Selective solvent free phosphorylation

A technology selected from compounds, applied in the direction of non-central analgesics, biocides, anti-inflammatory agents, etc., can solve problems such as hindering implementation and high toxicity

Inactive Publication Date: 2018-03-27
CHROMADEX +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, trialkyl phosphate solvents such as P(O)(OMe) 3 The use of solvents hampers their implementation in the preparation of materials for final human use, as such solvents are highly toxic (known carcinogens, not GRAS approved) and difficult to remove from the final polar product

Method used

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  • Selective solvent free phosphorylation
  • Selective solvent free phosphorylation
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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0241] The synthetic preparation of nicotinamide mononucleotide (NMN): the compound of formula (I): R 1 = hydrogen, n = 0, Z 2 =NH,R 2 -R 5 = Hydrogen, Y 1 = sodium, Y 2 = Inner salt with pyridinium.

[0242]

[0243] Nicotinamide Mononucleotide (NMN)

[0244] To a dry 35 mL PTFE milling vessel containing one PTFE sphere (0.8 cm diameter) was added nicotinamide riboside chloride (2000 mg, 6.88 mmol, 1.0 equiv) and POCl 3 (2.57 mL, 27.52 mmol, 4.0 equiv). The reaction was then milled at 30 Hz for 60 minutes or until the reaction had reached approximately 95% conversion via c-18 HPLC analysis. The gelled, gummed sphere was removed and placed in a wide neck flask, and the residue was dissolved in a minimal volume of distilled water on ice. The solution was adjusted to pH 6.0 by dropwise addition of 2M NaOH solution. The aqueous solution was then reduced to a small volume under high vacuum, and the pH was then adjusted to pH 3.0 using dilute nitric acid. Aceto...

example 2

[0258] Synthetic preparation of thiamine monophosphate.

[0259]

[0260] Thiamine monophosphate

[0261] To a dry 35 mL PTFE milling vessel containing one PTFE sphere (0.8 cm diameter) was added thiamine hydrochloride (2000 mg, 6.63 mmol, 1.0 equiv) and POCl 3 (2.43 mL, 26.51 mmol, 4.0 equiv). The reactants were then milled at 30 Hz for 60 minutes, or until the 1 H-NMR analysis The reaction has reached near completion. The white pasty residue was then dissolved in a minimum volume of distilled water on an ice bath, and then concentrated to give a fluffy white powder (92% conversion).

[0262] 1 H NMR (400MHz,D 2 O)δppm 9.51(s,1H,Ar),7.79(s,1H,Ar),5.38(s,2H),4.46(q,J=5.4Hz,2H),3.15(t,J=4.9Hz,2H ), 2.43(s,3H), 2.36(s,3H). 13 C NMR (125MHz,D 2 O) δ ppm 163.2, 163.0, 155.0, 154.9, 144.3, 143.3, 135.5, 106.2, 64.8, 49.9, 27.5 (d, J = 10.3 Hz), 20.9, 11.1. 31 P NMR (162MHz,D 2 O) δppm-0.62.

[0263] pass 1 The chemical shifts observed on H NMR at 2.99, 3.69, 7.83 a...

example 3

[0265] Synthesis and Preparation of Pyridoxine Monophosphate

[0266]

[0267] pyridoxine monophosphate

[0268] Pyridoxine (500mg, 2.99mmol, 1.0 equiv) and POCl 3 (1.12ml, 11.96mmol, 4.0eq) was added to a 50mL ceramic mortar and the mixture was then manually ground using a ceramic pestle for a total of 30 minutes. 1 H NMR analysis showed 20% conversion to the desired product. 1 H NMR (400MHz,D 2 O) δppm 8.01 (1H, s, aldehyde), 6.84 (1H, s, Ar), 5.24 (1H, m, CH 2 O),5.10(1H,m,CH 2 O),2.49(3H,s,CH 3 ). 31 P NMR (162MHz,D 2 O) δppm-1.03.

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Abstract

A synthetic process is provided for the preparation of phosphorylated analogs of nicotinamide riboside ("NR") having the formula (I), or salts thereof, and reduced or modified derivatives thereof, having the formula (II), wherein X-, Y1, Y2, Z1, Z2, n, R1, R2, R3, R4, R5, R6, and R7 are as defined herein. The present disclosure also relates to the preparation of phosphorylated analogs of nicotinicacid riboside ("NAR") having the formula (I), or salts thereof, and reduced or modified derivatives thereof, having the formula (II). Generally solvent-free conditions are employed using appropriatemechano-chemical techniques as described. (I) (II)

Description

technical field [0001] The present disclosure relates to a synthetic method for the preparation of phosphorylated analogs of nicotinamide riboside ("NR") or nicotinic acid riboside ("NAR") and reduced or modified derivatives thereof. The present disclosure also relates to the preparation of phosphorylated analogs of nicotinic acid riboside ("NAR") and reduced or modified derivatives thereof. The present disclosure also relates to the preparation of monophosphorylated species in an atom efficient manner in the absence of phosphate solvents using appropriate mechano-chemical techniques as described. Background technique [0002] Despite extensive optimization of solution-based methods for nucleotide preparation over the years, monophosphorylation of reactive hydroxyl groups remains difficult and problematic regarding low yields and product stability, as well as separation from polar solvents. Current methods also suffer from atomic inefficiency due to the high molar ratio of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/40A61K31/44
CPCC07F9/65616C07H1/04C07H19/04C07F9/58C07H19/048C07F9/65583C07H19/20A61P29/00A61P31/16C07F9/65586
Inventor 玛丽·尤金妮·米高德菲利浦·瑞德帕斯凯丽·克罗西理查德·坎宁安特洛伊·鲁尼穆斯苏乐斯·文卡塔拉曼
Owner CHROMADEX
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