Nicotinamide-d4

Cat. No.: B132304

CAS No.: 347841-88-7

M. Wt: 126.15 g/mol

InChI Key: DFPAKSUCGFBDDF-RHQRLBAQSA-N

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Overview

1. Description

9. Synthesis routes and methods I

2. Mechanism of action

10. Synthesis routes and methods II

3. Biochemical analysis

11. Synthesis routes and methods III

4. Preparation methods

12. Synthesis routes and methods IV

5. Chemical reactions analysis

13. Retrosynthesis analysis

6. Scientific research applications

14. Q & A

7. Comparison with similar compounds

15. Disclaimer

8. Properties

Description

Nicotinamide is a form of vitamin B3 that plays essential roles in cell physiology through facilitating nicotinamide adenine dinucleotide (NAD+) redox homeostasis and providing NAD+ as a substrate for a class of enzymes that catalyze non-redox reactions .

Mechanism of Action

Target of Action

Nicotinamide-d4 (also known as niacinamide-d4) is an amide form of niacin (vitamin B3). It can be biosynthesized in vivo or obtained through the diet .
Additionally, this compound inhibits sirtuin 1 (SIRT1) with an IC50 of less than 50 µM . SIRT1 is involved in various cellular processes, including gene regulation, stress response, and longevity.

Mode of Action

Biochemical Pathways

It also influences DNA repair and cellular stress responses .

Pharmacokinetics

As an internal standard, it aids in accurate quantification by GC- or LC-MS methods .

Biochemical Analysis

Preparation Methods

Synthetic Routes and Reaction Conditions: The synthesis of nicotinamide-d4 typically involves the deuteration of nicotinamide. One common method is the catalytic exchange of hydrogen atoms with deuterium using deuterium gas (D2) in the presence of a suitable catalyst such as palladium on carbon (Pd/C). The reaction is carried out under controlled temperature and pressure conditions to ensure complete deuteration.

Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process involves the use of high-pressure reactors and continuous flow systems to achieve efficient deuteration. The purity of the final product is ensured through rigorous quality control measures, including high-performance liquid chromatography (HPLC) and mass spectrometry.

Chemical Reactions Analysis

Types of Reactions: Nicotinamide-d4 undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized to nicotinic acid-d4 using oxidizing agents such as potassium permanganate (KMnO4) or chromium trioxide (CrO3).

Reduction: It can be reduced to 1,4-dihydrothis compound using reducing agents like sodium borohydride (NaBH4).

Substitution: Halogenation reactions can introduce halogen atoms into the this compound molecule using reagents like bromine (Br2) or chlorine (Cl2).

Common Reagents and Conditions:

Oxidation: Potassium permanganate in acidic or neutral conditions.

Reduction: Sodium borohydride in methanol or ethanol.

Substitution: Halogenation using bromine or chlorine in the presence of a catalyst.

Major Products Formed:

Oxidation: Nicotinic acid-d4.

Reduction: 1,4-Dihydrothis compound.

Substitution: Halogenated derivatives of this compound.

Scientific Research Applications

Nicotinamide-d4 has a wide range of applications in scientific research:

Chemistry: Used as a tracer in metabolic studies to understand the pathways and mechanisms of nicotinamide metabolism.

Biology: Employed in studies of cellular redox states and the role of NAD+ in cellular processes.

Medicine: Investigated for its potential therapeutic effects in conditions related to NAD+ deficiency, such as aging and neurodegenerative diseases.

Industry: Utilized in the development of deuterated drugs with improved pharmacokinetic properties.

Comparison with Similar Compounds

Nicotinamide: The non-deuterated form of nicotinamide.

Nicotinamide mononucleotide (NMN): A direct precursor to NAD+.

Nicotinamide riboside (NR): Another NAD+ precursor with similar applications.

Uniqueness: Nicotinamide-d4 is unique due to its deuterium labeling, which provides enhanced stability and allows for detailed metabolic studies. The deuterium atoms also result in a slightly altered pharmacokinetic profile, which can be advantageous in certain therapeutic applications .

Properties

IUPAC Name	2,4,5,6-tetradeuteriopyridine-3-carboxamide	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C6H6N2O/c7-6(9)5-2-1-3-8-4-5/h1-4H,(H2,7,9)/i1D,2D,3D,4D	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	DFPAKSUCGFBDDF-RHQRLBAQSA-N	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	C1=CC(=CN=C1)C(=O)N	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Isomeric SMILES	[2H]C1=C(C(=C(N=C1[2H])[2H])C(=O)N)[2H]	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C6H6N2O	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

DSSTOX Substance ID	DTXSID20574036	Source
Record name	(~2~H_4_)Pyridine-3-carboxamide
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID20574036
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight	126.15 g/mol	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

CAS No.	347841-88-7	Source
Record name	(~2~H_4_)Pyridine-3-carboxamide
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID20574036
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Record name	347841-88-7
Source	European Chemicals Agency (ECHA)
URL	https://echa.europa.eu/information-on-chemicals
Description	The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness.
Explanation	Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.

Synthesis routes and methods I

Procedure details

The reaction was carried out in a reaction mixture (30 ml), comprising 500 mM 3-cyanopyridine, 40 mM potassium phosphate buffer (pH 7.0) and resting cells (dry weight 2.3 mg). During the reaction, 3-cyanopyridine (500 mM) was added 7 times as soon as it was consumed. In this manner, 4.0 M 3-cyanopyridine was added in the course of 15 h and 3.89 M (475 g/l) nicotinamide was formed, corresponding to a yield of 97.3%. Nicotinic acid was not formed.

Name

3-cyanopyridine

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

potassium phosphate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

[Compound]

Name

mixture

Quantity

30 mL

Type

solvent

Reaction Step Three

Name

nicotinamide

Yield

97.3%

Details

Synthesis routes and methods II

Procedure details

High performance liquid chromatography was used to detect Nampt reaction products. HPLC was performed with Waters 515 pumps and a 2487 detector (Waters, Mass.) with a Supelco LC-18-T column (15 cm×4.6 cm; Supelco, Pa.). The Nampt reaction was conducted at 37° C. for 15 min in 500 μl of reaction buffer (50 mM Tris-HCl [pH 7.5], 10 mM MgCl2, 50 mM nicotinamide, 0.2 mM PRPP) with 50 μg of the recombinant Nampt protein. The reaction was terminated by adding 125 μl of 1 M HClO4. Protein was then precipitated at 18,000 g, and 500 μl of the supernatant was neutralized with 40 μl of 3 M K2CO3. After centrifugation, 100 μl of sample was mixed with 400 μl of Buffer A (50 mM K2PO4/KHPO4, pH 7.0) and loaded into the HPLC system. The products from Nampt reaction were monitored by absorbance at 261 nm. Results of HPLC detection of Nampt reaction products showed that the mouse Nampt produced nicotinamide mononucleotide (NMN) from nicotinamide and PRPP (see, e.g., FIG. 4D). Nampt failed to catalyze the synthesis of nicotinic acid mononucleotide (NaMN) from nicotinic acid and PRPP (see, e.g., FIGS. 13A and 13B), confirming the substrate specificity of this enzyme. In isolated reactions, it was also confirmed that Nmnat catalyzed the synthesis of NAD from NMN and ATP.

Name

Tris-HCl

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

MgCl2

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

nicotinamide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

PRPP

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

nicotinamide mononucleotide

Name

nicotinamide

Name

PRPP

Details

Synthesis routes and methods III

Procedure details

0.096 mole of 3-cyanopyridine was dissolved in 5.556 mole of water and 0.0115 mole of MnO2, prepared by above method, was added to this. The mixture was refluxed at 105° C. for 8 hrs. The reaction mixture was cooled and filtered. The filtrate was evaporated in dryness to get solid nicotinamide 0.095 mole. Yield of isonicotinamide was 98.9 mole %.

Name

3-cyanopyridine

Quantity

0.096 mol

Type

reactant

Reaction Step One

Name

water

Quantity

5.556 mol

Type

reactant

Reaction Step One

Name

MnO2

Quantity

0.0115 mol

Type

catalyst

Reaction Step Two

Name

nicotinamide

Details

Synthesis routes and methods IV

Procedure details

In this Example a USP grade nicotinamide product was recovered from a crude nicotinamide product medium. The crude contained 39.7% nicotinamide, 2.15% sodium nicotinate and 0.14% 3-cyanopyridine. These and all other percentages given in this Example are percentages by weight unless indicated otherwise. The total sodium content of the medium was 0.38%. On a dry basis, the reaction crude contained 93.7% nicotinamide, 5.07% sodium nicotinate, 0.33% 3-cyanopyridine, and 0.9% total sodium. Cation and weak base resins were utilized in the recovery process. The cation exchange resin was Dowex Marathon C, a sulfonated copolymer of styrene and divinylbenzene (gel form). The weak base resin was Dowex Marathon WBA, a dimethylamine-functionalized chloromethylated copolymer of styrene and divinylbenzene (macroporous form with a monodisperse size distribution). After washing with deionized water, these resins were loaded into columns each having an inner diameter of 15 mm and a height of 30 cm, leaving about 1.5 inches head space at the top of the columns. The reaction crude was then successively treated over the cation-exchange resin (at 28 ml/min), the weak base resin (20 ml/min), the cation-exchange resin (28 ml/min), and the weak base resin (20 ml/min). The cation-exchange resin was regenerated after every ten bed volumes of reaction crude, by a cycle that included a water wash (20 ml/min, 1.25 bed volumes), a 12% sulfuric acid strip (7 ml/min, 1 bed volume), and another water wash (20 ml/min, 1.25 bed volumes). The weak base resin was regenerated after every five bed volumes of reaction crude, by a cycle including a water wash (20 ml/min, 1.6 bed volumes), a 4% sodium hydroxide strip (20 ml/min, 1 bed volume), and another water wash (2.6 bed volumes). The feeds were analyzed by HPLC after the first pass cation-exchange and weak base, and second pass cation-exchange and weak base. Typical results from such experiments are presented in Table 1 below, top. The lower section of Table 1 gives a typical product analysis on a water free basis. The extreme right hand column of Table 1 sets out the results of an analysis of the product after recovery by evaporation (no crystallization performed). As can be seen, this processing reduced the 0.9% initial sodium to an undetectable level, and the initial 5.07% nicotinate to 0.13% (as nicotinic acid) on a dry weight basis, providing a USP grade nicotinamide.

Name

sodium nicotinate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

3-cyanopyridine

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

sodium

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Three

Name

styrene

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Four

Name

divinylbenzene

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Five

Name

dimethylamine

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Six

Name

styrene

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Seven

Name

divinylbenzene

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Eight

Name

water

Quantity

0 (± 1) mol

Type

solvent

Reaction Step Nine

Name

water

Quantity

0 (± 1) mol

Type

solvent

Reaction Step Ten

Name

water

Quantity

0 (± 1) mol

Type

solvent

Reaction Step Eleven

Name

nicotinamide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Twelve

Name

nicotinamide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Thirteen

Name

nicotinamide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Fourteen

Name

sodium nicotinate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Fifteen

Name

3-cyanopyridine

Quantity

0 (± 1) mol

Type

reactant

Reaction Step 16

Name

sodium

Quantity

0 (± 1) mol

Type

reactant

Reaction Step 17

Name

nicotinamide

Quantity

0 (± 1) mol

Type

reactant

Reaction Step 18

Name

nicotinate

Yield

5.07%

Name

nicotinic acid

Name

nicotinamide

Details

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.

Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.

Strategy Settings

Precursor scoring	Relevance Heuristic
Min. plausibility	0.01
Model	Template_relevance
Template Set	Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph	6

Feasible Synthetic Routes

Reactant of Route 1

Nicotinamide-d4

Reactant of Route 2

Nicotinamide-d4

Reactant of Route 3

Nicotinamide-d4

Reactant of Route 4

Nicotinamide-d4

Reactant of Route 5

Nicotinamide-d4

Reactant of Route 6

Nicotinamide-d4

Customer

Q & A

Q1: What is the role of Nicotinamide-d4 in the analysis of water-soluble vitamins?

A1: In the study "Fast simultaneous determination of multiple water-soluble vitamins and vitamin-like compounds in infant formula by UPLC-MS/MS" [], this compound serves as an internal standard. Internal standards are compounds with similar chemical properties to the analytes of interest but are not present in the original sample.

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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.

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