Method for preparing 3-amino-1-butanol

Abstract

Optically active 3-amino-(C 3~6 )-Alkane-1-ol (e.g., optically active 3-amino-1-butanol, e.g., (R)-3-amino-1-butanol) containing 3-amino-(C 3~6 A method and process for preparing 3-(C)-alkane-1-ol is disclosed herein. This process involves 3-(C) 0~3 To provide )-alkyl-2-isoxazoline, in the presence of a base and a dehydrating agent, 1-nitro-(C 1~4 A step of contacting an alkane with a vinyl source or an acetylene source, and / or 3-amino-(C 3~6 To provide )-alkane-1-ol, the 3-(C 0~3 The process includes contacting )-alkyl-2-isoxazoline with hydrogen and a hydrogenation catalyst.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of U.S. Patent Application No. 63 / 419,979, filed on 27 October 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical field This disclosure, as a whole, describes optically active 3-amino-(C) 3~6 )-Alkane-1-ol (e.g., optically active 3-amino-1-butanol, e.g., (R)-3-amino-1-butanol) containing 3-amino-(C 3~6 The present invention relates to a method for preparing )-alkane-1-ols. [Background technology]

[0003] background (R)-3-amino-1-butanol is an important intermediate in the production of the antibiotic dolutegravir. While methods for producing 3-amino-1-butanol (including (R)-3-amino-1-butanol) have been described, these methods involve lengthy synthesis processes, expensive reduction processes, and the generation of large amounts of waste. Therefore, there is a need for novel and environmentally friendly methods for producing optically active 3-amino-1-butanol, such as (R)-3-amino-1-butanol, more efficiently and at lower cost. [Overview of the Initiative]

[0004] overview This technology utilizes optically active 3-amino-(C) 3~6 )-Alkane-1-ol (e.g., optically active 3-amino-1-butanol, e.g., (R)-3-amino-1-butanol) containing 3-amino-(C 3~6 This is partly based on the remarkable discovery that )-alkane-1-ols (e.g., 3-amino-1-butanol) can be produced using the methods described herein.

[0005] In one aspect, to provide a product selected from 3-(C 0~3 )-alkyl-2-isoxazoline where the 5-position may be substituted or 3-(C 0~3 )-alkyl-2-isoxazole where the 5-position may be substituted, a process is disclosed herein that includes contacting 1-nitro-(C 1~4 )-alkane with a vinyl source or an acetylene source in the presence of a base and a dehydrating agent.

[0006] In some embodiments, the process further includes contacting the product (3-(C 0~3 )-alkyl-2-isoxazolidine where the 5-position may be substituted or 3-amino-(C 3~6 )-alkane-1-ol where the 1-position may be substituted) with a reducing agent to provide a reduction product selected from 3-(C 0~3 )-alkyl-2-isoxazoline where the 5-position may be substituted or 3-(C 0~3 )-alkyl-2-isoxazole where the 5-position may be substituted. In some embodiments, the reducing agent is hydrogen and a hydrogenation catalyst, and 3-amino-(C 3~6 )-alkane-1-ol where the 1-position may be substituted, such as 3-amino-butan-1-ol, is provided.

[0007] In another aspect, a composition comprising (R)-3-(C 0~3 )-alkylisoxazolidine and having an (R)-3-(C 0~3 )-alkylisoxazolidine:(S)-3-(C 0~3 )-alkylisoxazolidine mirror image isomer ratio greater than 1.00, such as (R)-3-methylisoxazolidine:(S)-3-methylisoxazolidine (e.g., a composition prepared according to any of the methods described herein), is disclosed herein.

[0008] It should be recognized that all combinations of the above concepts and any further concepts discussed in more detail below (where such concepts are not contradictory) are intended to be part of the subject matter disclosed herein. In particular, all combinations of the subject matter described in the claims at the end of this disclosure are intended to be part of the subject matter disclosed herein. [Modes for carrying out the invention]

[0009] Detailed explanation definition The following terms will be used throughout as defined below.

[0010] As used herein and in the appended claims, singular articles and similar demonstrative pronouns such as “a,” “an,” and “the” in the context describing elements (particularly in the context of the appended claims) should be interpreted as encompassing both singular and plural forms unless otherwise specifically indicated herein or clearly inconsistent with the context. The descriptions of ranges of values ​​herein are intended solely as a convenient way to refer individually to each separate value that falls within the range, unless otherwise specifically indicated herein, and each separate value is incorporated into the specification as if it were individually described herein. All methods described herein may be carried out in any preferred order unless otherwise specifically indicated herein or clearly inconsistent with the context. Any use of any examples or illustrative terms provided herein (e.g., “~etc.”) is intended solely to clarify the aspects and does not constitute a limitation on the claims unless otherwise specifically indicated. The language in the specification should not be interpreted as indicating that elements not described in the claims are essential.

[0011] Unless otherwise specified, all temperatures are in degrees Celsius (°C).

[0012] Isolated: As used herein, the term “isolated” means (1) a substance and / or entity that was separated from at least some of the components to which it relates when it was first produced (whether in nature and / or in a laboratory environment), and / or (2) a substance and / or entity that was synthetically produced, prepared, and / or manufactured (i.e., not a natural product). In some embodiments, an isolated agent is a purity of 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 above values. As used herein, a substance is “pure” if it is substantially free of other components (for example, if the content is less than 5% by weight, 4% by weight, 3% by weight, 2% by weight, or 1% by weight). As used herein, the calculation of the percentage purity of isolated substances and / or entities does not include excipients (e.g., buffers, solvents, water, etc.).

[0013] Approximately or nearly: As used herein, the terms “approximately” or “nearly” apply to one or more subject values ​​to mean a value similar to the given baseline value. In certain embodiments, unless otherwise specifically stated or evident from the context, the terms “approximately” or “nearly” mean a value that is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% above or below the given baseline value (unless such a value exceeds 100% of the possible value).

[0014] As used in the specification and the attached claims, the singular forms “a,” “an,” and “the” also include the plural form of the referent, unless the context clearly indicates otherwise. Thus, for example, a reference to “composition” includes a mixture of two or more such compositions.

[0015] "Optional" or "optional" means that the event or situation described below may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur.

[0016] The term "stereoisomer" refers to an isomer that has the same composition but differs in the arrangement of atoms in space. Enantiomers and diastereoisomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and cannot be superimposed. The term "diastereoisomer" refers to a stereoisomer that is not a mirror image of each other. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomer species that does not have optical activity.

[0017] The term "chiral" refers to a structural characteristic of a molecule that makes it impossible to superimpose its mirror image onto it. The term "homochiraral" refers to a state of pure enantiomerism. The term "optical activity" refers to the degree to which homochiral molecules or non-racemic mixtures of chiral molecules rotate the plane of polarization.

[0018] "Stereoselective," "enantiomeric," "diastereoselective," and their variations refer to a given process (e.g., ester hydrolysis, hydrogenation, hydroformylation, palladium coupling, hydrosilylation, hydrocyanation, olefin metathesis, hydroacylation, allylamine isomerization, etc.) that yields more of one stereoisomer, enantiomer, or diastereoisomer than the other.

[0019] "Stereoisomerically enriched," "enantiomerically enriched," "diastereoisomerically enriched," and variations thereof refer to samples of compounds that contain more of one stereoisomer, enantiomer, or diastereoisomer than the other, respectively. The degree of enrichment can be determined by the percentage of the total product, or by ee or de in the case of a pair of enantiomers or diastereoisomers.

[0020] "Substantially pure stereoisomers," "substantially pure enantiomers," "substantially pure diastereoisomers," and their variations refer to samples in which a particular stereoisomer, enantiomer, or diastereoisomer constitutes at least approximately 95% of the sample, respectively. For pairs of enantiomers and diastereoisomers, substantially pure enantiomers or diastereoisomers would correspond to samples in which ee or de constitutes approximately 90% or more.

[0021] "Pure stereoisomers," "pure enantiomers," "pure diastereoisomers," and their variations refer to samples containing stereoisomers, enantiomers, or diastereoisomers that make up at least approximately 99.5% of the sample, respectively. For pairs of enantiomers and diastereoisomers, "pure enantiomers" or "pure diastereoisomers" would correspond to samples where ee or de make up approximately 99% or more.

[0022] Solvates: These may include, but are not limited to, solvates of a compound that retain one or more of its activity and / or properties, and that are not undesirable. Examples of solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or compounds combined with any combination thereof.

[0023] Solvents: may include nonpolar, polar aprotic, and polar protic solvents without limitation. Examples of nonpolar solvents include, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, xylene, 1,4-dioxane, chloroform, diethyl ether, and dichloromethane (DCM). Examples of polar aprotic solvents include, without limitation, tetrahydrofuran (THF), ethyl acetate, isopropyl acetate (IPAc), acetone, dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile (MeCN), butyronitrile, dimethyl sulfoxide (DMSO), nitromethane, and propylene carbonate. Examples of polar protic solvents include, without limitation, formic acid, n-butanol, isopropanol (IPA), n-propanol, ethanol, methanol, acetic acid, and water.

[0024] Acid: A molecule or ion capable of donating hydrogen (a proton or hydrogen ion H) + ) or, alternatively, a molecule or ion capable of accepting an electron pair (e.g., a Lewis acid). Acids include, but are not limited to, mineral acids, sulfonic acids, carboxylic acids, halogenated carboxylic acids, and vinylous carboxylic acids.

[0025] Base: As used herein, “base” refers to a compound that can accept a proton or donate a lone pair of electrons. Examples of bases are alkalis (OH - ), carbonate, bicarbonate, alkoxide (alkyl-O( - This includes 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).

[0026] Organic bases: As used herein, “organic bases” refers to carbon-containing compounds having one or more functional groups capable of accepting a proton from an acidic group. For example, organic bases may contain basic nitrogen such as an amine group or an aromatic ring nitrogen. Exemplary organic bases include trimethylamine, triethylamine, benzyldiethylamine, dimethylethylamine, imidazole, pyridine, and piperidine.

[0027] Dehydrating agent: As used herein, “dehydrating agent” refers to an agent or compound that can remove water molecules in a chemical reaction.

[0028] Generally, references to specific elements, such as hydrogen or H, imply the inclusion of all isotopes of that element. For example, if an R group is defined as containing hydrogen or H, this also includes deuterium and tritium. Tritium, C 14 , P 32 and S 35 Compounds containing radioactive isotopes such as those mentioned above are therefore within the scope of this technology. Methods for inserting such labels into compounds of this technology will be readily apparent to those skilled in the art based on the disclosures herein.

[0029] Alkanes and alkyl groups refer to saturated linear and branched hydrocarbons and hydrocarbon groups having 1 to 12 carbon atoms (unless otherwise specified), and in some embodiments, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms, respectively. Examples of linear alkane / 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 alkane / alkyl groups include, non-limitingly, isopropane / isopropyl, isobutane / isobutyl, and 2,2-dimethylpropane / 2,2-dimethylpropyl. Alkanes / alkyl groups may be substituted with 1, 2, or 3 substituents, such as nitro, hydroxy, and halo(F, Cl, Br, I).

[0030] Salts of the compounds described herein are within the scope of this technology and include acid or base addition salts. If the compounds of this technology have a basic group such as an amino group, they can form salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (such as alginates, 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). If the compounds of this technology have an acidic group such as a carboxylic acid group, they can form salts with metals such as alkalis and alkaline earth metals (for example, Na + Li + , K + Ca 2+ Mg 2+ Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine, and ornithine) can form salts. Such salts can also be prepared in situ during the isolation and purification of the compound, or by separately reacting the purified compound in the form of a free base or free acid with a suitable acid or base, respectively, and then isolating the salts thus formed.

[0031] As will be understood by those skilled in the art, for all purposes, particularly in providing a written description, all scopes disclosed herein also encompass all possible sub-scopes and combinations of sub-scopes. Any enumerated scope is readily apparent as sufficiently describing and enabling that the same scope may be divided into at least equal parts, one-third, one-quarter, one-fifth, one-tenth, etc. As a non-limiting example, each scope considered herein can be readily divided into a lower third, a middle third, an upper third, etc. Also as will be understood by those skilled in the art, terms such as “up to,” “at least,” “greater than,” and “less than” all include the given numbers and refer to scopes that may later be divided into sub-scopes as considered above. Finally, as will be understood by those skilled in the art, a scope includes individual elements. Thus, for example, a group having 1 to 3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms refers to a group having 1, 2, 3, 4, or 5 atoms, and so on.

[0032] Method of this technology Optically active, optionally substituted at position 1, 3-amino-(C) 3~6 )-Alkane-1-ol (e.g., optically active 3-amino-1-butanol, e.g., (R)-3-amino-1-butanol), comprising 3-amino-(C 3~6 )-Alkane-1-ol (e.g., 3-amino-1-butanol) and 3-amino-(C) substituted at position 1 3~6 )-Alkane-1-ols, and their intermediates (e.g., 3-(C) methyl-2-isoxazoline, etc.) 0~3 Methods and processes for preparing ()-alkyl-2-isoxazolines) are disclosed herein. In certain embodiments, the processes disclosed herein may be carried out simultaneously, in the order described herein, or in any possible order thereof.

[0033] 3-(C) may be substituted in the 5th position. 0~3 Formation of )-alkyl-2-isoxazoline In one aspect, this disclosure may have the 5th position replaced by 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) or 3-(C) which may be substituted at the 5-position. 0~3 To provide a product selected from )-alkyl-2-isoxazole, 1-nitro-(C) in the presence of a base and a dehydrating agent 1~4 The present invention provides a process comprising the step of contacting an alkane (e.g., nitroethane) with a vinyl source or an acetylene source. In any embodiment, the product is 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) or 3-(C 0~3 Selected from )-alkyl-2-isoxazole.

[0034] The vinyl source may be any compound that serves as a source of ethylene or a vinyl-containing compound. Similarly, the acetylene source may serve as a source of acetylene or an alkyne-containing compound. In any embodiment, the vinyl source and / or acetylene source may contain 2 to 6 carbon atoms (i.e., 2, 3, 4, 5, or 6 carbon atoms). Non-limiting examples of vinyl and acetylene sources include ethylene, acetylene, vinyl acetate, vinyl ether, and trimethylsilylacetylene.

[0035] In some embodiments, the vinyl source is ethylene, which is 1-nitro(C) 1~4 )- Reacts with an alkane to produce the corresponding ring addition product (e.g., 3-(C 0~3 It is used directly in the processes described herein that produce 1-nitro-(C)-alkyl-2-isoxazoline products. In some embodiments, a vinyl compound or acetylene compound such as vinyl acetate, vinyl ether, acetylene, or trimethylsilylacetylene is used. 1~4 )- Reacts with an alkane to produce the corresponding ring addition product (e.g., 3-(C 0~3 )-alkyl-2-isoxazoline product or 3-(C 0~3Used in processes described herein to produce )-alkylisoxazole products. In some embodiments, the alkyl is a C1 alkyl, and the ring addition product has the following structure: The compound has TIFF2026510091000001.tif18128, where alkyl is C 1~3 It is an alkyl group, and R is H or a substituent. In some embodiments, R is -OC(O)Me, -O-(C 1~3 )-alkyl, H, OH or trimethylsilyl. Therefore, 3-(C) as described herein 0~3 )-alkyl-2-isoxazoline or 3-(C 0~3 )-alkylisoxazole may have a substitution at the 5-position 3-(C 0~3 )-alkyl-2-isoxazoline (for example, substituted with an R group) or 3-(C) which may be substituted at the 5-position. 0~3 It should be recognized as containing )-alkylisoxazole (for example, which may be substituted with an R group).

[0036] In some embodiments, the ring addition product (e.g., 3-(C) 0~3 )-alkyl-2-isoxazoline product or 3-(C 0~3 )-alkylisoxazole product) is 3-amino-(C 3~6 It can be subjected to further processes that provide )-alkane-1-ol (for example, processes described herein).

[0037] In some embodiments, 1-nitro-(C 1~4 )-Alkanes are nitromethane, nitroethane, 1-nitropropane, or 1-nitrobutane. In some embodiments, 1-nitro-(C 1~4 The )-alkane is a nitroethane, and for example, the product is selected from 3-methyl-2-isoxazoline or 3-methyl-2-isoxazole, which may be substituted at the 5-position. In some embodiments, the product is 3-(C 0~3)-alkyl-2-isoxazoline, for example, 3-methyl-2-isoxazoline. In some embodiments, the product is 3-(C 0~3 )-alkyl-2-isoxazolines, for example, 3-ethyl-2-isoxazoline.

[0038] In some embodiments, the base is an organic base. For example, the organic base used in the processes described herein may be trimethylamine or triethylamine. In some embodiments, the base (e.g., an organic base) and 1-nitro-(C 1~4 )-Alkanes (e.g., nitroethane) have a molar ratio (base: 1-nitro-(C 1~4 )-alkanes exist in a range of approximately 0.1:100 to approximately 20:100, for example, approximately any of the following ratios, or between and including such 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. Therefore, bases and 1-nitro(C) are present in a range of approximately 0.1:100 to approximately 20:100. 1~4 Alkanes may be present in molar ratios ranging from approximately 0.5:100 or approximately 1:100 to approximately 15:100, or from approximately 1:100 to approximately 6:100.

[0039] In some embodiments, the dehydrating agent used in the processes described herein may be an isocyanate such as phenyl isocyanate or toluene diisocyanate. In some embodiments, the dehydrating agent used in the processes described herein may be an anhydride such as acetic anhydride or phthalic anhydride. In some embodiments, the dehydrating agent used in the processes described herein may be a chloride such as phosphorus oxychloride, ethyl chloroformate, or thionyl chloride. In some embodiments, the dehydrating agent (e.g., an isocyanate such as phenyl isocyanate or toluene diisocyanate, or an anhydride such as acetic anhydride or phthalic anhydride (e.g., hexahydrophthalic anhydride)) and 1-nitro-(C 1~4 )-Alkanes (e.g., nitroethane) are used in molar ratios ranging from approximately 1:1 to approximately 5:1 (dehydrating agent: 1-nitro-(C 1~4 It exists as an alkane. Therefore, typical ratios include approximately one of the following ratios: 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, and 5:1, or a range that includes any two of the above ratios. For example, a dehydrating agent and 1-nitro-(C 1~4 The molar ratio of )-alkanes may therefore be from about 1:1 to about 2:1.

[0040] In some embodiments, the process involves contacting (for example, 1-nitro-(C) 1~4 The step of contacting the 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 may be benzene, toluene, xylene, or any combination of two or more of these.

[0041] In some embodiments, the contacting step described herein (for example, 1-nitro-(C 1~4The process of contacting an alkane with a vinyl source or an acetylene source is carried out at a pressure of approximately 1 to approximately 500 psi, for example, approximately any of the following: approximately 1, 5, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500 psi, or between any two of the above values ​​and including them. Thus, in some embodiments, the pressure is approximately 100 to approximately 350 psi, or approximately 200 to approximately 250 psi.

[0042] In some embodiments, the contacting step described herein (for example, 1-nitro-(C 1~4 The step of contacting the alkane with a vinyl source or an acetylene source is carried out at a high temperature. For example, the contact step may be carried out at approximately 40 to approximately 70°C. Typical temperatures include any of the following: approximately 40°C, 45°C, 50°C, 55°C, 50°C, 65°C, 70°C, or any two of the above values, and including these ranges. Thus, in some embodiments, the temperature range may be approximately 55 to approximately 65°C, or approximately 50 to approximately 60°C.

[0043] As described above, the process is 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) can be provided. In some embodiments, the process may result in the obtained 5-position being substituted 3-(C 0~3 )-alkyl-2-isoxazoline or 3-(C) which may have a substituted position at the 5th position. 0~3 The process further comprises isolating and / or purifying )-alkyl-2-isoxazole from the reaction mixture. For example, the process may include one or more of the following steps: filtering the reaction mixture, washing the resulting filter cake (e.g., washing with a poor solvent such as hexane), and distilling the filtrate.

[0044] In some embodiments, the process described herein may have the 5th position replaced by 3-(C 0~3)-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) or 3-(C) which may be substituted at the 5-position. 0~3 Provide )-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%.

[0045] 3-amino-(C) may have a substitution at position 1. 3~6 Formation of )-alkane-1-ol In some embodiments, the process described herein is 3-(C 0~3 )-alkylisoxazole or 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) is 3-amino-(C 3~6 The present disclosure further includes a step of converting to 3-amino-(C)-alkane-1-ol (e.g., 3-amino-1-butanol). 3~6 The process for preparing )-alkane-1-ols (e.g., 3-amino-1-butanol) is also provided.

[0046] In some embodiments, 3-(C 0~3 )-Alkylisoxazole has the following structure: It is a compound having TIFF2026510091000002.tif15128. In some embodiments, 3-(C 0~3 )-Alkyl-2-isoxazoline has the following structure: It is a compound having TIFF2026510091000003.tif14128. Therefore, 3-(C) described herein 0~3 )-Alkylisoxazolidines have structures such as the following: 3-(C) which has TIFF2026510091000004.tif15128, where the 5th position may be replaced. 0~3 )-alkylisoxazolidine (including its enantiomers), comprising 3-amino-(C) as described herein. 3~6 Alkane-1-ol has the following structure: Should be recognized as including 3-amino-(C 3~6 ), where the 1-position may be substituted, of an alkane-1-ol (including its enantiomers). In the above embodiment, the alkyl is C 1~3 an alkyl group, for example, a methyl group. In some embodiments, R is -OC(O)Me, -O-(C 1~3 ), an alkyl, H, OH, or trimethylsilyl.

[0047] In some embodiments, the process described herein is carried out in the presence of a reducing agent (e.g., borane, metal hydride, silane, hydrogen and a hydrogenation catalyst) to convert 3-(C 0~3 )-alkylisoxazole to the corresponding 3-(C 0~3 )-alkyl-2-isoxazoline. In some embodiments, 3-(C 0~3 )-alkylisoxazole is directly converted to the corresponding 3-amino-(C[[ID=1十七]] 3~6 )-alkane-1-ol.

[0048] Similarly, 3-(C 0~3 )-alkyl-2-isoxazoline from the first step or from 3-(C 0~3 )-alkylisoxazole may be reduced to the corresponding 3-amino-(C 3~6 )-alkane-1-ol using any suitable reducing agent including those disclosed herein. In particular, catalytic hydrogenation may be used to reduce 3-(C 0~3 )-alkyl-2-isoxazoline.

[0049] In some embodiments, 3-(C 0~3 )-alkyl-2-isoxazoline is directly converted to the corresponding 3-amino-(C 3~6 )-alkane-1-ol. In some embodiments, 3-(C 0~3 )-alkyl-2-isoxazoline is converted to the corresponding 3-amino-(C 0~3 )-alkane-1-ol via a 3-(C 3~6)-Alkan-1-ol is converted.

[0050] In some embodiments, the process described herein provides 3-amino-(C 3~6 )-alkan-1-ol (e.g., 3-amino-1-butanol) by contacting 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) with hydrogen and a hydrogenation catalyst (e.g., in a reactor). In some embodiments, the process described herein provides 3-(C 0~3 )-alkylisoxazolidine by contacting 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) with hydrogen and a hydrogenation catalyst (e.g., in a reactor), and then converting this in the presence of a reducing agent to 3-amino-(C 3~6 )-alkan-1-ol (e.g., 3-amino-1-butanol).

[0051] In some embodiments, 3-(C 0~3 )-alkyl-2-isoxazoline is 3-methyl-2-isoxazoline. In some embodiments, 3-amino-(C 3~6 )-alkan-1-ol is 3-amino-1-butanol.

[0052] In some embodiments, the contacting step described herein (e.g., the step of 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 step may be carried out in the presence of an alcohol such as MeOH. In some embodiments, the contacting step (e.g., 3-(C 0~3The step of contacting the )-alkyl-2-isoxazoline with hydrogen is carried out at a high temperature. For example, the contact step may be carried out at a temperature of about 20-100°C, about 50-80°C, or about 60-70°C for a certain period of time (e.g., about 1-48 hours). In some embodiments, hydrogen is present at a pressure of about 10-2500 psi, 50-900 psi, about 500-900 psi, or about 600-800 psi.

[0053] In some embodiments, the hydrogenation catalyst used in the processes described herein is not an optically active catalyst, but rather the corresponding 3-amino-(C 3~6 )-alkane-1-ol product is racemic 3-amino-(C 3~6 )-alkane-1-ol (e.g., racemic 3-amino-1-butanol). For example, the hydrogenation catalyst may be Raney nickel or palladium catalyst. In some embodiments, the hydrogenation catalyst (e.g., Raney nickel) and 3-(C 0~3 )-alkyl-2-isoxazolines (e.g., 3-methyl-2-isoxazoline) in molar ratios ranging from approximately 1:100 to approximately 20:100, or from approximately 15:100 to approximately 20:100 (hydrogenation catalyst: 3-(C 0~3 It exists as ()-alkyl-2-isoxazoline).

[0054] In some embodiments, the hydrogenation catalyst used in the processes 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 The )-alkane-1-ol product is enriched with one enantiomer (e.g., (R)-enantiomer enriched). In some embodiments, the hydrogenation product enriched with (R)-enantiomer (e.g., 3-(C) 0~3 )-alkylisoxazolidine or 3-amino-(C 3~6)-alkane-1-ol) has an enantiomer ratio ((R)-enantiomer:(S)-enantiomer) 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 formula ML n A metal catalyst having the following characteristics: In some embodiments, M is iridium, rhodium, ruthenium, nickel, or other transition metals, or contains them. 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, a hydrogenation catalyst (e.g., ML) is present. n ) and 3-(C 0~3 )-alkyl-2-isoxazoline (e.g., 3-methyl-2-isoxazoline) is used in molar ratios ranging from approximately 1:100 to approximately 20:100, or from approximately 15:100 to approximately 20:100 (e.g., approximately 1:, 2:, 3:, 4:, 5:, 6:, 7:, 8:, 9:, 10:, 11:, 12:, 13:, 14:, 15:, 16:, 17:, 18:, 19:, or 20:100, or any two of the above values, and including them) (hydrogenation catalyst: 3-(C 2~6 It exists as ()-alkyl-2-isoxazoline).

[0055] In some embodiments, the enantiomer-enriched hydrogenation product is 3-(C 0~3 )-alkylisoxazolidine, which has an enantiomer ratio of ((R)-3-(C 0~3 )-Alkylisoxazolidine:(S)-3-(C 0~3 The ratio of ()-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 enantiomer-enriched hydrogenation product is 3-amino-(C 3~6 )-alkane-1-ol, and this is the enantiomer ratio ((R)-3-amino-(C 3~6 )-Alkane-1-ol:(S)-3-amino-(C 3~6The ratio of ()-alkane-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. Optical purity may be further improved by chiral chromatography and / or diastereomer salt recrystallization.

[0056] In some embodiments, 3-(C 0~3 )-alkyl-2-isoxazolines are enantiomer-enriched (e.g., (R)-enantiomer-enriched) 3-amino-(C) in the presence of an optically active reducing agent (e.g., borane, metal hydride, silane, hydrogen) containing an optically active boron-containing reagent. 3~6 It is converted to )-alkane-1-ol. For example, WO2020094528A1 discloses a method for reducing carbon-nitrogen double bonds in substituted oximes. Optically active boron-containing reduction catalysts such as oxazaborolidine can be used to reduce oxime ethers to optically active amines. In some embodiments, the optically active boron-containing reagent is 3-(C 2~6 It is present in amounts of approximately 0-0.5, 0.5-1, 1-3, or 3-5 equivalents (e.g., molar equivalents) relative to )-alkyl-2-isoxazoline.

[0057] As described above, the process is 3-amino-(C 3~6 )-alkane-1-ol (e.g., 3-amino-1-butanol) can be obtained. In some embodiments, the process yields 3-amino-(C 3~6 The process further comprises isolating and / or purifying the )-alkane-1-ol from the reaction mixture. For example, the process may include one or more of the following steps: filtering the reaction mixture, washing the resulting filter case (e.g., washing with a poor solvent), and distilling the filtrate.

[0058] In some embodiments, the process involves the formation of (R)- and (S)-enantiomers, for example, 3-amino-(C) 3~6 (R)- and (S)-enantiomers of )-alkane-1-ol, or 3-(C0~3 The process further includes separating the (R)- and (S)-enantiomers of the )-alkylisoxazolidine (for example, the (R)- and (S)-enantiomers prepared by the processes described herein). Typical separation methods are described herein. For example, 3-amino-(C 3~6 (R)-3-amino-(C)-alkane-1-ol is obtained by chiral chromatography and / or diastereomer salt recrystallization. 3~6 )-alkane-1-ol and (S)-3-amino-(C 3~6 )-alkane-1-ol may be separated. In some embodiments, 3-amino-(C 3~6 )-Alkane-1-ol is 3-amino-(C 3~6 The (R)- and (S)-enantiomers are separated using diastereomer salt recrystallization, which includes a step of neutralizing )-alkane-1-ol with a chiral acid and a step of separating the resulting diastereoisomers by crystallization. Optically enriched 3-amino-(C 3~6 Alkane-1-ols can be isolated after treating the salt with a base. The crystallization process may be repeated several times to achieve the desired optical purity. A typical chiral separation method is provided in U.S. Patent No. 9115052B2.

[0059] In some embodiments, the process described herein is 3-amino-(C 3~6 Provides )-alkane-1-ol (e.g., 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%.

[0060] Any or both steps of the processes disclosed herein may be carried out in batch, semi-batch, or continuous manner using apparatus and techniques known in the art.

[0061] The examples provided herein are provided to illustrate the advantages of the Art and to further assist those skilled in the art in preparing or using the Art. The examples provided herein are also presented to provide a more detailed explanation of specific aspects of the Art. The examples should not be construed as limiting the scope of the Art as defined by the appended claims. The examples may include or incorporate any of the various variations, aspects, or aspects of the Art described above. Furthermore, each of the various variations, aspects, or aspects described above may further include or incorporate any other variations, aspects, or variations of the Art. [Examples]

[0062] General method Example 1 - Synthesis of 3-methyl-2-isoxazoline using phenyl isocyanate Phenyl isocyanate (119.2 g, 1.0 mol), triethylamine (2.02 g, 0.02 mol), and benzene (190 g) were added to a 1 L Parr reactor. The reactor was purged several times with nitrogen, and then pressurized to 220 psi with ethylene while mixing. The mixture was heated to 50°C. Nitroethane (47.5 g, 0.626 mol) was added to the reactor at a rate of 2.25 mL / min. The temperature of the reaction mixture rose to 58°C during the addition. After the addition was complete, the mixture was stirred at 55-60°C for 1 hour. The mixture was cooled to room temperature and degassed. The reaction mixture was filtered, and the filter cake was washed. The filtrate was distilled to obtain 30 g of 3-methyl-2-isoxazoline (yield 70%) (purity 99.1% by GC-FID). NMR data confirmed the assigned structure. TIFF2026510091000006.tif12134

[0063] Example 2 - Synthesis of 3-methyl-2-isoxazoline using toluene diisocyanate Benzene (100 g), toluene diisocyanate (17.42 g, 0.10 mol), and triethylamine (0.4 g, 0.004 mol) were added to a 500 mL three-necked round-bottom flask. The mixture was stirred, and ethylene was bubbled through the mixture at room temperature for 10 minutes. While maintaining the ethylene flow, nitroethane (7.507 g, 0.10 mol) was added dropwise to the mixture over 1 hour. After the addition of nitroethane was complete, ethylene bubbling was continued for 3 hours. The mixture was stirred at ambient temperature for 18 hours. GC-FID analysis showed a conversion rate of 58% from nitroethane to 3-methyl-2-isoxazoline.

[0064] Example 3. Synthesis of 3-methyl-2-isoxazoline using hexahydrophthalic anhydride 77.08 g, 0.5 mol hexahydrophthalic anhydride, 100 g benzene, and 37.54 g, 0.5 mol nitroethane were added to a 1 L Pearl reactor. The reactor was then sealed and mixing was started. The reactor was purged four times with nitrogen at 30 psi. The reactor was pressurized with ethylene to 270 psi. The reaction mixture was heated to 65°C. A solution of triethylamine (51.6 g, 0.51 mol) containing 4-dimethylaminopyridine (1.0 g, 0.082 mol) was supplied to the reactor at 3 mL / min. After heating at 65°C for 16 hours, GC-FID analysis showed a conversion rate of 17%. The reaction mixture was further heated to 80°C for 4 hours. 3-methyl-2-isoxazoline was collected by distillation of the reaction mixture, and the isolated amount was 12 g (yield 30%).

[0065] Example 4. Synthesis of 3-amino-1-butanol from 3-methyl-2-isoxazoline 100 g of methanol and 5 g of Raney® nickel were added to a 1 L Pearl reactor. The reactor was purged three times with nitrogen and then with hydrogen. The reaction mixture was heated to 65°C and pressurized with hydrogen to 700 psi. A solution of 3-methyl-2-isoxazoline (30 g, 0.35 mol) in 30 mL of methanol was supplied to the reactor at a rate of 3 mL / min. After the addition was complete, the reaction mixture was held at 65°C for 30 minutes. The mixture was cooled to room temperature, evacuated to atmospheric pressure, and the catalyst was removed by filtration. The filtrate was distilled to obtain 18.9 g of 3-amino-1-butanol (60% yield). NMR data confirmed the assigned structure. TIFF2026510091000007.tif19158

[0066] Equivalents While specific aspects have been shown and described, those skilled in the art, after reading the above specification, can make modifications, substitutions of equivalents, and other kinds of alterations to the compositions of the Art described herein. Each aspect and aspect described above may include or incorporate any or all of such variations or aspects disclosed in relation to other aspects and aspects.

[0067] This technology is also not limited to any particular aspect described herein, which is intended merely as an example of the individual aspects of this technology. As will be apparent to those skilled in the art, many modifications and variations of this technology can be made without departing from its spirit and scope. In addition to those listed herein, functionally equivalent methods within the scope of this technology will be apparent to those skilled in the art from the above description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that this technology is not limited to any particular method, reagent, compound, or composition, which may, of course, vary. It should also be understood that the terms used herein are intended solely to describe and not to limit any particular aspect. Thus, this specification is considered merely illustrative, and the degree, scope, and spirit of this technology are intended to be indicated only by the appended claims, their definitions, and any equivalents thereof.

[0068] Embodiments described exemplary herein may be preferably carried out in the absence of any element or group of elements, limitations or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be read broadly and non-restrictively. In addition, the terms and expressions used herein are descriptive, not restrictive, and the use of such terms and expressions is not intended to exclude any equivalents of the indicated and described features or parts thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Therefore, the use of terms such as “comprising,” “including,” and “containing” should be understood as disclosing embodiments of the terms “essentially consisting of” and “consisting of.” The expression “essentially consisting of” should be understood to include the specifically described elements, as well as additional elements that do not substantially affect the basic and novel features of the claimed technology. The expression “consisting of” excludes any elements not specifically identified.

[0069] In addition, where any feature or aspect of this disclosure is described by the Markush Group, a person skilled in the art will recognize that the disclosure also describes any individual member or subgroup of a member of the Markush Group. Each of the narrower groups of species and subgenera included in the genus disclosure also forms part of this art. This includes the description of a genus in this art with a proviso or negative limitation that excludes any subject matter from a genus, regardless of whether the excluded items are specifically described herein.

[0070] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced herein are 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 whole. Definitions contained in the texts incorporated by reference are excluded where they conflict with the definitions in this disclosure.

[0071] Other embodiments are described in the appended claims, along with the entire scope of equivalents to which such claims are entitled.

Claims

1. 3-(C) may be substituted in the 5th position. 0～3 )-alkyl-2-isoxazoline or 3-(C) which may have a substituted position at the 5th position. 0～3 To provide a product selected from )-alkyl-2-isoxazole, 1-nitro-(C) in the presence of a base and a dehydrating agent 1～4 A method comprising the step of contacting an alkane with a vinyl source or an acetylene source.

2. The aforementioned 1-nitro-(C 1～4 The method according to claim 1, wherein the )-alkane is nitroethane, and the product is selected from 3-methyl-2-isoxazoline which may be substituted at the 5-position, or 3-methyl-2-isoxazole which may be substituted at the 5-position.

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

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

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

6. The base and the 1-nitro-(C) 1～4 The method according to any one of the claims, wherein the molar ratio of the alkanes is in the range of about 0.1:100 to about 20:100, about 1:100 to about 15:100, or about 1:100 to about 6:

100.

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

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

9. The dehydrating agent and the 1-nitro-(C 1～4 The method according to any one of the claims, wherein the molar ratio of the alkanes is in the range of about 1:1 to about 5:1 or about 1:1 to about 2:

1.

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

11. The method according to any one of the claims, wherein the contact step 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 of these.

13. The method according to any one of the claims, wherein the contact step is performed at a high temperature.

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

15. The obtained 5th position may be substituted in 3-(C 0～3 )-alkyl-2-isoxazoline or 3-(C) which may have a substituted position at the 5th position. 0～3 The method according to any one of the claims, further comprising the step of isolating and purifying )-alkyl-2-isoxazole.

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

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

18. The method according to claim 16 or claim 17, wherein the reducing agent is optically active.

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

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

21. The aforementioned contact step involves a 3-amino-(C) which may be substituted at position 1. 3～6 The method according to any one of claims 16 to 20, which directly provides )-alkane-1-ol.

22. The aforementioned contact step may involve substitution of position 5. 3-(C 0～3 A method according to any one of claims 16 to 20, which provides an alkylisoxazolidine.

23. The aforementioned substituted 3-(C 0～3 )-alkylisoxazolidine may be substituted at position 1, 3-amino-(C 3～6 The method according to claim 22, further comprising the step of converting to )-alkane-1-ol in the presence of a reducing agent.

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

100.

25. The method according to any one of claims 16 to 24, wherein the contact step 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 to 27, wherein the hydrogen is present at a pressure of about 10 to 2500 psi, about 50 to 900 psi, about 500 to 900 psi, or about 600 to 800 psi.

29. The method according to any one of claims 16 to 28, wherein the contact step is performed at a high temperature.

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

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

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

33. The aforementioned 3-amino-(C 3～6 )-Alkane-1-ol is enriched with (R)-enantiomers, and (R)-3-amino-(C 2～6 )-Alkane-1-ol:(S)-3-amino-(C 3～6 The method according to any one of claims 16 to 30, wherein the enantiomer ratio of )-alkane-1-ol is greater than 1:

1.

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

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

36. The obtained may be substituted 3-amino-(C 3～6 )-alkane-1-ol or possibly substituted with 3-(C 0～3 The method according to any one of claims 16 to 35, further comprising the step of isolating and purifying an alkylisoxazolidine.

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

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

39. (R)-3-(C 0～3 (R)-3-(C 0～3 )-Alkylisoxazolidine:(S)-3-(C 0～3 A composition prepared according to any one of claims 16 to 30 or 33 to 38, wherein the (R) / (S) enantiomer ratio of the )-alkylisoxazolidine is greater than 1.00.

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