A One-Step Ring Transformation/Ring Annulation Approach to Pyrrolo[2,3-d]pyrimidines. A New Synthesis of the Potent Dihydrofolate Reductase Inhibitor TNP-351

Taylor, Edward C.; Patel, Hemantkumar H.; Jun, Jong‐Gab

doi:10.1021/jo00126a017

Cited by 36 publications

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“…pyrrolo [2,3-d]pyrimidine and was in agreement with the reported value for 1a [5]. The benzylic CH 2 group in the furan 3e gave a singlet at δ 3.61, and thus was less deshielded than the same proton in the pyrrole 1e (δ 4.00).…”

Section: Synthesis Of New 24-diamino-7h-pyrrolo[23-d]pyrimidinessupporting

confidence: 91%

“…In the present work we were interested in preparing compounds in which the two halves of the molecule are joined via a shorter bridge in order to assess the effect of this particular structural modification on potency and selectivity. To this end, we took advantage of an elegant strategy first described by Taylor and coworkers [5,6], called "one-step ring-transformation/ring annulation". At the heart of this strategy is the intriguing [2,3-d]pyrimidines with methyl, ethyl, phenyl groups at the 5-and/or 6-position were obtained in similar fashion, as well as analogs in which the 5-substituent was a 2-phenylethyl or 3-phenylpropyl group with a CO 2 Me group at the para position.…”

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confidence: 99%

“…As shown in Scheme 1, aldol condensation of appropriately substituted benzaldehydes with paraformaldehyde in the presence of N-ethylbenzothiazolium bromide and triethylamine [5][6][7] afforded the desired α-hydroxyketones 2a-d. Further reaction of 2a-d with malononitrile and triethylamine in refluxing methanol yielded the furans 3a-d, which upon heating with 1.5 molar equivalents of guanidine in refluxing ethanol, typically for 30 hours, were converted to the pyrrolopyrimidines 1a-d. In the case of 1e, phenylacetaldehyde was used in place of benzaldehyde, giving rise to the α-hydroxyketone 2e and the furan 3e.…”

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Synthesis of new 2,4‐diamino‐7H‐pyrrolo[2,3‐d]pyrimidines via the Taylor ring transformation/ring annulation strategy

Rosowsky

Queener

2001

Journal of Heterocyclic Chem

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Selected examples 2,4-diamino-7H-pyrrolo [2,3-d]pyrimidines with a phenyl or benzyl group at the 5-position were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii and Toxoplasma gondii, two potentially life-threatening opportunistic pathogens associated with AIDS and other disorders of the immune system. Aldol condensation of paraformaldehyde with substituted benzaldehydes or with phenylacetaldehyde afforded α-hydroxyketones with a phenyl or benzyl group at the 4-position. Further reaction of the hydroxyketones with malononitrile afforded 2-aminofuran-3-carbonitriles, which upon heating with guanidine underwent ring transformation/ring annulation to produce 2,4-diamino-7H-pyrrolo[2,3-d]pyrimidines rather than 2,4-diaminofuro[2,3-d]pyrimidines. One of the target compounds obtained in this manner, 2,4-diamino-5-(3,4,5-trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1d), may be viewed as a conformationally restricted analogue of trimethoprim, an antimicrobial agent widely used in combination with a sulfa drug to treat P. carinii and T. gondii opportunistic infections in patients with AIDS. Compound 1d inhibited P. carinii and T. gondii DHFR with IC 50 values of 8.3 and 14 µM, respectively. This potency was somewhat greater than that of trimethoprim. However, because this compound was also more potent than trimethoprim against mammalian (rat liver) DHFR rat liver it lacked species selectivity. The other 2,4-diamino-7H-pyrrolo[2,3-d]pyrimidines synthesized were neither potent nor selective.

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Section: Synthesis Of New 24-diamino-7h-pyrrolo[23-d]pyrimidinessupporting

confidence: 91%

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Synthesis of new 2,4‐diamino‐7H‐pyrrolo[2,3‐d]pyrimidines via the Taylor ring transformation/ring annulation strategy

Rosowsky

Queener

2001

Journal of Heterocyclic Chem

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“…Molecular modeling (Sybyl 7.0) 6 suggested that an extension of the 5-methyl group to an ethyl group might enhance the potency and selectivity against some pathogenic DHFR. Thus, a series of nonclassical 5-ethyl-6-[(substituted-phenyl)-sulfanyl]-7H-pyrrolo [2,3-d]pyrimidine-2,4-diamines (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were also synthesized.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Classical and Nonclassical 6-Arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as Antifolates

et al. 2007

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The classical antifolate N-{4- [(2,4-diamino-5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)sulfanyl]benzoyl}-L-glutamic acid (2) and 15 nonclassical analogues (3-17) were synthesized as potential dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. 5-Ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (20) served as the key intermediate to which various aryl thiols and a heteroaryl thiol were appended at the 6-position via an oxidative addition reaction. The classical analogue 2 was synthesized by coupling the benzoic acid derivative 18 with diethyl L-glutamate followed by saponification. The classical compound 2 was an excellent inhibitor of human DHFR (IC 50 = 66 nM) as well as a two digit nanomolar (<100 nM) inhibitor of the growth of several tumor cells in culture. Some of the nonclassical analogues were potent and selective inhibitors of DHFR from two pathogens (Toxoplasma gondii and Mycobacterium avium) that cause opportunistic infections in patients with compromised immune systems.

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“…Taylor et al 21 have reported the synthesis of various 2,4-diamino-5-alkyl-7 H -pyrrolo[2,3- d ]py-rimidines by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans. These furans were in turn obtained by the condensation of suitable α-hydroxy ketones with malonodinitrile in the presence of a suitable base such as triethylamine.…”

Section: Chemistrymentioning

confidence: 99%

The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents

et al. 2008

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Novel classical antifolates (3 and 4) and 17 nonclassical antifolates (11-27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11-27 were 2,4-diamino-5-alkylsubstituted-7H-pyrrolo[2,3-d]pyrimidines, 31 and 38, prepared by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I2. The condensation of α-hydroxy ketones with malonodinitrile afforded the furans. For the classical analogues 3 and 4, the ester precursors were deprotected, coupled with diethyl-l-glutamate, and saponified. Compounds 3 (IC50 = 60 nM) and 4 (IC50 = 90 nM) were potent inhibitors of human DHFR. Compound 3 inhibited tumor cells in culture with GI50 ≤ 10−7 M. Nonclassical 17 (IC50 = 58 nM) was a potent inhibitor of Toxoplasma gondii (T. gondii) DHFR with >500-fold selectivity over human DHFR. Analogue 17 was 50-fold more potent than trimethoprim and about twice as selective against T. gondii DHFR.

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A One-Step Ring Transformation/Ring Annulation Approach to Pyrrolo[2,3-d]pyrimidines. A New Synthesis of the Potent Dihydrofolate Reductase Inhibitor TNP-351

Cited by 36 publications

References 0 publications

Synthesis of new 2,4‐diamino‐7H‐pyrrolo[2,3‐d]pyrimidines via the Taylor ring transformation/ring annulation strategy

Synthesis of new 2,4‐diamino‐7H‐pyrrolo[2,3‐d]pyrimidines via the Taylor ring transformation/ring annulation strategy

Design and Synthesis of Classical and Nonclassical 6-Arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as Antifolates

The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents

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