Process for producing optically active alpha-methylcysteine derivative

Abstract

The present invention provides a simple industrial process for producing an L- or D-optically active α-methylcysteine derivative or its salt, which is a useful pharmaceutical intermediate, from readily available, inexpensive raw materials. In a process for producing an L- or D-optically active α-methylcysteine derivative or its salt, a racemic N-carbamoyl-α-methylcysteine derivative or its salt is D-selectively cyclized with hydantoinase to produce a D-5-methyl-5-thiomethylhydantoin derivative or its salt and an N-carbamoyl-α-methyl-L-cysteine derivative or its salt, which are then subjected to deprotection of the amino group and the sulfur atom, and hydrolysis.

1 . A process for producing a D-5-methyl-5-thiomethylhydantoin derivative represented by formula (2) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms); and an N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as the above), the process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as the above).  
   
   
       2 . The process according to  claim 1 , wherein the hydantoinase is derived from microorganisms of the genus  Agrobacterium, Bacillus , or  Pseudomonas.    
   
   
       3 . The process according to  claim 1 , wherein the hydantoinase is derived from  Agrobacterium  sp. KNK712 (FERM BP-1900),  Bacillus  sp. KNK245 (FERM BP-4863), or  Pseudomonas putida  IFO 12996.  
   
   
       4 . The process according to  claim 1 , wherein the hydantoinase is used as an immobilized enzyme.  
   
   
       5 . The process according to  claim 1 , wherein R 1  is a substituted or unsubstituted tertiary alkyl group having 4 to 15 carbon atoms.  
   
   
       6 . The process according to  claim 5 , wherein the tertiary alkyl group is a tert-butyl group.  
   
   
       7 . A process for producing an α-methyl-L-cysteine derivative represented by formula (4) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 2  represents R 1  or a hydrogen atom and R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), the process comprising decarbamoylating an N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salts, and, if required, deprotecting the sulfur atom:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as above)  
   
   
       8 . The process according to  claim 7 , wherein decarbamoylation is performed by treatment with nitrous acid, or a nitrite and an acid, to produce a compound represented by formula (4) in which R 2  is the same as R 1  in formula (3).  
   
   
       9 . The process according to  claim 7 , wherein decarbamoylation is performed by treatment with an alkali to produce a compound represented by formula (4) in which R 2  is the same as R 1  in formula (3).  
   
   
       10 . The process according to  claim 9 , wherein the alkali used in the decarbamoylation is sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide, or calcium hydroxide.  
   
   
       11 . The process according to  claim 9 , wherein the alkali used in the decarbamoylation is lithium hydroxide.  
   
   
       12 . The process according to  claim 9 , comprising adding an acid to the reaction solution after decarbamoylation reaction to decrease the pH, thereby crystallizing a compound represented by formula (4) in which R 2  is the same as R 1  in formula (3).  
   
   
       13 . The process according to  claim 12 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       14 . The process according to  claim 12 , wherein the acid used is hydrochloric acid.  
   
   
       15 . The process according to  claim 12 , wherein the pH of the reaction solution is decreased to 9.5 or less.  
   
   
       16 . The process according to  claim 7 , wherein the N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt is produced by a process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 1  in formula (3)).  
   
   
       17 . A process for producing an α-methyl-L-cysteine represented by formula (5) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising treating, with an acid, a compound produced by the process according to  claim 7  and represented by formula (4) in which R 2  is the same as R 1  in formula (3), to deprotect the sulfur atom.  
   
   
       18 . The process according to  claim 17 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       19 . The process according to  claim 17 , wherein the acid used is hydrochloric acid.  
   
   
       20 . A process for producing an α-methyl-L-cysteine represented by formula (5) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising treating, with an acid, an N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms, to simultaneously perform decarbamoylation and deprotection of the sulfur atom.  
   
   
       21 . The process according to  claim 20 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       22 . The process according to  claim 20 , wherein the acid used is hydrochloric acid.  
   
   
       23 . The process according to  claim 20 , wherein the N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt in which R 1  is a tertiary alkyl group having 4 to 15 carbon atoms is produced by a process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 1  in formula (3)).  
   
   
       24 . A process for producing L-5-methyl-5-thiomethylhydantoin represented by formula (6) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising cyclizing an N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), and deprotecting the sulfur atom thereof.  
   
   
       25 . The process according to  claim 24 , comprising cyclizing the N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt to produce an L-5-methyl-5-thiomethylhydantoin derivative represented by formula (7) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as R 1  in formula (3), and then treating the derivative or its salt with an acid to deprotect the sulfur atom thereof.  
   
   
       26 . The process according to  claim 25 , wherein cyclization reaction is performed using an alkali.  
   
   
       27 . The process according to  claim 26 , wherein the alkali used is sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide, or calcium hydroxide.  
   
   
       28 . The process according to  claim 24 , comprising treating the N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt with an acid to simultaneously perform cyclization and deprotection of the sulfur atom.  
   
   
       29 . The process according to  claim 25  or  28 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       30 . The process according to  claim 25  or  28 , wherein the acid used is hydrochloric acid.  
   
   
       31 . The process according to  claim 24 , wherein the N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt is produced by a process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 1  in formula (3)).  
   
   
       32 . A process for producing an α-methyl-L-cysteine represented by formula (5) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising hydrolyzing the L-5-methyl-5-thiomethylhydantoin represented by formula (6) or its salt which is produced by the process according to  claim 24 .  
   
   
       33 . The process according to  claim 32 , wherein hydrolysis is performed with an acid.  
   
   
       34 . The process according to  claim 33 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       35 . The process according to  claim 33 , wherein the acid used is hydrochloric acid.  
   
   
       36 . A process for producing an α-methyl-D-cysteine derivative represented by formula (8) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 2  is R 1  or a hydrogen atom and R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), the process comprising hydrolyzing a D-5-methyl-5-thiomethylhydantoin derivative represented by formula (2) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as the above), and, if required, deprotecting the sulfur atom thereof.  
   
   
       37 . The process according to  claim 36 , wherein hydrolysis is performed with an alkali to produce a compound represented by formula (8) in which R 2  is the same as R 1  in formula (2).  
   
   
       38 . The process according to  claim 37 , wherein the alkali used in the hydrolysis is sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium hydroxide, or calcium hydroxide.  
   
   
       39 . The process according to  claim 36 , comprising adding an acid to the reaction solution after hydrolysis reaction to decrease the pH and crystallize a compound represented by formula (8) in which R 2  is the same as R 1  in formula (2), thereby obtaining the compound as crystals.  
   
   
       40 . The process according to  claim 39 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       41 . The process according to  claim 39 , wherein the acid used is hydrochloric acid.  
   
   
       42 . The process according to  claim 39 , wherein the pH of the reaction solution is decreased to 9.5 or less.  
   
   
       43 . A process for producing α-methyl-D-cysteine represented by formula (9) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising treating an α-methyl-D-cysteine derivative represented by formula (8) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 2  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), with an acid to deprotect the sulfur atom.  
   
   
       44 . The process according to  claim 43 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       45 . The process according to  claim 43 , wherein the acid used is hydrochloric acid.  
   
   
       46 . A process for producing α-methyl-D-cysteine represented by formula (9) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising treating, with an acid, a compound represented by formula (2):  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms, to simultaneously perform hydrolysis reaction and deprotection of the sulfur atom.  
   
   
       47 . The process according to  claim 46 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       48 . The process according to  claim 46 , wherein the acid used is hydrochloric acid.  
   
   
       49 . The process according to  claim 46 , wherein the compound represented by formula (2) is produced by a process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (I) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 1  in formula (2).  
   
   
       50 . A process for producing D-5-methyl-5-thiomethylhydantoin represented by formula (11) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising carbamoylating a compound represented by formula (8):  
     
       
         
         
             
             
         
       
     
     wherein R 2  is the same as R 1  in formula (10), to produce an N-carbamoyl-α-methyl-D-cysteine derivative represented by formula (10) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), and then cyclizing the derivative or its salt and deprotecting the sulfur atom thereof.  
   
   
       51 . The process according to  claim 50 , wherein carbamoylation is preformed with an alkali metal cyanate and an acid.  
   
   
       52 . The process according to  claim 50 , wherein the deprotection of the sulfur atom and cyclization reaction are performed with an acid.  
   
   
       53 . The process according to  claim 52 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       54 . The process according to  claim 52 , wherein the acid used is hydrochloric acid.  
   
   
       55 . The process according to  claim 50 , wherein the compound represented by formula (8) in which R 2  is the same as R 1  in formula (10) is produced by a process comprising hydrolyzing a D-5-methyl-5-thiomethylhydantoin derivative represented by formula (2) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 1  in formula (1).  
   
   
       56 . A process for producing a D-5-methyl-5-thiomethylhydantoin represented by formula (11) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising treating, with an acid, a D-5-methyl-5-thiomethylhydantoin derivative represented by formula (2) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms) to deprotect the sulfur atom.  
   
   
       57 . The process according to  claim 56 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       58 . The process according to  claim 56 , wherein the acid used is hydrochloric acid.  
   
   
       59 . The process according to  claim 56 , wherein the compound represented by formula (2) is produced by a process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 1  in formula (2)).  
   
   
       60 . A process for producing α-methyl-D-cysteine represented by formula (9) or its salt:  
     
       
         
         
             
             
         
       
     
     the process comprising hydrolyzing the D-5-methyl-5-thiomethylhydantoin represented by formula (11) or its salt which is produced by the process according to  claim 56 .  
   
   
       61 . The process according to  claim 60 , wherein hydrolysis is preformed with an acid.  
   
   
       62 . The process according to  claim 61 , wherein the acid used is any one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, acetic acid, and trifluoroacetic acid, or a mixed acid of at least two acids selected therefrom.  
   
   
       63 . The process according to  claim 61 , wherein the acid used is hydrochloric acid.  
   
   
       64 . A process for crystallizing optically active α-methylcysteine or its salt, comprising crystallizing the optically active α-methylcysteine or its salt from an aqueous solution of the compound in the presence of an organic solvent.  
   
   
       65 . The process according to  claim 64 , wherein a salt of the optically active α-methylcysteine with an acid is obtained.  
   
   
       66 . The process according to  claim 65 , wherein a salt of the optically active α-methylcysteine with a hydrohalic acid is obtained.  
   
   
       67 . The process according to  claim 65 , wherein optically active α-methylcysteine hydrochloride is obtained.  
   
   
       68 . A process for crystallizing optically active α-methylcysteine or its salt, comprising producing the optically active α-methylcysteine or its salt by a process according to  claim 7 ,  17 ,  20 ,  32 ,  36 ,  43 ,  46 , or  60 , and then crystallizing the so-produced optically active α-methylcysteine or its salt from an aqueous solution of the compound in the presence of an organic solvent.  
   
   
       69 . The process according to  claim 64 , comprising concentrating the aqueous solution of the optically active α-methylcysteine or its salt in the presence of the organic solvent to remove water from the system and replacing water by the organic solvent, thereby crystallizing the compound.  
   
   
       70 . The process according to  claim 69 , wherein the organic solvent used has low or no compatibility with water.  
   
   
       71 . The process according to  claim 69 , wherein the organic solvent used is a hydrocarbon solvent, an ester solvent, or an ether solvent.  
   
   
       72 . The process according to  claim 69 , wherein the organic solvent used is a hydrocarbon solvent.  
   
   
       73 . The process according to  claim 72 , wherein the hydrocarbon solvent used is one selected from toluene, benzene, xylene, hexane, cyclohexane, and heptane, or a mixed solvent of at least two selected therefrom.  
   
   
       74 . The process according to  claim 69 , wherein the optically active α-methylcysteine or its salt is crystallized at a concentration of 1% by weight to 70% by weight.  
   
   
       75 . The process according to  claim 69 , wherein the aqueous solution is concentrated to replace water by the organic solvent until the residual water content is 100% by weight or less relative to the optically active α-methylcysteine or its salt, thereby obtaining the optically active α-methylcysteine or its salt as crystals.  
   
   
       76 . The process according to  claim 69 , wherein the evaporation rate in concentration is controlled to 1000 L/h·m 2  or less.  
   
   
       77 . The process according to  claim 69 , wherein the evaporation rate in concentration is controlled to 600 L/h·m 2  or less.  
   
   
       78 . The process according to  claim 69 , wherein the evaporation rate in concentration is controlled to 300 L/h·m 2  or less.  
   
   
       79 . The process according to  claim 69 , wherein the degree of vacuum in concentration is controlled to 500 mmHg or less.  
   
   
       80 . The process according to  claim 64 , comprising concentrating the aqueous solution of the optically active α-methylcysteine or its salt in the presence of the organic solvent to remove water from the system and replace water by the organic solvent, filtering off the precipitated slightly soluble inorganic salt, and then crystallizing the compound from a solution thereof by adding a poor solvent, cooling, or concentrating.  
   
   
       81 . The process according to  claim 80 , wherein the water is removed from the system until the residual water content is 100% by weight or less relative to the optically active α-methylcysteine or its salt.  
   
   
       82 . The process according to  claim 80 , wherein the organic solvent used for replacement is a single alcohol solvent, a single ether solvent, or a mixed solvent thereof at any desired ratio.  
   
   
       83 . The process according to  claim 82 , wherein the alcohol solvent is one selected from methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, isobutyl alcohol, or tert-butyl alcohol, or a mixed solvent of at least two selected therefrom.  
   
   
       84 . The process according to  claim 82 , wherein the ether solvent is one selected from diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, or methyl tert-butyl ether, or a mixed solvent of at least two selected therefrom.  
   
   
       85 . The process according to  claim 80 , wherein the poor solvent is added for crystallizing the α-methylcysteine or its salt.  
   
   
       86 . The process according to  claim 85 , wherein the poor solvent is any one of a hydrocarbon solvent, an ester solvent, and an ether solvent, or a mixed solvent of at least two of these solvents.  
   
   
       87 . The process according to  claim 85 , wherein the poor solvent is a hydrocarbon solvent.  
   
   
       88 . The process according to  claim 87 , wherein the hydrocarbon solvent is any one of toluene, xylene, hexane, and heptane, or a mixed solvent of at least two of these solvents.  
   
   
       89 . The process according to  claim 80 , wherein the optically active α-methylcysteine or its salt is crystallized at a concentration of 1% by weight to 70% by weight.  
   
   
       90 . A process for producing a racemic N-carbamoyl-α-amino acid derivative represented by formula (13) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 3  and R 4  independently represent a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), the process comprising hydrolyzing, with an organic base or an alkali metal hydroxide, a racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 3  and R 4  represent the same as the above).  
   
   
       91 . The process according to  claim 90 , wherein the alkali metal hydroxide used is sodium hydroxide or potassium hydroxide.  
   
   
       92 . The process according to  claim 90 , wherein water is used in an amount of 0.1 times to 10 times the weight of the racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt.  
   
   
       93 . The process according to  claim 90 , wherein water is used in an amount of 0.2 times to 3 times the weight of the racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt.  
   
   
       94 . The process according to  claim 90 , wherein the base is used in an amount of 1 molar equivalent to 10 molar equivalents relative to the racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt.  
   
   
       95 . The process according to  claim 90 , wherein the base is used in an amount of 2 molar equivalents to 5 molar equivalents relative to the racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt.  
   
   
       96 . The process according to  claim 90 , wherein water is used in an amount of 0.2 times to 3 times the weight of the racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt, and the base is used in an amount of 2 molar equivalents to 5 molar equivalents relative to the racemic 5,5-disubstituted hydantoin derivative represented by formula (12) or its salt.  
   
   
       97 . The process according to  claim 90 , wherein a solvent comprising water alone or a mixture of water and an organic solvent is used.  
   
   
       98 . The process according to  claim 97 , wherein the organic solvent used in combination with the water is a hydrocarbon organic solvent.  
   
   
       99 . The process according to  claim 90 , wherein the reaction temperature is 80° C. to 110° C.  
   
   
       100 . The process according to  claim 90 , wherein R 3  in formula (12) is a substituted or unsubstituted primary alkyl group having 1 to 6 carbon atoms.  
   
   
       101 . The process according to  claim 100 , wherein R 3  in formula (12) is a methyl group.  
   
   
       102 . The process according to  claim 90 , wherein a compound represented by formula (14):  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms) is used as the racemic 5,5-disubsituted hydantoin derivative represented by formula (12) to produce a compound presented by formula (1) as the racemic N-carbamoyl-α-amino acid derivative represented by formula (113):  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as the above).  
   
   
       103 . The process according to  claim 102 , wherein R 1  in formula (14) is a tert-butyl group.  
   
   
       104 . A process for producing a D-5-methyl-5-thiomethylhydantoin derivative represented by formula (2) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms); and an N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as the above), the process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt with a hydantoinase to selectively cyclize the D-isomer:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents the same as the above), wherein the racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt is produced by the process according to  claim 102  or  103 .  
   
   
       105 . A racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms).  
   
   
       106 . An L- or D-optically active N-carbamoyl-α-methylcysteine derivative represented by formula (3):  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), or formula (10):  
     
       
         
         
             
             
         
       
     
     (wherein R 1  represent the same as the above), or its salt.  
   
   
       107 . The compound according to  claim 105  or  106 , wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms.  
   
   
       108 . The compound according to  claim 107 , wherein the tertiary alkyl group is a tert-butyl group.  
   
   
       109 . A D- or L-optically active 5-methyl-5-thiomethylhydantoin derivative represented by formula (2):  
     
       
         
         
             
             
         
       
     
     or formula (7):  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms, or its salt.  
   
   
       110 . The compound according to  claim 109 , wherein the tertiary alkyl group is a tert-butyl group.  
   
   
       111 . An L- or D-optically active α-methylcysteine derivative represented by formula (4):  
     
       
         
         
             
             
         
       
     
     or formula (8):  
     
       
         
         
             
             
         
       
     
     (wherein R is a substituted or unsubstituted alkyl group having 1 to 20 atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), or its salt.  
   
   
       112 . The compound according to  claim 111 , wherein R 2  is a tertiary alkyl group having 4 to 15 carbon atoms.  
   
   
       113 . The compound according to  claim 112 , wherein the tertiary alkyl group is a tert-butyl group.  
   
   
       114 . An L- or D-optically active 5-methyl-5-thiomethylhydantoin represented by formula (6):  
     
       
         
         
             
             
         
       
     
     or formula (11):  
     
       
         
         
             
             
         
       
     
     or its salt.  
   
   
       115 . A process according to  claim 43 , wherein the α-methly-D-cysteine-derivative represented by formula (8) or its salt is produced by a process comprising hydrolyzing a D-5-methyl-5-thiomethylbydantoin derivative represented by formula (2) or its salt:  
     
       
         
         
             
             
         
       
     
     (wherein R 1  is the same as R 2  in formula (8)).