PROCESS FOR THE PREPARATION OF MORPHOLINE DERIVATIVES AND INTERMEDIATES THEREFORE

摘要

Processes for the preparation of a compound of formula (IIIA)(I), or a salt thereof; wherein; Z represents a bond, CO, SO2, CR10R7(CH2)n, (CH2)nCR10R7, CHR7(CH2)nO, CHR7(CH2)nS, CHR7(CH2)nOCO, CHR7(CH2)nCO, COCHR7(CH2)n or SO2CHR7(CH2)n; R6 represents C1-6 alkyl, C2-6 alkenyl, aryl, heteroaryl, aryl-C2-6 alkenyl-, -CN or a group of formula -Y2-J3; R7 represents hydrogen, C1-4 alkyl, CONR8R9 or COOC1-6 alkyl;a and b represent 1 or 2, such that a+b represents 2 or 3;n represents an integer from 0 to 4; M represents a C3-8 cycloalkyl or C3-8 cycloalkenyl group fused to a monocyclic aryl or monocyclic heteroaryl group; J3 represents a moiety of formula (K): (II), wherein X1 represents oxygen, NR11 or sulphur, X2 represents CH2, oxygen, NR12 or sulphur, m1 represents an integer from 1 to 3 and m2 represents an integer from 1 to 3, provided that m1+m2 is in the range from 3 to 5, also provided that when both X1 and X2 represent oxygen, NR11, NR12 or sulphur, m1 and m2 must both not equal less than 2, wherein (K) is optionally substituted by one or more (eg. 1 or 2) -Y3-aryl, -Y3-heteroaryl, -Y3-CO-aryl, -COC3-8 cycloalkyl, -Y3-CO-heteroaryl, -C1-6 alkyl, -Y3-COOC1-6 alkyl, -Y3-COC1-6 alkyl, -Y3-W, -Y3-CO-W, -Y3-NR15R16, -Y3-CONR15R16, hydroxy, oxo, -Y3-SO2NR15R16, -Y3-SO2C1-6 alkyl, -Y3-SO2aryl, -Y3-SO2heteroaryl, -Y3-NR13C1-6 alkyl, -Y3-NR13SO2C1-6 alkyl, -Y3-NR13CONR15R16, -Y3-NR13COOR14 or -Y3-OCONR15R16 groups, and is optionally fused to a monocyclic aryl or heteroaryl ring; R8, R9, R10, R11, R12, R13 and R14 independently represent hydrogen or C1-6 alkyl; R15 and R16 independently represent hydrogen or C1-6 alkyl or R15 and R16 together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring; R17 and R18 independently represent hydrogen or C1-6 alkyl; W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally substituted with one or more C1-6 alkyl, halogen or hydroxy groups; Y1, Y2 and Y3 independently represent a bond or a group of formula -(CH2)pCRcRd(CH2)q- wherein Rc and Rd independently represent hydrogen or C1-4 alkyl or Rc and Rd may together with the carbon atom to which they are attached form a C3-8 cycloalkyl group, and p and q independently represent an integer from 0 to 5 wherein p + q is an integer from 0 to 5;, and; k is 1 or 2;are disclosed.