Process for the preparation of substituted cycloserines

Abstract

The present invention relates to processes (I) for preparing substituted cycloserine compounds of formula (I) wherein R 1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6cycloalkyl, aryl or aryl substituted by one to five R 11 substituted aryl, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R 11 substituted aryl; and each R 11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen; the invention also relates to intermediates resulting from these processes. Compounds of formula (I) are useful intermediates for the production of compounds in the agricultural and pharmaceutical fields.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201810808594.7 entitled "Method for Preparing Substituted Cyclic Serine", filed on April 30, 2015, with a priority date of April 30, 2014.

[0002] This invention relates to the production of 2-substituted cyclic serine (4-amino-isoxazolidine-3-one) and intermediates useful in the preparation of 2-substituted cyclic serine.

[0003] 2-Substituted cycloserines are useful intermediates in the preparation of certain insecticidal compounds, such as those described in WO 2011 / 067272 and WO 2012 / 163959. Some cycloserines are also used as broad-spectrum antibiotics.

[0004] In WO 2011 / 067272, 2-substituted cyclic serines were prepared according to the method described in Chem. Pharm. Bull. 2002, 50(4)554-557, which involves alkylating the parental cyclic serine or a cyclic serine derivative, such as tert-butoxycarbonyl. A similar procedure is described in Tet. Lett. 2012, 2564-2567.

[0005] The main drawbacks of known methods for alkylating cycloserine include the formation of isomer byproducts resulting from O-alkylation rather than the desired N-alkylation, and the potential epimerization of the cycloserine steric center, especially under strongly basic conditions. Limitations are also imposed by the low reactivity and accessibility of the corresponding alkylating agents.

[0006] The insecticides described in WO 2011 / 067272 and WO 2012 / 163959 have been found to be more effective when the cyclic serine group is present in molecules with a D stereoconfiguration, making it particularly desirable to find ways to derive cyclic serine with reduced epimerization.

[0007] Although the regioselective derivatization of cycloserine has been described in Tetrahedral Communications (Tet. Lett.) 2012, 2564-2567, it requires specialized equipment and is not suitable for commercial-scale production.

[0008] It has now been unexpectedly discovered that methods for deriving cyclic serine allow for the preparation of 2-substituted cyclic serines without requiring cyclic serine starting materials. These methods also offer additional advantages by avoiding the need for protecting groups and allowing the preparation of 2-substituted cyclic serines with defined stereoconfigurations.

[0009] In one aspect, the present invention provides a method for preparing a compound having chemical formula (I).

[0010] (I)

[0011] in

[0012] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0013] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0014] include

[0015] a. To cause a compound having chemical formula (II) or a salt thereof to...

[0016] (II)

[0017] Where R 1 This is as defined for compounds having chemical formula (I).

[0018] Reaction with a compound having chemical formula (III)

[0019] (III)

[0020] Where R 2 It is a leaving group, such as halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester; and

[0021] Each R 11 As defined for compounds having chemical formula (I), the reaction is carried out in the presence of a base.

[0022] Examples of suitable and preferred bases for step a are given below.

[0023] In one aspect, the present invention provides a method for preparing a compound having chemical formula (I).

[0024] (I)

[0025] in

[0026] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0027] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0028] include

[0029] a-1. To react a compound having chemical formula (II) with a compound having chemical formula (III) to produce a compound having chemical formula (IV) or a salt thereof.

[0030] (IV)

[0031] Where R 1 and R 2 As defined for compounds having chemical formula (I) and chemical formula (III), the reaction proceeds in the presence of a suitable acid; and

[0032] a-2. To convert a compound having chemical formula (IV) into a compound having chemical formula (I) in the presence of a suitable base.

[0033] Examples of suitable acids and preferred acids for step a-1 are given below. Examples of suitable bases and preferred bases for step a-2 are given below.

[0034] In another aspect, the present invention provides a method for preparing a compound having chemical formula (IV), the method comprising performing step a-1 as defined above. In another aspect, the present invention provides a method for preparing a compound having chemical formula (I).

[0035] (I)

[0036] in

[0037] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0038] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0039] The method includes step a-2

[0040] a-2. Transformation of compounds with chemical formula (IV)

[0041] (IV)

[0042] in

[0043] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0044] R 2 It is a C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R... 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester; and

[0045] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0046] For compounds having chemical formula (I), the transformation is carried out in the presence of a suitable base.

[0047] In another aspect, the present invention provides a method for preparing a compound having chemical formula (I), the method comprising performing steps a-2 as defined above. In another aspect, the present invention provides a method for preparing a compound having chemical formula (IV).

[0048] (IV)

[0049] Where R 1 and R 2 This is as defined for compounds having chemical formulas (I) and (III).

[0050] The method includes, according to step a-1, reacting a compound having chemical formula (II) with a compound having chemical formula (III) to produce a compound having chemical formula (IV).

[0051] In one aspect, the present invention relates to a method for preparing a compound having chemical formula (I).

[0052] (I)

[0053] in

[0054] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0055] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0056] include

[0057] To make a compound having chemical formula (II) or a salt thereof...

[0058] (II)

[0059] Where R 1 This is as defined for compounds having the chemical formula (I);

[0060] Reaction with a compound having chemical formula (III)

[0061] (III)

[0062] The reaction proceeds in the presence of a base.

[0063] in

[0064] R 2 It is a leaving group, selected from halogens, C1-C8 alkylsulfonyloxy groups, C1-C8 haloalkylsulfonyloxy groups, C1-C8 arylsulfonyloxy groups, or groups surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester; and each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0065] In one aspect, the present invention relates to a method for preparing a compound having chemical formula (I).

[0066] (I)

[0067] in

[0068] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0069] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0070] include

[0071] a-1. To cause compounds having chemical formula (II) to...

[0072] (II)

[0073] Reaction with compounds having chemical formula (III)

[0074] (III)

[0075] The reaction is carried out in the presence of a suitable acid.

[0076] in

[0077] R 2 It is a leaving group, selected from halogens, C1-C8 alkylsulfonyloxy groups, C1-C8 haloalkylsulfonyloxy groups, C1-C8 arylsulfonyloxy groups, or groups surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester; and each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0078] To produce compounds having the chemical formula (IV) or their salts.

[0079] (IV)

[0080] Where R 1 and R 2 This is as defined for compounds having chemical formulas (I) and (III).

[0081] as well as

[0082] a-2. To convert a compound having chemical formula (IV) into a compound having chemical formula (I) in the presence of a suitable base.

[0083] In one aspect, the present invention relates to a method for preparing a compound having the chemical formula (IV).

[0084] (IV)

[0085] include

[0086] a-1. To cause compounds having chemical formula (II) to...

[0087] (II)

[0088] Reaction with compounds having chemical formula (III)

[0089] (III)

[0090] The reaction is carried out in the presence of a suitable acid.

[0091] in

[0092] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0093] R 2 It is a leaving group, selected from halogens, C1-C8 alkylsulfonyloxy groups, C1-C8 haloalkylsulfonyloxy groups, C1-C8 arylsulfonyloxy groups, or groups surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy groups, or phosphate esters;

[0094] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0095] In one aspect, the present invention relates to a method for preparing a compound having chemical formula (I).

[0096] (I)

[0097] The method includes step a-2

[0098] a-2. Transformation of compounds with chemical formula (IV)

[0099] (IV)

[0100] For compounds having chemical formula (I), the transformation is carried out in the presence of a suitable base.

[0101] in

[0102] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0103] R 2 It is a C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R... 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester; and

[0104] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0105] In one aspect, the present invention relates to a compound having the chemical formula (IV).

[0106] (IV)

[0107] in

[0108] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0109] R 2 It is a C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R... 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester; and

[0110] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0111] Or its salts or N-oxides.

[0112] In one aspect, the present invention relates to a method for preparing a compound having chemical formula (I).

[0113] (I)

[0114] include

[0115] i. To make a compound having chemical formula (II) or a salt thereof

[0116] (II)

[0117] Reaction with a compound having the chemical formula (V)

[0118] (V)

[0119] The reaction proceeds in the presence of a suitable base to produce a compound having the chemical formula (VI).

[0120] (VI)

[0121] as well as

[0122] ii. By treating a compound having chemical formula (VI) with an aqueous alkaline solution, a compound having chemical formula (VI) is converted into a compound having chemical formula (I).

[0123] in

[0124] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0125] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0126] R 7 It is a hydroxyl group, a halogen, or OM, where M is Na, K, or Li.

[0127] In one aspect, the present invention relates to a compound having the chemical formula (V).

[0128] (V)

[0129] Where R 7 It is OM, where M is Na, K, or Li.

[0130] A compound having the chemical formula (VI)

[0131] (VI)

[0132] in

[0133] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0134] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0135] Or its salts or N-oxides.

[0136] In one aspect, the present invention relates to a compound having the chemical formula (I).

[0137] (I)

[0138] Where R 1 It is aryl or composed of one to five R groups. 11 Substituted aryl groups;

[0139] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0140] A method for preparing a compound having the chemical formula (V)

[0141] (V)

[0142] Where R 7 It is OM, where M is Na, K, or Li.

[0143] This method includes making compound (XV)

[0144]

[0145] Where R 12 It is a C1-C4 alkyl group

[0146] It reacts with alkali metal salts MOH, where M is Na, K, or Li.

[0147] In one aspect, the present invention relates to a method for preparing a compound having the chemical formula (V).

[0148] (V)

[0149] Where R 7 It is OM, where M is Na, K, or Li.

[0150] This method includes making compound (XVI)

[0151]

[0152] R 13 It is a C1-C4 alkyl, benzyl, or phenyl group.

[0153] It reacts with alkali metal salts MOH, where M is Na, K, or Li.

[0154] In the above method, compounds having chemical formulas (I), (III), and (IV) are preferably those having chemical formula (I). (III) ) and (IV ) compounds or enriched mixtures thereof

[0155]

[0156] Where R 1 It is as defined for compounds having chemical formula (I), and R 2 It is a leaving group, or its salt or N-oxide.

[0157] In another aspect, the present invention provides a compound having chemical formula (IV).

[0158] (IV)

[0159] Where R 1 It is as defined for compounds having the chemical formula (I), and R 2 It is a leaving group as defined below, or its salt or N-oxide.

[0160] Preferably, the (IV) compound is a compound having the chemical formula (IV) ) compounds.

[0161] In another aspect, the present invention provides a method for preparing a compound having chemical formula (I).

[0162] (I)

[0163] in

[0164] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl, or surrounded by one to five Rs.11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0165] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0166] include

[0167] i. To make a compound having chemical formula (II) or a salt thereof

[0168] (II)

[0169] Where R 1 This is as defined for compounds having chemical formula (I).

[0170] Reaction with a compound having the chemical formula (V)

[0171] (V)

[0172] Where R 7 It is a hydroxyl group, a halogen, or OM, where M is Na, K, or Li.

[0173] The reaction proceeds in the presence of a suitable base to produce a compound having the chemical formula (VI).

[0174] (VI)

[0175] Where R 1 It is as defined for compounds having chemical formula (I); and

[0176] ii. A compound having chemical formula (VI) is converted into a compound having chemical formula (I) by treating it with an aqueous solution of an alkali.

[0177] Examples of suitable bases for steps i and ii and preferred bases for steps i and ii are given below.

[0178] Preferably, R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0179] Each R 11It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0180] Preferably, R 7 It is a hydroxyl group or a halogen.

[0181] Similarly preferred R 1 It is a C3-C6 cycloalkyl group; and R 7 It is OM, where M is Na, K, and L.

[0182] In another aspect, the present invention provides a method for preparing a compound having chemical formula (VI) as defined above, the method comprising performing step i as defined above. In another aspect, the present invention provides a method for preparing a compound having chemical formula (I) as defined above, the method comprising performing step ii as defined above.

[0183] In the above method, compounds having chemical formulas (I), (III), and (IV) are preferably those having chemical formula (I). (III) ) and (IV Compounds or enriched mixtures thereof:

[0184]

[0185] Where R 1 It is as defined for compounds having chemical formula (I), and R 7 It is as defined for compounds having the chemical formula (V).

[0186] In another aspect, the present invention provides a compound having chemical formula (VI).

[0187] (VI)

[0188] Where R 1 It is as defined for a compound having chemical formula (I), or a salt or N-oxide thereof. Preferably, a compound having chemical formula (VI) is a compound having chemical formula (VI). ) compounds.

[0189] In another aspect, the present invention provides a compound having the chemical formula (V).

[0190] (V)

[0191] Where R 7 Is it OLi, ONa, or OK?

[0192] In another aspect, the present invention provides a compound having chemical formula (I).

[0193] (I)

[0194] Where R 1 It is aryl or composed of one to five R groups. 11 Substituted aryl groups.

[0195] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0196] All aspects of the invention may further include further processing of the compound having formula (I). Specifically, the method may include reacting the compound having formula (I) with a second compound, wherein the second compound comprises a carboxylic acid, acyl halide, ester, or thioester functional group, and the reaction includes reacting the amine functional group of the compound having formula (I) with the carboxylic acid, acyl halide, ester, or thioester functional group of the second compound, such that the compound having formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound comprises a dicarbonate group, and the reaction includes reacting the amine functional group having formula (I) with the dicarbonate group of the second compound, such that the compound having formula (I) is coupled to the second compound via a carbamate functional group.

[0197] In one embodiment, the second compound is a compound having the chemical formula (XII).

[0198] (XII)

[0199] in

[0200] X is a leaving group, cyano, formyl, acetyl, C(O)CH=C(R) 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 or group A

[0201] (A)

[0202] -B 1 -B 2 -B 3 - is -C=NO-, -C=N-CH2-, -C=CH-O-, or -N-CH2-CH2-;

[0203] A1 A 2 A 3 And A 4 CH and CR are independent of each other. 5 or nitrogen;

[0204] R 3 It is a C1-C8 haloalkyl;

[0205] R 4 It is aryl or composed of one to three Rs. 6 Substituted aryl, or R 4 It is a heterocyclic group or composed of one to three R groups. 6 Substituted heterocyclic groups;

[0206] Each R 5 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkoxycarbonyl-, or two R on adjacent carbon atoms. 5 Together they form a -CH=CH-CH=CH- bridge or a -N=CH-CH=CH- bridge;

[0207] Each R 6 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy;

[0208] R 8 It is a hydroxyl group, a C1-C6 alkoxy group, or a chlorine, fluorine, bromine, or SR group. x , where R x It is hydrogen, C1-C6 alkyl, imidazole, or pyrrole; and

[0209] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0210] This method produces a compound with the chemical formula (VIII).

[0211] (VIII)

[0212] Where A 1 A 2 A 3 A 4 And X is as defined for compounds having the chemical formula (XII), and R 1It is as defined for compounds having the chemical formula (I).

[0213] In another embodiment, the second compound is a compound having the chemical formula (XIII).

[0214] (XIII)

[0215] Where R 9 It is hydrogen, C1-C8 alkyl, or C1-C8 haloalkyl, and R 8 This is as defined for compounds having the chemical formula (XII);

[0216] This method produces a compound with the chemical formula (IX).

[0217] (IX)

[0218] Where R 1 It is as defined for compounds having chemical formula (I), and R 9 This is as defined for compounds having the chemical formula (XIII).

[0219] In another embodiment, the second compound is a compound having the chemical formula (XIVa) or (XIVb).

[0220] (XIVa)

[0221] (XIVb)

[0222] Each R 10 It is independently a C1-C8 alkyl, C1-C8 haloalkyl, aryl-C1-C4 alkylene, or surrounded by one to five R... 11 Substituted aryl-C1-C4 alkylene-, wherein each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0223] This method produces a compound with the chemical formula X.

[0224] (X)

[0225] Where R 1 It is as defined for a compound (I) having the chemical formula and R 10 This is as defined for compounds having the chemical formulas (XIVa) and XIVb.

[0226] In another aspect, the present invention provides a method in which a compound having chemical formula (I) reacts with a second compound, wherein the second compound comprises a carboxylic acid, acyl halide, ester, or thioester functional group, and the reaction comprises reacting an amine functional group of the compound having chemical formula (I) with a carboxylic acid, acyl halide, ester, or thioester functional group of the second compound, such that the compound having chemical formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound comprises a dicarbonate group, and the reaction comprises reacting an amine functional group of the compound having chemical formula (I) with a dicarbonate group of the second compound, such that the compound having chemical formula (I) is coupled to the second compound via a carbamate functional group. Particularly in this method, the reaction of the compound having chemical formula (I) with the second compound...

[0227] in

[0228] The second compound is a compound having the chemical formula (XII).

[0229] (XII)

[0230] This method produces a compound with the chemical formula (VIII).

[0231] (VIII)

[0232] in

[0233] X is a leaving group, selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester, cyano, formyl, acetyl, C(O)CH=C(R) 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 or group A

[0234] (A)

[0235] -B 1 -B 2 -B 3 - is -C=NO-, -C=N-CH2-, -C=CH2-O-, or -N-CH2-CH2-;

[0236] A 1 A 2 A 3 And A 4 CH and CR are independent of each other.5 or nitrogen;

[0237] R 3 It is a C1-C8 haloalkyl;

[0238] R 4 It is aryl or composed of one to three Rs. 6 Substituted aryl, or R 4 It is a heterocyclic group or composed of one to three R groups. 6 Substituted heterocyclic groups;

[0239] Each R 5 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkoxycarbonyl-, or two R on adjacent carbon atoms. 5 Together they form a -CH=CH-CH=CH- bridge or a -N=CH-CH=CH- bridge;

[0240] Each R 6 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy;

[0241] R 8 It is hydroxyl, C1-C6 alkoxy, fluorine, chlorine, bromine, or SR x , where R x It is hydrogen, C1-C6 alkyl, imidazole, or pyrrole; and

[0242] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0243] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0244] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0245] or

[0246] The second compound is a compound having the chemical formula (XIII).

[0247] (XIII)

[0248] This method produces a compound with the chemical formula (IX).

[0249] (IX)

[0250] in

[0251] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0252] R 9 It is hydrogen, C1-C8 alkyl, or C1-C8 haloalkyl and R 8 This is as defined for compounds having the chemical formula (XII);

[0253] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0254] or

[0255] The second compound is a compound having the chemical formula (XIVa) or (XIVb).

[0256] (XIVa)

[0257] (XIVb)

[0258] This method produces a compound with the chemical formula X.

[0259] (X)

[0260] in

[0261] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0262] Each R 10 It is independently a C1-C8 alkyl, C1-C8 haloalkyl, aryl-C1-C4 alkylene, or surrounded by one to five R...11 Substituted aryl-C1-C4 alkylene groups;

[0263] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0264] In another aspect, the present invention provides a method for preparing a compound having the chemical formula (VIII) or a salt or N-oxide thereof.

[0265] (VIII)

[0266] This includes the preparation of a compound having chemical formula (I).

[0267] (I)

[0268] The preparation is carried out by the method according to any one of claims 1, 2, 3, 4, or 6, and involves reacting a compound having chemical formula (I) with a compound having chemical formula (XII).

[0269] (XII)

[0270] in

[0271] X is a leaving group, selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester, cyano, formyl, acetyl, C(O)CH=C(R) 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 or group A

[0272] (A)

[0273] -B 1 -B 2 -B 3 - is -C=NO-, -C=N-CH2-, -C=CH2-O-, or -N-CH2-CH2-;

[0274] A 1 A 2 A 3 And A 4 CH and CR are independent of each other. 5 or nitrogen;

[0275] R3 It is a C1-C8 haloalkyl;

[0276] R 4 It is aryl or composed of one to three Rs. 6 Substituted aryl, or R 4 It is a heterocyclic group or composed of one to three R groups. 6 Substituted heterocyclic groups;

[0277] Each R 5 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkoxycarbonyl-, or two R on adjacent carbon atoms. 5 Together they form a -CH=CH-CH=CH- bridge or a -N=CH-CH=CH- bridge;

[0278] Each R 6 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy;

[0279] R 8 It is hydroxyl, C1-C6 alkoxy, chlorine, fluorine, bromine, or SR. x , where R x It is hydrogen, C1-C6 alkyl, imidazole or pyrrole;

[0280] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups; and

[0281] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0282] The compounds of this invention can exist in various geometric or optical isomers or tautomers. Specifically, the compounds of this invention may contain one or more asymmetric carbon atoms and may exist as enantiomers (or diastereomer pairs) or as mixtures of such isomers. This invention covers all such isomers and tautomers, as well as mixtures thereof in all proportions, together with isotopic forms, such as deuterated compounds. The compounds and the methods of this invention include, where possible, N-oxides and salts.

[0283] Alkyl groups (alone or as part of a larger group, such as alkoxy-, alkathio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl-, or alkoxycarbonyl-) can be in straight-chain or branched form and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-1-yl, or 2-methyl-prop-2-yl. These alkyl groups are preferably C1-C6 alkyl groups, more preferably C1-C4 alkyl groups, and most preferably C1-C3 alkyl groups. When an alkyl moiety is considered to be substituted, the alkyl moiety is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0284] The alkylene group can be in straight-chain or branched form, and is, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-. These alkylene groups are preferably C1-C3 alkylene groups, more preferably C1-C2 alkylene groups, and most preferably C1 alkylene groups. When an alkylene moiety is considered to be substituted, the alkyl moiety is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0285] The alkenyl group can be in straight-chain or branched form, and can (where appropriate) have ( E )-or( Z The configuration is )-. Examples are vinyl and allyl. These alkenyl groups are preferably C2-C6 alkenyl groups, more preferably C2-C4 alkenyl groups, and most preferably C2-C3 alkenyl groups. When an alkyl moiety is considered to be substituted, the alkyl moiety is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0286] The alkynyl group can be in straight-chain or branched form. Examples are ethynyl and propynyl. These alkenyl groups are preferably C2-C6 alkynyl groups, more preferably C2-C4 alkynyl groups, and most preferably C2-C3 alkynyl groups. When an alkynyl moiety is considered to be substituted, the alkyl moiety is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0287] Halogens are fluorine, chlorine, bromine, or iodine.

[0288] A haloalkyl group (alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl-, or haloalkylsulfonyl-) is an alkyl group substituted with one or more identical or different halogen atoms and is, for example, difluoromethyl, trifluoromethyl, dichlorofluoromethyl, or 2,2,2-trifluoroethyl.

[0289] A haloalkenyl group is an alkenyl group substituted with one or more identical or different halogen atoms, and is, for example, 2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.

[0290] A halogenated alkynyl group is an alkynyl group substituted with one or more identical or different halogen atoms, and is, for example, 1-chloro-prop-2-alkynyl.

[0291] The cycloalkyl group or carbocyclic ring can be in mono- or bi-cyclic form and is, for example, cyclopropyl, cyclobutyl, cyclohexyl, and bicyclo[2.2.1]heptane-2-yl. These cycloalkyl groups are preferably C3-C8 cycloalkyl groups, more preferably C3-C6 cycloalkyl groups. When a cycloalkyl moiety is considered to be substituted, the cycloalkyl moiety is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0292] Aryl groups (alone or as part of a larger group, such as aryl-alkylene-) are in the form of aromatic rings, which can be mono-, di-, or tri-cyclic. Examples of such rings include phenyl, naphthyl, anthraceneyl, indenyl, or phenanthrene. Preferred aryl groups are phenyl and naphthyl, with phenyl being the most preferred. When an aryl moiety is considered to be substituted, it is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0293] Heteroaryl groups (alone or as part of a larger group, such as heteroaryl-alkylene-) are aromatic ring systems that include at least one heteroatom and consist of a single ring or two or more fused rings. Preferably, the monocyclic ring will contain up to three heteroatoms and the bicyclic system will contain up to four heteroatoms, which are preferably selected from nitrogen, oxygen, and sulfur. Examples of monocyclic groups include pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl (e.g., 1,2,4-triazolyl), furanyl, phenylthio, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, and thiadiazolyl. Examples of bicyclic groups include purinyl, quinolinyl, cenolinyl, quinoxalolinyl, indolyl, inazolyl, benzimidazolyl, benzobenzenethio, and benzothiazolyl. Monocyclic heteroaryl groups are preferred, with pyridinyl being the most preferred. When the heteroaryl moiety is considered to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, and most preferably by one to three substituents.

[0294] A heteroaryl group or heterocycle (alone or as part of a larger group, such as heterocyclic-alkylene-) is defined as including a heteroaryl group and other unsaturated or partially unsaturated analogues thereof. Examples of monocyclic groups include isoxazolyl, thiohexacyclobutane, pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydrothiophene, [1,3]dioxopentyl, piperidinyl, piperazine, [1,4]dioxacyclohexyl, morpholinyl, thiophene, oxacyclobutyl, tetrahydrofuranyl, 3-oxo-isooxazolyl-, 2,5-dioxo-1-pyrrolyl-, 2-oxo-1-pyrrolyl-, 4-oxo-1,3-oxazinyl, 1-oxa-3,4-diazolyl, including their oxidized forms, such as 1-oxo-thiohexacyclobutane and 1,1-dioxo-thiohexacyclobutane, thiophene 1-oxide, thiophene 1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide, or dihydrothiophene 1,1-dioxide. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[1,4]dioxolane, benzo[1,3]dioxolane, chromium, and 2,3-dihydro-benzo-[1,4]-dioxinyl. Where the heterocyclic moiety is considered to be substituted, it is preferably substituted by one to four substituents, most preferably by one to three substituents. The heterocyclic groups (and heteroaryl groups) according to the invention do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent sulfur and oxygen atoms. Preferred heterocyclic groups are thiophene, thiophene 1-oxide, thiophene 1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide, dihydrothiophene 1,1-dioxide, pyridinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrroleyl, imidazolyl, and triazolyl.

[0295] The leaving group according to the present invention includes halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or with one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy groups, wherein each R 11 Independently, it is a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen (aryl is preferably phenyl), and a phosphate ester (e.g., -OP(O)(OR)2, where R is methyl or ethyl). Preferably, the leaving group is a halogen, specifically chlorine or bromine.

[0296] The preferred definition is any combination, as shown below.

[0297] Preferably A 1 It is CR 5 .

[0298] Preferably A 2 A 3 A 4Each is CH.

[0299] Preferably - B 1 -B 2 -B 3 -is-C=NO-.

[0300] Preferably, R 1 It is a C1-C8 alkyl, a C1-C8 haloalkyl, more preferably ethyl or trifluoroethyl, and even more preferably ethyl or 2,2,2-trifluoroethyl.

[0301] Preferably, R 2 It is chlorine or bromine, more preferably chlorine.

[0302] Preferably, R 3 It is trifluoromethyl, difluoromethyl, or chlorodifluoromethyl, with trifluoromethyl being the most preferred.

[0303] Preferably, R 4 It is a group (B).

[0304] (B)

[0305] Where X 2 It is CX 4 or nitrogen (preferably CX) 4 ); X 1 X 3 and X 4 Each is independently hydrogen, halogen, or trihalomethyl, for example, where X is... 1 X 3 and X 4 At least two of them are not hydrogen.

[0306] Preferably, R 4It is 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-bromophenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3,5-dichloro-4-iodophenyl, 3,4,5-trifluorophenyl, 3-chloro-5-bromophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-bromo-5-( (trifluoromethyl)phenyl, 3,4-dichloro-5-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-chloro-3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl, 2,6-bis(trifluoromethyl)-4-pyridyl, 2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl, more preferably 3,5-dichloro-phenyl, 3- Chloro-5-bromophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl, 2,6-bis(trifluoromethyl)-4-pyridyl, 3,5-dichloro-4-bromophenyl, 3-bromo-5-(trifluoromethyl)phenyl, 3,5-dibromophenyl Or 3,4-dichlorophenyl, 2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl, even more preferably 3,5-dichlorophenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, most preferably 3,5-dichlorophenyl, 3,5-dichloro-4-fluorophenyl, or 3,4,5-trichlorophenyl-. In a group of compounds, R 4 It is 3,5-dichloro-phenyl. In a group of compounds, R... 4 It is 3,5-dichloro-4-fluorophenyl-. In a group of compounds, R 4 It is 3,4,5-trichlorophenyl-. In a group of compounds, R 4 It is 3,5-bis(trifluoromethyl)phenyl.

[0307] Preferably each R 5 It is independently a halogen, cyano, methyl, halomethyl, methoxy or halomethoxy, more preferably chlorine, fluorine, cyano or methyl.

[0308] Preferably each R 6 Independently, it is a halogen, a C1-C8 alkyl, a C1-C8 haloalkyl, a C1-C8 alkoxy, a C1-C8 haloalkoxy, a C1-C8 alkylthio, or a C1-C8 haloalkylthio, more preferably bromine, chlorine, fluorine, trifluoromethyl, methoxy, or methylthio, and most preferably trifluoromethyl, fluorine, or chlorine.

[0309] Preferably, R 7It is hydroxyl, ONa, OLi, OK, chlorine or bromine, more preferably ONa, OLi or chlorine.

[0310] Preferably, R 8 It is hydroxyl, chlorine or bromine, more preferably chlorine.

[0311] Preferably, R 9 It is hydrogen or C1-C6 alkyl, more preferably methyl.

[0312] Preferably each R 10 Independently, it is a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, and most preferably a tert-butyl group.

[0313] In a preferred embodiment, the compounds having chemical formulas (I), (II), (III), and (IV) are compounds, wherein R 1 It is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl), and R 2 It is chlorine or bromine, preferably chlorine.

[0314] In another preferred embodiment, the compound having chemical formula (IV) is a compound wherein R 1 It is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R 2 It is chlorine or bromine, preferably chlorine.

[0315] In another preferred embodiment, the compounds having chemical formulas (I), (II), (III), and (IV) are compounds, wherein R 1 It is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R 7 It is hydroxyl, ONa, OLi or chlorine.

[0316] In another preferred embodiment, the compound having chemical formulas (I), (II), and (VI) is a compound, wherein R 1 It is ethyl, trifluoroethyl, or phenyl.

[0317] In another preferred embodiment, the compound having chemical formula (VI) is a compound, wherein R 1 It is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl).

[0318] In another preferred embodiment, the compound having chemical formulas (VIII) and (XII) is a compound, wherein

[0319] A 1 It is CR 5 ;

[0320] A 2 A3 A 4 Each is CH;

[0321] R 3 It is trifluoromethyl, difluoromethyl, or dichlorofluoromethyl;

[0322] X represents chlorine, bromine, cyano, formyl, acetyl, or C(O)CH=C(R). 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 Or a group (A) as defined above;

[0323] R 4 It is a group (B) as defined above;

[0324] X 2 It is CX 4 or nitrogen (preferably CX) 4 ); X 1 X 3 and X 4 Each is independently a halogen or a trihalomethyl;

[0325] Each R 5 It is independently a halogen, cyano, methyl, halomethyl, methoxy, or halomethoxy, more preferably chlorine, fluorine, cyano, or methyl.

[0326] In another preferred embodiment, the compound having chemical formulas (VIII) and (XII) is a compound, wherein

[0327] X is an acetyl group, C(O)CH=C(R) 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 or group (A);

[0328] A 1 It is CR 5 ;

[0329] A 2 A 3 A 4 Each is CH;

[0330] X is a group (A)

[0331] (A)

[0332] -B 1 -B 2 -B 3- is -C=NO-, -C=N-CH2-, -C=CH-O- or -N-CH2-CH2-, preferably -C=NO-;

[0333] R 1 It is a C1-C8 alkyl, C1-C8 haloalkyl, aryl, or surrounded by one to five Rs. 11 Substituted aryl, or aryl-C1-C4 alkylene, or with one to five R 11 Substituted aryl-C1-C4 alkylene groups;

[0334] R 3 It is trifluoromethyl, difluoromethyl, or dichlorofluoromethyl;

[0335] R 4 It is a group (B).

[0336] (B)

[0337] Where X 2 It is CX 4 Or nitrogen, X 1 X 3 and X 4 Each is independently hydrogen, halogen, or trihalomethyl.

[0338] R 5 It is halogen, cyano, methyl, halomethyl, methoxy, or halomethoxy;

[0339] Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

[0340] In a preferred embodiment, the compound having chemical formulas (IX) and (XIII) is a compound, wherein R 9 It is a C1-C6 alkyl group.

[0341] In a preferred embodiment, the compound having chemical formulas (X) and (XIV) is a compound, wherein each R 10 It is a C1-C6 alkyl group, preferably tert-butyl.

[0342] In the enrichment mixture of the present invention, there is a chemical formula (I) (III) (IV) ), (V ), and / or (VI) The molar proportion of the compound in the mixture is, for example, greater than 50%, or at least 60%, 70%, 80%, 90%, or at least 95% of the total molar amount of the enantiomer pair.

[0343] The following scheme describes the reaction of the present invention in more detail. Substituents are defined as they are defined above.

[0344] Option 1

[0345]

[0346] Step a

[0347] A compound having formula (I) can be prepared by reacting a compound having formula (III) with a compound having formula (II) or a salt thereof. Suitable salts of compounds having formula (II) include, but are not limited to, halides, organic acids, and sulfur-based salts such as chlorides, oxalates, sulfates, trifluoroacetates, methanesulfonates, and bromides.

[0348] Reactions of compounds having chemical formulas (III) and II are preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to, nitrogen-based organic bases, such as amines, pyridines and their derivatives, such as triethylamine, tri-n-propylamine, pyridine and diisopropylethylamine.

[0349] Reactions of compounds having chemical formulas III and II are preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to, organic solvents, such as halogenated hydrocarbon organic solvents or ethanol, such as chloroform, dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene, methanol, ethanol, isopropanol, tert-butanol, cyclohexanol, heptanol, octanol, or longer-chain alcohols, and diethylene glycol, preferably chloroform, dichloromethane, isopropanol, and ethanol. This reaction may also be carried out in a mixture of organic solvent and water.

[0350] The reaction can be carried out at temperatures ranging from -20°C to 100°C, preferably from 0°C to 30°C (e.g., not lower than -20°C, preferably not lower than 0°C, e.g., not higher than 100°C, preferably not higher than 30°C).

[0351] Reactions of compounds having chemical formulas (III) and II are preferably carried out in the presence of a catalyst. Suitable catalysts include, but are not limited to, nucleophilic catalysts capable of promoting acyl transfer reactions, such as 4-dialkylaminopyridine, N-alkylimidazolium, phosphine derivatives, imidazole carbides, 1,2-diamines, bicyclic amidines, isothioureas and guanidines, triazoles, suitable alcohols, iodides and cyanide salts, preferably 4-dimethylaminopyridine.

[0352] Step a-1

[0353] A compound having chemical formula (IV) can be prepared by reacting a compound having chemical formula (III) with a compound having formula (II) or a salt thereof, as described in step a.

[0354] The reaction is preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to, polar organic solvents, such as acetic acid, propionic acid or longer-chain carboxylic acids, trifluoroacetic acid, methanol, ethanol, isopropanol, tert-butanol, cyclohexanol, heptanol, octanol or longer-chain alcohols, trifluoroethanol, ethylene glycol, acetonitrile, propionitrile, preferably acetic acid. The reaction may also be carried out in mixtures of organic solvents or in mixtures of organic solvents and water.

[0355] The reaction is preferably carried out in the presence of a suitable acid. Suitable acids include, but are not limited to, organic acids, such as acetic acid, propionic acid or longer-chain carboxylic acids, and trifluoroacetic acid. A preferred acid is acetic acid.

[0356] The reaction can be carried out at temperatures ranging from -20°C to 100°C, preferably from 0°C to 30°C (e.g., not lower than -20°C, preferably not lower than 0°C, e.g., not higher than 100°C, preferably not higher than 30°C).

[0357] Depending on the conditions of use, it would be advantageous to isolate compound IV into the corresponding salt. This salt can be formed with an acid already present in the reaction mixture, or by adding another acid to the reaction mixture. Suitable acids include mineral acids and organic acids, such as HCl, HBr, sulfuric acid, acetic acid, and trifluoroacetic acid.

[0358] Step a-2

[0359] Compounds of formula (I) can be prepared by treating a compound of formula (IV) or a salt thereof with a base, as described in step a-1. Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and their derivatives such as Na₂CO₃, K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine, and diisopropylethylamine.

[0360] The reaction is preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to, organic solvents such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert-butylmethyl ether, tetrahydrofuran, 2-methyl-THF, and dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene, and 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone-2-butanone, and methyl isobutyl ketone; ethers such as anisole; nonpolar solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide; and alcohols such as methanol, ethanol, isopropanol, tert-butanol, cyclohexanol, heptanol, octanol, or longer-chain alcohols, and diethylene glycol. Preferably, the organic solvents include tetrahydrofuran, dioxane, and acetonitrile.

[0361] The reaction can be carried out at temperatures ranging from -20°C to 100°C, preferably from 0°C to 30°C.

[0362] Compounds having chemical formula (I) can be isolated in a free form or formed as salts by adding an acid to a compound having chemical formula (I) in a free base form. Suitable acids include mineral acids and organic acids, such as HCl, HBr, sulfuric acid, acetic acid, and trifluoroacetic acid.

[0363] When compounds having chemical formulas (II) and (III) are reacted under acidic conditions as described for step a-1, the compound having chemical formula (IV) is isolated. When the compound having chemical formula (IV) is treated under alkaline conditions as described for step a-2, the compound having chemical formula (I) is formed.

[0364] When compounds having chemical formulas (II) and (III) react under alkaline conditions as described for step a, the intermediate compound having chemical formula (IV) cannot be separated and directly forms a compound having chemical formula (I).

[0365] Steps 1-1, 1-2 and 1-3

[0366] This is described below under scheme 3. Steps a and 1-1, 1-2 and 1-3 can be carried out in the same reaction vessel (one-pot reaction) without separating the compound having chemical formula (I), for example when the solvent is chloroform. In other words, compounds having chemical formulas (VIII), (IX) and (X) can be prepared from compounds having chemical formula (III) without separating the compound having chemical formula (I) or (IV). Alternatively, steps a-2 and 1-1, 1-2 and 1-3 can be carried out in the same reaction vessel (one-pot reaction) without separating the compound having chemical formula (I).

[0367] Option 2

[0368]

[0369] Step ia

[0370] Compounds of formula (Va) can be prepared from compounds of formula (XI) by treatment with alkyl chlorides or their derivatives, such as dialkyl chlorides, trialkyl chlorides, ethyl chloroformate, or benzyl chloroformate, following a similar procedure described in Synthetic Comm 1993, 23, 2839, which is incorporated herein by reference.

[0371] Step i

[0372] A compound having chemical formula (VI) can be prepared by reacting a compound having chemical formula (Va) with a compound having chemical formula (II). Preferably, the reaction comprises preparing the corresponding acidic halide (preferably an acyl chloride) of the compound having chemical formula (Va), compound (Vb), wherein R 7 It is a halogen, which promotes the conversion into a compound having the chemical formula (VI). This acyl halide, compound (Vb), wherein R... 7 It is a halogen and can be prepared from a compound having the chemical formula (Va) under conditions well known to those skilled in the art, for example by treatment with thionyl chloride, oxalyl chloride, carbamate, dicarbamate or tricarbamate.

[0373] Alternatively, compound (Vb) can be prepared from an alkali metal (Li, Na, K) salt of a compound having the chemical formula (Va), compound (Vc), by treatment with oxalyl chloride, thionyl chloride, carbamate, dicarbamate, or tricarbamate in the presence of a phase transfer catalyst, wherein R 7 It is a halogen. Suitable phase transfer catalysts include, but are not limited to, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylammonium chloride, and Aliquat. ® 336 and (1-hexadecimal)trimethylammonium chloride

[0374] Option 2a

[0375]

[0376] An alkali metal salt of a compound having the chemical formula (V) can be prepared as shown in Scheme 2a, wherein M is Li, Na or K, and the compound is Vc.

[0377] Steps iii and iv

[0378] Compounds with the chemical formula (XV) can be treated with LiOH, NaOH, or KOH, where R... 12 It is a C1-C4 alkyl group, or a compound having the chemical formula (XVI) obtained by treating it with LiOH, NaOH, or KOH, wherein R 13 The compounds (Vc) are prepared by using C1-C4 alkyl, benzyl, or phenyl groups, where M is Li, Na, or K. Suitable solvents include, but are not limited to, alcohols such as ethanol, methanol, and isopropanol; and polar organic solvents such as acetonitrile, dioxane, THF, and 2-methyl-THF together with water. Preferred solvents are ethanol and acetonitrile.

[0379] An acyl halide of a compound having the chemical formula (V), compound (Vb)_, wherein R 7 This is a reaction of a halogen with a compound having the chemical formula (II), preferably carried out in the presence of a base. Suitable bases include, but are not limited to, carbonates, hydroxides, nitrogen-containing organic bases, such as amines, pyridines and their derivatives, such as triethylamine, tripropylamine, pyridine, diisopropylethylamine, Na₂CO₃, NaHCO₃, NaOH and N-methylmorpholine.

[0380] An acyl halide of a compound having the chemical formula (V), compound Vb, wherein R 7 This is a reaction of a halogen with a compound having the chemical formula (II), optionally carried out in the presence of a nucleophilic catalyst. Suitable catalysts include, but are not limited to, nucleophilic catalysts, such as 4-dimethylaminopyridine.

[0381] Suitable solvents include, but are not limited to, ethers, such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert-butylmethyl ether, tetrahydrofuran, 2-methyl-THF, dioxane; halogenated solvents, such as chloroform, dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones, such as ethyl acetate, acetone, 2-butanone, methyl isobutyl ketone; anisoles; polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide; or water / two-phase systems (as known under the so-called Schottten-Baumann conditions) together with hydrocarbons, such as toluene and xylene, as pure isomers and mixtures of isomers.

[0382] Compounds with chemical formula (II) can be used in this way or in the form of their salts and acids, such as HCl, HBr, trifluoroacetic acid, oxalic acid, sulfuric acid and methanesulfonic acid.

[0383] The reaction can be carried out at temperatures ranging from -20°C to 100°C, preferably from -10°C to 30°C, specifically between -5°C and +10°C, and more preferably, at temperatures ranging from 0°C to +10°C.

[0384] Alternatively, the reaction can be carried out in a biphasic system comprising an organic solvent, preferably ethyl acetate, 2-methyltetrahydrofuran, or dichloromethane, and an aqueous solvent, preferably sodium bicarbonate or sodium carbonate, or an organic amine, such as triethylamine or dimethylacetamide.

[0385] Alternatively, the reaction of a compound having formula (V) with a compound having formula (II) can be carried out in the presence of a coupling agent, such as N,N'-dicyclohexylcarbodiimide (“DCC”), 1-ethyl-3-(3-dimethylaminopropyl)phosphonochloride (“EDC”), or bis(2-oxo-3-oxazolidinyl)phosphonochloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole (“HOBT”).

[0386] Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridines and their derivatives such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0387] Examples of suitable solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert-butyl methyl ether, THF, 2-methyl-THF, and dioxane; halogenated hydrocarbon solvents, such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, and 4-fluorotoluene; esters and ketones, such as ethyl acetate, acetone, 2-butanone, and methyl isobutyl ketone; anisole; polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide; and hydrocarbons, such as toluene and xylene, as pure isomers and mixtures of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, 2-methyl-THF, or dioxane.

[0388] The reaction can be carried out at temperatures ranging from -20°C to 100°C, preferably from -10°C to 30°C, specifically from -5°C to +5°C, and more preferably from 0°C to +5°C.

[0389] Step ii

[0390] Compounds of formula (I) can be prepared by treating compounds of formula (VI) with a base. Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridines and their derivatives such as Na₂CO₃, K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine, N-methylmorpholine, and diisopropylethylamine.

[0391] The reaction can be carried out in a mixture of organic solvent and water or in water alone. Preferably, the reaction involves the presence of water.

[0392] Examples of organic solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert-butylmethyl ether, THF, 2-methyl-THF, and dioxane; halogenated hydrocarbon solvents, such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, and 4-fluorotoluene; esters and ketones, such as ethyl acetate, acetone, 2-butanone, and methyl isobutyl ketone; anisole; polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide; and alcohols, such as methanol, ethanol, propanol, t-BuOH, cyclohexanol, heptanol, octanol, or longer-chain alcohols and diethylene glycol; and aromatic hydrocarbons, such as toluene and xylene, as pure isomers and as mixtures of isomers. Preferred organic solvents include tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, and DMF.

[0393] Alternatively, the reaction may be carried out in a biphase system comprising an organic solvent (preferably ethyl acetate, 2-methyltetrahydrofuran, or dichloromethane) that is immiscible with water as described in step ii above, and an aqueous solvent (preferably a solution of sodium bicarbonate, sodium carbonate, or an organic amine, such as triethylamine or diisopropylethylamine). The reaction may also be carried out in an aqueous solvent without the addition of a base.

[0394] The reaction can be carried out at a temperature ranging from 0°C to 100°C, preferably from 20°C to 70°C, specifically at 50°C (e.g., not lower than 0°C, preferably not lower than 20°C, e.g., not higher than 100°C, preferably not higher than 70°C). A temperature not lower than 20°C is preferred to reduce the reaction time.

[0395] Compounds having chemical formula (I) can be isolated in a free form or formed as salts by adding an acid to a compound having chemical formula (I) in a free base form. Suitable acids include mineral acids and organic acids, such as HCl, HBr, H₂SO₄, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, and trifluoroacetic acid.

[0396] Steps 1-1, 1-2 and 1-3

[0397] This is described in Scheme 3 below. Steps i, ii, and 1-1, 1-2, and 1-3 can be carried out in the same reaction vessel (one-pot reaction) without the need to separate the compound having chemical formula (I). In other words, compounds having chemical formulas (VIII), (IX), and (X) can be prepared from compounds having chemical formula (V) without the need to separate compounds having chemical formulas (VI) or (I).

[0398] Option 3

[0399]

[0400] Step 1-1

[0401] A compound of formula (VIII) can be prepared by reacting a compound of formula (I) with a compound of formula (XII), wherein the substituents are as defined herein. When R 8 When the hydroxyl group is present, such reactions are typically carried out in the presence of a coupling agent, such as N,N'-dicyclohexylcarbodiimide (“DCC”), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (“EDC”), or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole (“HOBT”).

[0402] Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridines and their derivatives such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0403] Suitable solvents include, but are not limited to, polar organic solvents, such as halogenated organic solvents or ethers, such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene, THF, 2-methylTHF, dioxane, dimethoxyethane, toluene, acetonitrile, and xylene, preferably chloroform, dichloromethane, or THF.

[0404] When R 8 When the chlorine is present, this reaction is typically carried out in the presence of a base and optionally in the presence of a nucleophilic catalyst, such as 4-dimethylaminopyridine (“DMAP”).

[0405] Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridines and their derivatives such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0406] Examples of solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert-butyl methyl ether, THF, 2-methyl-THF, and dioxane; halogenated hydrocarbon solvents, such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, and 4-fluorotoluene; esters and ketones, such as ethyl acetate, acetone, 2-butanone, and methyl isobutyl ketone; anisole; polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide; and aromatic hydrocarbons, such as toluene and xylene, as pure isomers and mixtures of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, 2-methyltetrahydrofuran, or dioxane.

[0407] Alternatively, the reaction can be carried out in a biphase system comprising an organic solvent (preferably ethyl acetate, toluene, xylene, as a single isomer or a mixture of isomers, or dichloromethane) and an aqueous solvent (preferably a solution of sodium bicarbonate, or sodium carbonate, or an organic amine, such as triethylamine or diisopropylethylamine).

[0408] The reaction can be carried out at a temperature ranging from 0°C to 100°C, preferably from 15°C to 30°C, specifically at ambient temperature (e.g., not lower than 0°C, preferably not lower than 15°C, e.g., not higher than 100°C, preferably not higher than 30°C).

[0409] Step 1-2

[0410] Compounds having the chemical formula (IX), wherein R 9 As defined above, it can be prepared by reacting a compound having chemical formula (I) with a compound having chemical formula (XIII) under the conditions described in 1-1, wherein the substituents are as defined herein.

[0411] Steps 1-3

[0412] A compound having chemical formula X can be prepared by reacting a compound having chemical formula (I) with a compound according to chemical formula (XIVa) or (XIVb). An example of a compound according to chemical formula (XIVa) ditert-butyl dicarbonate is given in the presence of a base. Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridines and their derivatives such as Na₂CO₃, K₂CO₃, NaHCO₃, NaOH, triethylamine, pyridine, N-methylmorpholine, and diisopropylethylamine.

[0413] Examples of solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert-butylmethyl ether, THF, 2-methyl-THF, and dioxane; halogenated hydrocarbon solvents, such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, and 4-fluorotoluene; esters and ketones, such as ethyl acetate, acetone-2-butanone, and methyl isobutyl ketone; anisole; polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide; and alcohols, such as methanol, ethanol, propanol, t-BuOH, cyclohexanol, heptanol, octanol, or longer-chain alcohols, and diethylene glycol; and aromatic hydrocarbons, such as toluene and xylene, as pure isomers and mixtures of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, or dioxane. Alternatively, the reaction may also be carried out in a mixture of these solvents and water.

[0414] Alternatively, the reaction may be carried out in a two-phase system comprising an organic solvent (preferably ethyl acetate, toluene, xylene, or dichloromethane) as described above in 1-3, and an aqueous solvent (preferably a solution of sodium bicarbonate or sodium carbonate).

[0415] The reaction can be carried out at a temperature ranging from -20°C to 100°C, preferably from 0°C to 40°C, specifically at ambient temperature (e.g., not lower than -20°C, preferably not lower than 0°C, e.g., not higher than 100°C, preferably not higher than 40°C).

[0416] Option 4

[0417]

[0418] Scheme 4 illustrates how a compound having chemical formula (VIII) can react to produce an insecticidal compound as described in WO 2011 / 067272 and WO 2013 / 069731, with the reaction conditions described therein. Other methods using the present invention to achieve a compound having chemical formula (VIIIc) will be apparent to those skilled in the art and are also described in WO 2011 / 067272.

[0419] Possible combinations of substituents are shown in Table 1.

[0420] Table 1

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] Unless otherwise specified, atmospheric pressure is preferred in all reactions.

[0430] The temperature is specified as ranging from X to Y, with X and Y included in the temperature range.

[0431] When compounds having chemical formulas (I), (III), (IV), (V), and (VI) are compounds having chemical formula (I) (III) (IV) ), (V ) and (VI The reaction conditions described above also apply when dealing with compounds containing ) .

[0432] The invention will now be described by way of non-limiting examples.

[0433] Example

[0434] Example 1: ( R Preparation of 4-amino-2-ethylisoxazolidin-3-one

[0435]

[0436] At ambient temperature, to N A solution of ethyl(hydroxy)ammonium oxalate (5.5 g, 25.7 mmol) in a mixture of ethanol (70 ml) and water (14 ml) was prepared, and triethylamine (9.8 ml, 70.2 mmol) was added dropwise, and the solution was stirred for 15 min. S 4-(chloromethyl)oxazolidine-2,5-dione (7.0 g, 46.8 mmol) was added in fractions. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to provide a residue purified by grinding with DCM (300 ml) to provide a white solid. R )-4-amino-2-ethylisoxazolidin-3-one (3.6 g). 1H NMR (400MHz, CD3OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H), 1.2 (t, 3H).

[0437] Example 2: ( R Preparation of 4-amino-2-ethylisoxazolidin-3-one

[0438]

[0439] At room temperature, to N A solution of ethyl(hydroxy)ammonium oxalate (0.42 g, 1.8 mmol) and triethylamine (0.7 ml, 5.0 mmol) in chloroform (3 ml) was slowly added. S 4-(chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) (in fractions) was reacted with the resulting reaction mixture at room temperature for 1 h, and then stirred at 50°C for 1.5 h. The reaction mixture was evaporated under reduced pressure, and the desired product was separated by grinding with DCM to provide a white solid. R )-4-amino-2-ethylisoxazolidin-3-one (196 mg). 1 H NMR (400MHz, CD3OD) δ 4.6 (t,1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H), 1.2 (t, 3H).

[0440] Example 3: 4-acetyl- N -[(4 R )-2-Ethyl-3-oxo-isoxazolidine-4-yl)-2-methyl-benzamide

[0441]

[0442] Dimethylformamide (0.2 ml) was added to a suspension of 4-acetyl-2-methylbenzoic acid (5.0 g, 28 mmol) in dichloromethane (20 ml), followed by dropwise addition of oxaloyl chloride (4.6 g, 36.48 mmol). The reaction mixture was stirred at ambient temperature until gas evolution was complete (approximately 4 h). The solvent was evaporated under reduced pressure to provide crude 4-acetyl-2-methylbenzoyl chloride, and diluted with acetonitrile (20 ml). At 0°C, the solution prepared above was added dropwise to acetonitrile (80 ml)... RA solution of 4-amino-2-ethylisoxazolidin-3-one (4.6 g, 36 mmol) and potassium carbonate (15.0 g, 110 mmol) was prepared. The reaction mixture was allowed to be heated to room temperature and stirred for an additional 2 h before evaporation under reduced pressure. Additional water was added and the aqueous phase was extracted with DCM (3 x 50 ml). The organic phase was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-40% ethyl acetate in hexane) to provide 4-acetyl-N-[(4-ethylhexyl) as a pale yellow solid. R 2-Ethyl-3-oxo-isoxazolidine-4-yl)-2-methylbenzamide (4.3 g). Chiral HPLC analysis (Chiralpack IA, acetonitrile: THF: water = 58:2:40, 0.81 ml / min, retention times 5.29 min (major enantiomer, 98.3%) and 4.67 min (minor enantiomer, 1.7%).

[0443] 1 H NMR (400 MHz, CDCl3) δ 7.8 (s, H), 7.76 (d, H), 7.54 (d, H), 6.54(brs, 1H), 4.97 (t, 1H), 4.90-4.80 (m, 1H), 4.10-4.00 (m, 1H), 3.80-3.60 (m,2H), 2.60 (s, 3H), 2.5 (s, 3H), 1.25 (t, 3H). LC-MS, (methanol, ESI): m / z = 291 (M +H, RT = 1.33).

[0444] Example 4: tert-butyl N -[(4 R Preparation of 2-ethyl-3-oxo-isoxazolidine-4-yl]carbamate (one-pot) Method, steps a and 1-3)

[0445]

[0446] In a mixture of ethanol (2 ml) and water (0.5 ml) N A solution of ethyl(hydroxy)ammonium oxalate (0.16 g, 0.74 mmol) was used N,N - Diisopropylethylamine (0.26 g, 2 mmol) was treated at room temperature for 10 min. At 0°C, it was added once to ethanol (3 ml). S4-Amino-2-ethylisooxazolidin-3-one (0.2 g, 1.34 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to provide crude 4-amino-2-ethylisooxazolidin-3-one as a pale yellow gel, diluted with water (5 ml) and THF (10 ml). Triethylamine (0.18 ml, 1.34 mmol) and di-tert-butyl dicarbonate (0.3 g, 1.34 mmol) were added sequentially at 0°C. The reaction mixture was allowed to warm to room temperature before evaporation under reduced pressure, and stirred for an additional 5 h. Water (10 ml) was added, and the aqueous phase was extracted with DCM (2 x 25 ml). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-10% EtOAc in cyclohexane) to provide tert-butyl as a colorless liquid. N -[(4 R 2-Ethyl-3-oxo-isoxazolidine-4-yl]carbamate (0.16 g). Chiral HPLC analysis (Chiralpack IA, acetonitrile: THF: water = 58: 2: 40, 0.81 ml / min, retention times 5.43 min (major 96.6%) and 4.89 min (minor 2.8%).

[0447] 1 H NMR (400 MHz, CDCl3) δ 5.11 (brs, 1H), 4.78-4-67 (m, 1H), 4.59-4.47(m, 1H), 3.95 (dd, 1H), 3.72-3.54 (m, 2H), 1.45 (s, 9H), 1.23 (t, 3H)

[0448] Example 5: (2) S )-2-amino-3-chloro- N -hydroxy- N Preparation of 2,2,2-trifluoroethyl)propionamide hydrochloride

[0449]

[0450] Add acetic acid (2 ml) to ( S The reaction mixture was prepared in a mixture of 4-(chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) and N-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride (0.56 g, 3.68 mmol). The reaction mixture was stirred at room temperature for 12 h and evaporated under reduced pressure to provide 985 mg of the title compound as a white solid (75% quantitative NMR purity).

[0451] 1H NMR (400 MHz, CD3OD) δ = 4.88-4.85 (m, 1H), 4.51-4.48 (m, 2H), 4.21-4.09 (m, 2H) ppm.

[0452] 19 F NMR (400 MHz, DMSO) δ = -69.2 ppm.

[0453] Example 6: (4) R Preparation of 4-amino-2-(2,2,2-trifluoroethyl)isoxazolidin-3-one

[0454]

[0455] (2) S )-2-amino-3-chloro- N -hydroxy- N -(2,2,2-trifluoroethyl)propionamide hydrochloride (0.10 g, 0.27 mmol, 75% by mass purity), potassium carbonate (0.11 g, 0.80 mmol), and acetonitrile (1 ml) were stirred at 0°C for 1 h and then at room temperature for 12 h. The reaction mixture was filtered and evaporated under reduced pressure to give 25 mg of the title compound as a white solid (60% quantitative NMR purity).

[0456] 1 H NMR (400 MHz, CD3CN) δ 4.48 (t, 1H), 4.23-4.05 (m, 2H), 3.92-3.81 (m, 2H).

[0457] 19 F NMR (400 MHz, DMSO) δ = -69.2 ppm.

[0458] Example 7: 4-Acetyl-2-methyl- N -[(4 R )-3-O-2-(2,2,2-trifluoroethyl)isoxazolidine-4-yl]benzene formamide

[0459]

[0460] (2) S )-2-amino-3-chloro- N -hydroxy- N2,2,2-Trifluoroethyl)propionamide hydrochloride (150 mg, 0.43 mmol, 75% by mass), potassium carbonate (0.28 g, 2.0 mmol), and acetonitrile (2 ml) were stirred at 0°C for 1 h. A solution of 4-acetyl-2-methylbenzoyl chloride (138 mg, 0.70 mmol) in acetonitrile (2 ml) was added dropwise at 0°C, and the reaction mixture was then allowed to heat to room temperature and stirred at this temperature for 1 h. The reaction mixture was filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexane) to provide 4-acetyl-2-methylbenzoyl chloride as a white solid. N -[(4 R [3-O-2-(2,2,2-trifluoroethyl)isoxazolidine-4-yl]benzamide (107 mg). Chiral HPLC analysis (Chiralpack Ia, hexane:2-propanol = 90:10, 1 ml / min, retention times 13.2 min (major 98%) and 15.1 min (minor 2%).

[0461] 1 HNMR (CDCl3): δ 7.82 (s, 1H), 7.79 (d, 1H, 8Hz), 7.52 (d, 1H, 8Hz), 6.46 (bs, 1H), 5.06-4.93 (m, 1H), 4.31-4.06 (m, 2H), 2.52 (s,3H) ppm.

[0462] 19 F NMR (CDCl3): δ -70.28 ppm

[0463] Example 8: (4) R Preparation of 4-N-ethyl-N-hydroxy-2-oxazolidine-4-carboxamide

[0464]

[0465] To (4) R Three drops of dimethylformamide were added to a suspension of 2-oxazolidine-4-carboxylic acid (0.500 g, 3.81 mmol) in 1,2-dichloroethane (5 ml), followed by the addition of oxaloyl chloride (0.543 g, 4.20 mmol). The reaction mixture was stirred at ambient temperature until gas evolution was complete (approximately 1 h). The solution prepared above was then added dropwise at 0°C to... N1,2-Ethyl(hydroxy)ammonium oxalate (0.874 g, 4.12 mmol) and triethylamine (1.38 g, 13.5 mmol) were in a solution of 1,2-dichloroethane (5 ml). The reaction mixture was allowed to heat to room temperature and stirred for an additional 2 h before evaporation under reduced pressure. Tetrahydrofuran (20 ml) was added to the residue, and the mixture was heated to 40°C for 15 min. The precipitate was filtered off, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0–5% MeOH in DCM) to provide a pale yellow solid (4... R )- N -Ethyl- N -Hydroxy-2-oxazolidine-4-carboxamide (0.409 g). Chiral HPLC analysis (Chiralpack IC, ethanol: 2-propanol = 0.5: 95, 1 ml / min, retention time 4.54 min (enantiomers only).

[0466] 1 H NMR (400 MHz, CD3OD) δ 4.84 (m, 1H), 4.67 (t, 1H), 4.33 (dd, 1H), 3.64 (dq, 2H), 1.19 (t, 3H)

[0467] Example 9: (4) R Preparation of 4-amino-2-ethyl-isoxazolidin-3-one

[0468]

[0469] To (4) R (4R)-4-amino-2-ethyl-isoxazolidin-3-one (0.0172 mmol) was added to a solution of (4R)-N-ethyl-N-hydroxy-2-oxazolidin-4-carboxamide (0.030 g, 0.172 mmol) in THF (0.4 ml) and water (0.13 ml), and the resulting reaction mixture was stirred at room temperature for 16 h. Additional water was added, and the aqueous phase was extracted with DCM (3x). The aqueous phase was evaporated under reduced pressure to provide (4R)-4-amino-2-ethyl-isoxazolidin-3-one (0.0175 g) as a white solid.

[0470] 1 H NMR (400 MHz, CD3OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m,2H), 1.2 (t, 3H).

[0471] Example 10: tert-butyl N -[(4 R Preparation of 2-ethyl-3-oxo-isoxazolidine-4-yl]carbamate

[0472]

[0473] To (4) R Triethylamine (0.117 g, 1.15 mmol) was added to a solution of 4-(N-ethyl-N-hydroxy-2-oxazolidine-4-carboxamide) (0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml), and the resulting reaction mixture was stirred at room temperature for 16 h. Di-tert-butyl dicarbonate (0.136 g, 0.603 mmol) was added, and the reaction mixture was stirred for an additional 1 h. Additional water was added, and the aqueous phase was extracted with ethyl acetate (3x). The combined organic phases were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc in cyclohexane) to provide tert-butyl as a white crystalline solid. N -[(4 R 2-Ethyl-3-oxo-isoxazolidine-4-yl]carbamate (0.0850 g). Chiral HPLC analysis (Chiralpack IC, hexane:ethanol = 80:20, 1 ml / min, retention times 2.85 min (minor enantiomer, 0.4%) and 4.73 min (major enantiomer, 99.6%). 1 H NMR (400MHz, CDCl3) δ 5.11 (brs, 1H), 4.78-4-67 (m, 1H), 4.59-4.47 (m, 1H), 3.95 (dd,1H), 3.72-3.54 (m, 2H), 1.45 (s, 9H), 1.23 (t, 3H)

[0474] Alternatively, the title compound can be obtained by performing the following procedure:

[0475] To (4) R )- N -Ethyl- N 4-Hydroxy-2-oxazolidine-4-carboxamide (0.100 g, 0.574 mmol) was added to a solution of THF (1.2 ml) and water (0.4 ml) with K₂CO₃ (0.0794 g, 0.574 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h. Di-tert-butyl dicarbonate (0.136 g, 0.603 mmol) was added, and the reaction mixture was stirred for an additional 1 h. Additional water was added, and the aqueous phase was extracted with ethyl acetate (3x). The combined organic phases were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc in cyclohexane) to provide a white crystalline solid. tert-butyl N -[(4 R 2-Ethyl-3-oxo-isoxazolidine-4-yl]carbamate (0.070 g). Chiral HPLC analysis (Chiralpack IC, hexane:ethanol = 80:20, 1 ml / min, retention times 2.85 min (minor enantiomer, 0.4%) and 4.73 min (major enantiomer, 99.6%).

[0476] Example 11: ( Preparation of 4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide

[0477]

[0478] To (4) R Dimethylformamide was added dropwise to a suspension of 2-oxazolidine-4-carboxylic acid (0.150 g, 1.14 mmol) in dry THF (1.5 ml), followed by the addition of oxaloyl chloride (0.11 ml, 1.25 mmol). The reaction mixture was stirred at ambient temperature for 20 minutes. The solution prepared above was then added dropwise to [a specific concentration] at 0°C. N 1-Phenylated hydroxylamine (0.158 g, 1.37 mmol) and Na₂CO₃ (0.182 g, 1.72 mmol) were in suspension in THF (1.5 ml). The resulting reaction mixture was stirred at ambient temperature for 1.5 h. The precipitate was filtered off and dried, and aqueous saturated NaHCO₃ and ethyl acetate were added to the filtrate. These phases were separated, and the aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried over anhydrous MgSO₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0–5% MeOH in DCM) to provide (4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide (0.1802 g) as a beige solid.

[0479] 1 H NMR (400 MHz, CD3OD) δ 7.71-7.61 (m, 2H), 7.45-7.34 (m, 2H), 7.26-7.18 (m, 1H), 5.04 (dd, J = 9.2, 5.0 Hz, 1H), 4.78 (t, J = 9.2 Hz), 4.50 (dd,J = 8.8, 5.0 Hz, 1H).

[0480] Example 12: Preparation of tert-butyl N-[(4R)-3-oxo-2-phenyl-isoxazolidine-4-yl]carbamate

[0481]

[0482] Triethylamine (0.127 ml, 0.900 mmol) was added to a solution of (4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide (0.100 g, 0.450 mmol) in THF (1.0 ml) and water (0.3 ml). The solution was then heated to 70 °C. The resulting solution was stirred in a sealed vial for 2.5 h at C. The reaction mixture was cooled to ambient temperature, and di-tert-butyl dicarbonate (0.111 g, 0.495 mmol) was added. The reaction mixture was stirred for another 1.5 h, diluted with water, and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-23% EtOAc in cyclohexane) to provide tert-butyl N-[(4R)-3-oxo-2-phenyl-isoxazolidine-4-yl]carbamate (0.0902 g) as a beige solid.

[0483] 1 H NMR (400 MHz, CDCl3) δ 7.73-7.67 (m, 2H), 7.43-7.36 (m, 2H), 7.22-7.16 (m, 1H), 5.23 (br, 1H), 5.00-4.89 (m, 1H), 4.85-4.74 (m, 1H), 4.19 (dd,J = 8.5, 11.0 Hz, 1H), 1.48 (s, 9H).

[0484] Example 13: Preparation of N-hydroxy-N-methyl-2-oxazolidine-4-carboxamide

[0485]

[0486] One drop of dimethylformamide was added to a suspension of 2-oxazolidine-4-carboxylic acid (0.200 g, 1.53 mmol) in dry 1,2-dichloroethane (2.0 ml), followed by the addition of oxaloyl chloride (0.144 ml, 1.68 mmol). The reaction mixture was stirred at ambient temperature for 30 min. The solution prepared above was added dropwise to a suspension prepared by mixing triethylamine (0.52 ml, 3.66 mmol) and N-methylhydroxylamine hydrochloride (0.143 g, 1.68 mmol) in 1,2-dichloroethane (2.0 ml). The resulting brown reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated under reduced pressure, and the residue was suspended in THF (8.0 ml). The suspension was then heated at 50 °C. Heating at C for 10 min and filtering out the remaining precipitate. Evaporating the filtrate under reduced pressure to provide a crude product as a viscous yellow oil. Purification by silica gel chromatography (0-10% MeOH in DCM) to provide N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide (0.120 g) as a colorless oil that solidifies upon standing.

[0487] 1 H NMR (400 MHz, CD3OD) δ 4.87 (dd, J = 9.5, 5.1 Hz, 1H), 4.67 (t, J =9.4 Hz, 1H), 4.36 (dd, J = 9.0, 5.3 Hz, 1H), 3.23 (s, 3H).

[0488] Example 14: Preparation of tert-butyl N-(2-methyl-3-oxo-isoxazolidine-4-yl)carbamate

[0489]

[0490] Triethylamine (0.21 ml, 1.50 mmol) was added to a solution of N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide (0.120 g, 0.749 mmol) in a mixture of THF (1.5 ml) and water (0.50 ml), and the resulting solution was stirred at ambient temperature for 18 h. Di-tert-butyl dicarbonate (0.173 g, 0.787 mmol) was added, and the reaction mixture was stirred for an additional 2 h. The reaction mixture was diluted with DCM and water, the aqueous phase was extracted with DCM (3x), and the combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-50% EtOAc in cyclohexane) to provide tert-butyl N-(2-methyl-3-oxo-isooxazolidine-4-yl)carbamate (0.0546 g) as a white powder.

[0491] 1 H NMR (400 MHz, CDCl3) δ 5.32 (br, 1H), 4.71-4.60 (m, 1H), 4.58-4.44(m, 1H), 3.96 (dd, J = 10.3, 8.4 Hz, 1H), 3.17 (s, 3H), 1.41 (s, 9H).

[0492] Example 15: (4) R Preparation of 4-N-ethyl-N-hydroxy-2-oxazolidine-4-carboxamide

[0493]

[0494] In 0 C down, towards (4)R Three drops of DMF were added to a suspension of 2-oxazolidine-4-carboxylic acid (10.0 g, 75.9 mmol) in dry THF (50 ml), followed by the addition of oxalyl chloride (7.31 ml, 83.5 mmol). After the addition, the reaction mixture was stirred at ambient temperature for an additional 30 min. In a separate flask, triethylamine (37.2 ml, 266 mmol) was slowly added to a solution of N-ethylhydroxylamine hydrochloride in THF (100 ml). At 0 °C, after 45 min, the solution of the acyl chloride prepared above was added to the resulting thick white suspension. After the addition was complete, the reaction mixture was heated to ambient temperature, another 50 ml of THF was added, and the reaction mixture was heated to reflux. The remaining precipitate (triethylamine hydrochloride) was filtered off, and the filtrate was concentrated under reduced pressure to provide a crude product (15.9 g). Quantitative NMR analysis using trimethoxybenzene as an internal standard indicated that the mixture contained (4-oxazolidine-4-carboxylic acid). R The main component was 11.39 g of 4-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide. The crude product was crystallized from methanol to provide a white powder. R )-N-ethyl-N-hydroxy-2-oxazolidine-4-carboxamide (8.86 g).

[0495] 1 H NMR (400 MHz, D2O) δ 5.01 (dd, J = 9.9, 5.9 Hz), 4.77 (t, J = 9.2Hz, 1H), 4.39 (dd, J = 9.0, 5.7 Hz, 1H), 3.65 (q, J = 7.1 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H).

[0496] Example 16: Preparation of (4R)-4-amino-2-ethyl-isoxazolidine-3-one hydrochloride

[0497]

[0498] To (4) R(4R)-4-amino-2-ethyl-isoxazolidine-3-one hydrochloride (13.09 g, 74.8 mmol) was added to a suspension of (35 ml) of (4R)-N-ethyl-N-hydroxy-2-oxazolidine-3-one in water (13.09 g, 74.8 mmol) with triethylamine (1.05 ml, 7.48 mmol) added, and the resulting mixture was heated at 70°C for 2 h (clear solution at this temperature). The reaction mixture was cooled to ambient temperature, and 37% aqueous HCl (7.5 ml, 89.7 mmol) was slowly added. The resulting mixture was evaporated under reduced pressure, and the residue was dried under vacuum to provide (4R)-4-amino-2-ethyl-isoxazolidine-3-one hydrochloride (13.6 g) as a white powder mixed with 10% triethylamine hydrochloride. Stereochemical integrity was achieved by treating the hydrochloride with triethylamine (1.1 eq) and di-tert-butyl dicarbonate (1.2 eq) in THF, converting a small fraction of the product to tert-butyl N -[(4 R The assay was performed using 2-ethyl-3-oxo-isoxazolidine-4-yl]carbamate (see Example 10). Chiral HPLC analysis (Chiralpack IA, hexane:ethanol = 80:20, 1 ml / min, retention times 2.82 min (minor enantiomer, 0%) and 4.10 min (major enantiomer, 100%)) was used. 1 H NMR (400 MHz, D2O) δ 4.58 (t, J = 8.1 Hz, 1H), 4.10-4.04 (m, 1H), 4.02-3.96 (m, 1H), 3.68-3.51 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H).

[0499] Alternatively, the title compound can be obtained by performing the following procedure:

[0500] At 0-5°C, (4) R Sodium 2-oxazolidine-4-carboxylate (10.06 g, 85.1% purity, 55.9 mmol) and Aliquat ® A suspension of 336 (0.56 g, 1.39 mmol) in 2-methyltetrahydrofuran (70 ml) was sequentially used with N, N Dimethylformamide (0.21 g, 2.87 mmol) and oxalyl chloride (8.58 g, 67.6 mmol) were used for treatment. The reaction mixture was stirred at ambient temperature for 90 min, and triethylamine (13.1 g, 0.129 mol) was added dropwise at -5°C. N4-Ethylhydroxylamine hydrochloride (4.99 g, 89.9% purity, 0.046 mol) was in a suspension of 2-methyltetrahydrofuran (40 ml). The resulting brown compound was stirred at ambient temperature for 30 min and washed with water (2 x 75 ml). The combined aqueous layer containing the intermediate (4R)-N-ethyl-N-hydroxy-2-oxazolidine-4-carboxamide was heated to 45°C and washed with aqueous NaOH (30%). w / w The solution (2.95 g, 22.1 mmol) was treated and stirred for an additional 60 min. A portion of the water (35 g) was removed by distillation, and the mixture was treated with 32% aqueous HCl. w / w (9.3 g, 81.6 mmol) was treated until pH 1 was reached. Distillation was continued until the final crude (4 g) was obtained. R )-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride (56 g, in approximately 9% solution in water, by quantitative analysis) 1 (Analysis was performed using H-NMR analysis).

[0501] Alternatively, the title compound can be obtained by performing the following procedure:

[0502] (4 R Sodium 2-oxazolidine-4-carboxylate (10.0 g, 95.0% purity, 62.1 mmol) and Aliquat ® A suspension of 336 (0.66 g, 1.63 mmol) in ethyl acetate (80 ml) was sequentially instilled with HCl (4 M solution, 3.1 ml, 12.4 mmol) in dioxane and N,N Dimethylformamide (0.23 g, 3.15 mmol) was used for treatment. The resulting mixture was treated with a solution of thionyl chloride (9.0 g, 75.6 mmol) in ethyl acetate (10 ml) for 70 min at 10°C–15°C, with stirring for an additional 2 h at ambient temperature, and then, dropwise, triethylamine (15.4 g, 0.152 mol) and... N 4-Ethylhydroxylamine hydrochloride (6.4 g, 77.0% purity, 50.5 mol) was suspended in ethyl acetate (65 ml). The resulting brown mixture was stirred at ambient temperature for 60 min and washed with water (2 x 50 ml). The combined aqueous layer containing the intermediate (4R)-N-ethyl-N-hydroxy-2-oxazolidine-4-carboxamide was heated to 40°C and washed with aqueous NaOH (30%). w / wThe solution (13.6 g, 0.102 mmol) was treated and stirred for an additional 60 min. A portion of the water (25 g) was removed by distillation, and the mixture was treated with aqueous HCl (32%). w / w The solution (12.2 g, 0.107 mmol) was treated until pH 1 was reached. The mixture was completely evaporated to obtain a crude (4) solid in the form of an orange solid. R )-4-amino-2-ethyl-isoxazolidine-3-one hydrochloric acid (27.1 g, approximately 11.8% purity, as determined by quantitative analysis) 1 (confirmed by HNMR analysis).

[0503] Example 17: Preparation of (4R)-N-phenyl-N-hydroxy-2-oxazolidine-4-carboxamide

[0504]

[0505] In 0 At C, 2 drops of DMF were added to a solution of (4R)-2-oxoxazolidine-4-carboxylic acid (0.300 g, 2.29 mmol) in dry tetrahydrofuran (3.0 mL), followed by the addition of oxaloyl chloride (0.22 mL, 2.52 mmol). After stirring at rt for 20 min, the resulting solution was heated to 0 °C. The mixture was slowly added at C to a suspension of sodium carbonate (0.603 g, 7.1 mmol) and N-phenylhydroxylamine hydrochloride (0.438 g, 2.75 mmol) in tetrahydrofuran (6.0 ml). The reaction mixture was stirred at rt for 2 h. The remaining precipitate was filtered off and aqueous saturated NaHCO3 was added to the filtrate. The aqueous phase was extracted with EtOAc (3x), and the combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0–5% MeOH in dichloromethane) to provide (4R)-N-phenyl-N-hydroxy-2-oxazolidine-4-carboxamide (0.393 g) as a white powder.

[0506] 1 H NMR (400 MHz, CD3OD) δ 7.38-7.27 (m, 5H), 4.88 (dd, J = 9.7, 5.3Hz, 1H), 4.77 (s, 2H), 4.65 (t, J = 9.4 Hz, 1H), 4.32 (dd, J = 9.0, 5.3 Hz,1H), 3.35 (s,1H).

[0507] Example 18: Preparation of tert-butyl N-[(4R)-2-phenyl-3-oxo-isoxazolidine-4-yl]carbamate

[0508]

[0509] Triethylamine (0.24 ml, 1.69 mmol) was added to a solution of (4R)-N-phenyl-N-hydroxy-2-oxazolidine-4-carboxamide (0.200 g, 0.847 mmol) in a mixture of THF (1.0 ml) and water (2.0 ml). The solution was then heated to 70 °C. The resulting reaction mixture was heated in a sealed vial for 3 h at C. The reaction mixture was diluted with water and extracted with dichloromethane (3x). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-40% EtOAc in CyH) to provide 0.136 g of tert-butyl N-[(4R)-2-phenyl-3-oxo-isoxazolidine-4-yl]carbamate as a colorless oil, which solidified upon standing.

[0510] 1 H NMR (400 MHz, CD3OD) δ 7.39-7.29 (m, 5H), 5.16 (br, 1H), 4.78 (d, J= 15.4 Hz, 1H), 4.75-4.68 (m, 1H), 4.68 (d, J = 15.8 Hz, 1H), 4.64-4.55 (m,1H), 3.94 (dd, J = 10.6, 8.4 Hz, 1H), 1.46 (s, 9H).

[0511] Example 19: (4) R Preparation of sodium 2-oxazolidine-4-carboxylate

[0512]

[0513] At 35°C, (2) R 2-(ethoxycarbonylamino)-3-hydroxypropionic acid (80 g, 0.452 mol) was dissolved in ethanol (800 ml) and, in portions, treated with sodium hydroxide (24.0 g, 0.600 mol, microparticles) at 25°C. After the addition was complete, the reaction mixture was heated to 40°C and stirred overnight. The precipitated solid was filtered off, washed with ethanol, and dried under reduced pressure to give a white powder containing approximately 20% residual solvent. R )-2-oxazolidine-4-carboxylate sodium (50.7 g).

[0514] 1 H NMR (400 MHz, DO) δ 4.57-4.63 (m, 1H), 4.25-4.31 (m, 2H).

[0515] 1 H NMR (400 MHz, D2O / DMSO-d6 4 : 1) δ 4.63 (dd, J = 9.6, 8.5 Hz, 1H), 4.33 (dd, J = 8.5, 5.8 Hz, 1H), 4.27 (dd, J = 9.6, 5.7 Hz, 1H).

[0516] Alternatively, the title compound can be obtained by performing the following procedure:

[0517] At 21°C, within 60 min, the methyl group (4) in acetonitrile (100 g) was removed. R A solution of methyl 2-oxazolidine-4-carboxylate (20.0 g, 91.0% purity, 0.125 mol) was used in methanol (16.2%). w / w The solution (37.0 g, 0.150 mol) was treated with sodium hydroxide (microparticles) and stirred for an additional 30 min at ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile (3 x 25 g), and dried under vacuum at 100°C to give a pale yellow solid (4... R )-2-oxazolidine-4-carboxylate sodium (20 g, 83.2% purity, determined by quantitative analysis) 1 (determined by H NMR analysis).

[0518] Example 20: Preparation of lithium 2-oxazolidine-4-carboxylate

[0519]

[0520] A solution of methyl 2-oxazolidine-4-carboxylate (1.0 g, 6.89 mmol) in 2-methyltetrahydrofuran (5 g) was treated with a solution of lithium hydroxide (0.167 g, 6.97 mmol) in methanol (2 ml) over 15 min at 0–5°C. After the addition was complete, more methanol (1 ml) was added, and the reaction mixture was stirred for an additional 60 min at 0–5°C. The resulting precipitate was filtered off and dried under vacuum to give lithium 2-oxazolidine-4-carboxylate (610 mg) as a white solid containing approximately 3% residual solvent.

[0521] 1 H NMR (400MHz, D2O) δ 4.57-4.63 (m, 1H), 4.25-4.31 (m, 2H).

Claims

1. A method for preparing a compound having chemical formula (I). (I) in R 1 It is a C1-C8 alkyl or a C1-C8 haloalkyl; The method includes To make a compound having chemical formula (II) or a salt thereof... (II) Where R 1 This is as defined for compounds having the chemical formula (I); Reaction with compounds having chemical formula (III) (III) The reaction proceeds in the presence of a base. in R 2 It is a leaving group, selected from halogens, C1-C8 alkylsulfonyloxy groups, C1-C8 haloalkylsulfonyloxy groups, and C1-C8 arylsulfonyloxy groups.

2. The method according to claim 1, wherein the base is selected from nitrogen-based organic bases.

3. A method according to claim 1, further comprising reacting a compound having formula (I) with a second compound, wherein the second compound comprises a carboxylic acid, acyl halide, ester, or thioester functional group, and the reaction comprising reacting an amine functional group of the compound having formula (I) with a carboxylic acid, acyl halide, ester, or thioester functional group of the second compound, such that the compound having formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound comprises a dicarbonate group, and the reaction comprises reacting an amine functional group of the compound having formula (I) with a dicarbonate group of the second compound, such that the compound having formula (I) is coupled to the second compound via a carbamate functional group.

4. The method according to claim 3, wherein The second compound is a compound having the chemical formula (XII). (XII) This method produces compounds with the chemical formula (VIII). (VIII) in X is a leaving group, selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester, cyano, formyl, acetyl, C(O)CH=C(R) 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 or group A (A) -B 1 -B 2 -B 3 - is -C=NO-, -C=N-CH2-, -C=CH2-O-, or -N-CH2-CH2-; A 1 A 2 A 3 And A 4 CH and CR are independent of each other. 5 or nitrogen; R 3 It is a C1-C8 haloalkyl; R 4 It is aryl or composed of one to three Rs. 6 Substituted aryl, or R 4 It is a heterocyclic group or composed of one to three R groups. 6 Substituted heterocyclic groups; Each R 5 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkoxycarbonyl-, or two R on adjacent carbon atoms. 5 Together they form a -CH=CH-CH=CH- bridge or a -N=CH-CH=CH- bridge; Each R 6 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy; R 8 It is hydroxyl, C1-C6 alkoxy, fluorine, chlorine, bromine, or SR x , where R x It is hydrogen, C1-C6 alkyl, imidazole, or pyrrole; and Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen; R 1 It is a C1-C8 alkyl or a C1-C8 haloalkyl; or The second compound is a compound with the chemical formula (XIII). (XIII) This method generates compounds with the chemical formula (IX). (IX) in R 1 It is a C1-C8 alkyl or a C1-C8 haloalkyl; and R 9 It is hydrogen, C1-C8 alkyl, or C1-C8 haloalkyl and R 8 This is as defined for compounds having the chemical formula (XII); or The second compound is a compound having the chemical formula (XIVa) or (XIVb). (XIVa) (XIVb) This method generates compounds with the chemical formula X. (X) in R 1 It is a C1-C8 alkyl or a C1-C8 haloalkyl; Each R 10 It is independently a C1-C8 alkyl, C1-C8 haloalkyl, aryl-C1-C4 alkylene, or surrounded by one to five R... 11 Substituted aryl-C1-C4 alkylene groups; Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

5. A method for preparing a compound having the chemical formula (VIII) or a salt or N-oxide thereof. (VIII) Including the preparation of compounds having chemical formula (I) by the method according to claim 1. (I) And the compound having chemical formula (I) is reacted with the compound having chemical formula (XII). (XII) in X is a leaving group, selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy, or surrounded by one to five R groups. 11 Substituted C1-C8 arylsulfonyloxy group, or phosphate ester, cyano, formyl, acetyl, C(O)CH=C(R) 3 )R 4 C(O)CH2C(OH)(R 3 )R 4 or group A (A) -B 1 -B 2 -B 3 - is -C=NO-, -C=N-CH2-, -C=CH2-O-, or -N-CH2-CH2-; A 1 A 2 A 3 And A 4 CH and CR are independent of each other. 5 or nitrogen; R 3 It is a C1-C8 haloalkyl; R 4 It is aryl or composed of one to three Rs. 6 Substituted aryl, or R 4 It is a heterocyclic group or composed of one to three R groups. 6 Substituted heterocyclic groups; Each R 5 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 haloalkynyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkoxycarbonyl-, or two R on adjacent carbon atoms. 5 Together they form a CH=CH-CH=CH- bridge or a -N=CH-CH=CH- bridge; Each R 6 It is independently a halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy; R 8 It is hydroxyl, C1-C6 alkoxy, chlorine, fluorine, bromine, or SR. x , where R x It is hydrogen, C1-C6 alkyl, imidazole or pyrrole; R 1 It is a C1-C8 alkyl or a C1-C8 haloalkyl; and Each R 11 It is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, or halogen.

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