654671-78-0 Usage
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
654671-78-0Relevant articles and documents
Process for preparing sitagliptin
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Paragraph 0053-0055, (2021/06/01)
The present technology relates to a method for manufacturing sitagliptin, which is a representative drug among DPP-4 inhibitors which are drugs used for the treatment of diabetes. The method of the present invention uses CDI for the condensation reaction of specific compounds, and through a specific subsequent process, high-purity sitagliptin phosphate monohydrate can be manufactured in a high yield. In particular, the manufacturing method of the present invention is suitable for mass production.
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
Preparation method of sitagliptin phosphate monohydrate crystal form
-
Paragraph 0022-0057, (2021/05/05)
The invention relates to a preparation method of a sitagliptin phosphate monohydrate crystal form. The method comprises the following steps: adding sitagliptin free alkali, phosphoric acid, water and a specific organic solvent into a reactor, and reacting
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.
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.
Synthesis of (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal Synthesis of Sitagliptin Phosphate
Achanta, Srinivas,Bandichhor, Rakeshwar,Chaudhari, Pramod S.,Cobley, Christopher J.,Dahanukar, Vilas,Llewellyn-Beard, Fiona,Sreenivasulu, Kurella,Sud, Abhishek
, (2020/05/08)
An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β-amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc-amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.
Preparation method of sitagliptin phosphate
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Paragraph 0011; 0014-0015; 0018-0019; 0022, (2020/10/14)
The invention discloses a preparation method of sitagliptin phosphate. The preparation method comprises the following steps: taking 4-(2, 4, 5-trifluorophenyl)-3-methyl oxobutyrate I as a raw material; the reaction is mainly divided into five steps: carrying out asymmetric reduction on the raw material I through an N-heterocyclic carbene palladium catalyst to obtain chiral alcohol ester s-4-(2, 4,5-trifluorophenyl)-3-methyl hydroxybutyrate II; carrying out intramolecular condensation cyclization on the II to obtain chiral lactam quaternary ring (R)-N-benzyloxy-4-[1-methyl-(2, 4, 5-trifluorophenyl)]-2-azetidinone III; carrying out ring opening on the III under an alkaline condition to obtain IV; performing condensation reaction to form amide to obtain V; carrying out catalytic reduction onthe V through recycled N-heterocyclic carbene palladium to remove benzyloxy and form phosphate to obtain sitagliptin phosphate VI, wherein the N-heterocyclic carbene palladium catalyst is Pd (IPr-NHC) (acac) Cl or Pd (IPr-NHC) (acac) Oac or Pd (IPr-NHC) (dba) Cl or Pd (IPr-NHC) (dba) OAc; the catalyst is cheap and easily available, can be recycled, and is beneficial to batch production.
Preparation method of sitagliptin phosphate anhydrous hydrate
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Paragraph 0029-0038, (2020/03/12)
The invention relates to a preparation method, of a crystal form of sitagliptin phosphate anhydrous crystal, which is used for preparing sitagliptin phosphate anhydrous crystal form, with high yield, purity, particles after heating the solution, filtering
PROCESSES FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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Page/Page column 18-19, (2020/06/19)
The present application relates to improved processes for the preparation of Sitagliptin and pharmaceutically acceptable salts thereof. The present application also relates to the improved crystallization process for the preparation of Sitagliptin Phosphate. The present application also relates to the improved crystallization process for the preparation of Sitagliptin Hydrochloride monohydrate.
Preparation method of Sitagliptin phosphate monohydrate crystal form
-
Paragraph 0055-0059, (2019/04/30)
The invention relates to a preparation method of a Sitagliptin phosphate monohydrate crystal form, and the method specifically comprises the following steps: taking water as a solvent, heating, dissolving, cooling, carrying out suction filtration, and dry
