# US 11,897,913 B2 · Synthesis of 3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)]phosphate (NUC-738)

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- Number: US 11,897,913 B2
- Document ID: US11897913B2
- Status: Granted
- Kind: B2
- Application number: 16/623,272
- Filed: 2018-06-14
- Published: 2020-06-11
- Granted: 2024-02-13
- Earliest claimed: 2017-06-14
- Assignees: NuCana plc
- Applicants: NuCana plc
- Inventors: Venkata Lakshmi Narasimha Rao Dammalapati; Mani Bushan Kotala
- Web page: https://patentgrep.com/patent/US11897913B2

## CPC

- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- C07H 1/02: Phosphorylation
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention generally relates to a novel process for the preparation of 3′-deoxyadenosine derivatives, and particularly NUC-7738 (3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate) an anticancer ProTide of deoxyadenosine.

## Claims

### Claim 1

A process for the preparation of NUC-7738 (I)
the process comprising steps b), c), d), e) and f):
b) treating a compound of formula (VI) with a hydride reducing agent to provide a compound of formula (V)
c) introducing the protecting group P2 onto the 2′ hydroxy group of a compound of formula (V) to provide a compound of formula (II)
d) removing the protecting group P1 from a compound of formula (II) to provide 2′-protected Cordycepin (I)
wherein P1 and P2 are silyl protecting groups and P3 and P4 are each independently selected from H and a protecting group;
e) converting the compound of formula (I) into a compound of formula (IV)
(IV); and
f) removing protecting group P2 and, where P3 and P4 are protecting groups, removing P3 and P4 to provide NUC-7738;
wherein the overall yield of steps b), c), and d) is 70%-100%.

### Claim 2 (depends on 1)

The process of claim 1, wherein the process further comprises step a):
a) introducing the protecting group P1 onto the 5′ hydroxy group of a compound of formula (VII) to provide a compound of formula (VI)

### Claim 3 (depends on 1)

The process of claim 1, wherein P3 and P4 are each H.

### Claim 4 (depends on 1)

The process of claim 1, wherein step d) is achieved with trifluoroacetic acid (TFA).

### Claim 5 (depends on 4)

The process of claim 4, wherein step d) is achieved in a mixture of acetonitrile and water.

### Claim 6 (depends on 4)

The process of claim 4, wherein step d) is carried out at a temperature between 0° C. and 20° C.

### Claim 7 (depends on 1)

The process of claim 1, wherein the NUC-7738 is formed as a mixture of diastereoisomers.

### Claim 8 (depends on 7)

The process of claim 7, wherein step e) comprises: reacting the compound of formula (I) with a compound of formula (III) in the presence of a base (B1) to provide a compound of formula (IV); wherein the compound of formula (III) is:
and wherein B1 is a nitrogen base, an organometallic base or a metal hydride base.