# US 9,434,744 B2 · Low temperature synthesis of rapamycin derivatives

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- Number: US 9,434,744 B2
- Document ID: US9434744B2
- Status: Granted
- Kind: B2
- Application number: 14/804,714
- Filed: 2015-07-21
- Published: 2015-11-12
- Granted: 2016-09-06
- Earliest claimed: 2013-01-22
- Assignees: Biosensors International Group, Ltd.
- Applicants: Biosensors International Group, Ltd.
- Inventors: Margaret W. Kayo; Richard S. Fornicola; Ivan Kovacik
- Web page: https://patentgrep.com/patent/US9434744B2

## CPC

- C07D 498/18: Bridged systems
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides improved processes for obtaining rapamycin derivatives including Biolimus A9.

## Claims

### Claim 1

A method for obtaining a compound having the structure of Formula I
the method comprising:
a) combining in a reaction mixture an organic solvent, an organic base compound having a nitrogen heteroatom, a compound having the structure of Formula II
and
a compound having the structure of Formula III
b) maintaining the reaction mixture at a temperature of from 25° C. to 55° C.; and
c) separating from the reaction mixture a compound having the structure of Formula I;
wherein
R1 is (CH2)e—O—(CH2)f—H;
e is an integer selected from 1-5;
f is an integer selected from 1-5; and
R2 is hydrogen;
thereby obtaining a compound having the structure of Formula I.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound having the structure of Formula I is

### Claim 3 (depends on 1)

The method of claim 1, wherein R1 is CH2—CH2—O—CH2—CH3.

### Claim 4 (depends on 1)

The method of claim 1, wherein the organic base compound having a nitrogen heteroatom has the structure of Formula IV
wherein:
Rc, Rd, Re, Rf, and Rg are each independently selected from the group consisting of H, C1-5alkyl, OH, and NH2.

### Claim 5 (depends on 1)

The method of claim 1, wherein the organic base compound having a nitrogen heteroatom is selected from 2,6-lutidine and N,N-diisopropylethylamine.

### Claim 6 (depends on 1)

The method of claim 1, wherein the organic base compound having a nitrogen heteroatom is 2,6-lutidine.

### Claim 7 (depends on 1)

The method of claim 1, wherein the maintaining in part (b) is for 2-10 hours.

### Claim 8 (depends on 7)

The method of claim 7, wherein the maintained temperature in part (b) is from 25 to 40° C.

### Claim 9 (depends on 1)

The method of claim 1 wherein the organic solvent is toluene or methylene chloride.

### Claim 10 (depends on 1)

The method of claim 1, wherein the molar ratio of the compound having the structure of Formula III to the compound having the structure of Formula II is from 30 to 1 to 60 to 1.

### Claim 11 (depends on 1)

The method of claim 1, wherein the molar ratio of the organic base compound having a nitrogen heteroatom to the compound having the structure of Formula II is from 80 to 1 to 120 to 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the ratio is 104 to 1.

### Claim 13 (depends on 1)

The method of claim 1, wherein the organic base compound having a nitrogen heteroatom is added in two separate portions.

### Claim 14 (depends on 1)

The method of claim 1, wherein separating the compound having the structure of Formula I comprises using chromatography.

### Claim 15 (depends on 14)

The method of claim 14, wherein the chromatography is selected from the group consisting of silica gel column chromatography, high-pressure liquid chromatography, and thin layer chromatography.

### Claim 16 (depends on 15)

The method of claim 15, wherein the chromatography is silica gel column chromatography, and wherein the chromatography is conducted using a mobile phase comprising one or more solvents selected from the group consisting of ethyl acetate, hexane, and heptane.

### Claim 17 (depends on 1)

The method of claim 1, further comprising solidifying the compound having the structure of Formula I.

### Claim 18 (depends on 17)

The method of claim 17, wherein solidifying the compound having the structure of Formula I comprises
a) solubilizing the compound having the structure of Formula I in methanol; and
b) precipitating the compound having the structure of Formula I from water;
thereby solidifying the compound having the structure of Formula I.