Jun.22,2006  8  US 2006/0135784 Al  steric configuration at 2-position carbon of N-protected-3- aminopropionic acid derivatives (3) to convert into the  above substituted-3-amino-2-hydroxypropionic acid deriva› tives ( 4) in the coexistence of water from the beginning.  [0088]  Water is required to make the above by-products  (8) responsible for the above impurity (9) harmless. The  amount of water used is not limited to a particular range, and  it is usually used in a molar amount above I-fold, preferably  in a molar amount above 10-fold, more preferably in a molar  amount above 20-fold, and most preferably in a molar  amount above 50-fold, relative to the N-protected-3-amino› propionic acid derivatives (3). In general, as the amount of  water used becomes larger, the effects become larger and  duration required for treatment may be shortened. In this  connection, from the viewpoint of productivity, water is  usually used in a molar amount below 1000-fold, preferably  in a molar amount below 500-fold, and more preferably in  a molar amount below 100-fold, although there is no prob› lem even if a large amount of water is used.  [0089]  The temperature of the above heat treatment car› ried out in contact with water is not limited to a particular  range if the temperature is below the boiling point of the  reaction mixture. In general, as the temperature becomes  higher, the effects by the contact with water become larger  and duration required for treatment may be shortened. The  treating temperature varies depending on various conditions  such as the kind of substituted-3-amino-2-hydroxypropionic  acid derivatives ( 4), the amount of water used, the contact  duration with water, the acidity of a reaction mixture or the  like, and can not be defined uniformly. The temperature may  be preferably above 40°  C., more preferably above 60°  C.,  and most preferably above 80°  C.  [0090]  The above contact with water is carried out under  acidic to neutral conditions. In general, as the acidity  becomes higher, the effects by the contact with water  become larger and duration required for treatment may be  shortened. The above contact is usually carried out under  acidic to neutral conditions, preferably under acidic condi› tions, and more preferably under strongly acidic conditions.  Also, a gradual shift from neutral to acidic conditions may  be preferably carried out with the progress of the reaction.  [0091]  In the above contact with water, in order to main› tain the reaction under acidic to neutral conditions, prefer› ably under acidic conditions, and more preferably strongly  acidic conditions and/or in order to shift the reaction to these  conditions, if necessary, the reaction may be preferably  carried out in the coexistence of an acidic substance. The  acidic substance is not limited to a particular one. For  example, organic acids include sulfonic acids such as meth› anesulfonic acid, ethanesulfonic acid, p-toluenesulfonic  acid, o-, p- or m-nitrobenzenesulfonic acid; carboxylic acids  such as formic acid, acetic acid, trifluoroacetic acid or  benzoic acid, and inorganic acids include hydrochloric acid,  sulfuric acid, sulfurous acid, phosphoric acid or the like.  [0092]  The amount of acidic substances used is not limited  to a particular range, and they are usually used in a molar  amount of0.01 to 100-fold, preferably in a molar amount of  0.05 to 50-fold, and more preferably in a molar amount of  0.1 to 20-fold, for example, relative to N-protected-3-ami› nopropionic acid derivatives (3).  [0093]  In this connection, if the acidity in the above  contact with water is expressed using a pH value as an  indicator (standard), the acidic to neutral conditions refer to  usually a range below pH 9, preferably a range below pH 8,  and more preferably a range below pH 7. Also, the acidic  conditions refer to a range below pH 4 and the strongly  acidic conditions refer to a range below pH 2.  [0094]  Next described is the third step wherein substi› tuted-3-amino-2-hydroxypropionic acid derivatives ( 4) are  converted into 3-amino-2-hydroxypropionic acid deriva› tives (1 ).  [0095]  In this step, the substituents to be eliminated (sub› stituent S 4  on the oxygen atom of the carboxyl group,  substituent S $^{5 }$on the oxygen atom at 2-position carbon, and  substituent S $^{6 }$on the nitrogen atom at 3-position carbon) on  the substituted-3-amino-2-hydroxypropionic acid deriva› tives ( 4) having an inverted steric configuration at 2-position  carbon, which are obtained in the second step, are eliminated  to convert into 3-amino-2-hydroxypropionic acid deriva› tives (1).  If  each of S 4 , S 5  and S 6  is a hydrogen atom,  substituents to be eliminated are not present on each of  oxygen and nitrogen atoms, of course.  [0096]  Methods for eliminating substituents to be elimi› nated are not limited to particular ones and include, for  example, methods described in PROTECTIVE GROUPS IN  ORGANIC SYNTHESIS, 2nd ed., JOHN WILLY & SONS  pub!. (1991). Although preferable methods vary depending  on the kind of protecting groups, they include, for example,  acid treatment, base treatment, hydrolysis, catalytic reduc› tion, electrolytic reduction, Zn/AcOH treatment or the like.  Among others, acid treatment or hydrolysis is convenient  and generally used. In particular, hydrolysis is convenient  and generally used. Hereinafter, a method by hydrolysis for  eliminating the above substituents to be eliminated is spe› cifically described.  [0097]  In this step, the amount of water used for hydroly› sis is not limited to a particular range, and it is usually used  in a molar amount above I-fold, preferably in a molar  amount above 10-fold, more preferably in a molar amount  above 20-fold, and most preferably in a molar amount above  50-fold, relative to substituted-3-amino-2-hydroxypropionic  acid derivatives ( 4). Water may be used in an excess amount,  also as a reaction solvent, and usually used so. In this  connection, from the viewpoint of productivity, water is  usually used in a molar amount below 1000-fold, preferably  in a molar amount below 500-fold, and more preferably in  a molar amount below 100-fold, although there is no prob› lem even if a large amount of water is used.  If  the treatment  of contact with water is carried out in the above second step,  water used in the treatment of contact with water may be  used for hydrolysis in this step as it is, of course.  [0098]  In the above hydrolysis, various organic solvents  usually used may coexist in a range not affecting the  reaction, in addition to water used as reaction reagents. In  general, the above substituted-3-amino-2-hydroxypropionic  acid derivatives ( 4) have a tendency to dissolve hardly in  water, and therefore, organic solvents having a high dissolu› bility may be used together for the purpose of promotion of  the reaction, improvement of the property of the reaction  solution or the like. Examples of the various organic sol› vents include aliphatic hydrocarbons such as hexane, hep› tane or methylcyclohexane; aromatic hydrocarbons such as  toluene or xylene; halogenated hydrocarbons such as meth› ylene chloride or chloroform; ethers such as tetrahydrofuran, 