# US 10,308,665 B2 · Method for the synthesis of rapamycin derivatives

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- Number: US 10,308,665 B2
- Document ID: US10308665B2
- Status: Granted
- Kind: B2
- Application number: 15/737,861
- Filed: 2016-06-22
- Published: 2019-01-10
- Granted: 2019-06-04
- Earliest claimed: 2015-06-23
- Assignees: Synbias Pharma AG
- Applicants: Synbias Pharma AG
- Inventors: Oleksandr Zabudkin; Christian Schickaneder; Iaroslav Matviienko; Volodymyr Sypchenko
- Web page: https://patentgrep.com/patent/US10308665B2

## CPC

- C07D 498/16: Peri-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 498/18: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a method for the production of a rapamycin derivative of formula (I), the method comprising the preparation of a 2-(tri-substituted silyl)oxyethyl triflate by reacting ethylene oxide and a tri-substituted silyl triflate, reaction of the resulting 2-(tri-substituted silyl)oxyethyl triflate with rapamycin in the presence of a molar excess of organic base, and deprotection to obtain the rapamycin derivative of compound (I).

## Claims

### Claim 1

Method for the production of a rapamycin derivative of formula (I), comprising:
(a) preparing a 2-(tri-substituted silyl)oxyethyl triflate of formula 4 by reacting ethylene oxide and a tri-substituted silyl triflate of formula 3
wherein R1, R2, and R3 are independently selected from the group consisting of C1-C12 alkyl and C1-C12 aryl;
(b) reacting the 2-(tri-substituted silyl)oxyethyl triflate of formula 4 obtained in step (a) with rapamycin in the presence of a molar excess of organic base to obtain a protected rapamycin derivative of formula 5; and
(c) deprotecting the protected rapamycin derivative of formula 5 to obtain the rapamycin derivative if formula (I).

### Claim 2 (depends on 1)

The method of claim 1, wherein R1, R2, and R3 are independently selected from the group consisting of C1-C6 alkyl and C6-C12 aryl.

### Claim 3 (depends on 1)

The method of claim 1, wherein R1, R2, and R3 each are isopropyl; or R1 and R2 each are methyl and R3 is t-butyl; or R1 and R2 each are phenyl and R3 is t-butyl; or R1 and R2 each are methyl and R3 is t-hexyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein step (a) is performed at a reaction temperature of 15° C.-45° C. in an organic solvent.

### Claim 5 (depends on 4)

The method of claim 4, wherein the organic solvent is toluene.

### Claim 6 (depends on 1)

The method of claim 1, wherein the ethylene oxide is used in an amount of 1.1-1.2 molar equivalents of the amount of tri-substituted silyl triflate of formula 3.

### Claim 7 (depends on 1)

The method of claim 1, wherein the 2-(tri-substituted silyl)oxyethyl triflate of formula 4 obtained in step (a) is used without further purification.

### Claim 8 (depends on 1)

The method of claim 1, wherein step (b) is performed at a reaction temperature of 40° C.-55° C. in an organic solvent.

### Claim 9 (depends on 8)

The method of claim 8, wherein the organic solvent is a mixture of 85-95% (v/v) toluene and 5-15% (v/v) dimethoxyethane.

### Claim 10 (depends on 1)

The method of claim 1, wherein the 2-(tri-substituted silyl)oxyethyl triflate of formula 4 is used in an amount of 4-12 molar equivalents of the amount of rapamycin.

### Claim 11 (depends on 1)

The method of claim 1, wherein the organic base in step (b) is N,N-diisopropylethylamine.

### Claim 12 (depends on 1)

The method of claim 1, wherein the protected rapamycin derivative of formula 5 obtained in step (b) is used without further purification.

### Claim 13 (depends on 1)

The method of claim 1, wherein deprotection is accomplished by reacting the protected rapamycin derivative of formula 5 with an agent selected from the group consisting of hydrochloric acid, acetic acid, tetra-n-butylammonium fluoride, and pyridine hydrofluoride.

### Claim 14 (depends on 1)

The method of claim 1, further comprising purifying the rapamycin derivative of formula (I) obtained in step (c).