657-24-9

Basic information

• Product Name: Metformin
• Synonyms: 1,1-dimethyl-biguanid;dimethylbiguanide;dmgg;flumamine;gliguanid;haurymelin;la6023;melbin
• CAS NO: 657-24-9
• Molecular Formula: C₄H₁₁N₅
• Molecular Weight: 129.16
• EINECS: 211-517-8
• Mol File: 657-24-9.mol

Chemical Properties

• Melting Point: 199-200 °C
• Boiling Point: 229.23°C (rough estimate)
• Flash Point: 89.3 °C
• Appearance: /
• Density: 1.0743 (rough estimate)
• Refractive Index: 1.5760 (estimate)
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: Acetonitrile (Slightly), Aqueous Acid (Slightly), Dichloromethane (Slightly), DM
• PKA: pKa 2.8(H2O,t =32) (Uncertain)
• CAS DataBase Reference: Metformin(CAS DataBase Reference)
• NIST Chemistry Reference: Metformin(657-24-9)
• EPA Substance Registry System: Metformin(657-24-9)

Safety Data

• Hazardous Substances Data: 657-24-9(Hazardous Substances Data)

Usage

Description

The study of metformin and its hypoglycemic effects originated from the study of goat’s rue plants, also known as Galega officinalis(French lilac). Goat’s rues are native plants in the Middle East and introduced to Europe later and have been used as forage and ornamental plants throughout the world, including China. As early as in the Middle Ages in Europe, it was found that goat’s rues could ease polyuria, which is one of the typical symptoms of diabetes. While goat’s rues were used to treat a variety of other diseases in the Middle Ages, it was found to cause poisoning symptoms in livestock. Goat’s rues are still used as medical plants at present, mainly for diabetes, diuretic, hepatoprotection, aiding in digestion and promoting lactation, etc. In China, goat’s rues were recorded first in the dictionary of Chinese seed plants and mainly used for the treatment of diabetes. However, because of high toxicity, it is rarely used in traditional Chinese medicines at present.

Physical properties

Appearance: white crystalline or crystalline powder, odorless. Solubility: freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or ether. Melting point: 223–226°C.

History

Metformin is a biguanide compound which originated from the extraction of goat’s rue plants. The structure of metformin was identified by British scholars in the early 1920s. In 1922, Werner and Bell et?al. first synthesized metformin in 31 institutes in Dublin, Ireland. In 1929, Slotta and Tschesche found metformin’s hypoglycemic action. However, because of other potent antidiabetic drugs such as insulin which were widely used in clinical practice, the pharmacological effects of metformin didn’t receive much attention.Until the 1950s, a French diabetic scientist Jean Sterne found the hypoglycemic effect of metformin through the study of galegine. Then the drug was used in diabetic patients for the first time, and the results were published in 1957. UKPDS, which began from 1977 and ended in 1997 and was then followed up for 10?years, is the longest in the history of clinical trials and has a significant impact on practice and guidelines for prevention and treatment of diabetes mellitus. In this trial, metformin was found to reduce the risk of diabetic complications by 32%. In addition, it was proved for the first time that metformin can reduce blood glucose and protect against cardiovascular function, especially in obese patients. In 1994, metformin was approved by the US FDA for type 2 diabetes treatment. Currently, metformin has become the world’s most widely used antidiabetic drug.Aiming at improving the stability of the absorption of metformin, chemists have also carried out a series of structural renovation and modification. Metformin activates with carbonyl, esters, chlorides, and aldehydes to form triazine compounds, with 1,3-diketone to produce pyrimidine compounds, and with disulfides to produce C-S coupling products, etc.

Uses

non-insulin dependent diabetes mellitus

Indications

Metformin (Glucophage) was used in Europe for many years before it was approved for use in the United States in 1995. Metformin is the only approved biguanide for the treatment of patients with NIDDM that are refractory to dietary management alone. Metformin does not affect insulin secretion but requires the presence of insulin to be effective. The exact mechanism of metformin’s action is not clear, but it does decrease hepatic glucose production and increase peripheral glucose uptake. When used as monotherapy, metformin rarely causes hypoglycemia.

Definition

ChEBI: Metformin is a member of the class of guanidines that is biguanide the carrying two methyl substituents at position 1. It has a role as a hypoglycemic agent, a xenobiotic, an environmental contaminant and a geroprotector. It is functionally related to a biguanide. It is a conjugate base of a metformin(1+).

Therapeutic Function

Oral hypoglycemic

Biological Functions

Metformin can lower free fatty acid concentrations by 10 to 30%. This antilipolytic effect may help to explain the reduction in gluconeogenesis through reduced levels of available substrate (65). When given as a monotherapy, metformin treatment does not lead to hypoglycemia, so it is better described as an antihyperglycemic agent rather than a hypoglycemic agent.

General Description

Metformin, N,N-dimethylimidodicarbonimidicdiamide hydrochloride (Glucophage), is a bisguanidine.This class of agents is capable of reducing sugar absorptionfrom the gastrointestinal tract. Also, they can decrease gluconeogenesiswhile increasing glucose uptake by muscles andfat cells. These effects, in turn, lead to lower blood glucoselevels. Unlike the sulfonylureas, these are not hypoglycemicagents but rather can act as antihyperglycemics. This differencein nomenclature is caused by the inability of these agentsto stimulate the release of insulin from the pancreas. Often,metformin is coadministered with the nonsulfonylureas to improvethe efficacy of those agents.

Pharmacology

As a traditional antidiabetic drug, metformin can reduce the levels of blood glucose and lipid, as well as regulating cell growth, anti-inflammation, antiaging, etc. The main pharmacological mechanisms are inhibition of hepatic gluconeogenesis, the activation of AMP-activated protein kinase (AMPK), and the regulation of mitochondrial function. Improvement of Insulin Resistance and Decrease of Blood Glucose Levels The main pharmacological effects of biguanide drugs are to reduce blood glucose output and improve peripheral insulin resistance. Metformin inhibits hyperglycemia mainly by inhibiting hepatic glucose production (hepatic gluconeogenesis), increasing muscle glucose uptake. Regulation of Lipid Metabolism and Reducing Body Weight Metformin can reduce the blood triglycerides in circulation, improve liver steatosis, promote the oxidation of brown adipose tissue and VLDL-fatty acid triglyceride uptake, and inhibit fat formation; the process may be related with the activation of AMPK. AMPK can phosphorylate acetyl coenzyme A carboxylase (ACC) and inhibit the conversion of acetyl coenzyme A into malonyl-CoA. Malonyl-CoA is a precursor of fatty acid production and is an allosteric inhibitor of fatty acid transporting to mitochondria. Prevention and Treatment of Tumors Epidemiological studies have shown that metformin reduced the risk of multiple types of tumors in type 2 diabetes and nondiabetes patients and reduced tumor-related mortality. Metformin also has a therapeutic effect on various tumors. The antitumor effect of metformin may be through the reduction of serum insulin and insulin-like growth factor-1 (IGF-1) levels or activation of LKB1/AMPK, thereby blocking the mammalian target of rapamycin-sensitive complex 1 (mTORC1) signaling pathway. Antiaging Antiaging effect is a major discovery in the new role of metformin. FDA approved the phase 4 of clinical trial of metformin for antiaging effect, and the trial is ongoing. The study suggests that the antiaging effect of metformin is closely related to the mitochondria, through the regulation of mitochondrial function to activate AMPK and inhibit mTOR, thereby reducing energy consumption. Furthermore, metformin can regulate oxidative stress, reduce tissue inflammation, and reduce the growth factor level and cell proliferation. The above effects and the combinational effect result in the improvement of health and achieving longevity. Other Effects Studies have shown that metformin helps to prevent type 2 diabetes. For young people with a high body mass index, metformin is more effective than lifestyle control. In addition, metformin can improve and prevent vascular disease, improve mitochondrial function, and serve as anti-inflammatory agent and antioxidant. Metformin is hydrophilic and distributed in tissues in an active manner. After oral administration, metformin is absorbed quickly and rapidly distributed into various tissues, mainly in the liver, gastrointestinal tract, and kidney.

Clinical Use

Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformintreated individuals. Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity.

Safety Profile

Poison by subcutaneous and intraperitoneal routes. Mildly toxic by parenteral route. Experimental teratogenic effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx

Metabolism

Metformin is quickly absorbed from the small intestine. Bioavailability is from 50 to 60%, and the drug is not protein bound. Peak plasma concentrations occur at approximately 2 hours. The drug is widely distributed in the body and accumulates in the wall of the small intestine. This depot of drug serves to maintain plasma concentrations. Metformin is excreted in the urine, via tubular excretion, as unmetabolized drug with a half-life of approximately 2 to 5 hours; therefore, renal impairment as well as hepatic disease are contraindications for the drug.

InChI:InChI=1/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)

Synthetic route

metformin hydrochloride (1115-70-4) → dimethylbiguanide (657-24-9)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.5h;	100%
With sodium hydroxide In water at 20℃; for 0.5h;	99%
With sodium hydroxide In ethanol for 5h;	99%

N,N-dimethylimidodicarbonimidic diamide hydrochloride → dimethylbiguanide (657-24-9)

Conditions	Yield
With sodium hydroxide In isopropyl alcohol at 0 - 40℃; for 18.2h; Temperature; Solvent;	93%
With sodium hydroxide In isopropyl alcohol at 39.84℃; for 3h;
With sodium In ethanol at 60℃; for 1h; Reagent/catalyst; Solvent; Temperature;

N,N-dimethylammonium chloride (506-59-2) + N-Cyanoguanidine (127099-85-8, 780722-26-1) → dimethylbiguanide (657-24-9)

Conditions	Yield
at 130 - 140℃;
In butan-1-ol for 6h; Reflux;

N-Cyanoguanidine (127099-85-8, 780722-26-1) + dimethylamine- → dimethylbiguanide (657-24-9)

Conditions	Yield
at 160℃;

dimethyl amine (124-40-3) + N-Cyanoguanidine (127099-85-8, 780722-26-1) → dimethylbiguanide (657-24-9) + N,N-dimethyl-guanidine

Conditions	Yield
at 180℃; beim Erhitzen des Hydrochlorids;

N1,N1-dimethyl-S-cyclohexyl-N4-thiohydroxybiguanidine (1170667-82-9) → dimethylbiguanide (657-24-9)

Conditions	Yield
With hydrogenchloride In water at 37℃; pH=1.0; Reactivity;

N1,N1-dimethyl-S-phenyl-N4-thiohydroxybiguanidine (1170667-83-0) → dimethylbiguanide (657-24-9)

Conditions	Yield
With human serum at 37℃; pH=7.4; Reactivity; Enzymatic reaction; Aqueous phosphate buffer;

N,N-dimethylebiguanidinium chloride (1378856-94-0) → dimethylbiguanide (657-24-9)

Conditions	Yield
With sodium hydroxide In ethanol for 2h;

dimethylbiguanide (657-24-9) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → N,N-dimethylimidodicarbonimidic diamide R-(+)-lipoate (959986-37-9)

Conditions	Yield
In methanol for 2h; Product distribution / selectivity;	100%
In acetonitrile for 0.166667h; Product distribution / selectivity;	95%
In acetone for 0.166667 - 0.5h; Product distribution / selectivity;	95%
In methanol; acetone for 0.333333h; Product distribution / selectivity;

((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl)-L-leucyl-L-leucinate + dimethylbiguanide (657-24-9) → amino(3,3-dimethylguanidino)methaniminium (S)-2-((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-4-methylpentanamido)-4-methylpentanoate

Conditions	Yield
In tetrahydrofuran at 20℃; for 1h;	100%

all cis-5,8,11,14,17-eicosapentaenoic acid (10417-94-4) + L-leucyl-L-leucine (3303-31-9) + dimethylbiguanide (657-24-9) → C12H24N2O3*C4H11N5*C20H30O2

Conditions	Yield
In methanol at 20℃; for 5h;	100%

((6Z,9Z,12Z)-octadeca-6,9,12-trienoyl)-L-isoleucyl-L-isoleucine + dimethylbiguanide (657-24-9) → ((6Z,9Z,12Z)-octadeca-6,9,12-trienoyl)-L-isoleucyl-L-isoleucine N,N-dimethyl-imidodicarbonimidic diamide

Conditions	Yield
In water; acetone at 50℃; for 6h;	99.6%

all cis-5,8,11,14,17-eicosapentaenoic acid (10417-94-4) + L-Aspartic acid (56-84-8) + dimethylbiguanide (657-24-9) → bis[{[(dimethylamino)(imino)methyl]amino}(imino)methanaminium]-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate-(3S)-3-ammonio-3-carboxypropanoate

Conditions	Yield
In methanol at 60℃; for 1.5h;	99%

Adipic acid (124-04-9) + dimethylbiguanide (657-24-9) → metformin adipate (2:1)

Conditions	Yield
In methanol at 40℃; Product distribution / selectivity;	98.9%
In methanol; ethyl acetate at 40℃; Product distribution / selectivity;	98.9%
In water; acetone at 20 - 40℃; Product distribution / selectivity;	93.9%

dimethylbiguanide (657-24-9) + butyric acid (107-92-6) → metformin butyric acid salt (1261952-47-9)

Conditions	Yield
In acetone at 20℃; for 2h;	98%

((7Z,10Z,13Z,16Z,19Z)-docosa-7,10,13,16,19-pentaenoyl)-L-isoleucine + dimethylbiguanide (657-24-9) → ((7Z,10Z,13Z,16Z,19Z)-docosa-7,10,13,16,19-pentaenoyl)-L-isoleucine N,N-dimethyl-imidodicarbonimidic diamide

Conditions	Yield
In water; acetone at 50℃; for 6h;	98%

formaldehyd (50-00-0) + 5-chloroindole 2,3-dione (17630-76-1) + dimethylbiguanide (657-24-9) + 2-(piperazin-1-ylmethyl)-1H-benzimidazole (59052-85-6) → C25H29ClN10O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol for 2h; Reflux;	98%

formaldehyd (50-00-0) + 5-methyl-indole-2,3-dione (608-05-9) + dimethylbiguanide (657-24-9) + 2-(piperazin-1-ylmethyl)-1H-benzimidazole (59052-85-6) → C26H32N10O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol for 2h; Reflux;	98%

2-hydroxy-benzoic acid, 2-carboxyphenyl ester (552-94-3) + dimethylbiguanide (657-24-9) → {[amino(imino)methyl]amino}(dimethylamino)methaniminium 2-[(2-hydroxybenzoyl)oxy]benzoate (1411413-55-2)

Conditions	Yield
In acetonitrile at 0 - 20℃; for 2h;	96%

5-chloroindole 2,3-dione (17630-76-1) + dimethylbiguanide (657-24-9) → C12H13ClN6O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol Reflux;	96%

(S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoic acid + L-glutamic acid (56-86-0) + dimethylbiguanide (657-24-9) → metformin-L-glutamic acid-(S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoic acid salt

Conditions	Yield
Stage #1: L-glutamic acid; dimethylbiguanide In methanol at 30℃; for 0.5h; Stage #2: (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoic acid In methanol at 30℃; for 48h;	95.4%

1,5-pentanedioic acid (110-94-1) + dimethylbiguanide (657-24-9) → metformin glutarate (2:1)

Conditions	Yield
Stage #1: dimethylbiguanide In water; acetone at 40℃; Stage #2: 1,5-pentanedioic acid In water; acetone at 10℃; Product distribution / selectivity;	95.3%
In water; acetone at 10 - 40℃; Product distribution / selectivity;	95.3%
In ethanol at 10 - 20℃; Product distribution / selectivity;	62.8%
With sodium hydroxide In ethanol at 70℃; Product distribution / selectivity;	57.7%
In methanol at 40℃; Product distribution / selectivity;	43.8%

formaldehyd (50-00-0) + 5-Bromo-1H-indole-2,3-dione (87-48-9) + dimethylbiguanide (657-24-9) + 2-(piperazin-1-ylmethyl)-1H-benzimidazole (59052-85-6) → C25H27BrN10O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol for 2h; Reflux;	95%

formaldehyd (50-00-0) + 5-Bromo-1H-indole-2,3-dione (87-48-9) + dimethylbiguanide (657-24-9) + 2-(piperazin-1-ylmethyl)-1H-benzimidazole (59052-85-6) → C25H29BrN10O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol for 2h; Reflux;	95%

formaldehyd (50-00-0) + 5-chloroindole 2,3-dione (17630-76-1) + dimethylbiguanide (657-24-9) + 2-(piperazin-1-ylmethyl)-1H-benzimidazole (59052-85-6) → C25H27ClN10O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol for 2h; Reflux;	95%

ursolic acid (77-52-1) + dimethylbiguanide (657-24-9) → ursolic acid metformin salt (1541169-42-9)

Conditions	Yield
In acetonitrile for 16h;	94%

cis-dichlorobis(dimethylsulfoxide)platinum(II) (75992-73-3, 25794-47-2, 30729-25-0, 15274-33-6, 22840-91-1, 14568-13-9) + dimethylbiguanide (657-24-9) → [Pt(metformin)(dimethylsulfoxide)Cl]Cl (164177-46-2)

Conditions	Yield
In methanol; water at 20℃; for 24h;	93.6%

5-Bromo-1H-indole-2,3-dione (87-48-9) + dimethylbiguanide (657-24-9) → C12H13BrN6O

Conditions	Yield
With sulfonic acid immobilized on metformin-p-formylbenzoic acid-based schiff base-coated Fe3O4 nanocatalyst In ethanol Reflux;	93%

trifluoromethylsulfonic anhydride (358-23-6) + dimethylbiguanide (657-24-9) → N-(trifluoromethanesulfonyl)metformin

Conditions	Yield
With potassium hydroxide In acetone at 20℃;	92%

dimethylbiguanide (657-24-9) + 4-Methoxybenzyl alcohol (105-13-5) → 6-(4-methoxyphenyl)-N2,N2-dimethyl-1,3,5-triazine-2,4-diamine (43153-42-0)

Conditions	Yield
With potassium tert-butylate In 1,4-dioxane at 100℃; for 10h;	92%

pseudothiohydantoin (556-90-1) + dimethylbiguanide (657-24-9) → C4H11N5*C3H4N2OS

Conditions	Yield
In ethanol at -10 - 80℃; Inert atmosphere;	92%

docosahexaenoic acid (6217-54-5) + dimethylbiguanide (657-24-9) → metformin DHA salt (1384513-23-8)

Conditions	Yield
In acetonitrile at 20℃; for 1.08333h; Darkness;	91%
With Tocopherol In methanol; ethyl acetate at 55℃;	88%

4-hydroxy-benzaldehyde (123-08-0) + dimethylbiguanide (657-24-9) → N-(4-hydroxybenzylidene)metformin

Conditions	Yield
With acetic acid In ethanol at 78℃; for 6h;	91%
With acetic acid In ethanol at 78℃;	88%

dimethylbiguanide (657-24-9) + Ethanesulfonyl chloride (594-44-5) → N-(ethylsulfonyl)metformin

Conditions	Yield
With potassium hydroxide In acetone at 20℃;	91%
With potassium hydroxide In acetonitrile at 20℃; Inert atmosphere;	72%

dimethylbiguanide (657-24-9) + cyclohexanesulfonyl chloride (4837-38-1) → N-(cyclohexanesulfonyl)metformin

Conditions	Yield
With potassium hydroxide In acetone at 20℃;	91%
With potassium hydroxide In acetonitrile at 20℃; Inert atmosphere;	82%

succinic acid anhydride (108-30-5) + dimethylbiguanide (657-24-9) → N-succinylmetformin

Conditions	Yield
With potassium hydroxide In acetone at 20℃;	91%