Jun.22,2006  7  US 2006/0135784 Al  methyl acetate, ethyl acetate or isopropyl acetate; nitrites  such as acetonitrile; alcohols such as methanol, ethanol,  isopropanol or benzyl alcohol; water. Among others, aro› matic hydrocarbons, ethers, aliphatic acid esters or water are  preferably used. Toluene is a particularly preferable aro› matic hydrocarbon, 1,4-dioxane is a particularly preferable  ether, and ethyl acetate is a particularly preferable aliphatic  acid ester. These solvents may be used alone or in a mixture  of two or more solvents. Besides, if the above reaction  accelerator is liquid at the above reaction temperature, the  above reaction accelerator may be used so as to also serve  as a reaction solvent.  [0076]  The substituted-3-amino-2-hydroxypropionic acid  derivatives  (4)  synthesized as described above may be  isolated and/or purified by a conventional mathod such as  extraction, crystallization, distillation, chromatography or  the like. Alternatively, the reaction mixture may be used next  in the third step as it is.  [0077]  In the meantime, if the above reaction mixture, in  particular, the reaction mixture obtained by carrying out the  above second step under non-aqueous conditions is next  supplied to the third step as it is without isolation and/or  purification, an impurity is apt to be produced secondarily  and the yield tends to decrease. The present inventors have  intensively investigated the causes of the secondary produc› tion of the impurity as well as the decrease of the yield. As  a result, they found that a by-product [hereinafter, also  referred to as by-product (8)] represented by the following  general formula  (8):  L-R 4  (8)  [0078]  wherein L and R 4  are as defined above,  is produced secondarily in the second step, and it serves as  a certain alkylating agent, whereby a N-substituted-3- amino-2-hydroxypropionic acid derivative [hereinafter, also  referred to as impurity (9)], in which R 4  is introduced onto  the nitrogen atom in the above 3-amino-2-hydroxypropionic  acid derivatives  (1),  and which is represented by the fol› lowing general formula (9):  invention, in particular, 2-oxazolidinone-5-carboxylic acid  ester derivatives  (4’)  [compounds of the general formula  (4)  wherein S 4  is an ester residue and S 5  and S 6 , taken together,  are a carbonyl group] are isolated and/or purified by crys› tallization into an almost pure form (as crystals), the deriva› tives may be purified and crystallized well using aromatic  hydrocarbons as a solvent for crystallization. The aromatic  hydrocarbons are not limited to particular ones, and include  benzene, toluene, o-, m- or p-xylene, mesitylene, chloroben› zene or the like. Among others, toluene is used preferably.  [0082]  In the crystallization of the above substituted-3- amino-2-hydroxypropionic acid derivatives  (4),  usual crys› tallization procedures such as cooling and/or concentration  may be used without any limitation.  [0083]  In the above crystallization, a solvent in a solution  of the above substituted-3-amino-2-hydroxypropionic acid  derivatives (  4)  other than the above aromatic hydrocarbons  may be replaced to a solvent selected from the above  aromatic hydrocarbons. Of course, with the progress of the  solvent-replacement procedures, the above substituted-3- amino-2-hydroxypropionic acid derivatives (  4)  may be crys› tallized (so-called solvent-replacement crystallization). The  above solvents other than aromatic hydrocarbons are not  limited to particular ones, and include, for example, acetic  acid esters such as ethyl acetate or isopropyl acetate; ethers  such as tert-butyl methyl ether, tetrahydrofuran or  1,4- dioxane; alcohols such as methanol, ethanol or isopropanol;  water.  [0084]  The concentration of crystallization solution may  be in a range capable of maintaining the fluidity of a  crystallization solution. In general, the concentration is  preferably below about 60% (w/v), more preferably below  about  40%  (w/v), and most preferably below about 20%  (w/v).  [0085]  The temperature at which the above crystallization  is carried out is not limited to a particular range. In order to  obtain a crystallization solution (slurry) having a good  property, a slow progress of crystallization, for example, by  a slow cooling is suitable. Also, addition of seed crystals is  suitable for smooth crystallization  [0086]  The above substituted-3-amino-2-hydroxypropi› onic acid derivatives (  4)  crystallized may be separated using  usual solid-liquid separation procedures such as filtration,  centrifugation or the like.  If  necessary, separated wet solids  of the substituted-3-amino-2-hydroxypropionic acid deriva› tives  (4)  may be further washed using, for example, the  above aromatic hydrocarbons, and then dried at atmospheric  pressure or under reduced pressure.  [0087]  On the other hand, if a reaction mixture containing  the above substituted-3-amino-2-hydroxypropionic acid  derivatives (  4)  is used as it is without isolation and/or  purification, the above reaction mixture is contacted with  water and subjected to heat treatment to hydrolyze the above  by-products (8) responsible for the above impurity (9),  whereby the above by-products (8) may be made harmless  to obtain effects similar to those obtained when carrying out  isolation and/or purification. The above heat treatment in  contact with water may be carried out in the second step,  after carrying out the conversion into the above substituted- 3-amino-2-hydroxypropionic acid derivatives  (4)  in a non› aqueous system, or simultaneously with the inversion of a  [0079]  wherein R1, R 2 , R 3  and R 4  are as defined above, is  produced secondarily as an impurity and the derivative  causes the decrease of the yield and quality of the 3-amino- 2-hydroxypropionic acid derivatives  (1  ).  (9)  [0080]  Accordingly, in order to minimize the secondary  production of the impurity (9) and to maximize the yield in  the third step, it is preferable to remove the above by› product (8) responsible for the above impurity (9), for  example, by carrying out isolation and/or purification of the  above substituted-3-amino-2-hydroxypropionic acid deriva› tives (  4)  to a pure form, for example, by obtaining the  derivatives as crystals by crystallization.  [0081]  If  the above substituted-3-amino-2-hydroxypropi› onic acid derivatives (  4)  obtained according to the present 