Process for the production of (1r,2s)-2,6-dimethyl-1-indanamine using dynamic kinetic stereoisomer resolution

A method for preparing (1R,2S)-2,6-dimethyl-1-indanamine, the method comprising:

• a first step, wherein a mixture of four stereoisomers of 2,6-dimethyl-1-indanamine (I) is reacted with an acylation or carboxylation agent R—C(═O)R1
• a) in the presence of a protein having the activity of a lipase selectively to form the corresponding amide or carbamate (II) and a mixture (III) of unreacted stereoisomers of 2,6-dimethyl-1-indanamine, and
• b) the mixture (III) is isomerized in the presence of a metal catalyst and under hydrogen pressure at the same time as the biocatalytic conversion to form the four stereoisomers of 2,6-dimethyl-1-indamine (I):
• wherein the protein is encoded by an amino acid sequence selected from the group consisting of
• I. proteins having at least 80% identity to the amino acid sequence shown under SEQ ID No. 1,
• II. proteins having at least 80% identity to the amino acid sequence shown under SEQ ID No. 1 wherein the amino acid sequence has a modification selected from the group consisting of:
• i. an amino acid at position 186 different from L;
• ii. an amino acid at position 280 different from L;
• iii. an amino acid at position 312 different from P;
• iv. a amino acid at position 3 different from M;
• v. an amino acid at position 29 different from N;
• vi. an amino acid at position 17 different from L;
• vii. an amino acid at position 4 different from S;
• viii. a amino acid at position 18 different from V;
• ix. an amino acid at position 202 different from A;
• x. an amino acid at position 301 different from D;
• xi. an amino acid at position 309 different from P;
• xii. an amino acid at position 31 different from Q;
• xiii. an amino acid at position 111 different from Q;
• xiv. an amino acid at position 85 different from W;
• xv. an amino acid at position 8 different from K;
• xvi. an amino acid at position 79 different from E;
• xvii. an amino acid at position 40 different from K;
• a second step, wherein the amide or carbamate (II) is separated from secondary components by crystallization;
• and
• a third step, wherein the amide or carbamate (II) is converted to the (1R,2S)-2,6-dimethyl-1-indanamine (IV) using a base or an acid,
• in which R means a radical from the group consisting of CH2OCH3, CH2OCH2CH3, CH3, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH2CH3,
• and
• in which R1 means a radical from the group consisting of OCH3, OCH2CH3, OCH(CH3)2 and OCH2CH2CH2CH3.