one pot synthesis of aryl thiophosphoramidate derivatives of azt

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ONE POT SYNTHESIS OF ARYL THIOPHOSPHORAMIDATEDERIVATIVES OF AZTZhi-Wei Miao a , Hua Fu a , Guang-Zhong Tu b & Yu-Fen Zhao ca The Key Laboratory of Bioorganic Phosphorus Chemistry , Ministry of Education ,Department of Chemistry , School of Life Sciences and Engineering , Tsinghua University ,Beijing, 100084, Chinab Beijing Institute of Microchemistry , Beijing, 100091, Chinac The Key Laboratory of Bioorganic Phosphorus Chemistry , Ministry of Education ,Department of Chemistry , School of Life Sciences and Engineering , Tsinghua University ,Beijing, 100084, ChinaPublished online: 16 Aug 2006.

To cite this article: Zhi-Wei Miao , Hua Fu , Guang-Zhong Tu & Yu-Fen Zhao (2002) ONE POT SYNTHESIS OF ARYLTHIOPHOSPHORAMIDATE DERIVATIVES OF AZT, Synthetic Communications: An International Journal for Rapid Communication ofSynthetic Organic Chemistry, 32:21, 3301-3309, DOI: 10.1081/SCC-120014036

To link to this article: http://dx.doi.org/10.1081/SCC-120014036

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©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

ONE POT SYNTHESIS OF ARYL

THIOPHOSPHORAMIDATE

DERIVATIVES OF AZT

Zhi-Wei Miao,1 Hua Fu,1 Guang-Zhong Tu,2

and Yu-Fen Zhao1,*

1The Key Laboratory of Bioorganic PhosphorusChemistry, Ministry of Education, Department of

Chemistry, School of Life Sciences and Engineering,Tsinghua University, Beijing 100084, China

2Beijing Institute of Microchemistry,Beijing 100091, China

ABSTRACT

Novel aryl thiophosphoramidate derivatives of the anti-HIVnucleoside analogue 30-azido-30-deoxythymidine (AZT) havebeen prepared by the thiophosphorochloridate chemistry.These materials were designed to act as membrane-solubleprodrugs of the bioactive free nucleotides.

Various 20,30-dideoxy-20,30-didehydro nucleosides are known as potentinhibitors of HIV, the causative agent of AIDS.[1–3] The anti-retroviraleffects of these compounds involve their conversion, through cellularenzymes, to the corresponding 50-triphosphates (ddNTPs) which interact

SYNTHETIC COMMUNICATIONSVol. 32, No. 21, pp. 3301–3309, 2002

3301

DOI: 10.1081/SCC-120014036 0039-7911 (Print); 1532-2432 (Online)Copyright & 2002 by Marcel Dekker, Inc. www.dekker.com

*Corresponding author. Fax: 86-10-62781695; E-mail: [email protected]

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with HIV-associated reverse transcriptase (RT). At the RT level, ddNTPsmay act as competitive inhibitors, preventing the incorporation of thenatural substrates (dNTPs), or as alternate substrates incorporated in thegrowing DNA chain, leading to the termination of newly synthesized viralnucleic acid.[4,5] Because of the structural differences of 30-azido-30-deoxy-thymidine (AZT) compared to natural nucleosides, the first thymidinekinase catalyzed phosphorylation into AZT-monophosphate is the limitingstep of the metabolization in CEM and MT-4 cells.[6] Several approacheshave been developed to overcome this dependence on nucleoside kinaseactivation, particularly the pronucleotide strategy. The viability of such anapproach is based on the ability to suitable modify the phosphate structureof a membrane-soluble masked nucleotide to enable intracellular to releasethe free phosphate form.[7–9]

The relative metabolic stability of nucleoside-50-phosphorothioates iswell-documented. For instance, AMP-S is relatively resistant to enzymatictransformations by adenylate deaminase, adenylate kinase, and50-nucleotidase,[10,11] and ATP-a-S diastereoisomers exhibit selectivemetabolic stability.[12]

For the purpose to develop new type of prodrugs, in this paper, wereport an efficient method to synthesize different aryl thiophosphoramidatesderivatives of AZT. The target compounds were synthesized as shown inSchs. 1 and 2. O-Aryl phosphorodichloridothioate (1) was used as astarting material. The key step was the coupling of AZT with aryl meth-oxyaminoacyl thiophosphorochloredate (3) to form a new conjugatedcompounds (5).

Reaction of amino acid methyl ester (2) with O-aryl phosphorodi-chloridothioate (1) was performed at 0�C under nitrogen atmosphere(Sch. 1). Triethylamine was added via syringe to the stirring solution. Thereaction was monitored by 31P NMR spectroscopy. It was found that O-arylphosphorodichloridothiate (1) with a 31P NMR shift at 53.39 ppm wastransferred into 3 at about 68 ppm within approximate 2 h, then a solutionof AZT (4) and triethylamine in THF was added to the reaction solution(Sch. 2). After 36 h at 70–80�C the reaction mixture was filtered andconcentrated in vacuo. The residue was dissolved in chloroform andwashed with 1 M hydrochloric acid solution, saturated sodium bicarbonatesolution, and then water. The organic phase was dried over MgSO4 andevaporated under vacuum, and the residue was purified by chromatographyon silica by elution with 5% methanol in chloroform. Pooling and evapora-tion of appropriate fractions gave the product (5) in 66–73% yields. Arylthiophosphoramidate derivatives of AZT (5) were obtained as a mixture ofdiastereoisomers due to the chirality at the phosphorus center. Hence the31P NMR chemical shifts appeared as a pair of peaks at about 72 ppm.

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Table 1 lists the products of aryloxy thiophosphoramidate derivatives ofAZT (5).

Formation of 5b was traced by 31P NMR spectroscopy as shown inFigs. 1 and 2. The starting material O-(4-chlorophenyl) phosphorodichlor-idothioate (1) in THF shows 31P NMR at 53.39 ppm, after the solution ofamino acid methyl ester hydrochloride (2) and triethylamine was added tothe solution of (1), the peak at 31P NMR 53.39 ppm was disappearedgradually within 2 h together with a pair of new peaks at 31P NMR 68.07and 69.25 ppm emerging corresponding to compound 3b (Fig. 1).

Table 1. Products of Aryloxy ThiophosphoramidateDerivatives of AZT (5)

5 R Z Yield (%)

5a H Cl 66.55b CH3 Cl 68.55c (CH3)2CH Cl 70.8

5d H NO2 72.65e CH3 NO2 71.35f (CH3)2CH NO2 72.4

5g CH2Ph NO2 66.3

Scheme 2.

Scheme 1.

ARYL THIOPHOSPHORAMIDATE DERIVATIVES OF AZT 3303

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When AZT (4) was added, two new peaks at 72.13 and 71.26 ppm wereappeared corresponding to compound 5b (Fig. 2). After 36 h the only apair of peaks at about 31P NMR 72 ppm were observed. Triethylamineacted as a catalytic reagent besides capturing hydrochloride produced inthe reactions.

Figure 2. The stack 31P NMR spectra of formation of compound 5b.

Figure 1. The stack 31P NMR spectra of formation of compound 3b.

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In conclusion, in this paper a convenient and efficient approach tosynthesis of aryl thiophosphoramidates derivatives of AZT under mildconditions had been developed. In the first step only one chloride ofO-aryl phosphorodichloridothioate is displaced by amino acid ester toform a new phosphorus–nitrogen bond. AZT thiophosphorylation takesplace at the 50-position. The reaction is a convenient two-step one pot syn-thesis, intermediate need not to be separated in the middle of reaction. Moredetailed investigations into these compounds and activity of anti-HIV arecurrently underway.

EXPERIMENTAL

General Information

All glassware was dried in an oven for at least 3 h at 120�C prior to use.Air sensitive materials were transferred under a nitrogen atmosphere. THFand triethylamine were dried over Na and CaH2 respectively. 1H NMR and13C NMR spectra were recorded in Bruker AM 500 spectrometer. TMS(�¼ 0.0) and CDCl3 (�¼ 7.24 ppm) were references for 1H and 13C NMRspectra respectively. 13C NMR spectra were all taken under 1H decoupledand 31P coupled conditions. 31P NMR spectra were taken on Bruker AC 200spectrometer at 81 MHz under 1H decoupled conditions. 31P NMR chemicalshifts are reported in ppm downfield (þ) or upfield (�) from external 85%H3PO4 as reference. Mass spectra were conducted on Bruker Esquire-LCmass spectrometer operated in positive and negative ion mode.

Synthesis of O-Aryl Phosphorodichloridothioate (1) and

Amino Acid Methyl Ester Hydrochloride (2)

The preparation of O-aryl phosphorodichloridothioate (1) and aminoacid methyl ester hydrochloride (2) were carried out according to the litera-ture.[13,14] All physical constants and spectroscopies data of the productssynthesized were in agreement with the literature.

General Procedure for Synthesis of Aryl Thiophosphoramidate

Derivatives of AZT (5)

A solution of triethylamine (1.4 mL, 1.0 g, 10.0 mmol) in THF (10 mL)was added dropwise with vigorous stirring to a solution of amino acid


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methyl ester hydrochloride (2, 5.02 mmol) and O-aryl phosphorodichlori-dothioate (1, 5.02 mmol) in THF (10 mL) at 0�C over a period of 15 min.The reaction mixture was slowly warmed to ambient temperature with stir-ring over 2 h, and the solvent was then removed in vacuum. The residue wastreated with THF (15 mL), the mixture was filtered, and the filtrate wasevaporated in vacuum to yield the product (3) as a colorless oil(5.02 mmol, 100%). A solution of AZT (5.02 mmol) was dissolved in THF(10 mL), and aryl methoxyalaninyl thiophosphorochloridate (3) (5.02 mmol)and triethylamine (0.7 mL, 0.5 g, 5.02 mmol) was added with vigorous stir-ring. After 34 h at 70–80�C the solvent was removed under vacuum. Theresidue was dissolved in chloroform (10 mL) and washed with 1 M hydro-chloric acid solution (2� 15 mL), saturated sodium bicarbonate solution(2� 10 mL), and then water (3� 15 mL). The organic phase was dried(MgSO4) and evaporated under vacuum, and the residue was purified bychromatography on silica by elution with 2% methanol in chloroform.Pooling and evaporation of appropriate fractions gave the product 5.

Compound 5a (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.73 for TLC). 1.82 g (yield 66.5%). 31P NMR (CDCl3, �: ppm, J:Hz): � 71.95, 71.65; 1H NMR (500 MHz, CDCl3): � 9.60 (1H, sb, NH),7.48 (2H, m, ortho-Ar), 7.29 (1H, m, H-6), 7.12 (2H, m, meta-Ar), 6.11(1H, m, H-10), 5.08 (1H, m, H-40), 4.41 (1H, m, H-30), 4.31 (2H, m, H-50),4.03 (2H, m, Gly-NH, Gly-CH), 3.60 (3H, s, OMe), 2.31 (2H, m, H-20), 1.82,1.81 (3H, d, 3J¼ 5.5, 5-Me); 13C NMR (500 MHz, CDCl3): � 174.15 (Gly-CO), 164.02 (C-2), 159.88 (Ph-para), 150.51 (C-4), 146.32 (Ph-ipso), 135.16(C-6), 121.65 (Ph-ortho), 116.38 (Ph-meta), 111.61 (C-5), 85.22 (C-10), 82.38(C-40), 65.82 (C-50), 60.44 (C-30), 52.83 (Gly-OMe), 50.41 (Gly-CH), 37.32(C-20), 12.64 (5-Me); ESI-MS (pos.): m/z 546 (MþH)þ; ESI-MS (neg.): m/z544 (M�H)�.

Compound 5b (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.77 for TLC). 1.92 g (yield 68.5%). 31P NMR (CDCl3, �: ppm, J:Hz): � 72.13, 71.26; 1H NMR (500 MHz, CDCl3): � 9.62 (1H, sb, NH),7.66 (2H, m, ortho-Ar), 7.29 (1H, m, H-6), 7.17 (2H, m, meta-Ar), 6.21(1H, m, H-10), 5.11 (1H, m, H-40), 4.34 (1H, m, H-30), 4.26 (2H, m, H-50),4.10 (2H, m, Ala-CH, Ala-NH), 3.65 (3H, s, OMe), 2.41 (2H, m, H-20), 1.80,1.79 (3H, d, 3J¼ 5.5, 5-Me), 1.31, 1.30 (3H, d, 3J¼ 6, Ala-Me); 13C NMR(500 MHz, CDCl3): � 171.33 (Ala-CO), 164.12 (C-2), 151.51 (C-4), 148.32(Ph-ipso), 135.41 (C-6), 135.12 (Ph-para), 130.41 (Ph-ortho), 119.99 (Ph-meta), 111.58 (C-5), 84.93 (C-10), 82.47 (C-40), 65.38 (C-50), 60.51 (C-30),52.72 (Ala-OMe), 50.44 (Ala-CH), 37.42 (C-20), 21.07 (Ala-Me), 12.66 (5-Me); ESI-MS (pos.): m/z 560 (MþH)þ; ESI-MS (neg.): m/z 558 (M�H)�.

Compound 5c (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.68 for TLC). 2.09 g (yield 70.8%). 31P NMR (CDCl3, �: ppm,

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J: Hz): � 71.35, 70.83; 1H NMR (500 MHz, CDCl3): � 9.55 (1H, sb, NH),7.61 (2H, m, ortho-Ar), 7.42 (1H, s, H-6), 7.07 (2H, m, meta-Ar), 6.23 (1H,m, H-10), 5.10 (1H, m, H-40), 4.53 (1H, m, H-30), 4.34 (2H, m, H-50), 4.12(2H, m, Val-CH, Val-NH), 3.71 (3H, s, OMe), 2.43 (2H, m, H-20), 1.90, 1.89(3H, d, 3J¼ 5.5, 5-Me), 1.62 (1H, m, Val-iPrCH), 0.98 (6H, m, Val-Me);13C NMR (500 MHz, CDCl3): � 174.43 (Val-CO), 164.07 (C-2), 150.54 (C-4),148.43 (Ph-ipso), 140.02 (Ph-para), 135.41 (C-6), 129.87 (Ph-ortho), 119.95(Ph-meta), 111.53 (C-5), 84.96 (C-10), 82.58 (C-40), 65.87 (C-50), 60.51 (C-30),52.83 (Val-OMe), 50.44 (Val-CH), 37.42 (C-20), 33.24 (Val-iPrCH), 20.37(Val-Me), 12.85 (5-Me); ESI-MS (pos.): m/z 588 (MþH)þ; ESI-MS (neg.):m/z 586 (M�H)�.

Compound 5d (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.71 for TLC). 2.02 g (yield 72.6%). 31P NMR (CDCl3, �: ppm, J:Hz): � 71.24, 70.38; 1H NMR (500 MHz, CDCl3): � 9.57 (1H, sb, NH),7.29 (3H, m, H-6, meta-Ar), 7.29 (1H, m,), 7.08 (2H, m, ortho-Ar), 6.21(1H, m, H-10), 5.10 (1H, m, H-40), 4.46 (1H, m, H-30), 4.37 (2H, m, H-50),4.07 (2H, m, Gly-NH, Gly-CH), 3.62 (3H, s, OMe), 2.33 (2H, m, H-20), 1.91,1.90 (3H, d, 3J¼ 5.5, 5-Me); 13C NMR (500 MHz, CDCl3): � 174.40 (Gly-CO), 164.22 (C-2), 158.78 (Ph-para), 151.11 (C-4), 145.80 (Ph-ipso), 133.86(C-6), 120.95 (Ph-ortho), 117.12 (Ph-meta), 112.45 (C-5), 84.11 (C-10), 82.58(C-40), 64.92 (C-50), 59.44 (C-30), 53.13 (Gly-OMe), 50.62 (Gly-CH), 37.74(C-20), 12.84 (5-Me); ESI-MS (pos.): m/z 556 (MþH)þ; ESI-MS (neg.): m/z554 (M�H)�.

Compound 5e (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.88 for TLC). 2.04 g (yield 71.3%). 31P NMR (CDCl3, �: ppm, J:Hz): � 71.33, 70.84; 1H NMR (500 MHz, CDCl3): � 9.31 (1H, sb, NH),7.66 (2H, m, ortho-Ar), 7.34 (1H, m, H-6), 7.21 (2H, m, meta-Ar), 6.23(1H, m, H-10), 5.10 (1H, m, H-40), 4.66 (1H, m, H-30), 4.30 (2H, m, H-50),4.11 (2H, m, Ala-CH, Ala-NH), 3.60 (3H, s, OMe), 2.41 (2H, m, H-20), 1.82,1.81 (3H, d, 3J¼ 6, 5-Me), 1.42 (3H, d, 3J¼ 6, Ala-Me); 13C NMR(500 MHz, CDCl3): � 174.23 (Ala-CO), 164.12 (C-2), 150.68 (C-4), 148.37(Ph-ipso), 141.42 (Ph-para), 135.44 (C-6), 129.13 (Ph-ortho), 119.91 (Ph-meta), 111.48 (C-5), 85.06 (C-10), 82.44 (C-40), 65.78 (C-50), 60.53 (C-30),52.62 (Ala-OMe), 50.33 (Ala-CH), 37.22 (C-20), 20.87 (Ala-Me), 12.66(5-Me); ESI-MS (pos.): m/z 570 (MþH)þ ESI-MS (neg.): m/z 568 (M�H)�.

Compound 5f (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.86 for TLC). 2.17 g (yield 72.4%). 13P NMR (CDCl3, �: ppm, J:Hz): � 71.87, 71.35; 1H NMR (500 MHz, CDCl3): � 9.51 (1H, sb, NH),7.71 (2H, m, ortho-Ar), 7.54 (1H, s, H-6), 7.31 (2H, m, meta-Ar), 6.18(1H, m, H-10), 5.12 (1H, m, H-40), 4.71 (1H, m, H-30), 4.38 (2H, m, H-50),4.07 (2H, m, Val-CH, Val-NH), 3.66 (3H, s, OMe), 2.54 (2H, m, H-20), 1.81,1.80 (3H, d, 3J¼ 6, 5-Me), 1.61 (1H, m, Val-iPrCH), 1.02 (6H, m, Val-Me);


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13C NMR (500 MHz, CDCl3): � 172.38 (Val-CO), 163.67 (C-2), 149.64 (C-4),147.83 (Ph-ipso), 138.42 (Ph-para), 135.55 (C-6), 130.17 (Ph-ortho), 120.32(Ph-meta), 111.07 (C-5), 85.07 (C-10), 82.48 (C-40), 63.98 (C-50), 59.49 (C-30),52.17 (Val-OMe), 50.65 (Val-CH), 36.82 (C-20), 33.45 (Val-iPrCH), 21.17(Val-Me), 12.85 (5-Me); ESI-MS (pos.): m/z 598 (MþH)þ; ESI-MS (neg.):m/z 596 (M�H)�.

Compound 5g (diastereoisomers): MeOH : CHCl3 (1 : 50) as eluent(Rf¼ 0.85 for TLC). 2.15 g (yield 66.3%). 31P NMR (CDCl3, �: ppm, J:Hz): � 72.08, 71.74; 1H NMR (500 MHz, CDCl3): � 9.81 (1H, sb, NH),7.22–7.61 (10H, m, Ph, H-6), 6.23 (1H, m, H-10), 5.22 (1H, m, H-40), 4.88(1H, m, H-30), 4.56 (2H, m, H-50), 4.17 (2H, m, Phe-CH, Phe-NH), 3.77 (3H,s, OMe), 3.15 (2H, m, Phe-CH2), 2.44 (2H, m, H-20), 1.91 (3H, s, 5-Me);13C NMR (500 MHz, CDCl3): � 172.91 (Phe-CO), 164.22 (C-2), 151.18 (C-4), 150.41 (m, Ph), 135.77 (Ph), 135.42 (C-6), 129.81 (Ph), 129.52 (Ph),128.71 (m, Ph), 127.11 (m, Ph), 125.47 (Ph), 120.21 (m, Ph), 111.51 (C-5),84.96 (C-10), 82.38 (C-40), 65.74 (C-50), 60.58 (C-30), 56.07 (Phe-CH), 52.61(Ala-OMe), 40.42 (m, Phe-CH2), 37.42 (C-20), 12.66 (5-Me); ESI-MS (pos.):m/z 646 (MþH)þ; ESI-MS (neg.): m/z 644 (M�H)�.

ACKNOWLEDGMENT

The authors would like to thank the financial supports from theNational Natural Science Foundation of China (No. 29902003, No.39870415), the Ministry of Science and Technology, the Ministry ofEducation and Tsinghua University.

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one pot synthesis of aryl thiophosphoramidate derivatives of azt

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