Process for the preparation of substituted cycloserine

Abstract

The present invention relates to a method for preparing a substituted cycloserine compound of formula (I) wherein R 1 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen; the present invention also relates to intermediates produced by these methods. 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 with the invention title "Method for Preparing Substituted Cycloserine", the filing date of which is: April 30, 2015, and the priority date is: April 30, 2014.

[0002] The present invention relates to the production of 2-substituted cycloserine (4-amino-isoxazolidin-3-one) and intermediates useful in the preparation of 2-substituted cycloserine.

[0003] 2-Substituted cycloserine is a useful intermediate in the preparation of certain insecticidal active 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 cycloserine was prepared according to the method described in Chem. Pharm. Bull. 2002, 50(4) 554-557, which involves alkylating the parent cycloserine or a cycloserine derivative, such as tert-butoxycarbonyl. A similar procedure is described in Tet. Lett. 2012, 2564-2567.

[0005] The main disadvantages of the known methods of alkylating cycloserine include the formation of isomeric by-products resulting from O-alkylation rather than the desired N-alkylation, and the possible epimerization of the stereocenters of cycloserine, especially when strong basic conditions are employed. There are also limitations imposed by the low reactivity and accessibility of the corresponding alkylating reagents.

[0006] It has been found that the insecticides described in WO 2011 / 067272 and WO 2012 / 163959 are more effective when the cycloserine group is present in a molecule with the D-stereoconfiguration, making it particularly desirable to find methods for derivatizing cycloserine that reduce epimerization.

[0007] Although the regioselective derivatization of cycloserine has been described in Tet. Lett. 2012, 2564-2567, special equipment is required and this method is not suitable for commercial scale production.

[0008] It has now unexpectedly been found that methods for derivatizing cycloserine allow the preparation of 2-substituted cycloserine, where no cycloserine starting material is required. These methods also offer additional advantages by avoiding the need for protecting groups and allowing the preparation of 2-substituted cycloserine with a defined stereoconfiguration.

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

[0010]

[0011] wherein

[0012] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and

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

[0014] comprising

[0015] a. reacting a compound having the chemical formula (II) or a salt thereof

[0016]

[0017] wherein R 1 is as defined for the compound having the chemical formula (I) with a compound having the chemical formula (III)

[0018]

[0019] wherein R 2 is a leaving group such as halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 substituents, or phosphate; and

[0020] each R 11 is as defined for the compound having the chemical formula (I), and the reaction is carried out in the presence of a base.

[0021] Examples of suitable and preferred bases for step a are given below.

[0022] In one aspect, the present invention provides a method for preparing a compound having the chemical formula (I)

[0023]

[0024] wherein

[0025] R 1is a C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five Rs 11 substituted aryl, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five Rs 11 ; and

[0026] each R 11 is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0027] comprising

[0028] a-1. Reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV) or a salt thereof

[0029]

[0030] wherein R 1 and R 2 are as defined for the compounds of formula (I) and formula (III), and the reaction is carried out in the presence of a suitable acid; and

[0031] a-2. Converting the compound of formula (IV) to a compound of formula (I) in the presence of a suitable base.

[0032] Examples of suitable acids for step a-1 and preferred acids for step a-1 are given below. Examples of suitable bases for step a-2 and preferred bases for step a-2 are given below.

[0033] In another aspect, the present invention provides a method for preparing a compound of formula (IV), which method comprises carrying out step a-1 as defined above. In another aspect, the present invention provides a method for preparing a compound of formula (I)

[0034]

[0035] wherein

[0036] R 1 is a C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five Rs 11 substituted aryl, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five Rs 11 ; and

[0037] each R 11independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0038] The method comprises step a-2

[0039] a-2. Converting a compound having the formula (IV)

[0040]

[0041] wherein

[0042] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents;

[0043] R 2 is C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 substituents, or phosphate; and

[0044] each R 11 independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0045] is a compound having the formula (I), and the conversion is carried out in the presence of a suitable base.

[0046] In another aspect, the present invention provides a method for preparing a compound having the formula (I), the method comprising carrying out step a-2 as defined above. In another aspect, the present invention provides a method for preparing a compound having the formula (IV)

[0047]

[0048] wherein R 1 and R 2 are as defined for the compounds having the formula (I) and the formula (III)

[0049] The method comprises reacting a compound having the formula (II) with a compound having the formula (III) according to step a-1 to produce a compound having the formula (IV)

[0050] In one aspect, the present invention relates to a method for preparing a compound having the formula (I)

[0051]

[0052] wherein

[0053] R 1 is a C1-C8 alkyl group, a C1-C8 haloalkyl group, an aryl group, or an aryl group substituted with one to five Rs 11 or an aryl-C1-C4 alkylene group or an aryl-C1-C4 alkylene group substituted with one to five Rs 11 ; and

[0054] each R 11 is independently a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a cyano group, or a halogen;

[0055] comprising

[0056] reacting a compound of formula (II) or a salt thereof

[0057]

[0058] wherein R 1 is as defined for the compound of formula (I);

[0059] with a compound of formula (III)

[0060]

[0061] the reaction being carried out in the presence of a base

[0062] wherein

[0063] R 2 is a leaving group selected from a halogen, a C1-C8 alkylsulfonyloxy group, a C1-C8 haloalkylsulfonyloxy group, a C1-C8 arylsulfonyloxy group, or a C1-C8 arylsulfonyloxy group substituted with one to five Rs 11 or a phosphate ester; and each R 11 is independently a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a cyano group, or a halogen.

[0064] In one aspect, the present invention relates to a method for preparing a compound of formula (I)

[0065]

[0066] wherein

[0067] R 1 is a C1-C8 alkyl group, a C1-C8 haloalkyl group, an aryl group, or an aryl group substituted with one to five Rs11 a substituted aryl, or an aryl-C1-C4 alkylene or a substituted aryl-C1-C4 alkylene; and 11 each R

[0068] is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen; 11 including

[0069] a-1. reacting a compound of formula (II)

[0070]

[0071]

[0072] with a compound of formula (III)

[0073]

[0074]

[0075] This reaction is carried out in the presence of a suitable acid wherein

[0076] R 2 is a leaving group selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or a C1-C8 arylsulfonyloxy substituted with one to five R 11 or a phosphate; and each R 11 is independently a C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0077] to produce a compound of formula (IV) or a salt thereof

[0078]

[0079] wherein R 1 and R 2 are as defined for the compounds of formula (I) and formula (III) and

[0080] a-2. converting the compound of formula (IV) to a compound of formula (I) in the presence of a suitable base.

[0081] In one aspect, the present invention relates to a method for preparing a compound of formula (IV)

[0082]

[0083] including

[0084] a-1. React a compound having the chemical formula (II)

[0085]

[0086] with a compound having the chemical formula (III)

[0087]

[0088] This reaction is carried out in the presence of a suitable acid

[0089] wherein

[0090] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents;

[0091] R 2 is a leaving group selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 substituents, or phosphate ester;

[0092] Each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen.

[0093] In one aspect, the present invention relates to a method for preparing a compound having the chemical formula (I)

[0094]

[0095] This method comprises step a-2

[0096] a-2. Convert a compound having the chemical formula (IV)

[0097]

[0098] into a compound having the chemical formula (I), and this conversion is carried out in the presence of a suitable base

[0099] wherein

[0100] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11Substituted aryl-C1-C4 alkylene;

[0101] R 2 is C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 substituents, or phosphate; and

[0102] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen.

[0103] In one aspect, the present invention relates to a compound having the formula (IV)

[0104]

[0105] wherein

[0106] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents;

[0107] R 2 is C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 substituents, or phosphate; and

[0108] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0109] or a salt or N-oxide thereof.

[0110] In one aspect, the present invention relates to a method for preparing a compound having the formula (I)

[0111]

[0112] comprising

[0113] i. reacting a compound having the formula (II) or a salt thereof

[0114]

[0115] with a compound having the formula (V)

[0116]

[0117] The reaction is carried out in the presence of a suitable base to produce a compound having the formula (VI).

[0118]

[0119] and

[0120] ii. The compound having the formula (VI) is converted into a compound having the formula (I) by treating the compound having the formula (VI) with an aqueous solution of a base.

[0121] wherein

[0122] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and

[0123] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0124] R 7 is hydroxy or halogen or OM, where M is Na, K, Li.

[0125] In one aspect, the present invention relates to a compound having the formula (V).

[0126]

[0127] wherein R 7 is OM, where M is Na, K, Li.

[0128] A compound having the formula (VI).

[0129]

[0130] wherein

[0131] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents;

[0132] each R 11independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0133] or a salt or N-oxide thereof.

[0134] In one aspect, the present invention relates to a compound having the chemical formula (I)

[0135]

[0136] wherein R 1 is aryl or aryl substituted with one to five R 11 substituents;

[0137] Each R 11 independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen.

[0138] A method for preparing a compound having the chemical formula (V)

[0139]

[0140] wherein R 7 is OM, where M is Na, K, Li,

[0141] The method comprises reacting a compound (XV)

[0142]

[0143] wherein R 12 is C1-C4 alkyl

[0144] with an alkali metal salt MOH, where M is Na, K, Li.

[0145] In one aspect, the present invention relates to a method for preparing a compound having the chemical formula (V)

[0146]

[0147] wherein R 7 is OM, where M is Na, K, Li,

[0148] The method comprises reacting a compound (XVI)

[0149]

[0150] R 13 is C1-C4 alkyl, benzyl or phenyl

[0151] with an alkali metal salt MOH, where M is Na, K, Li.

[0152] In the above method, the compounds having the chemical formulas (I), (III) and (IV) are preferably compounds having the chemical formulas (I*), (III*) and (IV*) or an enriched mixture thereof.

[0153]

[0154] wherein R 1 is as defined for the compound having the chemical formula (I), and R 2 is a leaving group, or a salt or N-oxide thereof.

[0155] In another aspect, the present invention provides a compound having the chemical formula (IV)

[0156]

[0157] wherein R 1 is as defined for the compound of formula (I), and R 2 is a leaving group as defined below, or a salt or N-oxide thereof.

[0158] Preferably, the compound of formula (IV) is a compound having the chemical formula (IV*).

[0159] In another aspect, the present invention provides a method for preparing a compound having the chemical formula (I)

[0160]

[0161] wherein

[0162] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and

[0163] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0164] comprising

[0165] i. reacting a compound having the chemical formula (II) or a salt thereof

[0166]

[0167] wherein R 1is reacted with a compound of formula (V) as defined for a compound of formula (I)

[0168]

[0169] wherein R 7 is hydroxy or halogen or OM, where M is Na, K, Li.

[0170] The reaction is carried out in the presence of a suitable base to produce a compound of formula (VI)

[0171]

[0172] wherein R 1 is as defined for a compound of formula (I); and

[0173] ii. The compound of formula (VI) is converted to a compound of formula (I) by treating the compound of formula (VI) with an aqueous solution of a base.

[0174] Examples of suitable bases for steps i and ii and preferred bases for steps i and ii are given below.

[0175] Preferably, R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 ; and

[0176] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0177] Preferably, R 7 is hydroxy or halogen.

[0178] Also preferably, R 1 is C3-C6 cycloalkyl; and R 7 is OM, where M is Na, K, L.

[0179] In a further aspect, the present invention provides a process for preparing a compound of formula (VI) as defined above, the process comprising carrying out step i as defined above. In a further aspect, the present invention provides a process for preparing a compound of formula (I) as defined above, the process comprising carrying out step ii as defined above.

[0180] In the above method, the compounds having the chemical formulas (I), (III), and (IV) are preferably compounds having the chemical formulas (I*), (III*), and (IV*) or an enriched mixture thereof:

[0181]

[0182] wherein R 1 is as defined for the compound having the chemical formula (I), and R 7 is as defined for the compound having the chemical formula (V).

[0183] In another aspect, the present invention provides a compound having the chemical formula (VI)

[0184]

[0185] wherein R 1 is as defined for the compound having the chemical formula (I), or a salt or N-oxide thereof. Preferably, the compound having the chemical formula (VI) is a compound having the chemical formula (VI*).

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

[0187]

[0188] wherein R 7 is OLi, ONa or OK

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

[0190]

[0191] wherein R 1 is aryl or aryl substituted with one to five R 11 substituents.

[0192] Each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen.

[0193] All aspects of the present invention can also include further processing of the compound with chemical formula (I). Specifically, the method can include reacting the compound with chemical formula (I) with a second compound, wherein the second compound includes a carboxylic acid, an acyl halide, an ester or a thioester functional group, and the reaction includes reacting the amine functional group of the compound with chemical formula (I) with the carboxylic acid, an acyl halide, an ester or a thioester functional group of the second compound, so that the compound with chemical formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound includes a dicarbonate group, and the reaction includes reacting the amine functional group of the compound with chemical formula (I) with the dicarbonate group of the second compound, so that the compound with chemical formula (I) is coupled to the second compound via a carbamate functional group.

[0194] In one embodiment, the second compound is a compound having formula (XII)

[0195]

[0196] in

[0197] 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

[0198]

[0199] -B 1 -B 2 -B 3 - is -C=NO-, -C=N-CH2-, -C=CH-O- or -N-CH2-CH2-;

[0200] A 1 , A 2 , A 3 and A 4 Independently of each other are CH, CR 5 , or nitrogen;

[0201] R 3 is a C1-C8 haloalkyl group;

[0202] R 4 is aryl or is substituted by one to three R 6 Substituted aryl, or R 4 is a heterocyclic group or is replaced by one to three R 6 substituted heterocyclic group;

[0203] Each R 5independently is 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 Rs on adjacent carbon atoms 5 together form a -CH=CH-CH=CH- bridge or a -N=CH-CH=CH- bridge;

[0204] each R 6 independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy;

[0205] R 8 is hydroxy, C1-C6 alkoxy or chlorine, fluorine, bromine, or SR x wherein R x is hydrogen, C1-C6 alkyl, imidazole or pyrrole; and

[0206] each R 11 independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0207] and the method produces a compound having the formula (VIII)

[0208]

[0209] wherein A 1 、A 2 、A 3 、A 4 and X are as defined for the compound having the formula (XII), and R 1 is as defined for the compound having the formula (I).

[0210] In another embodiment, the second compound is a compound having the formula (XIII)

[0211]

[0212] wherein R 9 is hydrogen, C1-C8 alkyl or C1-C8 haloalkyl, and R 8 is as defined for the compound having the formula (XII);

[0213] and the method produces a compound having the formula (IX)

[0214]

[0215] wherein R 1 is as defined for the compound of formula (I), and R 9 is as defined for the compound of formula (XIII).

[0216] In another embodiment, the second compound is a compound of formula (XIVa) or (XIVb)

[0217]

[0218] wherein each R 10 is independently C1-C8 alkyl, C1-C8 haloalkyl, aryl-C1-C4 alkylene- or aryl-C1-C4 alkylene- substituted with one to five R 11 wherein each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0219] and the method produces a compound of formula X

[0220]

[0221] wherein R 1 is as defined for the compound of formula (I) and R 10 is as defined for the compounds of formula (XIVa) and XIVb.

[0222] In a further aspect, the present invention provides a method wherein a compound of formula (I) is reacted with a second compound, wherein the second compound comprises a carboxylic acid, acyl halide, ester or thioester functional group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the carboxylic acid, acyl halide, ester or thioester functional group of the second compound such that the compound of 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 the amine functional group of the compound of formula (I) with the dicarbonate group of the second compound such that the compound of formula (I) is coupled to the second compound via a carbamate functional group. Particularly in the method, wherein the compound of formula (I) is reacted with the second compound

[0223] wherein

[0224] the second compound is a compound of formula (XII)

[0225]

[0226] And the method generates a compound having the chemical formula (VIII)

[0227]

[0228] wherein

[0229] X is a leaving group selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 substituents, or phosphate, cyano, formyl, acetyl, C(O)CH═C(R 3 )R 4 、C(O)CH2C(OH)(R 3 )R 4 or group A

[0230]

[0231] -B 1 -B 2 -B 3 - is -C═N-O-, -C═N-CH2-, -C═CH2-O- or -N-CH2-CH2-;

[0232] A 1 、A 2 、A 3 and A 4 are each independently C-H, C-R 5 、or nitrogen;

[0233] R 3 is C1-C8 haloalkyl;

[0234] R 4 is aryl or aryl substituted with one to three R 6 substituents, or R 4 is heterocyclic or heterocyclic substituted with one to three R 6 substituents;

[0235] Each R 5 is independently 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 5 on adjacent carbon atoms together form a -CH═CH-CH═CH- bridge or a -N═CH-CH═CH- bridge;

[0236] Each R 6independently is halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy;

[0237] R 8 is hydroxy, C1-C6 alkoxy, fluorine, chlorine, bromine, or SR x wherein R x is hydrogen, C1-C6 alkyl, imidazole or pyrrole; and

[0238] each R 11 independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0239] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and

[0240] each R 11 independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0241] or

[0242] the second compound is a compound having the chemical formula (XIII)

[0243]

[0244] wherein and the method produces a compound having the chemical formula (IX)

[0245]

[0246] wherein

[0247] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and

[0248] R 9 is hydrogen, C1-C8 alkyl or C1-C8 haloalkyl and R 8 is as defined for the compound having the chemical formula (XII);

[0249] each R 11independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0250] or

[0251] the second compound is a compound having the chemical formula (XIVa) or (XIVb)

[0252]

[0253]

[0254] and the method produces a compound having the chemical formula X

[0255]

[0256] wherein

[0257] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituted aryl, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituted;

[0258] each R 10 independently is C1-C8 alkyl, C1-C8 haloalkyl, aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituted;

[0259] each R 11 independently is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen;

[0260] 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

[0261]

[0262] comprising preparing a compound having the chemical formula (I)

[0263]

[0264] The preparation is carried out according to the method described in any one of claims 1 or 2 or 3 or 4 or 6, and the compound having the chemical formula (I) is reacted with a compound having the chemical formula (XII)

[0265]

[0266] Wherein

[0267] X is a leaving group selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 groups, or phosphate, cyano, formyl, acetyl, C(O)CH═C(R 3 )R 4 , C(O)CH2C(OH)(R 3 )R 4 or group A

[0268]

[0269] -B 1 -B 2 -B 3 - is -C═N-O-, -C═N-CH2-, -C═CH2-O- or -N-CH2-CH2-;

[0270] A 1 、A 2 、A 3 and A 4 are each independently C-H, C-R 5 、or nitrogen;

[0271] R 3 is C1-C8 haloalkyl;

[0272] R 4 is aryl or aryl substituted with one to three R 6 groups, or R 4 is heterocyclic or heterocyclic substituted with one to three R 6 groups;

[0273] Each R 5 is independently 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 5 on adjacent carbon atoms together form a -CH═CH-CH═CH- bridge or a -N═CH-CH═CH- bridge;

[0274] Each R 6 is independently halogen, cyano, nitro, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy;

[0275] R8 is hydroxy, C1-C6 alkoxy, chlorine, fluorine, bromine, or SR x , wherein R x is hydrogen, C1-C6 alkyl, imidazole or pyrrole;

[0276] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents; and

[0277] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen.

[0278] The compounds of the present invention can exist in different geometric or optical isomers or tautomeric forms. Specifically, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist as enantiomers (or diastereomeric pairs) or as mixtures thereof. The present invention encompasses all such isomers and tautomers and mixtures thereof in all proportions, together with isotopic forms, such as deuterated compounds. The compounds and the methods of the present invention include N-oxides and salts where possible.

[0279] Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, 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 with one to four substituents, most preferably with one to three substituents.

[0280] Alkylene groups can be in straight-chain or branched form and are, 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 group. When an alkylene moiety is considered to be substituted, the alkyl moiety is preferably substituted with one to four substituents, most preferably with one to three substituents.

[0281] The alkenyl group can be in a straight-chain or branched form and can be (where appropriate) of the (E)- or (Z)-configuration. 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 with one to four substituents, most preferably with one to three substituents.

[0282] The alkynyl group can be in a straight-chain or branched form. Examples are ethynyl and propargyl. These alkynyl 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 with one to four substituents, most preferably with one to three substituents.

[0283] Halogen is fluorine, chlorine, bromine or iodine.

[0284] The haloalkyl group (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-) is an alkyl group substituted by one or more identical or different halogen atoms and is, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoroethyl.

[0285] The haloalkenyl group is an alkenyl group substituted by one or more identical or different halogen atoms and is, for example, 2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.

[0286] The haloalkynyl group is an alkynyl group substituted by one or more identical or different halogen atoms and is, for example, 1-chloro-prop-2-ynyl.

[0287] The cycloalkyl group or carbocycle can be in a mono- or bi-cyclic form and is, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-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, most preferably by one to three substituents.

[0288] The aryl group (either alone or as part of a larger group, such as aryl-alkylene-) is in the form of an aromatic ring and can be in a mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthryl, indenyl or phenanthryl. Preferred aryls are phenyl and naphthyl, with phenyl being most preferred. When an aryl moiety is considered to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.

[0289] A heteroaryl group (either alone or as part of a larger group, such as heteroaryl-alkylene-) is an aromatic ring system that includes at least one heteroatom and consists of a single ring or two or more fused rings. Preferably, the monocyclic ring will contain up to three heteroatoms and the bicyclic system contains up to four heteroatoms, which are preferably selected from nitrogen, oxygen, and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g., 1,2,4-triazolyl), furyl, benzothienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, and thiadiazolyl. Examples of bicyclic groups include purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzobenzothienyl, and benzothiazolyl. Monocyclic heteroaryl groups are preferred, and pyridyl is most preferred. Where the heteroaryl moiety is considered to be substituted, the heteroaryl moiety is preferably substituted with one to four substituents, most preferably with one to three substituents.

[0290] A heteroaryl group or heterocycle (either alone or as part of a larger group, such as heterocyclyl-alkylene-) is defined to include heteroaryl groups and also their unsaturated or partially unsaturated analogs. Examples of monocyclic groups include isoxazolyl, thiacyclobutane, pyrrolidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, dihydrothiophene, [1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, morpholinyl, thiophene, oxetanyl, tetrahydrofuryl, 3-oxo-isoxazolidinyl-, 2,5-dioxo-1-pyrrolidinyl-, 2-oxo-1-pyrrolidinyl-, 4-oxo-1,3-oxazinanyl, 1-oxa-3,4-diazolyl, including their oxidized forms, such as 1-oxo-thiacyclobutane and 1,1-dioxo-thiacyclobutane, 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]dioxolanyl, benzo[1,3]dioxolanyl, chromanyl, and 2,3-dihydro-benzo-[1,4]-dioxinyl. Where the heterocyclyl moiety is considered to be substituted, the heterocyclyl moiety is preferably substituted with one to four substituents, most preferably with one to three substituents. The heterocyclyl groups (and heteroaryl groups) according to the present invention do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent sulfur and oxygen atoms. Preferred heterocyclyl groups are thiophene, thiophene 1-oxide, thiophene 1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide, dihydrothiophene 1,1-dioxide, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, imidazolyl, and triazolyl.

[0291] The leaving groups according to the present invention include halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy, C1-C8 arylsulfonyloxy or C1-C8 arylsulfonyloxy substituted with one to five R 11 , where each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen (the aryl is preferably phenyl), and phosphate esters (e.g., -OP(O)(OR)2, where R is methyl or ethyl). Preferably the leaving group is halogen, specifically chlorine or bromine.

[0292] The preferred definitions are in any combination, as shown below.

[0293] Preferably A 1 is C-R 5 .

[0294] Preferably A 2 , A 3 , A 4 are each CH.

[0295] Preferably -B 1 -B 2 -B 3 - is -C=N-O-.

[0296] Preferably, R 1 is C1-C8 alkyl, C1-C8 haloalkyl, more preferably ethyl or trifluoroethyl, even more preferably ethyl or 2,2,2-trifluoroethyl.

[0297] Preferably, R 2 is chlorine or bromine, more preferably chlorine.

[0298] Preferably, R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl, most preferably trifluoromethyl.

[0299] Preferably, R 4 is the group (B)

[0300]

[0301] where X 2 is C-X 4 or nitrogen (preferably C-X 4 ); X 1 , X 3 and X 4 are each independently hydrogen, halogen or trihalomethyl, for example where at least two of X 1 , X 3 and X 4 are not hydrogen.

[0302] Preferably, R 4 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-dichlorophenyl, 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 one group of compounds, R 4 is 3,5-dichlorophenyl. In one group of compounds, R 4 is 3,5-dichloro-4-fluorophenyl-. In one group of compounds, R 4 is 3,4,5-trichlorophenyl-. In one group of compounds, R 4 is 3,5-bis(trifluoromethyl)phenyl.

[0303] Preferably each R 5 is independently halogen, cyano, methyl, halomethyl, methoxy or halomethoxy, more preferably chlorine, fluorine, cyano or methyl.

[0304] Preferably each R 6 is independently halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkylthio, or C1-C8 haloalkylthio, more preferably bromine, chlorine, fluorine, trifluoromethyl, methoxy, or methylthio, most preferably trifluoromethyl, fluorine or chlorine.

[0305] Preferably, R 7 is hydroxy, ONa, OLi, OK, chlorine or bromine, more preferably ONa, OLi or chlorine.

[0306] Preferably, R 8 is hydroxy, chlorine or bromine, more preferably chlorine.

[0307] Preferably, R 9 is hydrogen or a C1-C6 alkyl group, more preferably methyl.

[0308] Preferably each R 10 is independently a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, most preferably tert-butyl.

[0309] In a preferred embodiment, the compounds having the chemical formulas (I), (II), (III) and (IV) are compounds wherein R 1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl), and R 2 is chlorine or bromine, preferably chlorine.

[0310] In another preferred embodiment, the compound having the chemical formula (IV) is a compound wherein R 1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R 2 is chlorine or bromine, preferably chlorine.

[0311] In another preferred embodiment, the compounds having the chemical formulas (I), (II), (III) and (IV) are compounds wherein R 1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R 7 is hydroxy, ONa, OLi or chlorine.

[0312] In another preferred embodiment, the compounds having the chemical formulas (I), (II) and (VI) are compounds wherein R 1 is ethyl, trifluoroethyl or phenyl.

[0313] In another preferred embodiment, the compound having the chemical formula (VI) is a compound wherein R 1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl)

[0314] In another preferred embodiment, the compounds having the chemical formulas (VIII) and (XII) are compounds wherein

[0315] A 1 is C-R 5 ;

[0316] A 2 、A3 and A 4 are each CH;

[0317] R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;

[0318] X is chlorine, bromine, cyano, formyl, acetyl, C(O)CH═C(R 3 )R 4 , C(O)CH2C(OH)(R 3 )R 4 or a group (A) as defined above;

[0319] R 4 is a group (B) as defined above;

[0320] X 2 is C-X 4 or nitrogen (preferably C-X 4 ); X 1 , X 3 and X 4 are each independently, halogen or trihalomethyl;

[0321] Each R 5 is independently halogen, cyano, methyl, halomethyl, methoxy or halomethoxy, more preferably chlorine, fluorine, cyano or methyl.

[0322] In another preferred embodiment, the compounds having the formulas (VIII) and (XII) are compounds wherein

[0323] X is acetyl, C(O)CH═C(R 3 )R 4 , C(O)CH2C(OH)(R 3 )R 4 or group (A);

[0324] A 1 is C-R 5 ;

[0325] A 2 、A 3 、A 4 are each CH;

[0326] X is group (A)

[0327]

[0328] -B 1 -B 2 -B 3- is -C=N-O-, -C=N-CH2-, -C=CH-O- or -N-CH2-CH2-, preferably -C=N-O-;

[0329] R 1 is C1-C8 alkyl, C1-C8 haloalkyl, aryl or aryl substituted with one to five R 11 substituents, or aryl-C1-C4 alkylene or aryl-C1-C4 alkylene substituted with one to five R 11 substituents;

[0330] R 3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;

[0331] R 4 is group (B)

[0332]

[0333] wherein X 2 is C-X 4 or nitrogen, X 1 、X 3 and X 4 are each independently hydrogen, halogen or trihalomethyl,

[0334] R 5 is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy;

[0335] each R 11 is independently C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano or halogen.

[0336] In a preferred embodiment, the compounds having the chemical formulas (IX) and (XIII) are compounds wherein R 9 is C1-C6 alkyl.

[0337] In a preferred embodiment, the compounds having the chemical formulas (X) and (XIV) are compounds wherein each R 10 is C1-C6 alkyl, preferably tert-butyl.

[0338] In the enrichment mixture of the present invention, the molar ratio of the compounds having the chemical formulas (I*), (III*), (IV*), (V*), and / or (VI*) in the mixture is, for example, greater than 50%, for example, at least 60%, 70%, 80%, 90% or at least 95% of the total molar amount of the enantiomeric pair.

[0339] The following scheme describes the reaction of the present invention in more detail. The substituent definitions are the same as those defined above.

[0340] Scheme 1

[0341]

[0342] Step a

[0343] The compound having the chemical formula (I) can be prepared by reacting a compound having the chemical formula (III) with a compound having the formula (II) or a salt thereof. Suitable salts of the compound having the formula (II) include, but are not limited to, halides, organic acids, and sulfur-based salts, such as chlorides, oxalates, sulfates, trifluoroacetates, methanesulfonates, and bromides.

[0344] The reaction of the compounds having the chemical formulas (III) and II is preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to, nitrogenous organic bases, such as amines, pyridines, and their derivatives, such as triethylamine, tri-n-propylamine, pyridine, and diisopropylethylamine.

[0345] The reaction of the compounds having the chemical formulas III and II is 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. It is also possible to carry out this reaction in a mixture of an organic solvent and water.

[0346] This reaction can be carried out at a temperature 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).

[0347] The reaction of the compounds having the chemical formulas (III) and II is 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-alkylimidazole, phosphines, imidazolium carbenes, 1,2-diamines, bicyclic amidines, isothioureas, and guanidines, triazoles, suitable alcohols, iodide, and cyanide salts, preferably 4-dimethylaminopyridine.

[0348] Step a-1

[0349] The compound having the chemical formula (IV) can be prepared by reacting a compound having the chemical formula (III) with a compound having the formula (II) or a salt thereof as described under step a.

[0350] 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. It is also possible to carry out the reaction in a mixture of organic solvents or in a mixture of an organic solvent and water.

[0351] 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, trifluoroacetic acid. A preferred acid is acetic acid.

[0352] The reaction can be carried out at a temperature 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).

[0353] Depending on the conditions used, it may be advantageous to isolate compound IV as the corresponding salt. The salt can be formed together with the acid already present in the reaction mixture or by adding an additional acid to the reaction mixture. Suitable acids include mineral acids and organic acids such as HCl, HBr, sulfuric acid, acetic acid and trifluoroacetic acid.

[0354] Step a-2

[0355] The compound of formula (I) can be prepared by treating the compound of formula (IV) or its salt with a base as described in step a-1. Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridine and its derivatives such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, diisopropylethylamine.

[0356] 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, diglyme, tert-butyl methyl 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; ethers such as anisole, non-polar solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols such as methanol, ethanol, isopropanol, tert-butanol, cyclohexanol, heptanol, octanol, or longer-chain alcohols, and diglycol. Preferred organic solvents include tetrahydrofuran, dioxane and acetonitrile.

[0357] The reaction can be carried out at a temperature from -20 °C to 100 °C, preferably from 0 °C to 30 °C.

[0358] The compound having the chemical formula (I) can be isolated in a free form or as a salt formed by adding an acid to the compound having the chemical formula (I) in the free base form. Suitable acids include mineral acids and organic acids such as HCl, HBr, sulfuric acid, acetic acid, and trifluoroacetic acid.

[0359] When the compounds having the chemical formula (II) and the chemical formula (III) react under acidic conditions as described for step a-1, the compound having the chemical formula (IV) is isolated. As described for step a-2, the compound having the chemical formula (IV) is treated under basic conditions to form the compound having the chemical formula (I).

[0360] When the compounds having the chemical formula (II) and the chemical formula (III) react under basic conditions as described for step a, the intermediate compound having the chemical formula (IV) cannot be isolated and the compound having the chemical formula (I) is directly formed.

[0361] Steps 1-1, 1-2 and 1-3

[0362] This is described in Scheme 3 below. Steps a and 1-1, 1-2, and 1-3 can be carried out in the same reaction vessel (one-pot reaction) without isolating the compound having the chemical formula (I), for example when the solvent is chloroform. In other words, the compounds having the chemical formula (VIII), (IX), and (X) can be prepared from the compound having the chemical formula (III) without isolating the compound having the 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 isolating the compound having the chemical formula (I).

[0363] Scheme 2

[0364]

[0365] Step i-a

[0366] The compound having the chemical formula (Va) can be prepared from the compound having the chemical formula (XI) by treatment with phosgene or its derivatives such as dichlorophosgene, trichlorophosgene, ethyl chloroformate, benzyl chloroformate in the presence of an aqueous solution of a base following a similar procedure described in Synthetic Comm 1993, 23, 2839, which is incorporated herein by reference.

[0367] Step i

[0368] A compound of formula (VI) can be prepared by reacting a compound of formula (Va) with a compound of formula (II). Preferably, the reaction involves preparing the corresponding acid halide (preferably an acyl chloride) of the compound of formula (Va), compound (Vb), wherein R 7 is a halogen, to facilitate the conversion to the compound of formula (VI). The acyl halide, compound (Vb), wherein R 7 is a halogen, can be prepared from the compound of formula (Va) under conditions well known to those of ordinary skill in the art, for example, by treating with thionyl chloride, oxalyl chloride, phosgene, dichlorophosgene or trichlorophosgene.

[0369] Alternatively, compound (Vb), wherein R 7 is a halogen, can be prepared from the alkali metal (Li, Na, K) salt of the compound of formula (Va), compound (Vc), by treating with oxalyl chloride, thionyl chloride, phosgene, dichlorophosgene or trichlorophosgene in the presence of a phase transfer catalyst. Suitable phase transfer catalysts include, but are not limited to, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylammonium chloride, 336 and (1 - hexadecyl)trimethylammonium chloride

[0370] Scheme 2a

[0371]

[0372] The alkali metal salt of the compound of formula (V), wherein M is Li, Na or K, compound Vc, can be prepared as shown in Scheme 2a.

[0373] Steps iii and iv

[0374] The compound of formula (Vc), wherein M is Li, Na or K, can be prepared by treating a compound of formula (XV), wherein R 12 is a C1 - C4 alkyl group, or by treating a compound of formula (XVI), wherein R 13 is a C1 - C4 alkyl group, benzyl or phenyl, with LiOH, NaOH or KOH. Suitable solvents include, but are not limited to, alcohols such as ethanol, methanol, isopropanol; polar organic solvents such as acetonitrile, dioxane, THF, 2 - methyl - THF together with water. Preferred solvents are ethanol and acetonitrile.

[0375] The acyl halide of the compound of formula (V), compound (Vb)_, wherein R 7It 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, pyridine and its derivatives such as triethylamine, tripropylamine, pyridine, diisopropylethylamine, Na2CO3, NaHCO3, NaOH and N-methylmorpholine.

[0376] The acyl halide of the compound having the chemical formula (V), compound Vb, wherein R 7 It 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.

[0377] Suitable solvents include, but are not limited to, ethers such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diglyme, tert-butyl methyl 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; anisole, polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone and dimethylacetamide; or a water / biphasic system (as known under the so-called Schotten Baumann conditions) together with hydrocarbons such as toluene and xylene, as pure isomers, and mixtures of isomers.

[0378] The compound having the chemical formula (II) can be used as such or in the form of their salts with acids, such as HCl, HBr, trifluoroacetic acid, oxalic acid, sulfuric acid and methanesulfonic acid.

[0379] The reaction can be carried out at a temperature ranging from -20 °C to 100 °C, preferably from -10 °C to 30 °C, specifically between -5 °C and +10 °C. More preferably, the reaction can be carried out at a temperature from 0 °C to +10 °C.

[0380] Alternatively, it is possible to carry out the reaction 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.

[0381] Alternatively, the reaction of the compound of formula (V) with the compound of formula (II) can be carried out in the presence of a coupling agent such as N,N'-dicyclohexylcarbodiimide ("DCC"), 1-ethyl-3-(3-dimethylaminopropyl)phosphonium chloride ("EDC") or bis(2-oxo-3-oxazolidinyl)phosphonium chloride ("BOP-Cl"), in the presence of a base, and optionally in the presence of a nucleophilic catalyst such as hydroxybenzotriazole ("HOBT").

[0382] Suitable bases include carbonates, hydroxides, nitrogenous organic bases such as amines, pyridine and its derivatives such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0383] Examples of suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diglyme, tert-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone, 2-butanone, methyl isobutyl ketone; anisole, polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, hydrocarbons such as toluene and xylene, as pure isomers, and as mixtures of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, 2-methyl-THF or dioxane.

[0384] The reaction can be carried out at a temperature from -20 °C to 100 °C, preferably from -10 °C to 30 °C, specifically from -5 °C to +5 °C, more preferably from 0 °C to +5 °C.

[0385] Step ii

[0386] The compound of formula (I) can be prepared by treating the compound of formula (VI) with a base. Suitable bases include carbonates, hydroxides, nitrogenous organic bases such as amines, pyridine and its derivatives such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0387] It is possible to carry out the reaction in a mixture of an organic solvent and water or in water alone. Preferably, the reaction involves the presence of water.

[0388] Examples of organic solvents include ethers such as diethyl ether, 1,2 - dimethoxyethane, diethoxymethane, diethylene glycol dimethyl ether, tert - butyl methyl ether, THF, 2 - methyl - THF, dioxane; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4 - fluorotoluene; esters and ketones such as ethyl acetate, acetone, 2 - butanone, methyl isobutyl ketone; anisole, polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N - methylpyrrolidone, 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, DMF.

[0389] Alternatively, it is possible to conduct the reaction in a biphasic system comprising an organic solvent immiscible with water (preferably ethyl acetate, 2 - methyltetrahydrofuran or dichloromethane) as described above under step ii, and an aqueous solvent (preferably a solution of sodium bicarbonate or sodium carbonate or an organic amine such as triethylamine or diisopropylethylamine). It is also possible to conduct the reaction in an aqueous solvent without adding a base.

[0390] The reaction can be carried out at a temperature 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.

[0391] The compound having formula (I) can be isolated in a free form or as a salt formed by adding an acid to the compound having formula (I) in the 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.

[0392] Steps 1-1, 1-2 and 1-3

[0393] 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 isolating the compound having formula (I). In other words, the compounds having formula (VIII), (IX), and (X) can be prepared from the compound having formula (V) without isolating the compounds having formula (VI) or (I).

[0394] Scheme 3

[0395]

[0396] Step 1-1

[0397] The compound of formula (VIII) can be prepared by reacting a compound (I) having a chemical formula with a compound of formula (XII), wherein the substituents are as defined herein. When R 8 is a hydroxyl group, 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)phosphinyl chloride ("BOP-Cl"), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole ("HOBT").

[0398] Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases, such as amines, pyridine and its derivatives, such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0399] 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-methyl THF, dioxane, dimethoxyethane, toluene, acetonitrile and xylene, preferably chloroform, dichloromethane or THF.

[0400] When R 8 is chlorine, such reactions are typically carried out in the presence of a base and optionally in the presence of a nucleophilic catalyst, such as 4-dimethylaminopyridine ("DMAP").

[0401] Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases, such as amines, pyridine and its derivatives, such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0402] Examples of solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diethoxymethane, diglyme, tert-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated hydrocarbon solvents, such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones, such as ethyl acetate, acetone 2-butanone, methyl isobutyl ketone; anisole, polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone and dimethylacetamide, aromatic hydrocarbons, such as toluene and xylene, as pure isomers, and as mixtures of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, 2-methyltetrahydrofuran or dioxane.

[0403] Alternatively, it is possible to carry out the reaction in a biphasic system comprising an organic solvent (preferably ethyl acetate, toluene, xylene, as a single isomer or as 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).

[0404] The reaction can be carried out at a temperature 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).

[0405] Step 1-2

[0406] A compound having the formula (IX), wherein R 9 as defined above, can be prepared by reacting a compound having the formula (I) with a compound having the formula (XIII) under the conditions described under 1-1, wherein the substituents are as defined herein disclosed.

[0407] Step 1-3

[0408] A compound having the formula X can be prepared by reacting a compound having the formula (I) with a compound according to formula (XIVa) or (XIVb). In the presence of a base, an example of a compound according to formula (XIVa) is di-tert-butyl dicarbonate. Suitable bases include carbonates, hydroxides, nitrogen-containing organic bases such as amines, pyridine and its derivatives, such as Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine.

[0409] 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, dioxane; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone 2-butanone, methyl isobutyl ketone; anisole, polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols such as methanol, ethanol, propanol, t-BuOH, cyclohexanol, heptanol, octanol, or longer-chain alcohols, and diethylene glycol; aromatic hydrocarbons such as toluene and xylene, as pure isomers, and as mixtures of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, or dioxane. Alternatively, it is also possible to carry out the reaction in a mixture of these solvents and water.

[0410] Alternatively, it is possible to carry out the reaction in a biphasic system comprising an organic solvent (preferably ethyl acetate, toluene, xylene or dichloromethane) as described above under 1 - 3, and an aqueous solvent (preferably a solution of sodium bicarbonate or sodium carbonate).

[0411] The reaction can be carried out at a temperature 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).

[0412] Scheme 4

[0413]

[0414] Scheme 4 illustrates how a compound of formula (VIII) can react to produce a compound having insecticidal activity as described in WO2011 / 067272 and WO 2013 / 069731, with the reaction conditions described therein. Other methods of using the present invention to arrive at a compound of formula (VIIIc) will be apparent to those of ordinary skill in the art and are also described in WO 2011 / 067272.

[0415] Possible combinations of substituents are shown in Table 1.

[0416] Table 1

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427] Unless otherwise stated, in all reactions the pressure is preferably atmospheric pressure.

[0428] Among them, the temperature is specified to be from X to Y, and X and Y are included in the temperature range.

[0429] When the compounds of formula (I), (III), (IV), (V) and (VI) are the compounds of formula (I*), (III*), (IV*), (V*) and (VI*), the reaction conditions described above are also applicable.

[0430] The present invention will now be described by way of non-limiting examples.

[0431] Example

[0432] Example 1: Preparation of (R)-4-amino-2-ethylisoxazolidin-3-one

[0433]

[0434] At ambient temperature, triethylamine (9.8 ml, 70.2 mmol) was added dropwise to a solution of N-ethyl(hydroxy)oxalamide (5.5 g, 25.7 mmol) in a mixture of ethanol (70 ml) and water (14 ml), and the solution was stirred for 15 min. (S)-4-(Chloromethyl)oxazolidine-2,5-dione (7.0 g, 46.8 mmol) was added in portions. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to give a residue which was purified by trituration with DCM (300 ml) to give (R)-4-amino-2-ethylisoxazolidin-3-one (3.6 g) as a white solid. 1 1H 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).

[0435] Example 2: Preparation of (R)-4-amino-2-ethylisoxazolidin-3-one

[0436]

[0437] At room temperature, (S)-4-(Chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) was added slowly (in portions) to a solution of N-ethyl(hydroxy)oxalamide (0.42 g, 1.8 mmol) and triethylamine (0.7 ml, 5.0 mmol) in chloroform (3 ml). The resulting reaction mixture was stirred at room temperature for 1 h and then at 50 °C for 1.5 h. The reaction mixture was evaporated under reduced pressure and the desired product was isolated by trituration with DCM to give (R)-4-amino-2-ethylisoxazolidin-3-one (196 mg) as a white solid. 11H 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).

[0438] Example 3: 4-Acetyl-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl)]-2-methyl-benzamide

[0439]

[0440] To a suspension of 4-acetyl-2-methyl-benzoic acid (5.0 g, 28 mmol) in dichloromethane (20 ml) was added dimethylformamide (0.2 ml), followed by dropwise addition of oxalyl chloride (4.6 g, 36.48 mmol). The reaction mixture was stirred at ambient temperature until gas evolution ceased (about 4 h). The solvent was evaporated under reduced pressure to afford crude 4-acetyl-2-methyl-benzoyl chloride, which was diluted with acetonitrile (20 ml). At 0 °C, the solution prepared above was added dropwise to a solution of (R)-4-amino-2-ethyl-isoxazolidin-3-one (4.6 g, 36 mmol) and potassium carbonate (15.0 g, 110 mmol) in acetonitrile (80 ml). The reaction mixture was allowed to warm 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 afford 4-acetyl-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl)]-2-methyl-benzamide (4.3 g) as a pale yellow solid. 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%)

[0441] 1 1H 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).

[0442] Example 4: Preparation of tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (one-pot method, steps a and 1-3)

[0443]

[0444] A solution of N-ethyl(hydroxy)oxalamide (0.16 g, 0.74 mmol) in a mixture of ethanol (2 ml) and water (0.5 ml) was treated with N,N-diisopropylethylamine (0.26 g, 2 mmol) at room temperature for 10 min. At 0 °C, (S)-4-(chloromethyl)oxazolidine-2,5-dione (0.2 g, 1.34 mmol) in ethanol (3 ml) was added in one portion. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to afford crude 4-amino-2-ethylisoxazolidin-3-one as a pale yellow gum, which was 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 and stirred for an additional 5 h before evaporation under reduced pressure. 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 afford tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.16 g) as a colorless liquid. 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%)).

[0445] 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)

[0446] Example 5: Preparation of (2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamide hydrochloride

[0447]

[0448] Acetic acid (2 ml) was added to a mixture of (S)-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 afford 985 mg of the title compound (75% quantitative NMR mass purity) as a white solid.

[0449] 1 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.

[0450] 19 19F NMR (400 MHz, DMSO) δ = -69.2 ppm.

[0451] Example 6: Preparation of (4R)-4-amino-2-(2,2,2-trifluoroethyl)isoxazolidin-3-one

[0452]

[0453] (2S)-2-Amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (0.10 g, 0.27 mmol, 75% 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 mass purity).

[0454] 1 1H NMR (400 MHz, CD3CN) δ 4.48 (t, 1H), 4.23 - 4.05 (m, 2H), 3.92 - 3.81 (m, 2H).

[0455] 19 19F NMR (400 MHz, DMSO) δ = -69.2 ppm.

[0456] Example 7: 4-Acetyl-2-methyl-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl]benz amide

[0457]

[0458] (2S)-2-Amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (150 mg, 0.43 mmol, 75% purity), 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-methyl-benzoyl chloride (138 mg, 0.70 mmol) in acetonitrile (2 ml) was added dropwise at 0 °C and then the reaction mixture was allowed to warm 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 afford 4-acetyl-2-methyl-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl]benzamide (107 mg) as a white solid. 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%).

[0459] 1 HNMR(CDCl3):δ7.82(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.

[0460] 19 F NMR(CDCl3):δ - 70.28ppm

[0461] Example 8: Preparation of (4R)-N-ethyl-N-hydroxy-2-oxo-isoxazolidine-4-carboxamide

[0462]

[0463] To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (0.500 g, 3.81 mmol) in 1,2-dichloroethane (5 ml) was added 3 drops of dimethylformamide, followed by dropwise addition of oxalyl chloride (0.543 g, 4.20 mmol). The reaction mixture was stirred at ambient temperature until gas evolution ceased (about 1 h). The solution prepared above was added dropwise at 0 °C to a solution of N-ethyl(hydroxy)oxalamide (0.874 g, 4.12 mmol) and triethylamine (1.38 g, 13.5 mmol) in 1,2-dichloroethane (5 ml). Before evaporation under reduced pressure, the reaction mixture was allowed to warm to room temperature and was additionally stirred for 2 h. 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 afford (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.409 g) as a pale yellow solid. Chiral HPLC analysis (Chiralpack IC, ethanol:2-propanol = 05:95, 1 ml / min, retention time 4.54 min (only enantiomer).

[0464] 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)

[0465] Example 9: Preparation of (4R)-4-amino-2-ethyl-isoxazolidin-3-one

[0466]

[0467] To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.030 g, 0.172 mmol) in THF (0.4 ml) and water (0.13 ml) was added triethylamine (0.035 g, 0.34 mmol), 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 afford (4R)-4-amino-2-ethyl-isoxazolidin-3-one (0.0175 g) as a white solid.

[0468] 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).

[0469] Example 10: Preparation of tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate

[0470]

[0471] To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml) was added triethylamine (0.117 g, 1.15 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 afford tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.0850 g) as a white crystalline solid. 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 (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)

[0472] Alternatively, the title compound can be obtained by carrying out the following procedure:

[0473] To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml) was added 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 afford tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.070 g) as a white crystalline solid. 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%)).

[0474] Example 11: ( Preparation of (4R)-N-hydroxy-2-oxo-N-phenyl-isoxazolidine-4-carboxamide

[0475]

[0476] To a suspension of (4R)-2-oxo-oxazolidine-4-carboxylic acid (0.150 g, 1.14 mmol) in dry THF (1.5 ml) was added dropwise dimethylformamide, followed by dropwise addition of oxalyl chloride (0.11 ml, 1.25 mmol). The reaction mixture was stirred at ambient temperature for 20 min. At 0 °C, the solution prepared above was added dropwise to a suspension of N-phenylhydroxylamine (0.158 g, 1.37 mmol) and Na2CO3 (0.182 g, 1.72 mmol) 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. The 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 afford (4R)-N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide (0.1802 g) as a beige solid.

[0477] 11H 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).

[0478] Example 12: Preparation of tert-butyl N-[(4R)-3-oxo-2-phenyl-isoxazolidin-4-yl]carbamate

[0479]

[0480] 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) was added triethylamine (0.127 ml, 0.900 mmol). The resulting solution was stirred in a sealed vial at 70 °C for 2.5 h. 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 an additional 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 afford tert-butyl N-[(4R)-3-oxo-2-phenyl-isoxazolidin-4-yl]carbamate (0.0902 g) as a beige solid.

[0481] 1 1H 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).

[0482] Example 13: Preparation of N-hydroxy-N-methyl-2-oxo-isoxazolidine-4-carboxamide

[0483]

[0484] A drop of dimethylformamide was added to a suspension of 2 - oxo - oxazolidine - 4 - carboxylic acid (0.200 g, 1.53 mmol) in dry 1,2 - dichloroethane (2.0 ml), and then oxalyl chloride (0.144 ml, 1.68 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 30 minutes. 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 heated at 50 °C for 10 min, and the remaining precipitate was filtered off. The filtrate was evaporated under reduced pressure to afford a crude product as a viscous yellow oil. Purification by silica gel chromatography (0 - 10% MeOH in DCM) provided N - hydroxy - N - methyl - 2 - oxo - oxazolidine - 4 - carboxamide (0.120 g) as a colorless oil, which solidified upon standing.

[0485] 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).

[0486] Example 14: Preparation of tert-butyl N-(2-methyl-3-oxo-isoxazolidin-4-yl)carbamate

[0487]

[0488] 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 afford tert - butyl N - (2 - methyl - 3 - oxo - isoxazolidin - 4 - yl)carbamate (0.0546 g) as a white powder.

[0489] 11H 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).

[0490] Example 15: Preparation of (4R)-N-ethyl-N-hydroxy-2-oxo-isoxazolidine-4-carboxamide

[0491]

[0492] At 0 °C, three drops of DMF were added to a suspension of (4R)-2-oxazolidine-4-carboxylic acid (10.0 g, 75.9 mmol) in dry THF (50 ml), followed by dropwise addition of oxalyl chloride (7.31 ml, 83.5 mmol). After the addition, the reaction mixture was stirred for an additional 30 min at ambient temperature. 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, over 45 min, the solution of the acyl chloride prepared above was added to the thick white suspension thus formed. After completion of the addition, the reaction mixture was warmed to ambient temperature, additional THF (50 ml) 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 afford the crude product (15.9 g). Quantitative NMR analysis using trimethoxybenzene as an internal standard indicated that the mixture contained (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (11.39 g) as the major component. The crude product was crystallized from methanol to afford (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (8.86 g) as a white powder.

[0493] 1 1H NMR (400 MHz, D2O) δ 5.01 (dd, J = 9.9, 5.9 Hz), 4.77 (t, J = 9.2 Hz, 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).

[0494] Example 16: Preparation of (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride

[0495]

[0496] To a suspension of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (13.09 g, 74.8 mmol) in water (35 ml) was added triethylamine (1.05 ml, 7.48 mmol), and the resulting mixture was heated at 70 °C for 2 h (a clear solution at this temperature). The reaction mixture was cooled to ambient temperature, and 37% aqueous HCl (7.5 ml, 89.7 mmol) was added slowly. The resulting mixture was evaporated under reduced pressure and the residue was dried in vacuo to afford (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride (13.6 g) as a white powder admixed with 10% of triethylamine hydrochloride. The stereochemical integrity was checked by treating the hydrochloride with triethylamine (1.1 eq) and di-tert-butyl dicarbonate (1.2 eq) in THF and converting a small portion of the product to tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-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%)) 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).

[0497] Alternatively, the title compound can be obtained by carrying out the following procedure:

[0498] At 0 - 5 °C, (4R)-2-oxo-oxazolidine-4-sodium carboxylate (10.06 g, 85.1% purity, 55.9 mmol) and A suspension of 336 (0.56 g, 1.39 mmol) in 2-methyl-tetrahydrofuran (70 ml) was sequentially treated with N,N-dimethylformamide (0.21 g, 2.87 mmol) and oxalyl chloride (8.58 g, 67.6 mmol). The reaction mixture was stirred at ambient temperature for 90 min and added dropwise at -5 °C to a suspension of triethylamine (13.1 g, 0.129 mol) and N-ethylhydroxylamine hydrochloride (4.99 g, 89.9% purity, 0.046 mol) in 2-methyl-tetrahydrofuran (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 layers containing the intermediate (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide were heated to 45 °C, treated with aqueous NaOH (30% (w / w) solution, 2.95 g, 22.1 mmol), and stirred for an additional 60 min. A portion of water (35 g) was removed by distillation and the mixture was treated with aqueous HCl (32% (w / w), 9.3 g, 81.6 mmol) to reach pH 1. Distillation was continued until the crude (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride (56 g, approximately 9% solution in water, analyzed by quantitative 1 H-NMR analysis) was obtained.

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

[0500] (4R)-Sodium 2-oxo-oxazolidine-4-carboxylate (10.0 g, 95.0% purity, 62.1 mmol) and A suspension of 336 (0.66 g, 1.63 mmol) in ethyl acetate (80 ml) was sequentially treated with HCl (4 M solution in dioxane, 3.1 ml, 12.4 mmol) and N,N-dimethylformamide (0.23 g, 3.15 mmol). At 10 °C - 15 °C, within 70 min, the resulting mixture was treated with a solution of thionyl chloride (9.0 g, 75.6 mmol) in ethyl acetate (10 ml), stirred for an additional 2 h at ambient temperature, and added dropwise at 0 - 5 °C to a suspension of triethylamine (15.4 g, 0.152 mol) and N-ethylhydroxylamine hydrochloride (6.4 g, 77.0% purity, 50.5 mmol) in ethyl acetate (65 ml). The resulting brown mixture was stirred for 60 min at ambient temperature and washed with water (2 x 50 ml). The combined aqueous layers containing the intermediate (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide were heated to 40 °C, treated with aqueous NaOH (30% (w / w) solution, 13.6 g, 0.102 mmol), and stirred for an additional 60 min. A portion of water (25 g) was removed by distillation, and the mixture was treated with aqueous HCl (32% (w / w) solution, 12.2 g, 0.107 mmol) to reach pH 1. The mixture was evaporated to dryness to afford crude (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride as an orange solid (27.1 g, approximately 11.8% purity, as determined by 1 HNMR analysis).

[0501] Example 17: Preparation of (4R)-N-phenyl-N-hydroxy-2-oxo-isoxazolidine-4-carboxamide

[0502]

[0503] At 0 °C, 2 drops of DMF were added to a solution of (4R)-2-oxo-oxazolidine-4-carboxylic acid (0.300 g, 2.29 mmol) in dry tetrahydrofuran (3.0 ml), followed by oxalyl chloride (0.22 ml, 2.52 mmol). After stirring for 20 min at rt, the resulting solution was slowly added at 0 °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 for 2 h at rt. 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 afford (4R)-N-phenyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide as a white powder (0.393 g).

[0504] 1 1H NMR (400 MHz, CD3OD) δ 7.38 - 7.27 (m, 5H), 4.88 (dd, J = 9.7, 5.3 Hz, 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).

[0505] Example 18: Preparation of tert-butyl N-[(4R)-2-phenyl-3-oxo-isoxazolidin-4-yl]carbamate

[0506]

[0507] To a solution of (4R)-N-phenyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.200 g, 0.847 mmol) in a mixture of THF (1.0 ml) and water (2.0 ml) was added triethylamine (0.24 ml, 1.69 mmol). The resulting reaction mixture was heated in a sealed vial at 70 °C for 3 h. 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 afford tert-butyl N-[(4R)-2-phenyl-3-oxo-isoxazolidin-4-yl]carbamate (0.136 g) as a colorless oil which solidified on standing.

[0508] 1 1H 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).

[0509] Example 19: Preparation of (4R)-2-oxoisoxazolidine-4-sodium formate

[0510]

[0511] At 35 °C, (2R)-2-(ethoxycarbonylamino)-3-hydroxy-propanoic acid (80 g, 0.452 mol) was dissolved in ethanol (800 ml) and treated at 25 °C in several portions with sodium hydroxide (24.0 g, 0.600 mol, microgranules). After the addition was complete, the reaction mixture was warmed to 40 °C and stirred overnight. The precipitated solid was filtered off, washed with ethanol and dried under reduced pressure to give (4R)-2-oxazolidine-4-carboxylic acid sodium salt (50.7 g) as a white powder containing approximately 20% residual solvent.

[0512] 1 H NMR (400 MHz, D2O) δ 4.57 - 4.63 (m, 1H), 4.25 - 4.31 (m, 2H).

[0513] 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).

[0514] Alternatively, the title compound can be obtained by carrying out the following procedure:

[0515] At 21 °C, within 60 min, a solution of methyl (4R)-2-oxazolidine-4-carboxylate (20.0 g, 91.0% purity, 0.125 mol) in acetonitrile (100 g) was treated with sodium hydroxide (microgranules) in methanol (16.2% (w / w) solution 37.0 g, 0.150 mol) 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 at 100 °C under vacuum to give (4R)-2-oxazolidine-4-carboxylic acid sodium salt (20 g, 83.2% purity, determined by quantitative 1 H NMR analysis).

[0516] Example 20: Preparation of 2-oxoisoxazolidine-4-lithium formate

[0517]

[0518] At 0 - 5 °C, within 15 min, a solution of methyl 2 - oxo - oxazolidine - 4 - carboxylate (1.0 g, 6.89 mmol) in 2 - methyl - tetrahydrofuran (5 g) was treated with a solution of lithium hydroxide (0.167 g, 6.97 mmol) in methanol (2 ml). 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 in vacuo to give lithium 2 - oxo - oxazolidine - 4 - carboxylate (610 mg) as a white solid containing approximately 3% of residual solvent.

[0519] 1 H NMR (400 MHz, D2O) δ 4.57 - 4.63 (m, 1H), 4.25 - 4.31 (m, 2H).

Claims

1. A method for preparing a compound having the formula (I) wherein R 1 is a C1-C8 alkyl or a C1-C8 haloalkyl; the method comprises a-1. reacting a compound having the formula (II) with a compound having the formula (III) the reaction being carried out in the presence of a suitable acid wherein R 2 is a leaving group selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy or C1-C8 arylsulfonyloxy; to produce a compound having the formula (IV) or a salt thereof wherein R 1 and R 2 are as defined for the compounds of formula (I) and formula (III) and a-2. converting the compound having the formula (IV) into a compound having the formula (I) in the presence of a suitable base.

2. A method for preparing a compound having the formula (IV) comprising a-1. reacting a compound having the formula (II) with a compound having the formula (III) the reaction being carried out in the presence of a suitable acid wherein R 1 is a C1-C8 alkyl or a C1-C8 haloalkyl; R 2 is a leaving group selected from halogen, C1-C8 alkylsulfonyloxy, C1-C8 haloalkylsulfonyloxy or C1-C8 arylsulfonyloxy.

3. A method, said method comprising the steps of: (i) preparing a compound having the formula (I) according to the method of claim 1, and (ii) reacting the compound having the formula (I) with a second compound, wherein the second compound comprises a carboxylic acid, acyl halide, ester or thioester functional group, and the reaction comprises reacting the amine functional group of the compound having the formula (I) with the carboxylic acid, acyl halide, ester or thioester functional group of the second compound, such that the compound having the 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 the amine functional group of the compound having the formula (I) with the dicarbonate group of the second compound, such that the compound having the 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 formula (XII) and the method produces a compound having the formula (VIII) wherein X is a leaving group which is acetyl A 1 , A 2 , A 3 and A 4 Independently of each other, CH or CR 5 ; Each R 5 is a C1-C8 alkyl group; R 8 is a hydroxyl group, fluorine, chlorine, or bromine; and R 1 is a C1-C8 alkyl or a C1-C8 haloalkyl; or the second compound is a compound having the formula (XIII) wherein and the method produces a compound having the formula (IX) wherein R 1 is a C1-C8 alkyl or a C1-C8 haloalkyl; and R 9 is hydrogen, a C1-C8 alkyl or a C1-C8 haloalkyl and R 8 is as defined for the compounds of formula (XII); or the second compound is a compound having the formula (XIVa) or (XIVb) and the method produces a compound having the formula X wherein R 1 is a C1-C8 alkyl or a C1-C8 haloalkyl; and Each R 10 is a C1-C8 alkyl group.

5. A method for preparing a compound having the formula (VIII) or a salt or N-oxide thereof comprising preparing a compound having the formula (I) according to the method of claim 1 and reacting the compound having the formula (I) with a compound having the formula (XII) wherein X is a leaving group which is acetyl A 1 , A 2 , A 3 and A 4 Independently of each other, CH, or CR 5 ; Each R 5 is a C1-C8 alkyl group; R 8 is a hydroxyl group, fluorine, chlorine, or bromine; R 1 is a C1-C8 alkyl or a C1-C8 haloalkyl.

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