Processes for producing optically active 2-amino-1-phenylethanol derivatives

A process for producing a 2-amino-1-phenylethanol derivative comprising;

• allowing (a) a compound shown by the general formula (III)
• 21
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group;
• or
• (b) a compound shown by the general formula (IV)
• 22
• wherein R1, R2, R3, R4 and R5 have the same meanings as defined above;
• Z represents a hydrogen atom or a protective group for hydroxyl group;
• and X represents a halogen atom;
• to react with a compound shown by the general formula (V)
• Y—NH2 (V)
• wherein Y represents a hydrogen atom or a group which can be left in the reaction, further, when Y is the group which can be left in the reaction, allowing Y to be left,
• to obtain the compound shown by the general formula (VI)
• 23
• wherein R1, R2, R3, R4, R5 and Z have the same meanings as defined above;
• which comprises adding an acid to the reaction products containing the compound of the general formula (VI) to precipitate or crystallize said compound as a salt and, thereby, isolating the compound of the general formula (VI).

A process for producing an (R)-2-amino-1-phenylethanol derivative which comprises:

• permitting a microorganism or a preparation thereof which is capable of acting on a compound shown by the general formula (VII)
• 24
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof, to produce a corresponding (R)-2-amino-1-phenylethanol compound shown by the general formula (IIa)
• 25
• wherein R1, R2, R3, R4 and R5 have the same meanings as defined above, or a salt thereof, to act on said compound or a salt thereof and
• harvesting or recovering the product optically active compound or a salt thereof.

A process for producing an (R,R)-1-phenyl-2-[(2-phenyl-1-alkylethyl)amino]ethanol derivative shown by the general formula (XI)

• 26
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group;
• and Z represents a hydrogen atom or a protective group for hydroxyl group;
• R7 and R8 represent,
• (A) respectively, a group selected from the group consisting of a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group and a hydroxyl group which may be protected with a protective group, or
• (B) R7 represents a group shown by the formula (IX):
• —O—R7a, and R8 represents a group shown by the formula (X):
• —O—R8a, wherein R7a and R8a may form an optionally substituted ring with the adjacent oxygen atoms;
• R6, R9 and R10 independently represent a group selected from a group consisting of a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, a hydroxyl group which may be substituted with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted aralkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group and an optionally substituted amino group;
• and R11 represents a lower alkyl group, which comprises:
• a reaction of an (R)-2-amino-1-phenylethanol compound shown by the general formula (II)
• 27
• wherein R1, R2, R3, R4, R5 and Z have the same meanings as defined above, or a salt thereof, with a compound shown by the general formula (VIII)
• 28
• wherein R6, R7, R8, R9, R10 and R11 have the same meanings as defined above, and
• a reducing reaction of the reaction product of said reaction.

A process for producing an (S)-2-amino-1-phenylethanol derivative, which comprises:

• permitting a microorganism or a preparation thereof which is capable of acting on a mixture of enantiomers of a 2-amino-1-phenylethanol compound of the general formula (I)
• 38
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof to produce a corresponding (S)-form shown by the general formula (XV)
• 39
• wherein R1, R2, R3, R4 and R5 have the same meanings as defined above, or a salt thereof to act on said mixture of enantiomers, and
• harvesting or recovering the product optically active compound shown by the general formula (XV) or a salt thereof.

A process for producing an (S)-2-amino-1-phenylethanol derivative which comprises:

• permitting a microorganism or a preparation thereof which is capable of acting on a compound shown by the general formula (VII)
• 40
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group or an optionally substituted amino group, or a salt thereof, to produce a corresponding optically active compound shown by the general formula (XV)
• 41
• wherein R1, R2, R3, R4 and R5 have the same meanings as defined above, or a salt thereof, to act on said compound or a salt thereof, and
• harvesting or recovering the product optically active compound shown by the general formula (XV) or a salt thereof.

A process for separating an optically active 2-amino-1-phenylethanol derivative from a mixture of enantiomers of said derivative which comprises:

• (1) subjecting a mixture of enantiomers of 2-amino-1-phenylethanol compound shown by the general formula (I)
• 42
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a group selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group and an optionally substituted amino group, or a salt thereof
• to a treatment with a microorganism or a preparation derived therefrom which is capable of selectively utilizing a corresponding (S)-form of said compound or a salt thereof,
• allowing the microorganism or a preparation derived therefrom to selectively utilize the (S)-form of said compound or a salt thereof, and
• recovering the (R)-form of said compound or a salt thereof;
• or
• (2) subjecting said mixture of enantiomers to a treatment with a microorganism or a preparation derived therefrom which is capable of selectively utilizing the corresponding (R)-form of said compound or a salt thereof,
• allowing the microorganism or a preparation derived therefrom to selectively utilize the (R)-form or a salt thereof, and
• recovering the (S)-form of said compound or a salt thereof.

A process for asymmetrically reducing an aminoketone derivative to a corresponding optically active 2-amino-1-phenylethanol derivative which comprises:

• (1) subjecting a compound shown by the general formula (VII)
• 43
• wherein R1, R2, R3, R4 and R5 represent, the same or different, a group selected from the group consisting of a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group which may be protected with a protective group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, an optionally substituted lower alkylthio group, an optionally substituted acyl group, a carboxyl group which may be protected with a protective group, an optionally substituted lower alkoxycarbonyl group, a nitro group and an optionally substituted amino group, or a salt thereof
• to a treatment with a microorganism or a preparation derived therefrom which is capable of asymmetrically reducing said compound or a salt thereof to a corresponding (R)-2-amino-1-phenylethanol derivative shown by the general formula (IIa)
• 44
• wherein R1, R2, R3, R4 and R5 have the same meanings as defined above, or a salt thereof, and
• recovering the product optically active compound or a salt thereof;
• or
• (2) subjecting said compound or a salt thereof to a treatment with a microorganism or a preparation derived therefrom which is capable of asymmetrically reducing said compound or a salt thereof to a corresponding (S)-2-phenylethanol derivative shown by the general formula (XV)
• 45
• wherein R1, R2, R3, R4 and R5 have the same meanings as defined above, or a salt thereof, and
• recovering the product optically active compound or a salt thereof.