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654671-78-0

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654671-78-0 Usage

Description

Sitagliptin phosphate is a 1:1 phosphoric acid salt of sitagliptin free base, a trizolopyrazine dipeptidyl peptidase IV inhibitor. It is the first novel dipeptidyl peptidase IV inhibitor from Merck for the treatment of type 2 diabetes without weight gain and with a hypoglycemia incidence similar to placebo. Sitagliptin acts by enhancing the body's incretin system, which helps to regulate glucose by affecting β and α cells in the pancreas. It is a white solid and is marketed in various tablet strengths and combination products.

Uses

Used in Pharmaceutical Industry:
Sitagliptin phosphate is used as an antidiabetic drug for the treatment of type 2 diabetes. It helps regulate glucose levels by enhancing the body's incretin system, which affects pancreatic β and α cells.
Used in Combination Therapy:
Sitagliptin phosphate is used in combination with metformin (Janumet) and may also be prescribed with a thiazolidinedione or possibly a sulfonylurea. These combination therapies aim to provide better glycemic control for patients with type 2 diabetes.
Used in Drug Formulation:
Sitagliptin phosphate is used as a pharmaceutical compound in the formulation of tablets, providing high water solubility and improved bioavailability (approximately 87%) for oral administration.

New antidiabetic drug

Sitagliptin phosphate is dipeptidyl peptidase Ⅳ(DDP-4) inhibitor class of drugs developed by the German Merck company and firstly obtained the US Food and Drug Administration approval for the treatment of type 2 diabetes, is a new antidiabetic drug, can improve the body's own ability to reduce high blood glucose levels, and the relatively increase naturally occurring incretin by inhibiting the activity of this enzyme, including the levels of glucagon-like peptide 1 and glucose-dependent insulinotropic peptide, thereby triggering the pancreas to improve insulin production and stop glucose production in liver, and ultimately reduce the clinical effect of blood glucose concentration. Features of this product is to stimulate insulin secretion, at the same time can alleviate hunger, but does not make weight gain, and also cannot happen hypoglycemia and edema, is not suitable for use in diabetic patients with poor glycemic control and often developed hypoglycemia. By verification of clinical 552 cases of mild to moderate type 2 diabetes, taken once a day Sitagliptin phosphate, once time 100 mg, after taking the drug for 12 weeks, can make glycated hemoglobin reduce 0.6%-1.1%. Incidence of adverse reactions is similar to placebo, the most frequently reported adverse reactions (incidence> 5% and greater than placebo) is a stuffy or runny nose, and sore throat, upper respiratory tract infection and headache. Clinical studies showed that the Sitagliptin phosphate as monotherapy in patients with type 2 diabetes, can make glycated hemoglobin (HbA1c) levels significantly reduce. When in combination with the metformin or TZDs, has a significant role of adjuvant therapy, can focus on three kinds of major defect in type 2 diabetes: insulin resistance, β-cell dysfunction (reduction of insulin release), and α-cell dysfunction (unsuppressed hepatic glucose generation) plays a role. But the drug should not be used for treatment of patients with type 1 diabetes or diabetic ketoacidosis. The above information is edited by the lookchem of Liu Yujie.

DPP-4 inhibitors

Sitagliptin phosphate (trade name Januvia) is the DPP-4 inhibitor first clinically approved for the treatment of type 2 diabetes, developed by Germany company Merck, and was listed in 2006 in Mexico and the United States in 2007, also obtained EU approval for the treatment of type 2 diabetes. China approval was soon, currently Sitagliptin phosphate tablets has become the second largest drug of oral diabetes drugs in US. Sitagliptin phosphate can enhance a called incretin system of human physiological system, resulting in physiological hypoglycemic effect. This physiological system itself can affect β cells and α cells of the islet, help to regulate glucose, and insulin reduction only caused by β-cell dysfunction can cause the increase of blood glucose, or because cells α and β-cell dysfunction cause loss of control in hepatic glucose synthesis and thus lead to elevated blood glucose, DPP-4 will produce efficacy. Sitagliptin phosphate exists dependent of glucose levels, it will not only know hypoglycemic blindly, not predatorily press islet, exhaust the pancreas function. In contrast, the test proved that it has the prospect of long-term protection of human β cells. In addition, it does not lead to side effects such as weight gain, decreased blood glucose, medication compliance of patient will be greatly enhanced. Therefore, in theory it's effective role in life will greatly exceed the current oral antidiabetic drug, insulin dependent of patients will be greatly delayed.

Synthesis

Synthesis of sitagliptin started with the slow addition of chloropyrazine (75) to 35% aqueous hydrazine at 60-65°C, controlling this exothermic reaction and making it process-friendly, and the resulting crude pyrazinyl hydrazine was acetylated with trifluoroacetic anhydride to afford bis-trifluoromethylhydrazide 76 in 49% yield from the chloropyrazine. Compound 76 was treated with superphosphoric acid, a diluted form of polyphosphoric acid, to give cyclized compound 77 which was hydrogenated with Pd/C and the resulting product was treated with HCl in IPA to afford compound 78 as its HCl salt in 51% yield from 76. Compound 78 was used later on in a coupling reaction to generate sitagliptin. Compound 79, a beta-ketoester, was subjected to asymmetric reduction with (S)-BinapRuCl2-triethylamine complex in methanol at 80°C, catalytic amount of hydrogen bromide, and 90 psi of hydrogen atmosphere to give the desired beta-hydroxy ester which was hydrolyzed to give carboxylic acid 80 in 94% e.e. and 83% yield. The carboxylic acid 80 was coupled with BnONH2-HCl in the presence of EDC and lithium hydroxide in THF/H2O to give coupled compound 81 which was cyclized to compound 82 with DIAD and triphenylphosphine in THF in 81% yield from compound 80. Compound 82 was then hydrolyzed to β-amino acid 83 with lithium hydroxide, and the acid was coupled with compound 78 at 0°C with EDC-HCl and NMM as base to give compound 84 in excellent yield. Compound 84 was hydrogenated with 10% Pd/C in an ethanol/H2O mix solvent system. The water was crucial to complete the reaction and restore catalyst activity. Finally, the ethanol solution of the hydrogenated product was treated with phosphoric acid, and sitagliptin (XI) was crystallized as its anhydrous phosphoric acid salt from aqueous ethanol solution.

in vitro

sitagliptin was a potent inhibitor for dpp-4 with an ic50 of 18 nm [1]. sitagliptin inhibited dpp-8 with an ic50 of 48 μm. sitagliptin showed no effect on several related peptidases, including dpp-9, dpp-ii, and amino peptidase p [1].

references

[1] biftu t, feng d, qian x, et al. (3r)-4-[(3r)-3-amino-4-(2, 4, 5-trifluorophenyl) butanoyl]-3-(2, 2, 2-trifluoroethyl)-1, 4-diazepan-2-one, a selective dipeptidyl peptidase iv inhibitor for the treatment of type 2 diabetes[j]. bioorganic & medicinal chemistry letters, 2007, 17(1): 49-52.[2] fleischer b. cd26: a surface protease involved in t-cell activation[j]. immunology today, 1994, 15(4): 180-184.[3] aschner p, kipnes m s, lunceford j k, et al. effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes[j]. diabetes care, 2006, 29(12): 2632-2637.[4] green j b, bethel m a, armstrong p w, et al. effect of sitagliptin on cardiovascular outcomes in type 2 diabetes[j]. new england journal of medicine, 2015, 373(3): 232-242.

Check Digit Verification of cas no

The CAS Registry Mumber 654671-78-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,5,4,6,7 and 1 respectively; the second part has 2 digits, 7 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 654671-78:
(8*6)+(7*5)+(6*4)+(5*6)+(4*7)+(3*1)+(2*7)+(1*8)=190
190 % 10 = 0
So 654671-78-0 is a valid CAS Registry Number.
InChI:InChI=1/C16H15F6N5O.H3O4P/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22;1-5(2,3)4/h4,6,9H,1-3,5,7,23H2;(H3,1,2,3,4)/t9-;/m1./s1

654671-78-0SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 12, 2017

Revision Date: Aug 12, 2017

1.Identification

1.1 GHS Product identifier

Product name Sitagliptin Phosphate

1.2 Other means of identification

Product number -
Other names Sitagliptin phosphate

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:654671-78-0 SDS

654671-78-0Relevant articles and documents

Synthesis of (?)-(R)-Sitagliptin by RhI-Catalyzed Asymmetric Hydroamination

Berthold, Dino,Breit, Bernhard

, p. 6247 - 6249 (2021/09/25)

We report of a concise synthesis of (R)-sitagliptin monophosphate – a drug predominantly applied in the treatment of type 2 diabetes. Utilizing our recently developed RhI-catalyzed hydroamination of allenes for the stereoselective construction of the inherent chiral amino function, a new approach to (R)-sitagliptin monophosphate on a 3.5 mmol scale was established.

Two methods for the preparation of sitagliptin phosphate: Via chemical resolution and asymmetric hydrogenation

Ye, Fei,Zhang, Zhifeng,Zhao, Wenxia,Ding, Jianhai,Wang, Yali,Dang, Xueyan

, p. 4805 - 4809 (2021/02/03)

Two effective processes have been developed for the preparation of sitagliptin phosphate. The approach of chemical resolution obtained R-sitagliptin in five steps from commercially available starting materials using the inexpensive NaBH4 to reduce the enamine and then using (-)-di-p-toluoyl-l-tartaric acid to resolve racemates in 11% yield overall. The route successfully avoids the use of expensive noble metal as catalysts compared with traditional synthesis methods, resulting in greatly reduced costs and simplified synthetic routes. Other alternative asymmetric hydrogenation of β-ketomide routes for the synthesis of sitagliptin were found, two of the intermediates were synthesized for the first time. This journal is

IMPROVED PROCESS FOR PREPARATION OF SITAGLIPTIN

-

Page/Page column 16, (2021/12/31)

Provided herein is a process for the preparation of specific enantiomeric Sitagliptin with good chiral purity and higher yield using improved biocatalyst and by engineering an enzyme to mediate the efficient conversion of ketoamide to obtain enantiomerically pure Sitagliptin in presence of an amino group donor.

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