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PROCESS FOR THE PREPARATION OF 10-PROPARGYL-10-CARBOMETHOXY-4-DEOXY-4-AMINO-10-DEAZAPTEROIC ACID METHYL ESTER

IP.com Disclosure Number: IPCOM000194934D
Publication Date: 2010-Apr-14
Document File: 2 page(s) / 30K

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     PROCESS FOR THE PREPARATION OF 10-PROPARGYL-10- CARBOMETHOXY-4-DEOXY-4-AMINO-10-DEAZAPTEROIC ACID METHYL ESTER 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester (referred as "PRP") of the following structure;

N

N

COOMe

NH2

N

N

COOMe

5

contains the 2,4-diaminopteridine moiety, which is present in numerous folic acid derivatives of relevant biological activity.

Described herein is the synthesis of PRP.

Example 1: 2,4-Diamino-6-chloromethylpteridine hydrochloride 2

OH

H2N

NH2

NH2

N N

SOCl2

HC(O)NH2

N N

N

N

N

N

Cl

H2N

.

H2N

HCl

.

HCl

1 2

To a suspension of 2,4-diamino-6-hydroxymethylpteridine hydrochloride 1 (25 g,
0.11 mol) in dry formamide (200 mL) at 50 °C, thionyl chloride was added (23.9 mL,
0.33 mol).

The resulting precipitate was filtered off and washed with acetone. 2,4-Diamino-6- chloromethylpteridine hydrochloride 2 was obtained as a yellow powder (27.2 g, 96% yield, 99% purity).

Example 2: α-Propargyl-homoterephtalic acid dimethyl ester 4

COOMe

C

OOMe

CO2Me

Cl

MeOOC

MeOOC

+

TBAI, NaH, THF

0 °C to RT

CO2Me 3

4

4b

To a suspension of NaH (11.5 g, 0.29 mol, 60% dispersion in mineral oil) in dry THF (350 mL) at 0 °C, 4-methoxycarbonylmethyl-benzoic acid methyl ester 3, (50 g, 0.24

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mol) in THF (150 mL) was added dropwise. The mixture was stirred for 0.5 h at 0 °C, then TBAI was added (27.1 g, 0.072 mol). The cooling bath was removed and propargyl chloride (21.2 mL, 0.29 mol) was added between 5 and 10 °C. The reacti...