[ CAS No. 2946-39-6 ]

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2D
Chemical Structure| 2946-39-6
Chemical Structure| 2946-39-6
Structure of 2946-39-6

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Product Details of [ 2946-39-6 ]

CAS No. :2946-39-6MDL No. :MFCD00005733
Formula :C10H12BrN5O4Boiling Point :717.7°C at 760 mmHg
Linear Structure Formula :C10H12N5O4BrInChI Key :-
M.W :346.14Pubchem ID :96544
Synonyms :

Computed Properties of [ 2946-39-6 ]

TPSA : 140 H-Bond Acceptor Count : 8
XLogP3 : - H-Bond Donor Count : 4
SP3 : 0.50 Rotatable Bond Count : 2

Safety of [ 2946-39-6 ]

Signal Word:WarningClassN/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2946-39-6 ]

  • Upstream synthesis route of [ 2946-39-6 ]

[ 2946-39-6 ] Synthesis Path-Upstream   1~7

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YieldReaction ConditionsOperation in experiment
82.5% With bromine; sodium acetate In water Example 1: Modified siRNA Molecules8-methoxyadenosine phosphoramidite was synthesized and incorporated into the anti- sense strand of caspase 2 siRNA. Figure 7A shows a schematic of the double-stranded positive control siRNA (SEQ ID NO: 20 (top) and SEQ ID NO: 21 (bottom)) and the double-stranded negative control siRNA (SEQ ID NO: 22 (top) and SEQ ID NO: 23 (bottom). Figure 7B shows a schematic for a singly modified siRNA, wherein the modification can be, but is not limited to, 8-proparglyoxyadenosine, 8-phenethyloxyadenosine, and 8-cyclohyexylethyloxyadenosine. In Figure 7B, 4AS corresponds to SEQ ID NO: 24, 6AS corresponds to SEQ ID NO: 25, 10AS corresponds to SEQ ID NO: 26, and 15AS corresponds to SEQ ID NO: 27.The bromination of adenosine is known in the art; generally, a three to four- fold excess of bromine generates a yield of about 75percent to about 82.5percent of 8-bromoadenosine. To protect the 2'-OH group during the synthesis of ribo-phosphoramidites, the 5' -OH ofN^-benzoyladenosine was first protected; and then t-butyldimethylsilyl chloride (TBDMS-C1) was used to protect the 2' -OH. Although the addition of Ag+ ion is recommended to minimize unavoidable reaction at the 3 '-OH, the unwanted reaction generally occurs and the overall yield is significantly reduced. Therefore, to accomplish a good overall yield, a novel protecting group di-ibutylsilyl ditriflate (DTBSDT), which protects the 5' -OH and the 3' -OH simultaneously and leaves the 2'-OH ready to be protected by TBDMS-C1 was used. The two reactions were basically a one- pot reaction, which eliminated the need for tedious separation. The reaction was almost quantitative with about 96percent to about 98percent product yield observed. (See Figures 3 and 4).Synthesis of the methoxy derivative using sodium methoxide reagent in methanol yielded the 8-methoxyadenosine derivative as well as the 8-oxoadenosine derivative. The separation of these two derivates was not trivial and the yield of the desired compound was below 50percent. Thus, the methoxy anion was generated in situ by reacting n-BuLi with excess anhydrous methanol. This reaction was much more efficient and yielded about 85percent to about 93percent of the desired product. The deprotection of 5' -OH and the 3'-OH was accomplished using a special fluoride reagent, HF -pyridine, at sub-zero temperature. These DMT reactions generated low yields (about 40percent to about 50percent) of the desired product. The phosphoramidite synthesis step yielded about 95percent to about 98percent of desired product. The 8- methoxy adenosine phosphoramidite was then incorporated into the antisense strand at position 9 or 14 (opposite to positions 11 and 6 of the sense strand, respectively), or both positions 9 and 14. The propargyl moiety at position 8 of adenosine can simplify the syntheses of other position 8 substituted adenosine analogs. The alkyne moiety of 8- propargyladenosine in siRNA can be "clicked" with suitable water-soluble azides leading to the formation of desirable minor groove modification.
81% With bromine In water at 20℃; for 47.00 h; aq. acetate buffer Saturated bromine-water (18.5 mL) was added slowly to a suspension of adenosine (0.5 g, 1.9 mmol) in NaOAc buffer (11.4 mL, 0.5 M, pH 4). The mixture was stirred at r.t. for 47 h. The solution was decolorized by the addition of 5 N NaHSO3, and the pH of the solution was then adjusted to 7 with 2 N NaOH. The resulting solids were collected by filtration, successively washed with water and acetone, and dried in vacuo to yield 19 (81percent). 1H NMR (270 MHz, DMSO-d6) δ: 3.46-3.74 (2H, m, H-5'), 3.98 (1 H, dd, J = 6.3, 4.0 Hz, H-4'), 4.16-4.22 (1 H, m, H-3'), 5.08 (1 H, dd, H-2'), 5.24 (1 H, d, J = 4.6 Hz, 3'-OH), 5.47 (1H, d, J = 6.3 Hz, H-1'), 5.52 (1 H, dd, J = 8.6, 4.0 Hz, 5'-OH), 5.83 (1 H, d, J = 6.5 Hz, 2'-OH), 7.56 (2H, br s, NH2), 8.11 (1H, s, H-2). ESI MS: m/z 345.1 Da [M+H]+,C10H12BrN5O4 Mol. Wt. 346.14.
73% With sodium azide; bromoisocyanuric acid monosodium salt In water; N,N-dimethyl-formamide at 20℃; for 0.50 h; General procedure: 5'-O-Monomethoxytrityl-N2-phenoxyacetylguanosine (33, 0.138 g, 0.2 mmol) was dissolved inaqueous DMF solution (H2O:DMF 1:4, 5 mL) under stirring. SMBI (1.1 equiv., 0.051 g, 0.22 mmol)was added at r.t. and the mixture stirred. Progress of the reaction was followed by TLC. An additionalamount of the reagent (0.15 equiv., 0.007 g) was added into the reaction mixture after 1.5 h. Oncompletion of the reaction by 2 h, the reaction mixture was filtered, evaporated to dryness underreduced pressure and coevaporated with water (2 × 2 mL). The crude reaction mixture was purified bycolumn chromatography (4percent–5percent MeOH in DCM, v/v) to afford nucleoside 34 (0.148 g, 96percent) in pureform as a white solid.8-Bromo-5'-O-monomethoxytrityl-N2-phenoxyacetylguanosine (34).
48% With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide at 25℃; for 5.00 h; Typical procedure for the bromination of unprotected nucleosides: DBH (323 mg, 1.13 mmol) was added to a stirred solution of 1d (500 mg, 2.05 mmol) in DMF (5 mL). The resulting pale-yellow solution was stirred at room temperature for 20 minutes or until TLC showed absence of starting material and formation of less polar product. Volatiles were evaporated and the residue was coevaporated with MeCN. The resulting pale solid was crystallized from hot acetone to give 2d (500 mg, 75percent) as colorless crystals with data as reported.14
53.1 kg
Stage #1: With sodium acetate; acetic acid In water at 75℃; for 0.50 h; Industrial scale
Stage #2: With bromine In water at 30℃; for 10.00 h; Industrial scale
First, in a 2t reactor, 50 kg (185 mol) of adenosine and 600 kg of water, acetic acid-sodium acetate buffer solution (0.4 M, pH 4.5) were sequentially added, and then the temperature was raised to 75 ° C, and the temperature was kept for 30 minutes until the reaction system was dissolved;Then, the temperature was lowered to 30 ° C, 59 kg of Br 2 was further added, and then reacted at 30 ° C for 10 h, and the reaction was carried out by a high-performance liquid phase method, and the reaction was terminated when the content of the raw material in the reaction system was less than 1percent.Finally, after the reaction is completed, the reaction system is cooled to room temperature.Unreacted Br2 was removed by adding 19.5 kg of NaHSO3, then the pH was adjusted to 7 with a 5percent NaOH solution, filtered, and the filter cake was washed with water.Drying in vacuo gave a yellow product, 8-bromoadenosine, 53.1 kg.

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YieldReaction ConditionsOperation in experiment
22% With bromine; sodium acetate; acetic acid In water at 45℃; for 2.50 h; 6-Benzylamino-9-(β-D-ribofuranosyl)purine (469.4 mg; 1.313 mmol) was suspended in 15 ml 1 M AcONa and 15 ml 1 M AcOH. Bromine water (12.7 ml) was added to suspension and mixture was heated for 2.5 h at 45° C.
Excess bromine was eliminated by addition of solid NaHSO3 and then the mixture was neutralized by 10percent NaOH and evaporated.
Residue was shaken out with water and chloroform.
Organic layer was separated, dried in MgSO4 and after filtration of desiccant evaporated to dryness.
The residue was purified by column chromatography in CHCl3-MeOH-NH4OH (95:5:0.5).
Yield 126.5 mg 6-benzylamino-8-bromo-9-(β-D-ribofuranosyl)purine (22percent), 42.2 mg starting material (9percent), 205 mg 8-bromoadenosine (45percent) and mixture of benzaldehyde and bromobenzaldehyde. Crystallization from CHCl3-hexan; mp: 98-100° C. MS ESI+: 436.2 [M+H+]. For C17H13BrN5O4 calculated 435.0542, found 436.0680 [M+H+]. 1H NMR (400 MHz; CDCl3) δ 3.75 (dd, J=2.7 Hz, 12.7 Hz, H5′), 3.90 (dd, J=2.4 Hz, 12.7 Hz, H5′), 4.20 (d, J=1.8 Hz, H4′), 4.39 (dd, J=1.8 Hz, 5.3 Hz, H3′), 4.81 (bs, —CH2—), 5.08 (dd, J=5.3 Hz, 7.2 Hz, H2′), 6.07 (d, J=7.2 Hz, H1′), 7.24 (m, H4-Ph), 7.31 (m, H3-Ph), 7.38 (m, H2-Ph), 8.19 (s, H2). MS ESI+ (8-bromoadenosine): 346.3 [M+H+]. GC: Rt (benzaldehyde)=321 s. MS EI (benzyldehyde): 105 (100percent), 77 (25percent). Rt (bromobenzyldehyde)=722 s. MS EI: 185 (100percent), 155 (50percent), 77 (45percent).
Reference: [1] Patent: US2013/72506, 2013, A1. Location in patent: Paragraph 0128
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Reference: [1] Patent: US2003/8841, 2003, A1
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Reference: [1] Patent: US2003/8841, 2003, A1
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Reference: [1] Patent: US2003/8841, 2003, A1
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Reference: [1] Patent: US2003/8841, 2003, A1
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Reference: [1] Patent: US2003/8841, 2003, A1
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