PROCESS FOR PREPARING AMINOCYCLOHEXYL ETHER COMPOUNDS
The present invention relates to a process for preparing aminocyclohexyl ether compounds of Formula I: or the pharmaceutically acceptable salts and esters thereof. In particular, the instant invention is directed towards a process for preparing (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane as well as various intermediates.
1 . A process for preparing compounds of Formula I:
where Y is selected from 3,4-dimethoxyphenyl, 3,4-dihydroxyphenyl or a 3,4-dihalophenyl, comprising the steps of:
a) mixing a cyclohexyl amine (iv)
with a malic acid derivative (v)
where R 2 is selected from hydrogen, esters, carbonates, carbamates, silyl ethers, phosphates or sulfates and where X and Z are independently selected from OH C 1 -C 6 alkoxy, esters, halides or O-acyl, said X and Z may optionally be joined to form a ring (v-a)
to obtain a hydroxy succinimide (vi)
and
b) reducing the hydroxy succinimide (vi) to obtain a compound of Formula I.
2 - 19 . (canceled)
20 . A D-malate salt of
21 . The salt of claim 20 which is in crystalline form.
22 . The crystalline salt of
of claim 21 characterized as by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 5.38, 9.41, 19.43 and 7.18 angstroms.
23 . The crystalline salt of
of claim 21 further characterized by the X-ray powder diffraction pattern of FIG. 1 .
24 . A process for preparing compounds of Formula I:
where Y is selected from 3,4-dimethoxyphenyl, 3,4-dihydroxyphenyl or a 3,4-dihalophenyl, comprising the step of:
a) adding a cyclohexyl amine salt (iv-a)
to a mixture of a second solvent and an inorganic base followed by addition of a 1,4-dielectrophile of formula vii-a or vii-b
where R 2 is selected from hydrogen, esters, carbonates, carbamates, silyl ethers, phosphates or sulfates and X is an activated leaving group, to provide a mixture comprising the compound of Formula (I).
25 . The process of claim 24 further comprising the steps:
b) adding a second solvent and a basic aqueous solution to the mixture, to thereby obtain a biphasic mixture of an aqueous layer and an organic layer;
c) discarding the aqueous layer; and
d) adding an acid to the organic layer to obtain a salt of a compound of Formula (I).
26 . The process of claim 24 wherein the activated leaving group X is selected from the group consisting of chloride, bromide, iodide, mesylate, tosylate, and triflate.
27 . The process of claim 24 wherein the 1,4-dielectrophile is a compound of formula vii-a where R2 is hydrogen and X is bromide, mesylate or tosylate.
28 . The process of claim 24 wherein the 1,4-dielectrophile is a compound of formula vii-b.
28 . The process of claim 24 wherein the 1,4-dielectrophile is (R)-1,4-dibromo-butan-2-ol.
29 . The process of claim 25 further comprising:
e) mixing a substituted ethanol (ii)
where Y is selected from 3, 4-dimethoxyphenyl, 3,4-dihydroxyphenyl or 3,4-dihalophenyl, with a zinc salt, a secondary amine and an organic base in a first solvent;
f) adding a substituted cycloalkanone (i)
where R1 is an activated leaving group and integer n is 2, to obtain a mixture;
g) adding an acidic aqueous solution to create a biphasic mixture and discarding the aqueous layer;
h) adding a second solvent to obtain an alkoxy ketone (iii)
i) mixing a co-factor with a slurry of a transaminase polypeptide in a basic buffer and an amine to produce a solution;
j) adding the alkoxy ketone (iii)
k) adding a third solvent to create a biphasic mixture and discarding the aqueous layer;
l) performing a solvent switch from the third solvent to a fourth solvent to obtain cyclohexyl amine (iv)
m) adding an acid to create a slurry; and
n) filtering the slurry to obtain the cyclohexyl amine salt (iv-a).
30 . The process of claim 29 , where a transaminase polypeptide having an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 206 is used.
31 . The process of claim 29 , where a transaminase polypeptide having a polynucleotide sequence of SEQ ID NO: 17 or SEQ ID NO: 205 is used.
32 . A process for preparing compounds of Formula I:
where Y is selected from 3,4-dimethoxyphenyl, 3,4-dihydroxyphenyl or a 3,4-dihalophenyl, comprising the step of:
o) mixing an alkoxy ketone (iii)
where Y is selected from 3,4-dimethoxyphenyl, 3,4-dihydroxyphenyl or a 3,4-dihalophenyl, with a co-factor, a transaminase polypeptide and an amine to produce a cyclohexyl amine (iv)
33 . The process of claim 32 further comprising mixing the cyclohexyl amine (iv) with an inorganic or organic protic acid, HW, to provide a salt of the formula
34 . The process of claim 33 wherein HW is selected from HCl, H2SO4, oxalic acid, pivalic acid, malic acid and maleic acid.
35 . The process of claim 11 wherein HW is maleic acid and the salt
form has the formula (iv-a)
36 . The process of claim 33 wherein HW is oxalic acid and the salt form has the formula (iv-b)
37 . The process of claim 33 wherein HW is malic acid and the salt form has the formula (iv-c)
38 . The process of claim 32 , where a transaminase polypeptide having an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 206 is used.
39 . The process of claim 32 , where a transaminase polypeptide having a polynucleotide sequence of SEQ ID NO: 17 or SEQ ID NO: 205 is used.