Method for preparing 3-amino-1-butanol

Abstract

Disclosed herein are methods and processes for the preparation of 3-amino-(C3-6)-alkane-1-alcohols, including optically active 3-amino-(C3-6)-alkane-1-alcohols (e.g., optically active 3-amino-1-butanol, e.g., (R)-3-amino-1-butanol). The process comprises contacting 1-nitro-(C1-4)-alkane with a vinyl source or an acetylene source in the presence of a base and a dehydrating agent to provide 3-(C0-3)-alkyl-2-isoxazoline; and / or contacting the 3-(C0-3)-alkyl-2-isoxazoline and hydrogen with a hydrogenation catalyst to provide the 3-amino-(C3-6)-alkane-1-ol.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of U.S. Patent Application No. 63 / 419,979, filed on October 27, 2022, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] This disclosure generally relates to methods for preparing 3 - amino-(C 3-6 )-alkan - 1 - ols, including optically active 3 - amino-(C 3-6 )-alkan - 1 - ols (e.g., optically active 3 - amino - 1 - butanol, e.g., (R)-3 - amino - 1 - butanol). Background art

[0004] (R)-3 - amino - 1 - butanol is a key intermediate in the manufacture of the antibiotic dolutegravir. Although methods for producing 3 - amino - 1 - butanol, including (R)-3 - amino - 1 - butanol, have been described, these methods involve lengthy syntheses, expensive reduction processes, and substantial waste generation. Accordingly, there is a desire for new environmentally friendly methods for producing 3 - amino - 1 - butanol, including optically active 3 - amino - 1 - butanol, e.g., (R)-3 - amino - 1 - butanol, while improving efficiency and reducing costs. Summary of the invention

[0006] This technology is partly based on the surprising discovery that 3 - amino-(C 3-6 )-alkan - 1 - ols (e.g., 3 - amino - 1 - butanol), including optically active 3 - amino-(C 3-6 )-alkan - 1 - ols (e.g., optically active 3 - amino - 1 - butanol, e.g., (R)-3 - amino - 1 - butanol), can be manufactured using the methods described herein.

[0007] In one aspect, a method is disclosed herein that includes contacting a 1 - nitro-(C 1-4 )-alkane with a vinyl source or an acetylene source in the presence of a base and a dehydrating agent to provide a product selected from optionally 5 - substituted 3-(C 0-3 )-alkyl - 2 - isoxazolines or optionally 5 - substituted 3-(C 0-3 )-alkyl - 2 - isoxazoles.

[0008] In some embodiments, the method further includes contacting the product (optionally 5 - substituted 3-(C 0-3 )-alkyl - 2 - isoxazoline or optionally 5 - substituted 3-(C 0-3 )-alkyl - 2 - isoxazole) with a reducing agent to provide a product selected from optionally 5 - substituted 3-(C0-3 )-alkyl-2-isoxazolidine or a reduction product of optionally 1-substituted 3-amino-(C 3-6 )-alkane-1-ol. In some embodiments, the reducing agent is hydrogen and a hydrogenation catalyst to provide an optionally 1-substituted 3-amino-(C 3-6 )-alkane-1-ol, such as 3-amino-butan-1-ol.

[0009] On the other hand, the present disclosure provides a composition (e.g., a composition prepared according to any of the methods described herein), wherein the composition comprises (R)-3-(C 0-3 )-alkylisoxazolidine and has an (R) / (S) enantiomeric ratio greater than 1.00, i.e., (R)-3-(C 0-3 )-alkylisoxazolidine:(S)-3-(C 0-3 )-alkylisoxazolidine, e.g., (R)-3-methylisoxazolidine:(S)-3-methylisoxazolidine.

[0010] It should be understood that all combinations of the foregoing concepts and other concepts discussed in more detail below (so long as such concepts are not mutually inconsistent) are considered to be part of the subject matter disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are considered to be part of the subject matter disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0012] Definition

[0013] The following terms are defined below and used throughout.

[0014] Unless otherwise indicated herein or clearly contradicted by context, as used herein and in the appended claims, in the context of describing an element (especially in the context of the following claims), singular articles such as "a" and "an" and the definite article "the" and similar reference terms shall be construed to cover both the singular and the plural. Unless otherwise indicated herein, a recitation of a numerical range herein is merely intended as a shorthand method of referring individually to each separate numerical value falling within the range, and each separate numerical value is incorporated into the specification as if it were individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein may be performed in any suitable order. Unless otherwise indicated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to better illustrate the embodiments and does not limit the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential.

[0015] Unless otherwise indicated, all temperatures are in degrees Celsius (°C).

[0016] Isolated: As used herein, the term "isolated" refers to a substance and / or entity that (1) has been separated from at least some of the components with which it was associated at the time of its initial production (whether in nature and / or in an experimental setting), and / or (2) has been produced, prepared, and / or manufactured synthetically (i.e., is not a product of nature). In some embodiments, the purity of an isolated preparation is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99%, or a range between and including any two of the foregoing values. As used herein, a substance is "pure" if it is substantially free of other components (e.g., contains less than 5 wt%, 4 wt%, 3 wt%, 2 wt%, or 1 wt% of the components). As used herein, the percentage purity of an isolated substance and / or entity is calculated excluding excipients (e.g., buffers, solvents, water, etc.).

[0017] About or approximately: As used herein, the terms "about" or "approximately" when applied to one or more target values refer to a value similar to the reference value. In certain embodiments, the terms "about" or "approximately" refer to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than the reference value) of the reference value, unless otherwise stated or apparent from the context (unless the number exceeds 100% of the possible value).

[0018] As used in the specification and the appended claims, unless the context clearly dictates otherwise, an indefinite article refers to a plural referent. Thus, for example, reference to "a composition" includes a mixture of two or more such compositions.

[0019] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur.

[0020] The term "stereoisomer" refers to isomers that have the same structure but different spatial arrangements of atoms. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecules that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomers, where the composition has no optical activity.

[0021] The term "chiral" refers to the molecular structural feature that renders a molecule non-superimposable on its mirror image. The term "homochirality" refers to the enantiomeric purity state. The term "optical activity" refers to the degree to which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarized light.

[0022] "Stereoselective", "enantioselective", "diastereoselective" and their variants refer to a given process (such as ester hydrolysis, hydrogenation, hydroformylation, palladium coupling, hydrosilylation, hydrocyanation, olefin metathesis, hydroacylation, allylamine isomerization, etc.) that produces more of one stereoisomer, enantiomer or diastereomer than another stereoisomer, enantiomer or diastereomer, respectively.

[0023] "Stereoisomerically enriched", "enantiomerically enriched", "diastereomerically enriched" and their variants refer, respectively, to a sample of a compound that has more of one stereoisomer, enantiomer or diastereomer than another stereoisomer, enantiomer or diastereomer. The degree of enrichment can be measured as a percentage of the total product, or for a pair of enantiomers or diastereomers, as ee or de.

[0024] "Substantially pure stereoisomer", "substantially pure enantiomer", "substantially pure diastereomer" and their variants refer, respectively, to a sample containing at least about 95% of the stereoisomer, enantiomer or diastereomer. For pairs of enantiomers and diastereomers, a substantially pure enantiomer or diastereomer corresponds to a sample with an ee or de of about 90% or higher.

[0025] "Pure stereoisomer", "pure enantiomer", "pure diastereomer" and their variants refer, respectively, to a sample containing at least about 99.5% of the stereoisomer, enantiomer or diastereoisomer. For pairs of enantiomers and diastereomers, "pure enantiomer" or "pure diastereomer" refers to a sample with an ee or de of about 99% or higher.

[0026] Solvate: may include, but is not limited to, one or more solvates that retain the activity and / or properties of the compound and are not undesired solvates. Examples of solvates include, but are not limited to, compounds combined with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

[0027] Solvents: may include but are not limited to non-polar solvents, polar aprotic solvents, and polar protic solvents. Illustrative examples of non-polar solvents include but are not limited to pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, xylene, 1,4-dioxane, chloroform, diethyl ether, and dichloromethane (DCM). Illustrative examples of polar aprotic solvents include but are not limited to tetrahydrofuran (THF), ethyl acetate, isopropyl acetate (IPAc), acetone, dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile (MeCN), butyronitrile, dimethyl sulfoxide (DMSO), nitromethane, and propylene carbonate. Illustrative examples of polar protic solvents include but are not limited to formic acid, n-butanol, isopropyl alcohol (IPA), n-propanol, ethanol, methanol, acetic acid, and water.

[0028] Acid: refers to a molecule or ion that can donate hydrogen (a proton or a hydrogen ion H + ), or can accept an electron pair (e.g., a Lewis acid). Acids may include but are not limited to mineral acids, sulfonic acids, carboxylic acids, halo-carboxylic acids, and vinyl carboxylic acids.

[0029] Base: As used herein, "base" refers to a compound that can accept a proton or provide a lone pair of electrons. Examples of bases include bases (OH - ), carbonates, bicarbonates, alkoxides (alkyl - O(-)), hydrides (alkali metal hydrides and CaH2), metal amides, and neutral nitrogen-containing bases such as trialkylamines (e.g., triethylamine) and heteroaromatic compounds (e.g., pyridine, imidazole), etc.

[0030] Organic base: As used herein, "organic base" refers to a carbon-containing compound having one or more functional groups capable of accepting a proton from an acid group. For example, an organic base may contain basic nitrogen, such as an amine group or an aromatic ring nitrogen. Exemplary organic bases include trimethylamine, triethylamine, benzyldiethylamine, dimethylethylamine, imidazole, pyridine, piperidine, etc.

[0031] Dehydrating agent: As used herein, "dehydrating agent" refers to a reagent or compound that can remove water molecules in a chemical reaction.

[0032] Generally, when referring to an element, such as hydrogen or H, it refers to all isotopes of that element. For example, if the R group is defined to include hydrogen or H, then it also includes deuterium and tritium. Thus, compounds containing radioactive isotopes such as tritium, C 14 , p 32 and S 35 fall within the scope of the present technology. According to the disclosure herein, the procedures for inserting such labels into the compounds of the present technology should be obvious to those skilled in the art.

[0033] Alkanes and alkyl groups refer to, unless otherwise specified, saturated straight-chain and branched-chain hydrocarbons and hydrocarbon groups having 1 - 12 carbon atoms or, in certain embodiments, 1 - 10, 1 - 8, 1 - 6, or 1 - 4 carbon atoms. Examples of straight-chain alkanes / alkyl groups include methane / methyl, ethane / ethyl, n-propane / n-propyl, n-butane / n-butyl, n-pentane / n-pentyl, and n-hexane / n-hexyl. Examples of branched-chain alkanes / alkyl groups include, but are not limited to, isopropane / isopropyl, isobutane / isobutyl, and 2,2-dimethylpropane / 2,2-dimethylpropyl. The alkanes / alkyl groups can be substituted with one, two, or three substituents such as nitro, hydroxy, and halogen (F, Cl, Br, I).

[0034] The salts of the compounds described herein are within the scope of the present technology and include acid addition salts or base addition salts. When the compounds of the present technology have a basic group (such as an amino group), salts can be formed with: inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (such as alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (such as aspartic acid and glutamic acid). When the compounds of the present technology have an acidic group, such as a carboxylic acid group, it can form salts with metals, such as alkali metals and alkaline earth metals (e.g.: Na + 、Li + 、K+, Ca 2+ 、Mg 2+ 、Zn 2+ ), ammonia, or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine, and ornithine). These salts can be prepared in situ during the separation and purification of the compounds, or by reacting the purified free base or free acid form of the compound with a suitable acid or base, respectively, and isolating the salt thus formed.

[0035] As will be understood by those skilled in the art, for any and all purposes, particularly in the context of providing a written description, all ranges disclosed herein also include any and all possible sub-ranges and combinations of sub-ranges. Any recited range can be readily viewed as sufficiently described and the same range can be readily broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into lower thirds, middle thirds, upper thirds, etc. As will be understood by those skilled in the art, all language such as "up to", "at least", "greater than", "less than", etc., includes the recited number and refers to a range that can then be broken down into the above-described sub-ranges. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to a group having 1, 2, 3, 4, or 5 atoms, and so on.

[0036] The method of the present technology

[0037] Disclosed herein are methods and processes for preparing 3-amino-(C 3-6 )-alkan-1-ols (such as 3-amino-1-butanol) and 1-substituted 3-amino-(C 3-6 )-alkan-1-ols, including optically active optionally 1-substituted 3-amino-(C 3-6 )-alkan-1-ols (e.g., optically active 3-amino-1-butanol, such as (R)-3-amino-1-butanol) and intermediates thereof (e.g., 3-(C 0-3 )-alkyl-2-isoxazolines, such as 3-methyl-2-isoxazoline). In certain embodiments, the methods disclosed herein can be carried out simultaneously, in the order described herein, or in any possible order thereof.

[0038] Optionally Via 5-Substituted 3-(C 0-3 )-alkyl-2-isoxazoline formation

[0039] In one aspect, the present disclosure provides a method comprising contacting a 1-nitro-(C 1-4 )-alkane (such as nitroethane) with a vinyl source or an acetylene source in the presence of a base and a dehydrating agent to provide a product selected from optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazolines (such as 3-methyl-2-isoxazoline) or optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazoles. In any embodiment, the product is selected from 3-(C 0-3 )-alkyl-2-isoxazolines (such as 3-methyl-2-isoxazoline) or 3-(C 0-3)-alkyl-2-isoxazole.

[0040] The vinyl source can be any compound that serves as a source of ethylene or vinyl-containing compounds. The acetylene source can likewise serve as a source of acetylene or alkyne-containing compounds. In any embodiment, the vinyl source and / or the acetylene source can include 2 to 6 carbon atoms (i.e., 2, 3, 4, 5, or 6 carbon atoms). Non-limiting examples of vinyl sources and acetylene sources include ethylene, acetylene, vinyl acetate, vinyl ether, and trimethylsilylacetylene.

[0041] In some embodiments, the vinyl source is ethylene, which is directly used in the method described herein to react with 1-nitro-(C 1-4 )-alkane to produce the corresponding cycloaddition product (e.g., 3-(C 0-3 )-alkyl-2-isoxazoline product). In some embodiments, a vinyl compound or an acetylene compound, such as vinyl acetate, vinyl ether, acetylene, or trimethylsilylacetylene, is used in the method described herein to react with 1-nitro-(C 1-4 )-alkane to produce the corresponding cycloaddition product (e.g., 3-(C 0-3 )-alkyl-2-isoxazoline product or 3-(C 0-3 )-alkylisoxazole product). In some examples, the alkyl is a C1 alkyl and the cycloaddition product is a compound having the following structure: wherein the alkyl is C 1- 3 alkyl and R is H or a substituent. In some embodiments, R is OC(O)Me, -O-(C 1-3 )-alkyl, H, OH, or trimethylsilyl. Thus, it should be recognized that the 3-(C 0-3 )-alkyl-2-isoxazoline or 3-(C 0-3 )-alkylisoxazole described herein includes optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazoline (e.g., optionally substituted with an R group) or optionally 5-substituted 3-(C 0-3 )-alkylisoxazole (e.g., optionally substituted with an R group).

[0042] In some embodiments, the cycloaddition product (e.g., 3-(C 0-3 )-alkyl-2-isoxazoline product or 3-(C 0-3 )-alkylisoxazole product) can be further processed (e.g., by the methods described herein) to provide 3-amino-(C 3-6 )-alkan-1-ol.

[0043] In some embodiments, 1-nitro-(C 1-4)-alkane is nitromethane, nitroethane, 1-nitropropane or 1-nitrobutane. In some embodiments, 1-nitro-(C 1-4 )-alkane is nitroethane. For example, the product is selected from optionally 5-substituted 3-methyl-2-isoxazoline or optionally 5-substituted 3-methyl-2-isoxazole. In some embodiments, the product is 3-(C 0-3 )-alkyl-2-isoxazoline, such as 3-methyl-2-isoxazoline. In some embodiments, the product is 3-(C 0-3 )-alkyl-2-isoxazoline, such as 3-ethyl-2-isoxazoline.

[0044] In some embodiments, the base is an organic base. For example, the organic base used in the methods described herein can be trimethylamine or triethylamine. In some embodiments, the molar ratio of the presence of the base (e.g., organic base) and 1-nitro-(C 1-4 )-alkane (e.g., nitroethane) (base: 1-nitro-(C 1-4 )-alkane) is from about 0.1:100 to about 20:100. For example, it is at any of about the following ratios or in a range between and including these ratios: 0.1:100, 0.2:100, 0.3:100, 0.4:100, 0.5:100, 0.75:100, 1:100, 1.5:100, 2:100, 2.5:100, 3:100, 4:100, 5:100, 6:100, 8:100, 10:100, 12.5:100, 15:100, and 20:100. Thus, the molar ratio of the presence of the base and 1-nitro(C 1-4 )-alkane can be about 0.5:100 or about 1:100 to about 15:100, or about 1:100 to about 6:100.

[0045] In some embodiments, the dehydrating agent used in the methods described herein can be an isocyanate, such as phenyl isocyanate or tolylene diisocyanate. In some embodiments, the dehydrating agent used in the methods described herein can be an acid anhydride, such as acetic anhydride or phthalic anhydride. In some embodiments, the dehydrating agent used in the methods described herein can be a chloride, such as phosphorus oxychloride, ethyl chloroformate, or thionyl chloride. In some embodiments, the molar ratio of the presence of the dehydrating agent (e.g., isocyanate, such as phenyl isocyanate, tolylene diisocyanate, or acid anhydride, such as acetic anhydride or phthalic anhydride (e.g., hexahydrophthalic anhydride)) and 1-nitro-(C 1-4 )-alkane (e.g., nitroethane) (dehydrating agent: 1-nitro-(C 1-4)-alkane) is from about 1:1 to about 5:1. Thus, representative ratios include any of the following: 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, or a range between and including any two of the above ratios. For example, the molar ratio of the dehydrating agent to 1-nitro-(C 1-4 )-alkane can also be from about 1:1 to about 2:1.

[0046] In some embodiments, the contacting (e.g., contacting 1-nitro-(C 1-4 )-alkane with a vinyl source or an acetylene source) is carried out in the presence of a solvent. In some embodiments, the solvent is a nonpolar solvent, such as an aromatic solvent. In some embodiments, the solvent can be benzene, toluene, xylene, or any combination of two or more thereof.

[0047] In some embodiments, the contacting described herein (e.g., contacting 1-nitro-(C 1-4 )-alkane with a vinyl source or an acetylene source) is carried out at a pressure of about 1 psi to about 500 psi, including for example any one of about 1 psi, 5 psi, 10 psi, 25 psi, 50 psi, 75 psi, 100 psi, 150 psi, 200 psi, 250 psi, 300 psi, 350 psi, 400 psi, 450 psi, or 500 psi, or a range between and including any two of the above values. Thus, in some embodiments, the pressure is from about 100 psi to about 350 psi, or from about 200 psi to about 250 psi.

[0048] In some embodiments, the contacting described herein (e.g., contacting 1-nitro-(C 1-4 )-alkane with a vinyl source or an acetylene source) is carried out at an elevated temperature. For example, the contacting can be carried out at a temperature of about 40 °C to about 70 °C. Representative temperatures include any one of about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, or a range between and including any two of the above values. Thus, in some embodiments, the temperature range can be from about 55 °C to about 65 °C, or from about 50 °C to about 60 °C.

[0049] As described above, the method can provide 3-(C 0-3 )-alkyl-2-isoxazoline (such as 3-methyl-2-isoxazoline). In some embodiments, the method further includes separating and / or purifying the optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazoline or the optionally 5-substituted 3-(C 0-3)-alkyl-2-isoxazole. For example, the method can include filtering the reaction mixture, washing the obtained filter cake (e.g., washing with a poor solvent such as n-hexane), and distilling one or more of the filtrate.

[0050] In some embodiments, the methods described herein provide optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) or optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazole in a yield of at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0051] Optionally via the formation of 1-substituted 3-amino-(C 3-6 )-alkan-1-ols

[0052] In some embodiments, the methods described herein further include converting 3-(C 0-3 )-alkylisoxazole or 3-(C 0-3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) to 3-amino-(C 3-6 )-alkan-1-ol (e.g., 3-amino-1-butanol). Accordingly, the present disclosure also provides a method for preparing 3-amino-(C 3-6 )-alkan-1-ol (e.g., 3-amino-1-butanol).

[0053] In some embodiments, 3-(C 0-3 )-alkylisoxazole is a compound having the following structure: In some embodiments, 3-(C 0-3 )-alkyl-2-isoxazoline is a compound having the following structure: Thus, it should be recognized that the 3-(C 0-3 )-alkylisoxazoles described herein include, for example, optionally 5-substituted 3-(C 0-3 )-alkylisoxazoles (including their enantiomers) having the following structure: And the 3-amino-(C 3-6 )-alkan-1-ols described herein include optionally 1-substituted 3-amino-(C 3-6 )-alkan-1-ols (including their enantiomers) having the following structure: In the above embodiments, the alkyl group is a C 1-3 alkyl group, such as methyl. In some embodiments, R is -OC(O)Me, O-(C 1-3 )-alkyl, H, OH, or trimethylsilyl.

[0054] In some embodiments, the methods described herein can include converting a 3-(C 0-3 )-alkylisoxazole to the corresponding 3-(C 0-3 )-alkyl-2-isoxazoline in the presence of a reducing agent (such as borane, metal hydride, silane, hydrogen, and a hydrogenation catalyst). In some embodiments, the 3-(C 0-3 )-alkylisoxazole is directly converted to the corresponding 3-amino-(C 3-6 )-alkan-1-ol.

[0055] Likewise, the 3-(C 0-3 )-alkyl-2-isoxazoline from the first step or from the 3-(C 0-3 )-alkylisoxazole can be reduced to the corresponding 3-amino-(C 3-6 )-alkan-1-ol using any suitable reducing agent (including the reducing agents disclosed herein). In particular, catalytic hydrogenation can be used to reduce the 3-(C 0-3 )-alkyl-2-isoxazoline.

[0056] In some embodiments, the 3-(C 0-3 )-alkyl-2-isoxazoline is directly converted to the corresponding 3-amino-(C 3-6 )-alkan-1-ol. In some embodiments, the 3-(C 0-3 )-alkyl-2-isoxazoline is converted to the corresponding 3-amino-(C 0-3 )-alkan-1-ol via a 3-(C 3-6 )-alkylisoxazolidine intermediate.

[0057] In some embodiments, the methods described herein include contacting a 3-(C 0-3 )-alkyl-2-isoxazoline (such as 3-methyl-2-isoxazoline) with hydrogen and a hydrogenation catalyst (such as in a reactor) to provide a 3-amino-(C 3-6 )-alkan-1-ol (such as 3-amino-1-butanol). In some embodiments, the methods described herein include contacting a 3-(C 0-3 )-alkyl-2-isoxazoline (such as 3-methyl-2-isoxazoline) with hydrogen and a hydrogenation catalyst (such as in a reactor) to provide a 3-(C 0-3 )-alkylisoxazolidine, which is then converted to a 3-amino-(C 3-6 )-alkan-1-ol (such as 3-amino-1-butanol) in the presence of a reducing agent.

[0058] In some embodiments, the 3-(C 0-3 )-alkyl-2-isoxazoline is 3-methyl-2-isoxazoline. In some embodiments, the 3-amino-(C 3-6)-Alkan-1-ol is 3-amino-1-butanol.

[0059] In some embodiments, the contacting described herein (e.g., contacting 3-(C 0-3 )-alkyl-2-isoxazoline with hydrogen and a hydrogenation catalyst) is carried out in the presence of a solvent. For example, the contacting can be carried out in the presence of an alcohol such as MeOH. In some embodiments, the contacting (e.g., contacting 3-(C 0-3 )-alkyl-2-isoxazoline with hydrogen) is carried out at an elevated temperature. For example, the contacting can be carried out at a temperature of about 20 - 100 °C, about 50 - 80 °C, or about 60 - 70 °C for a period of time (e.g., about 1 - 48 hours). In some embodiments, the pressure of the hydrogen present is about 10 - 2500 psi, 50 - 900 psi, about 500 - 900 psi, or about 600 - 800 psi.

[0060] In some embodiments, the hydrogenation catalyst used in the methods described herein is not an optically active catalyst, and the corresponding 3-amino-(C 3-6 )-alkan-1-ol product is racemic 3-amino-(C 3-6 )-alkan-1-ol (e.g., racemic 3-amino-1-butanol). For example, the hydrogenation catalyst can be a Raney nickel catalyst or a palladium catalyst. In some embodiments, the molar ratio of the hydrogenation catalyst (e.g., Raney nickel) to 3-(C 0-3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) present (hydrogenation catalyst: 3-(C 0-3 )-alkyl-2-isoxazoline) is about 1:100 to about 20:100 or about 15:100 to about 20:100.

[0061] In some embodiments, the hydrogenation catalyst used in the methods described herein is an optically active catalyst, and the corresponding hydrogenation product (e.g., 3-(C 0-3 )-alkylisoxazolidine or 3-amino-(C 3-6 )-alkan-1-ol product) is enriched in one enantiomer (e.g., enriched in the (R)-enantiomer). In some embodiments, the enantiomeric ratio ((R)-enantiomer:(S)-enantiomer) of the hydrogenation product enriched in the (R)-enantiomer (e.g., 3-(C 0-3 )-alkylisoxazolidine or 3-amino-(C 3-6 )-alkan-1-ol) is greater than 1:1, greater than 3:1, greater than 5:1, greater than 10:1, greater than 20:1, or greater than 50:1. In some embodiments, the optically active hydrogenation catalyst is of the formula ML na metal catalyst. In some embodiments, M is iridium, rhodium, ruthenium, nickel, or other transition metals, or M comprises iridium, rhodium, ruthenium, nickel, or other transition metals. In some embodiments, each L is independently a chiral ligand. In some embodiments, n is an integer from 1 to 4 (e.g., n is 1, 2, 3, or 4). In some embodiments, the molar ratio of the hydrogenation catalyst (e.g., ML n ) and 3-(C 0-3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) present (hydrogenation catalyst: 3-(C 2-6 )-alkyl-2-isoxazoline) is from about 1:100 to about 20:100 or from about 15:100 to about 20:100 (e.g., about 1:100, 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 11:100, 12:100, 13:100, 14:100, 15:100, 16:100, 17:100, 18:100, 19:100, or 20:100, or a range between and including any two of the above values).

[0062] In some embodiments, the enantiomerically enriched hydrogenation product is 3-(C 0-3 )-alkylisoxazolidine, and its enantiomeric ratio ((R)-3-(C 0-3 )-alkylisoxazolidine: (S)-3-(C 0-3 )-alkylisoxazolidine) is greater than 1:1, greater than 3:1, greater than 5:1, greater than 10:1, greater than 20:1, or greater than 50:1. In some embodiments, the enantiomerically enriched hydrogenation product is 3-amino-(C 3-6 )-alkan-1-ol, and its enantiomeric ratio ((R)-3-amino-(C 3-6 )-alkan-1-ol: (S)-3-amino-(C 3-6 )-alkan-1-ol) is greater than 1:1, greater than 3:1, greater than 5:1, greater than 10:1, greater than 20:1, or greater than 50:1. The optical purity can be further improved by chiral chromatography and / or diastereomeric salt recrystallization.

[0063] In some embodiments, in the presence of an optically active reducing agent (e.g., borane, metal hydride, silane, hydrogen) including an optically active boron-containing reagent, 3-(C 0-3 )-alkyl-2-isoxazoline is converted to an enantiomerically enriched (e.g., enriched (R)-enantiomer) 3-amino-(C 3-6)-alkan-1-ol. For example, WO2020094528A1 discloses a method for reducing the carbon-nitrogen double bond in a substituted oxime. An optically active boron-containing reducing catalyst, such as oxazaborolidine, can be used to reduce an oxime ether to an optically active amine. In some embodiments, the amount of the optically active boron-containing reagent present is about 0 - 0.5, about 0.5 - 1, about 1 - 3, or about 3 - 5 equivalents (e.g., molar equivalents) relative to 3-(C 2-6 )-alkyl-2-isoxazoline.

[0064] As described above, the method can provide 3-amino-(C 3-6 )-alkan-1-ol (e.g., 3-amino-1-butanol). In some embodiments, the method further comprises separating and / or purifying the obtained 3-amino-(C 3-6 )-alkan-1-ol from the reaction mixture. For example, the method can include one or more of filtering the reaction mixture, washing the obtained filter vessel (e.g., with a poor solvent), and distilling the filtrate.

[0065] In some embodiments, the method further comprises separating the (R)-enantiomer and the (S)-enantiomer, such as the (R)-enantiomer and the (S)-enantiomer of 3-amino-(C 3-6 )-alkan-1-ol, or the (R)-enantiomer and the (S)-enantiomer of 3-(C 0-3 )-alkylisoxazolidine (e.g., the (R)-enantiomer and the (S)-enantiomer prepared by the methods described herein). Representative separation methods are described herein. For example, 3-amino-(C 3-6 )-alkan-1-ol can be separated into (R)-3-amino-(C 3-6 )-alkan-1-ol and (S)-3-amino-(C 3-6 )-alkan-1-ol by chiral chromatography and / or diastereomeric salt recrystallization. In some embodiments, using the diastereomeric salt recrystallization method, which includes neutralizing 3-amino-(C 3-6 )-alkan-1-ol with a chiral acid and separating the obtained diastereomers by crystallization to separate 3-amino-(C 3-6 )-alkan-1-ol into the (R)-enantiomer and the (S)-enantiomer. After treating the salt with a base, the optically enriched 3-amino-(C 3-6 )-alkan-1-ol can be separated. The crystallization process can be repeated multiple times to achieve the desired optical purity. U.S. Patent No. 9115052B2 provides representative chiral separation methods.

[0066] In some embodiments, the methods described herein provide 3-amino-(C 3-6)-alkan-1-ol (such as 3-amino-1-butanol) in a yield of at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%.

[0067] Any one or two steps of the methods disclosed herein can be carried out in a batch, semi-batch or continuous manner using equipment and techniques known in the art.

[0068] To illustrate the advantages of the present technology and to further assist those of ordinary skill in the art in preparing or using the present technology, examples are provided herein. To more fully illustrate certain aspects of the present technology, examples are also provided herein. These examples should in no way be construed as limiting the scope of the present technology as defined by the appended claims. These examples may include or incorporate any variations, aspects or facets of the present technology described above. The above variations, aspects or facets may further each include or incorporate variations of any or all other variations, aspects or facets of the present technology. Examples

[0069] General method

[0070] Example 1 - Synthesis of 3-methyl-2-isoxazoline using phenyl isocyanate

[0071] Charge a 1 L Parr reactor with phenyl isocyanate (119.2 g, 1.0 mol), triethylamine (2.02 g, 0.02 mol) and benzene (190 g). Purge the reactor with nitrogen several times under pressure, then pressurize with ethylene to 220 psi while mixing. Heat the mixture to 50 °C. Feed nitroethane (47.5 g, 0.626 mol) into the reactor at a rate of 2.25 mL / min. During the addition, the temperature of the reaction mixture rises to 58 °C. After complete addition, stir the mixture at 55 - 60 °C for 1 hour. Cool the mixture to room temperature and vent. Filter the reaction mixture and wash the filter cake. Distill the filtrate to obtain 30 g (70% yield) of 3-methyl-2-isoxazoline (GC-FID purity 99.1%). NMR data supports the assigned structure. 1H NMR (500 MHz, CDCl3) δ: 4.31 - 4.25 (m, 2H), 2.95 - 2.89 (m, 2H), 2.01 (s, 3H). 13C NMR (500 MHz, CDCl3) δ: 155.5, 68.2 39.0, 13.0.

[0072] Example 2 - Synthesis of 3-methyl-2-isoxazoline using tolylene diisocyanate

[0073] Charge benzene (100 g), tolylene diisocyanate (17.42 g, 0.10 mol), and triethylamine (0.4 g, 0.004 mol) into a 500 mL three-necked round-bottom flask. Stir the mixture, and at room temperature, bubble ethylene into the mixture for 10 minutes. Add nitroethane (7.507 g, 0.10 mol) dropwise to the mixture over one hour while maintaining the flow of ethylene. After the addition of nitroethane is complete, ethylene bubbling continues for 3 hours. Stir the mixture at ambient temperature for 18 hours. GC-FID analysis shows that the conversion of nitroethane to 3-methyl-2-isoxazoline is 58%.

[0074] Example 3. Synthesis of 3-methyl-2-isoxazoline using hexahydrophthalic anhydride

[0075] Charge hexahydrophthalic anhydride (77.08 g, 0.5 mol), benzene (100 g), and nitroethane (37.54 g, 0.5 mol) into a 1 L Parr reactor. Then seal the reactor and start mixing. Purge the reactor 4 times with 30 psi nitrogen. Pressurize the reactor with ethylene to 270 psi. Heat the reaction mixture to 65 °C. Feed a solution of triethylamine (51.6 g, 0.51 mol) containing 4-dimethylaminopyridine (1.0 g, 0.082 mol) into the reactor at a rate of 3 mL / min. After heating at 65 °C for 16 hours, GC-FID analysis shows a conversion of 17%. Further heat the reaction mixture to 80 °C for 4 hours. Collect 3-methyl-2-isoxazoline by distilling the reaction mixture, and the separated amount is 12 g (yield 30%).

[0076] Example 4. Synthesis of 3-amino-1-butanol from 3-methyl-2-isoxazoline

[0077] Charge 100 g of methanol and 5 g of nickel into a 1 L Parr reactor. Purge the reactor three times with nitrogen and then with hydrogen. Heat the reaction mixture to 65 °C and pressurize it with hydrogen to 700 psi. Feed a solution of 3-methyl-2-isoxazoline (30 g, 0.35 mol) in 30 mL of methanol into the reactor at a rate of 3 mL / min. After complete addition, maintain the reaction mixture at 65 °C for 30 minutes. Cool the mixture to room temperature, vent to atmospheric pressure, and remove the catalyst by filtration. Distill the filtrate to obtain 18.9 g of 3-amino-1-butanol (yield 60%). The NMR data supports the assigned structure. 1 H NMR (500 MHz, CDCl3) δ: 3.81 - 3.71 (m, 2H), 3.13 - 3.09 (m, 1H), 2.81 (b, 3H), 1.64 - 1.57 (m, 1H), 1.53 - 1.44 (m, 1H), 1.13 - 1.11 (m, 3H). 1313C NMR (500 MHz, CDCl3) δ: 61.9, 47.5, 39.6, 25.5.

[0078] Equivalent solutions

[0079] Although certain embodiments have been illustrated and described, those of ordinary skill in the art can effect changes, equivalent substitutions, and other types of changes to the compositions of the present technology described herein after reading the above specification. Each aspect and embodiment described above may also include or incorporate changes or aspects disclosed for any or all other aspects and embodiments.

[0080] The present technology is also not limited to the specific aspects described herein, which are merely illustrative of individual aspects of the present technology. The present technology can be subject to many modifications and variations without departing from its spirit and scope, which will be apparent to those skilled in the art. In addition to the methods recited herein, functional equivalent methods within the scope of the present technology will be apparent to those skilled in the art from the above description. Such modifications and variations fall within the scope of the appended claims. It should be understood that the present technology is not limited to specific methods, reagents, compounds, or compositions, which can of course vary. It should also be understood that the terms used herein are for the purpose of describing specific aspects only and are not intended to be limiting. Accordingly, the present specification is to be regarded as illustrative only, and the breadth, scope, and spirit of the present technology are represented only by the appended claims, the definitions therein, and any equivalent description thereof.

[0081] The embodiments illustratively described herein can be suitably practiced without any one or more elements, any one or more limitations not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing", etc. should be construed broadly without limitation. In addition, the terms and expressions used herein are used as terms of description rather than limitation, and in using such terms and expressions, there is no intention to exclude any equivalents of the features shown and described or portions thereof, but it should be recognized that various modifications can be made within the scope of the claimed technology. Thus, for example, terms such as "comprising", "including", "containing", etc. should be understood to disclose embodiments using the phrases "consisting essentially of" and "consisting of". The phrase "consisting essentially of" should be understood to include those specifically recited elements and other elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" does not include any unrecited elements.

[0082] In addition, when describing the features or aspects of the present disclosure in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also described in terms of any single member or subgroup of members of the Markush group. Each narrower genus and subgenus grouping falling within the broader disclosed concept also forms part of the present technology. This includes the broader description of the present technology with qualifying conditions or negative limitations that exclude any subject matter from that broader concept, whether or not the excluded material is specifically recited herein.

[0083] All publications, patent applications, issued patents, and other documents (such as journals, articles, and / or textbooks) cited in this specification are hereby incorporated by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded if they are inconsistent with the definitions in the present disclosure.

[0084] The appended claims list additional embodiments, as well as the full scope of equivalents to which those claims are entitled.

Claims

1. A method comprising contacting a 1-nitro-(C 1-4 )-alkane with a vinyl source or an acetylene source in the presence of a base and a dehydrating agent to provide a product selected from optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazolines or optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazoles.

2. The method according to claim 1, wherein the 1-nitro-(C 1-4 )-alkane is nitroethane, and the product is selected from optionally 5-substituted 3-methyl-2-isoxazoline or optionally 5-substituted 3-methyl-2-isoxazole.

3. The method according to claim 1 or 2, wherein the vinyl source or acetylene source is selected from ethylene, acetylene, vinyl acetate, vinyl ether, and trimethylsilylacetylene.

4. The method according to any one of the preceding claims, wherein the base is an organic base.

5. The method according to any one of the preceding claims, wherein the base is trimethylamine or triethylamine.

6. The method according to any one of the preceding claims, wherein the molar ratio of the base to the 1-nitro-(C 1-4 )-alkane is from about 0.1:100 to about 20:100, from about 1:100 to about 15:100 or from about 1:100 to about 6:

100.

7. The method according to any one of the preceding claims, wherein the dehydrating agent is an isocyanate, an acid anhydride, or a chloride.

8. The method according to any one of the preceding claims, wherein the dehydrating agent is selected from phenyl isocyanate, tolylene diisocyanate, acetic anhydride, phthalic anhydride, phosphorus oxychloride, ethyl chloroformate, and thionyl chloride.

9. The method according to any one of the preceding claims, wherein the molar ratio of the dehydrating agent to the 1-nitro-(C 1-4 )-alkane is from about 1:1 to about 5:1 or from about 1:1 to about 2:

1.

10. The method according to any one of the preceding claims, wherein the vinyl source or acetylene source is present at a pressure of about 1 - 500 psi, about 100 - 350 psi, or about 200 - 250 psi.

11. The method according to any one of the preceding claims, wherein the contacting is carried out in the presence of a solvent.

12. The method according to claim 8, wherein the solvent is benzene, toluene, xylene, or any combination of two or more thereof.

13. The method according to any one of the preceding claims, wherein the contacting is carried out at an elevated temperature.

14. The method according to claim 10, wherein the elevated temperature is about 40 - 70 °C, about 55 - 65 °C, or about 50 - 60 °C.

15. The method according to any one of the preceding claims further comprises separating and purifying the optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazoline or the optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazole obtained.

16. The method according to any one of the preceding claims, further comprising contacting the product with a reducing agent to provide a reduction product selected from optionally 5-substituted 3-(C 0-3 )-alkyl-2-isoxazolidine or optionally 1-substituted 3-amino-(C 3-6 )-alkan-1-ol.

17. The method according to claim 16, wherein the reducing agent is selected from borane, metal hydride, silane, and hydrogen with a hydrogenation catalyst.

18. The method according to claim 16 or 17, wherein the reducing agent has optical activity.

19. The method according to any one of claims 16 - 18, wherein the reducing agent is an optically active boron-containing reagent.

20. The method according to any one of claims 16 - 18, wherein the reducing agent is hydrogen with a hydrogenation catalyst.

21. The method according to any one of claims 16 - 20, wherein said contacting directly provides an optionally 1 - substituted 3 - amino-(C 3-6 )-alkane - 1 - ol.

22. The method according to any one of claims 16 - 20, wherein said contacting provides an optionally 5 - substituted 3-(C 0-3 )-alkylisoxazolidine.

23. The method according to claim 22, further comprising, in the presence of a reducing agent, converting the optionally substituted 3-(C 0-3 )-alkylisoxazolidine into an optionally 1-substituted 3-amino-(C 3-6 )-alkan-1-ol.

24. The method according to any one of claims 16 - 23, wherein the reducing agent is hydrogen and a hydrogenation catalyst, and the molar ratio of the hydrogenation catalyst to the optionally 5 - substituted 3-(C 0-3 )-alkyl-2-isoxazoline is from about 1:100 to about 25:100 or from about 10:100 to about 20:

100.

25. The method according to any one of claims 16 - 24, wherein the contacting is carried out in the presence of a solvent.

26. The method according to claim 25, wherein the solvent is an alcohol.

27. The method according to claim 25 or 26, wherein the solvent is MeOH.

28. The method according to any one of claims 16 - 27, wherein the hydrogen is present at a pressure of about 10 - 2500 psi, about 50 - 900 psi, about 500 - 900 psi, or about 600 - 800 psi.

29. The method according to any one of claims 16 - 28, wherein the contacting is carried out at an elevated temperature.

30. The method according to claim 29, wherein the elevated temperature is about 20 - 100 °C, about 50 - 80 °C, or about 60 - 70 °C.

31. The method according to any one of claims 16 - 17 and 20 - 30, wherein the 3-amino-(C 3-6 )-alkane-1-ol is racemic 3-amino-(C 3-6 )-alkane-1-ol.

32. The method according to any one of claims 20 - 31, wherein the hydrogenation catalyst is Raney nickel or a palladium catalyst.

33. The method according to any one of claims 16 - 30, wherein the 3-amino-(C 3-6 )-alkan-1-ol is (R)-enantiomer-enriched, wherein the enantiomeric ratio of (R)-3-amino-(C 2-6 )-alkan-1-ol:(S)-3-amino-(C 3-6 )-alkan-1-ol is greater than 1:

1.

34. The method according to claim 33, wherein the reducing agent is hydrogen with an optically active hydrogenation catalyst.

35. The method according to claim 34, wherein the optically active catalyst is a metal catalyst having the formula ML n wherein M is iridium, rhodium or ruthenium; each L is independently a chiral ligand; and n is an integer from 1 to 4.

36. The method according to any one of claims 16 - 35 further comprises separating and purifying the optionally substituted 3 - amino-(C 3-6 )-alkane-1-ol or the optionally substituted 3-(C 0-3 )-alkylisoxazolidine obtained.

37. The method according to any one of claims 16 - 36, further comprising separating the (R)-enantiomer and the (S)-enantiomer of the optionally substituted 3-amino-(C 3-6 )-alkane-1-ol obtained, or the (R)-enantiomer and the (S)-enantiomer of the optionally substituted 3-(C 0-3 )-alkylisoxazolidine obtained.

38. The method according to claim 37, wherein the (R)-enantiomer and the (S)-enantiomer are separated by chiral chromatography or diastereomeric salt recrystallization.

39. A composition prepared according to any one of claims 16 - 30 or 33 - 38, wherein the composition comprises (R)-3-(C 0-3 )-alkylisoxazolidine, and the composition has an (R) / (S) enantiomeric ratio of (R)-3-(C 0-3 )-alkylisoxazolidine:(S)-3-(C 0-3 )-alkylisoxazolidine greater than 1.00.