Enantiomeric separation and purification of 2,3,4,9-tetrahydro-1h-carbazole-4-carboxylic acid amide derivatives

Patent metadata

Field	Value
Publication number	US-2016168091-A1
Application number	US-201414905649-A
Country	US
Kind code	A1
Filing date	Jul 17, 2014
Priority date	Jul 17, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

A method for the purification of cyclic indole compounds that provides advantages over previously-known methods. Using the method of the present invention allows for the facile preparation of a good quality solid form of these compounds.

First claim

What is claimed is:

1 . A method comprising:
separating an S-enantiomer from an R-enantiomer wherein said S-enantiomer and said R-enantiomer are provided in a racemic mixture and wherein each of said S-enantiomer and said R-enantiomer is a compound of Formula I:

wherein:
R 1 is C 1-4 alkylene-LG wherein LG is a leaving group;
R 2 is hydrogen, hydroxyl, halo, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 fluoroalkyl, or C 1-3 fluoroalkoxy;
R 3 and R 4 are independently C 1-3 alkyl, C 7-10 aralkyl, or R 3 and R 4 , together with the nitrogen to which they are attached, form a nitrogen-containing C 4-6 aliphatic ring optionally comprising 1 further heteroatom selected from nitrogen, oxygen and sulfur;
Y 1 is O, S, SO, SO 2 or CH 2 ;
Y 2 is CH 2 , CH 2 —CH 2 , CH(CH 3 )—CH 2 , CH 2 —CH 2 —CH 2 or CH—(CH—CH 2 —CH—CH 2 )—CH;
said variable bond is above the plane for the S-enantiomer and below the plane for the R-enantiomer as illustrated respectively in Formulas I-S and I-R:

dissolving one of said separated enantiomers in a suitable organic solvent;
precipitating said dissolved enantiomer out of the solution obtained in step (ii) wherein said precipitating step comprises addition of water;
isolating the precipitate obtained in step (iii).

2 . The method as defined in claim 1 wherein R 1 is bromo, chloro, iodo, tosylate, mesylate, nosylate or triflate.

3 . The method as defined in claim 1 wherein R 2 is hydrogen, halo, C 1-3 alkoxy or C 1-3 fluoroalkoxy.

4 . The method as defined in claim 1 wherein R 3 and R 4 are independently methyl, ethyl or benzyl.

5 . The method as defined in claim 1 wherein Y 1 is S.

6 . The method as defined in claim 5 wherein Y 2 is CH—(CH—CH 2 —CH—CH 2 )—CH.

7 . The method as defined in claim 1 wherein Y 1 is CH2.

8 . The method as defined in claim 7 wherein Y 2 is CH 2 —CH2.

9 . The method as defined in claim 1 wherein said separating is carried out by supercritical fluid chromatography (SFC).

10 . The method as defined in claim 1 wherein said organic solvent is an alcohol, 1,4-dioxane, tetrahydrofuran or acetonitrile.

11 . The method as defined in claim 10 wherein said organic solvent is selected from 2-propanol, ethanol, methanol and acetonitrile.

12 . A method to obtain an 18 -labelled PET tracer of Formula II:

wherein R 11 is C 1-3 alkylene- 18 F;
and wherein each of R 12 -R 14 and Y 11 -Y 12 is as defined for R 2 -R 4 and Y 1 -Y 2 in claim 1 ;
wherein said method comprises the method as defined in any one of claims 1 - 11 followed by reaction of a solution of said precipitate obtained in step (iv) with a suitable source of 18 F-fluoride.

13 . The method as defined in claim 12 which is automated.

14 . A compound of Formula I-S or Formula I-R as defined in claim 1 obtainable by the method as defined in claim 1 .

15 . A compound of Formula II as defined in claim 12 obtainable by the method as defined in claim 12 .

Assignees

• Ge Healthcare Ltd

Inventors

• Nilsen Sondre
• Mantzilas Dimitrios

Classifications

• G01N33/60

  involving radioactive labelled substances · CPC title

• C07D209/88

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system · CPC title

• C07D209/84 Primary

  Separation, e.g. from tar; Purification · CPC title

• A61K51/0446

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title