A priority patent/CN114554848A/zh
Priority to BR112022007354A priority patent/BR112022007354A2/pt
Publication of WO2021076681A1 publication Critical patent/WO2021076681A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • Chiral compounds such as these picolinamides can often be a challenge to manufacture on an industrial scale due to the need to control the absolute and relative stereochemistry of the product and intermediates. Moreover, the costs involved in multi-step syntheses at scale may significantly increase costs for each additional step required. Thus, operationally simple and limited-step processes to manufacture biologically active compounds at scale are highly desirable.
  • These compounds may be made by coupling a compound of Formula B wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO; with at least one of the compounds of Formula C and Formula C1 wherein X is Cl, Br, I, HSO 4 , H 2 PO 4 , CF 3 COO, or CH 3 SO 3.
  • Another aspect of the present disclosure provides a process for the preparation of a compound of Formula B wherein Z is CH 3 CH 2 CO comprising the steps of a) reacting a compound of Formula B, wherein Z is H with an acylating reagent, and a base; and b) isolating the compound of Formula B, wherein Z is CH 3 CH 2 CO from the mixture.
  • the disclosure provides a process wherein suitable acylating reagents may be selected from one of propionyl chloride and propionic anhydride, or mixtures thereof.
  • Another aspect of the present disclosure provides a process for the preparation of the compound of Formula C1: comprising the steps of a) creating a first mixture containing the compound of Formula G2 as predominantly a single enantiomer o-tolylmagnesium halide, and a copper catalyst; b) isolating the compound D2 from the first mixture; c) creating a second mixture containing the compound of Formula D2, N-(tert-butoxycarbonyl)-L-alanine, an acylating agent, a catalyst and optionally a base; d) isolating the compound of Formula F from the second mixture; e) creating a third mixture containing the compound of Formula F and a strong acid; wherein the strong acid is HCl, HBr, HI, H 2 SO 4 , H 3 PO 4
  • Another aspect of the present disclosure is the intermediate produced in the present process, viz., the compound: wherein Z is CH 3 CH 2 CO.
  • the resultant enantiomeric and/or diastereomeric enriched compounds are provided.
  • processes that make enantiomeric and/or diastereomeric enriched Formula A and intermediates thereof are provided.
  • compounds or mixtures disclosed herein are enantiomeric and/or diastereomeric enriched synthetic intermediates of Formula A and/or are protected forms or intermediates of Formula A; that is the compound is masked with a protecting organic functional group that when exposed to the appropriate conditions will cleave the covalent bond from the protecting group to produce Formula A.
  • the processes described herein make a compound that is a useful intermediate.
  • mixtures are made that comprise a high percentage of enantiomeric and/or diastereomeric enriched Formula A or intermediates thereof.
  • the processes described herein provide very low concentrations of undesired enantiomeric and/or diastereomeric compounds.
  • These organic compounds are impurities, i.e. side-products from addition reactions and/or are cumulative, meaning these compounds (impurities) are present because one or more impure intermediates were carried forward in steps for the total synthesis of the picolinamide.
  • the processes described herein provide a total synthesis for making enantiomeric and/or diastereomeric enriched Formula A.
  • the disclosure provides enantiomeric and/or diastereomeric enriched protected forms of Formula A or intermediates thereof.
  • mixtures comprising one or more compounds or salts thereof disclosed herein are provided.
  • the disclosure herein provides a compound that is selected from among certain specific compounds disclosed herein.
  • the compound is any one of the compounds that is reduced to practice in the Examples section of this disclosure.
  • methods of manufacture are provided. 4. DESCRIPTION 4.1.
  • Enantiomeric and/or diastereomeric enriched refers to the amount (mol%) of a particular desired compound in a mixture of organic compounds disclosed herein.
  • the other, undesired organic compounds in the mixture may be the enantiomer or the diastereomer of the desired compound, and as such these enantiomers and/or diastereomers are impurities. Otherwise, the impurity or impurities may be any one or more of the organic compounds disclosed herein.
  • “Substantially pure or free” refers to a mixture in which one organic compound of interest far exceeds the amount of other small organic compounds in the mixture as impurities, and is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99. 5%, at least 99. 7%, at least 99. 9%, by mol, of the desired compound.
  • “Pg or protecting group” refers to any organic functional group which is a mask or as is traditional known in the art, is a group that “protects” a certain organic functional group with the ability to form that certain functional group upon bond cleavage.
  • X or R are a variety of organic functional groups that are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino
  • salt refers to salts which are suitable for use in agriculture, i.e. they affect humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio in agriculture. These salts are well known in the art. Salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Additional interpretational conventions [0100] Generally, reference to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Compounds comprising radioisotopes such as tritium and 14 Care thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein. [0101] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • Racemic mixtures, and d or l enriched stereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • the compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates, among others.
  • the term “about,” when referring to a value can be meant to encompass variations of, in some aspects, ⁇ 100% in some aspects ⁇ 50%, in some aspects ⁇ 20%, in some aspects ⁇ 10%, in some aspects ⁇ 5%, in some aspects ⁇ 1%, in some aspects ⁇ 0.5%, and in some aspects ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • singular articles such as “a,” “an” and “the” and similar referents in the context of describing the elements are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
  • the picolinamide of Formula A wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO may be prepared by coupling a compound of Formula B wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO; with at least one of the compounds of Formula C and Formula C1 4.3.1.
  • the disclosure provides for a process for the preparation or manufacture of the compound of Formula A wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO, the process comprising contacting the following components: a compound of Formula B: or a salt thereof, a compound of Formula C: or a salt thereof, a coupling reagent, and a base.
  • the disclosure provides a process wherein the coupling reagent is pivaloyl chloride.
  • the disclosure provides for a process of manufacturing Formula A wherein the process comprises: wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO.
  • Picolinic acid B is first activated for coupling by converting it into (a) the corresponding mixed anhydride using an alkyl, aryl or benzyl chloroformate and a base, or a carboxylic acid chloride and a base, or (b) the corresponding acid chloride using oxalyl chloride or thionyl chloride.
  • the resulting derivative of picolinic acid B in the form of a mixed anhydride or an acid chloride, can be treated with the amine salt of Formula C, wherein X is Cl, Br, I, HSO 4 , H 2 PO 4 , CF 3 COO, or CH 3 SO 3 , and a base to provide the desired picolinamide of Formula A, wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO.
  • the compound of Formula A may be isolated by employing standard isolation and purification techniques. Suitable solvents for this process may include one or more of dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile.
  • Suitable chloroformate esters for use in the process may include those wherein R’ is a C 1 -C 4 alkyl, an aryl or a benzyl group.
  • Suitable acid chlorides i.e., R’COCl
  • R’ is a C 1 -C 4 alkyl.
  • the salt of a compound of Formula C is a salt where the structure is a compound of Formula C1 , wherein X is Cl, Br, I, HSO 4 , H 2 PO 4 , CF 3 COO or CH 3 SO 3 .
  • the disclosure provides a process wherein the organic amine is triethylamine. In some aspects, the disclosure provides a process wherein the organic amine is (1,4-diazabicyclo[2.2.2]octane) (DABCO). In some aspects, the disclosure provides a process wherein the organic amine is N-methylimidazole (NMI). In some aspects, the disclosure provides a process wherein the organic amine is imidazole. In some aspects, the disclosure provides a process wherein organic amine is 4- pyrrolidinopyridine (PPY). In some aspects, the disclosure provides a process wherein the organic amine is Quinidine, or an analog thereof.
  • DABCO (1,4-diazabicyclo[2.2.2]octane)
  • NMI N-methylimidazole
  • the disclosure provides a process wherein the organic amine is imidazole.
  • the disclosure provides a process wherein organic amine is 4- pyrrolidinopyridine (PPY). In some aspects, the
  • the disclosure provides a process wherein the organic amine is diisopropylethylamine (DIPEA), aromatic amines such as pyridine, metal carbonates such as potassium carbonate, and mixtures thereof.
  • the disclosure provides a process wherein the organic amine is selected from the group consisting of: DMAP, PPY, Quinidine diisopropylethylamine (DIPEA), pyridine, potassium carbonate, NMI, and mixtures thereof.
  • the disclosure provides for a method of manufacture of a compound according to any one of the aspects disclosed herein.
  • the disclosure provides for a method of manufacture of a compound wherein the process for the manufacture is any one of the process aspects described herein. 4.3.2. Preparation of Compound of Formula B [0114] In some aspects, the disclosure provides a process wherein the compound of Formula B, wherein Z is CH 3 CO, CH 3 CH 2 CO or (CH 3 ) 2 CHCO , may be prepared by acylation of the compound of Formula B, wherein Z is H, with an acylating reagent, base and optionally a catalyst.
  • suitable acylating reagents may include those wherein R is a C1-C3 alkyl, including acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, isobutyryl chloride and isobutyric anhydride.
  • Bases may be selected from pyridine, alkyl substituted pyridines, and trialkylamines, such as triethylamine.
  • Suitable catalysts for this process include, but are not limited to, DMAP (4-(dimethylamino)pyridine) and NMI (N- methyl imidazole).
  • Suitable solvents for this transformation may include DCM, THF, MeTHF, CPME, heptanes, hexanes, toluene and mixtures thereof.
  • the compound of Formula B may be isolated by employing standard isolation and purification techniques. 4.3.3.
  • the disclosure provides a process wherein the compound of Formula C1, wherein X is Cl, Br, I, HSO4, H2PO4, CF3COO, or CH3SO3, may be prepared in a process that comprises the following steps: a) creating a first mixture containing the compound of Formula G2 as predominantly a single enantiomer o-tolylmagnesium halide, and a copper catalyst; b) isolating the compound of Formula D2 from the first mixture.
  • the disclosure provides a process to prepare a compound of Formula D2, wherein the o-tolylmagnesium halide is o-tolylmagnesium chloride, o- tolylmagnesium bromide and mixtures thereof.
  • Suitable copper catalysts include, but are not limited to, copper salts such as copper (I) iodide, copper (I) bromide and copper (I) chloride.
  • Suitable solvents for this transformation may include THF, MeTHF, CPME, MTBE, heptanes, hexanes, toluene and mixtures thereof.
  • the disclosure provides a process to prepare the o- tolylmagnesium halide from magnesium and 2-halotoluene derivatives, such as 2- chlorotoluene and 2-bromotoluene.
  • the disclosure provides a process to prepare a compound of Formula F, wherein suitable acylating agents include, but are not limited to, acid chlorides such as pivaloyl chloride and acid anhydrides such as pivalic anhydride.
  • suitable catalysts for this process include, but are not limited to, DMAP (4- (dimethylamino)pyridine) and NMI (N-methyl imidazole).
  • Suitable bases may include, but are not limited to, trialkylamines such as triethylamine or diisopropylethylamine.
  • Suitable solvents for this transformation may include, but are not limited to, DCM, THF, MeTHF, CPME, MTBE, ethyl acetate, heptanes, heptane, hexanes, toluene and mixtures thereof.
  • the disclosure provides a process to prepare a compound of Formula C or a compound of Formula C1, wherein X is Cl, Br, I, HSO4, H2PO4, CF3COO, or CH3SO3.
  • Suitable solvents for this transformation may include, but are not limited to, dioxane, CPME, heptanes, heptane hexanes, toluene, methanol, ethanol, isopropanol and mixtures thereof.
  • the compound of Formula C1 may be prepared in an alternative process that comprises the following steps: a) creating a first mixture containing the compounds of Formula G1 and G2 as a racemic mixture of (R,R)- and (S,S)-enantiomers, b) o-tolylmagnesium halide, and a copper catalyst; c) isolating a second mixture containing the compounds of Formula D1 and D2 as a racemic mixture of (R,R)- and (S,S)-enantiomers d) creating a third mixture containing the compounds D1 and D2 as a racemic mixture of (R,R)- and (S,S)-enantiomers, a lipase enzyme, and an acyl donor; e) isolating the compound of Formula D2 as a fourth mixture containing the compound of Formula E1 wherein R’’ is C 1 -C 18 alkyl; f) creating a fifth mixture containing the compound of Formula D2, the compound of Formula E
  • the disclosure provides a process to prepare a mixture containing the compounds D1 and D2 as a racemic mixture of (R,R)- and (S,S)- enantiomers, wherein the o-tolylmagnesium halide is o-tolylmagnesium chloride, o- tolylmagnesium bromide and mixtures thereof.
  • Suitable copper catalysts include, but are not limited to, copper salts such as copper (I) iodide, copper (I) bromide, and copper (I) chloride.
  • Suitable solvents for this transformation may include THF, MeTHF, CPME, heptanes, hexanes, toluene and mixtures thereof.
  • the disclosure provides a process to prepare the o- tolylmagnesium halide from magnesium and 2-halotoluene derivatives, such as 2- chlorotoluene and 2-bromotoluene.
  • the disclosure provides a process to prepare a compound of Formula D2, wherein suitable lipase enzymes include, but are not limited to, Candida antarctica Lipase B, Burkholderia cepacia, Candida rugosa, Pseudomonas cepacia, Thermomyces lanuginosus, Rhizomucor miehei, Rhizopus oryzae.
  • the lipase enzymes could be free or immobilized such as different preparations of immobilized Cal B (Novozym® 435, Cal B Immo Plus TM , etc).
  • Suitable acyl donors may include, but are not limited to, isopropenyl acetate and unbranched C 1 -C 18 vinyl acetates including vinyl acetate.
  • Suitable solvents for this transformation may include, but are not limited to, toluene, heptane, heptanes, hexane, hexanes, MTBE (methyl tert-butyl ether), CPME (cyclopentyl methyl ether), THF, Me-THF and mixtures thereof.
  • the disclosure provides a process to prepare a compound of Formula F, wherein suitable acylating agents include, but are not limited to, acid chlorides such as pivaloyl chloride or acid anhydrides such as pivalic anhydride.
  • suitable catalysts for this process include, but are not limited to, DMAP (4- (dimethylamino)pyridine) and NMI (N-methyl imidazole).
  • Suitable bases may include, but are not limited to, trialkylamines such as triethylamine or diisopropylethylamine.
  • Suitable solvents for this transformation may include, but are not limited to, DCM, THF, MeTHF, CPME, MTBE, ethyl acetate, heptanes, heptane, hexanes, toluene and mixtures thereof.
  • the disclosure provides a process to prepare a compound of Formula C or a compound of Formula C1, wherein X is Cl, Br, I, HSO4, H2PO4, CF3COO, or CH3SO3.
  • Suitable solvents for this transformation may include, but are not limited to, dioxane, CPME, heptanes, heptane hexanes, toluene, methanol, ethanol, isopropanol and mixtures thereof.
  • the disclosure above provides a process wherein the compound of Formula C may be prepared.
  • the disclosure provides a process wherein the mixture of compounds of Formula D2 and Formula E1, wherein R’’ is C1-C18 alkyl, may be used without purification.
  • the disclosure provides a process wherein the compound of Formula D2 may be isolated by employing standard isolation and purification techniques.
  • the disclosure provides a process wherein the mixture of compounds of Formula F and Formula E1 may be used without purification. In another aspect, the disclosure provides a process wherein the compound of Formula F may be isolated by employing standard isolation and purification techniques. 4.3.4. Preparation of Compound of Formula G [0130] In some aspects, the disclosure provides a process to prepare a compound of Formula G (trans-2,3-epoxybutane) from meso-2,3-butanediol: wherein R 1 is alkyl, alkoxy or aryl, and Y is H or CO2R’’’, wherein R’’’ is alkyl or aryl.
  • meso-2,3-Butanediol is first converted into a sulfate or sulfonic ester (H). Depending on the conditions used, these transformations can be accomplished to afford racemic or enantioenriched sulfonic ester products of Formula G.
  • the sulfate or sulfonic esters H are treated with base to give (racemic or enantioenriched) trans-2,3-epoxybutane (G).
  • the disclosure provides a process in which a compound of Formula H, wherein R 1 is alkyl, alkoxy or aryl, and Y is H, is prepared by sulfonylation of meso-2,3-butanediol with a copper catalyst, a bisoxazoline ligand, a sulfonyl halide and a base.
  • Suitable copper catalysts for this process include, but are not limited to, copper salts such as copper (II) chloride, copper (II) bromide, copper (II) triflate and copper (II) acetate.
  • Suitable bisoxazoline ligands for this process include a compound of Formula I, wherein R 2 is C 1 -C 18 alkyl or aryl, and R 3 is H or C 1 -C 4 alkyl.
  • Suitable sulfonyl halides include, but are not limited to, methanesulfonyl chloride, benzenesulfonyl chloride and toluenesulfonyl chloride.
  • Suitable bases include, but are not limited to, an inorganic base such as sodium hydride, ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potasium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, or an organic base such as triethyl amine, trimethyl amine, diisopropyl ethyl amine (DIEA), pyridine, picoline, 1,8- Diazabicyclo(5.4.0)undec-7-ene (DBU).
  • an inorganic base such as sodium hydride, ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potasium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, or an organic base such as triethyl amine, trimethyl amine, diisopropyl ethyl amine (DIEA), pyridine, picoline, 1,8- Diazabicyclo
  • Suitable solvents for this transformation include, but are not limited to, DCM, dichloroethane, chloroform, chlorobenzene, THF, MeTHF, CPME, heptanes, hexanes, toluene, tert-amyl alcohol, tert-butanol and mixtures thereof.
  • Other methods to prepare a compound of Formula H, wherein R 1 is alkyl, alkoxy or aryl, and Y is H may include methods disclosed in: (1) Tetrahedron Lett. 2007, 48, 7605-7609, and (2) JP5108383.
  • the disclosure provides a process wherein the compound of Formula H, wherein R 1 is alkyl, alkoxy or aryl, and Y is H, may be used without purification.
  • the disclosure provides a process wherein the compound of Formula H, wherein R 1 is alkyl, alkoxy or aryl, and Y is H, may be isolated by employing standard isolation and purification techniques.
  • the disclosure provides a process wherein the compound of Formula G is prepared from a compound of Formula H, wherein R 1 is alkyl, alkoxy or aryl, and Y is H, with a base.
  • Suitable bases include, but are not limited to, an inorganic base such as sodium hydride, ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potasium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, or an organic base such as triethyl amine, trimethyl amine, diisopropyl ethyl amine (DIEA), pyridine, picoline, 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU).
  • an inorganic base such as sodium hydride, ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potasium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, or an organic base such as triethyl amine, trimethyl amine, diisopropyl ethyl amine (DIEA), pyridine, picoline, 1,8-Diazabicyclo
  • the disclosure provides a process wherein the compound of Formula G, may be isolated by employing standard isolation and purification techniques. 4.3.5. Preparation of Compound of Formula I [0135]
  • the disclosure provides a process to prepare a compound of Formula I wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H or C1-C4 alkyl.
  • the disclosure provides a process to prepare a compound of Formula I from malononitrile: wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H.
  • Malononitrile is first converted into a compound of Formula J, wherein R 4 is C1-C4 alkyl, and X is Cl, Br, I, HSO4, H2PO4, CF3COO, CH3COO or CH3SO3.
  • the compound of Formula J, wherein R 4 is C1-C4 alkyl, and and X is Cl, Br, I, HSO4, H2PO4, CF3COO, CH3COO or CH3SO3, is treated with a compound of Formula K, wherein R 2 is C1-C18 alkyl or aryl, to give a compound of Formula I, wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H.
  • the disclosure provides a process in which a compound of Formula J, wherein R 4 is C1-C4 alkyl, and X is Cl, Br, I, HSO4, H2PO4, CF3COO, CH3COO or CH3SO3, is prepared from malononitrile with an acid and alcohol.
  • Suitable acids for this process include, but are not limited to, HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , CF 3 COOH, or CH 3 SO 3 H.
  • Suitable forms of HCl may include HCl in solvent, HCl gas and HCl generated in-situ from acetyl chloride.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol and butanol.
  • Suitable solvents for this transformation include, but are not limited to, DCM, dichloroethane, chloroform, chlorobenzene, THF, MeTHF, CPME, dioxane, heptanes, hexanes, toluene, benzene, tert-amyl alcohol, tert-butanol, ethanol, and mixtures thereof.
  • the disclosure provides a process wherein the compound of Formula J, wherein R 4 is C1-C4 alkyl, and and X is Cl, Br, I, HSO4, H2PO4, CF3COO, CH3COO or CH3SO3, may be used without purification.
  • the disclosure provides a process wherein the compound of Formula J, wherein R 4 is C1- C4 alkyl, and X is Cl, Br, I, HSO4, H2PO4, CF3COO, CH3COO or CH3SO3, may be isolated by employing standard isolation and purification techniques.
  • the disclosure provides a process in which a compound of Formula I, wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H, is prepared from a compound of Formula J, wherein R 4 is C1-C4 alkyl, and X is Cl, Br, I, HSO4, H2PO4, CF3COO, CH3COO or CH3SO3, and a compound of Formula K, wherein R 2 is C1-C18 alkyl or aryl.
  • Suitable solvents for this transformation include, but are not limited to, DCM, dichloroethane, chloroform, chlorobenzene, THF, MeTHF, CPME, dioxane, heptanes, hexanes, toluene, benzene and mixtures thereof.
  • Other methods to prepare a compound of Formula I, wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H, may include methods disclosed in: (1) Org. Lett. 2018, 20, 154, (2) Organometallics, 2019, 38, 3852.
  • the disclosure provides a process wherein the compound of Formula I, wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H, may be used without purification.
  • the disclosure provides a process wherein the compound of Formula I, wherein R 2 is C1-C18 alkyl or aryl, and R 3 is H, may be isolated by employing standard isolation and purification techniques. 4.3.6. Reaction Conditions for processes [0140]
  • the disclosure provides a process wherein organic solvent is used and the organic solvent is aprotic.
  • the process uses organic solvent that is heptanes, dichloromethane, hexanes, cyclohexane, toluene, acetonitrile, tetrahydrofuran, 2- methylhydrofuran, ethyl acetate, dichloromethane (DCM), dichloroethane (DCE), dichlorobenzene, trifluorotoluene or methylcyclohexane tetrahydrofuran (THF), 2- tetrahydrofuran (2-MeTHF), DME, or dioxane or mixtures thereof.
  • organic solvent that is heptanes, dichloromethane, hexanes, cyclohexane, toluene, acetonitrile, tetrahydrofuran, 2- methylhydrofuran, ethyl acetate, dichloromethane (DCM), dichloroethane (DCE), dichlorobenzene
  • the process uses organic solvent that is a mixture that contains an aprotic organic solvent selected from the group consisting of: hepantes, THF (tetrahydrofuran), diethyl ether and mixtures thereof.
  • the disclosure provides a process wherein the process includes one or more organic co-solvents.
  • the disclosure provides a process wherein the mixture contains dimethylformamide (DMF) as a solvent.
  • the disclosure provides a process wherein the mixture contains dimethylformamide (DMF) as a solvent and a co-solvent.
  • the disclosure provides a process wherein the mixture contains heptanes as a solvent and a co-solvent.
  • the disclosure provides a process wherein the mixture contains heptanes as a solvent and THF co-solvent. In some aspects, the disclosure provides a process wherein the mixture contains heptanes as a solvent and DCM co-solvent. [0144] In some aspects, a process is provided wherein the process further comprises heating of the mixture. In some aspects, the heating is performed to no more than 25oC, 26oC, 27oC, 28oC, 29oC, 30oC, 40oC, 50oC, 60oC, 70oC, 80oC, 90oC, 100oC, 110oC, or 120oC. [0145] In some aspects, a process is provided wherein the process further comprises cooling of the mixture.
  • the cooling is performed to no more than - 20oC, -10oC, -5oC, 0oC, 5oC, 10oC, 15oC, 20oC, or 22oC.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA), CombiChem (San Diego, CA).
  • reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc. are given to make these compounds, minor modifications to these process conditions can also be used unless otherwise stated.
  • Optimum reaction conditions may vary with the particular reactant or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures as long as the reagents stay the same.
  • the process can be performed in a packed bed reactor in a continuous flow mode or recirculation mode.
  • the process can also be performed in a continuous stirred-tank reactor in a recirculation mode.
  • conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • compound mixtures comprise at least two or more compounds as described herein and are enantiomerically and/or diastereomerically enriched with a compound of formula A with an impurity from 0.01% to: no more than 0.1 mol%, no more than 0.5 mol%, no more than 1 mol%, no more than 2 mol%, no more than 3 mol%, no more than 4 mol%, no more than 5%, no more than 10%, or no more than 15%.
  • mixtures are enriched by about 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7% or 99.9% enantiomeric excess (ee).
  • mixtures are enriched by about 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7% or 99.9% diastereomeric excess (de).
  • the compound mixture comprises one or more compounds as described herein, and FORMULA A or salt thereof.
  • FORMULA A or salt thereof The skilled artisan will appreciate that these percentages for purity are based and calculated from the desired compound. Such determinations are routine in the field and examples can be found in syntheses and descriptions in the texts and references that have been cited herein. 5.
  • EXAMPLES [0153] The following synthetic examples are offered to illustrate this the present technology and are not to be construed in any way as limiting the scope of this the present technology.
  • LC-MS liquid chromatography-mass spectrometry
  • MS mass spectrometry
  • THF tetrahydrofuran
  • NaHCO3 sodium bicarbonate
  • DIEA diisopropylethylamine
  • LAH lithium aluminum hydride
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide equiv.
  • Example A1.2 (2S,3S)-3-(o-tolyl)butan-2-yl (4-methoxy-3- (propionyloxy)picolinoyl)-L-alaninate
  • 4-methoxy-3-(propionyloxy)picolinic acid (18.1 g, 58.0 mmol, 50.3 wt % solid along with Et3N•HCl salt and NMI•HCl salt) and DCM (53 mL).
  • the suspension was cooled to –10 °C and then triethylamine (5.6 mL, 4.1 g, 41 mmol) was added slowly.
  • the biphasic mixture was stirred for 15 minutes and then the layers were separated.
  • the organic layer was returned to the reaction vessel and 1 M HCl (75 mL) was added.
  • the mixture was stirred for 15 minutes and then the layers were separated.
  • the organic layer was concentrated under reduced pressure to give an orange oil.
  • the crude material was dissolved in isopropanol (30 mL) and then concentrated under reduced pressure to remove residual DCM and water.
  • the crude oil was suspended in isopropanol (20 mL) and heated to 50 °C until a homogenous solution formed. The mixture was stirred at room temperature for 3 h and then cooled to 0 °C for 1 h.
  • the layers were separated and the organic layer was concentrated under reduced pressure.
  • the crude material was taken up in isopropanol ( ⁇ 250 mL) and concentrated under reduced pressure to give an off-white solid.
  • the crude solid was suspended in i-PrOH (700 mL) and warmed to 55 °C until the mixture was homogenous. The solution was allowed to slowly cool to room temperature overnight. The solid was collected via vacuum filtration and the flask was rinsed with cold isopropanol. The filter cake was then washed with heptane (500 mL) and allowed to dry for 3 h.
  • Example B1.2 4-methoxy-3-(propionyloxy)picolinic acid
  • 3-hydroxy-4-methoxypicolinic acid 25 g, 148 mmol
  • the reaction was stirred for 3.5 days.
  • the reaction mixture was then added to 650 mL heptane over ⁇ 30 min.
  • the reaction mixture was cooled to 0 °C for ⁇ 30 minutes and then the solids were collected via vacuum filtration.
  • Example B1.3 4-methoxy-3-(propionyloxy)picolinic acid [0181] A 500 mL flask equipped with a stirbar, a nitrogen inlet, and a temperature probe was charged with 3-hydroxy-4-methoxypicolinic acid (25 g, 148 mmol), propionic anhydride (47 mL, 48.1 g, 370 mmol), and DCM (25 mL).
  • Triethylamine 23 mL, 16.5g, 65 mmol
  • 1-methylimidazole 1.2 mL, 1.21 g, 5.9 mmol
  • the heterogeneous reaction mixture became a homogeneous solution after ca. 3 h and was stirred overnight at RT.
  • the reaction mixture was slowly added to a solution of HCl in CPME (75 mL, 3 M HCl in CPME, 222 mmol) and heptane (250 mL) at 0 °C.
  • the heterogeneous mixture was stirred for 0.5 h and then the solids were collected via vacuum filtration.
  • Example B1.4 4-methoxy-3-(isobutyryloxy)picolinic acid [0182] A 250 mL flask equipped with a stirbar, a nitrogen inlet, and a temperature probe was charged with 3-hydroxy-4-methoxypicolinic acid (5 g, 30 mmol), isobutyric anhydride (14 g, 88 mmol), and DCM (5 mL).
  • Triethylamine (4.6 mL, 3.3 g, 33 mmol) and 1-methylimidazole (0.24 g, 3 mmol) were then added.
  • the heterogeneous reaction mixture became a homogeneous solution after ca. 4 h and was stirred overnight at RT. After consumption of the starting material was observed by 1H NMR analysis, the reaction mixture was slowly added to a solution of HCl in CPME (15 mL, 3 M HCl in CPME, 44 mmol) and heptane (50 mL) at RT. The heterogeneous mixture was stirred for 0.5 h and then the solids were collected via vacuum filtration.
  • the filter cake was washed successively with heptane (50 mL), ethyl acetate (50 mL), and heptane (50 mL)
  • the wetcake was dried to give the title compound (10.5 g total, 48 wt% of the title compound, 71% yield) along with the hydrochloride salts of triethylamine and NMI as a tan solid.
  • Novozym® 435 (immobilized CAL-B lipase) (4.8 g, 10 wt %) was added and the reaction was stirred at 45 °C for 28 h. The reaction mixture was cooled to RT and filtered to remove the immobilized enzyme. The immobilized enzyme was washed with Me-THF (about 100 mL) and the combined filtrate was concentrated to afford 89.2 g of a mixture of (2S,3S)-3-(o-tolyl)butan-2-ol and (2R,3R)-3-(o- tolyl)butan-2-yl acetate in Me-THF.
  • Pivalic anhydride (2.45 mL, 12 mmol) was added, the reaction was heated to 50 °C and 1-methyl-1H-imidazole (0.040 mL, 0.5 mmol) was added. The reaction was stirred at 50 °C for 25 h until the reaction was judged to be complete by HPLC analysis. A 10 wt% aqueous solution of potassium carbonate (30 mL) was added and the resulting biphasic mixture was stirred for 5 minutes. The biphasic mixture was transferred to a separatory funnel and the layers were separated.
  • reaction mixture was stirred at 40 °C for 30 h, cooled to RT and filtered to remove the immobilized enzyme.
  • the immobilized enzyme was washed with heptaneand the filtrate was concentrated to afford a mixture of (2S,3S)-3-(o-tolyl)butan-2-ol and (2R,3R)-3-(o- tolyl)butan-2-yl acetate in heptane.
  • (2S,3S)-3-(o-tolyl)butan-2-yl L-alaninate hydrochloride [0204] To a 250 mL jacket reactor equipped with mechanical agitator, thermoprobe, 1/4” Teflon dip tube and reflux condenser was loaded (2S,3S)-3-(o-tolyl)butan-2-yl (tert-butoxycarbonyl)-L-alaninate crude product solution (57.1 g, 28.0 wt%, 47.7 mmol) containing (2R,3R)-3-(o-tolyl)butan-2-yl acetate ( ⁇ 50 mmol) .
  • HCl gas (6.2 g, 3.5 eq.) was slowly fed into the solution through 1/4” Teflon dip tube subsurface over 2 h at 22 °C. The solution was then stirred at 22 °C for 5 h. Heptanes (95 mL) was slowly added using a dropping funnel over 1 h at 19 °C. The mixture was stirred for 2 h and the resultant was cooled down to 10 °C over 1 h. The slurry was drained and filtered through a filter crock under vacuum ( ⁇ 500 mmHg).
  • Example D1.1 (2S,3S)- and (2R,3R)-3-(o-tolyl)butan-2-ol [0205] In a 3 L flask equipped with a mechanical stirrer, condenser, nitrogen inlet and temperature probe: copper(I) iodide (9.83 g, 51.1 mmol) was stirred in THF (304 mL). The mixture was cooled to -20 °C.
  • the reaction mixture was heated to reflux ( ⁇ 65 °C).
  • 2-chlorotoluene (70.2 g, 1.25 eq.) was added via syringe pump in 2 hr while refluxing.
  • the reaction was heated for 16-18 hr till the 2-chlorotoluene conversion was greater than 99%.
  • the reaction mixture was cooled to rt and agitation was stopped.
  • the freshly prepared Grignard reagent was cannulated into another 1L jacket reactor, equipped with a thermal couple, condensor with nitrogen pad.
  • the reagent was cooled to 0 °C, then CuCl (2.2g, 0.05eq.) was added in one shot.
  • the mixture was stirred for 1 hr at 10 °C before the addition of trans-2,3-epoxybutane (32 g, 1 eq.) via syringe pump in 3 hr. After the addition, the reaction was reacted at 10 °C for 2-16 hr before warming to rt, and the progress was monitored by GC method. After the completion the reaction was warmed to RT and 40% ammonium acetate (300 mL) was added to quench the reaction mixture. The mixture was stirred for 2 hr while oxygen was bubbled through the system. The aqueous phase was discarded and the organic phase was further washed with a 20% aqueous NaCl solution. The aqeuous NaCl solution was discarded.
  • Example D1.4 (2S,3S)- and (2R,3R)-3-(o-tolyl)butan-2-ol
  • o-tolyl magnesium chloride in MeTHF (2.5 M, 12 mL), Mg turnings (7.2 g, 296 mmol), and CPME (60 mL).
  • the mixture was stirred at reflux for 10 minutes at which time a solution of 2-chlorotoluene (35.4 g, 280 mmol) in CPME (30 mL) was added via syringe pump in 2 hr.
  • the reaction was heated for 2 days until the conversion was greater than 94% as judged by GC analysis.
  • Example D2.2 (2S,3S)-3-(o-tolyl)butan-2-ol and (2R,3R)-3-(o-tolyl)butan-2-yl dodecanoate [0217]
  • a 50 mL jacketed reactor equipped with overhead stirring and a temperature probe was charged with (2S,3S)- and (2R,3R)-3-(o-tolyl)butan-2-ol (5.0 g, 30.4 mmol, 1:1 mixture of enantiomers), MTBE (15 mL) and vinyl laurate (5.54 mL, 21.3 mol).
  • Novozym® 435 (immobilized CAL-B lipase) (1.0 g, 20 wt %) was added and the reaction was stirred at 150 rpm and 40 °C overnight. The reaction mixture was cooled to RT and filtered to remove the immobilized enzyme. The immobilized enzyme was washed with MTBE and the combined filtrate was concentrated.
  • Example D2.3 (2S,3S)-3-(o-tolyl)butan-2-ol and (2R,3R)-3-(o-tolyl)butan-2- yl acetate
  • (2S,3S)- and (2R,3R)-3-(o-tolyl)butan-2-ol 54.1 g, 329 mmol, 1:1 mixture of enantiomers
  • isopropenyl acetate 143 mL, 3.3 mol.
  • Novozym® 435 immobilized CAL-B lipase
  • reaction mixture was cooled to RT and filtered to remove the immobilized enzyme.
  • the immobilized enzyme was washed with MTBE and the combined filtrate was concentrated.
  • the crude material was purified via silica gel chromatography (gradient ethyl acetate in hexanes) to afford (2S,3S)-3-(o-tolyl)butan- 2-ol (22 g, 127 mmol, 40 % yield) as a pale yellow oil and (2R,3R)-3-(o-tolyl)butan-2-yl acetate (31.7 g, 151 mmol, 46 % yield) as a colorless oil.
  • reaction flask was cooled to 0 °C, at which time solid copper (I) chloride (0.13 g, 1.33 mmol) was added to the flask.
  • solid copper (I) chloride (0.13 g, 1.33 mmol) was added to the flask.
  • (2S,3S)-2,3-dimethyloxirane (0.960 g, 13.31 mmol) in toluene (30 mL) was added to the mixture via syringe.
  • the reaction was stirred overnight and allowed to warm to room temperature. After 21 h, the reaction was cooled to 0 °C and non-saturated ammonium chloride (6.14 mL, 18.41 mmol) was added via syringe.
  • the reaction mixture was stirred for 1.5 hours.
  • Aqueous NaOH (2M, 154 mL, 307.5 mmol) was added dropwise via an additional funnel. After 1 hour, 100 mL of 5% acetic acid was added to the reaction and the mixture was stirred for 30 mins. The layers were separated and the organic layer was washed with brine.
  • the distillation set-up involved a 250 mL, 3-neck round bottomed flask equipped with an internal temperature probe, a distillation head with an overhead thermocouple, an ice-water cooled condenser and nitrogen inlet. The flask was charged with 82.5 g of the toluene mixture obtained above. The flask was heated to 90 °C.
  • (2S,3S)-2,3-epoxybutane [0231] A 2-dram vial was charged with (2R,3S)-3-hydroxybutan-2-yl 4- methylbenzenesulfonate (50 mg, 0.205 mmol) followed by deuterated chloroform (1 ml) and the mixture was cooled to 10 °C. 1N aqueous sodium hydroxide (246 ⁇ l, 0.246 mmol) was added dropwise and the mixture was stirred at rt for 30 mins. Stirring was stopped and the layers were separated. The CDCl3 layer was passed over magnesium sulfate and the clear solution was analyzed by NMR.
  • (2S,3S)-2,3-epoxybutane [0232] A 250 mL 3-neck round bottom flask equipped with a stir bar, temperature probe, and nitrogen inlet was charged with (2R,3S)-3-hydroxybutan-2-yl 4- methylbenzenesulfonate (14.3 g, 58.5 mmol) and toluene (30 mL). The toluene solution was treated with sodium hydroxide (43.9 mL, 88 mmol) and stirred at room temperature. The reaction was terminated after 2 h stirring and the mixture was transferred to a separatory funnel. The organic layer was separated, dried over sodium sulfate, and filtered. The in-pot yield was determined by GC using an internal standard.
  • (2S,3S)- and (2R,3R)-2,3-epoxybutane [0234] A 250 mL 3-neck round bottom flask equipped with a stir bar, temperature probe, and nitrogen inlet was charged with (2R,3S)- and (2S,3R)-3- ((methylsulfonyl)oxy)butan-2-yl acetate (15 g, 71.3 mmol) and toluene (45 mL). Sodium hydroxide (17.84 mL, 214 mmol, 12 N) was added followed by methyl tributyl ammonium chloride (2.33 mL, 7.13 mmol, 75 wt% in water). The biphasic mixture was stirred at room temperature.
  • Potassium carbonate (104 g, 751 mmol) was added and 20 mL of 9:1 toluene : tAmOH was used to rinse residual solid into the reactor. After 20 min, meso-2,3-butanediol (40 g, 417 mmol) was added. Water (3.7 mL, 209 mmol) was added and the reaction mixture was stirred for 30 min. Benzenesulfonyl chloride (64.5 mL, 501 mmol) added in portions by syringe over 28 min. After 18 hours, reaction was sampled and sulfonate was found to be 89% ee by HPLC assay.
  • Example G1.11 Base screening for (2S,3S)-2,3-epoxybutane To a 2 dram vial was added bis((S)-4-isobutyl-4,5-dihydrooxazol-2-yl)methane (29.6 mg, 0.111 mmol) followed by toluene (5 mL).
  • Benzenesulfonyl chloride (0.172 mL, 1.33 mmol) was then added last to each vial. The mixture was stirred at ambient for 16 h and analyzed by H NMR. Additional base was added to vial A, D and E according to the recipe below.
  • E Proton Sponge (476 mg, 2 eq.)
  • Each the reaction mixture was then heated to 50 °C and stirred ⁇ 16 h. H NMR analysis indicated conversions of the sulfonate to the epoxide below.
  • Example H1.3 (2R,3S)-3-hydroxybutan-2-yl 4-methylbenzenesulfonate [0239] To a 500 mL single neck flask equipped with a stir bar and nitrogen inlet was added racemic (2S,3R)- and (2R,3S)-3-hydroxybutan-2-yl 4-methylbenzenesulfonate (40 g, 164 mmol) and toluene (200 mL). Triethylamine (8.0 mL, 57.3 mmol), isopropenyl acetate (37.4 mL, 344 mmol), and Cal B Immo Plus (8 g, 20 wt %) were added sequentially.
  • reaction mixture was transferred to a separatory funnel.
  • the organic layer was separate, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a waxy off-white solid (21.6 g, 91%).
  • the material was used without further purification.
  • Example H2.2.1 (2S,3R)-3-((methylsulfonyl)oxy)butan-2-yl propionate [0244] A 100 mL round bottom flask equipped with a stir bar and nitrogen inlet was meso-butane-2,3-diyl dipropionate (10 g, 49.4 mmol), EtOH (20 mL) and Cal B Immo Plus (2.0 g, 20 wt %). The reaction was stirred at 25 °C for 6 days. The reaction was terminated by filtration of the slurry under vacuum. The immobilized enzyme beads were washed with EtOAc.
  • a 500 mL 3-neck round bottom flask equipped with a nitrogen inlet, stirring bar and temperature probe was charged with a solution of (2S,3R)-3-hydroxybutan-2-yl propionate (3.5 g, 26.5 mmol) (69% (2S,3R)-3-hydroxybutan-2-yl propionate meso-2,3- butanediol and meso-butane-2,3-diyl dipropionate by GC) in toluene (50 mL).
  • Example H2.2.2 (2S,3R)-3-((methylsulfonyl)oxy)butan-2-yl propionate
  • a 400 mL reactor equipped with a mechanical stirrer and nitrogen inlet was meso-butane-2,3-diyl dipropionate (49.5 g, 79 wt%, 193 mmol), EtOH (100 mL) and Cal B Immo Plus (20 g).
  • the reaction was stirred at 25 °C for 70 h.
  • the reaction was terminated by filtration of the slurry under vacuum.
  • the immobilized enzyme were washed with EtOAc.
  • Example I1.1 Bis((S)-4-isobutyl-4,5-dihydrooxazol-2-yl)methane To a 1 L jacketed reactor under nitrogen was added malononitrile (25.0 g, 375 mmol, 1.0 eq.) and ethanol (250 mL).

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Abstract

La présente technologie concerne des procédés, des mélanges et des intermédiaires utiles pour la fabrication de fongicides à base de picolinamide. Les composés de picolinamide sont préparés par des procédés qui comprennent le couplage d'un acide 4-méthoxy-3-acyloxypicolinique avec des esters de 2-amino-L-alaninate clés dérivés de 2-phényléthanols substitués.
PCT/US2020/055658 2019-10-18 2020-10-15 Procédé de synthèse de picolinamides WO2021076681A1 (fr)

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US17/754,977 US20220411375A1 (en) 2019-10-18 2020-10-15 Process for synthesis of picolinamides
EP20877148.5A EP4044811A4 (fr) 2019-10-18 2020-10-15 Procédé de synthèse de picolinamides
CN202080072411.5A CN114554848A (zh) 2019-10-18 2020-10-15 用于合成吡啶酰胺的方法
BR112022007354A BR112022007354A2 (pt) 2019-10-18 2020-10-15 Processo para síntese de picolinamidas

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WO2019173665A1 (fr) * 2018-03-08 2019-09-12 Dow Agrosciences Llc Picolinamides en tant que fongicides

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WO2019173665A1 (fr) * 2018-03-08 2019-09-12 Dow Agrosciences Llc Picolinamides en tant que fongicides

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