654671-77-9

Basic information

• Product Name: Sitagliptin phosphate monohydrate
• Synonyms: 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)Butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazinephosphatemonohydrate;Sitagliptin phosphate monohydrate 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate monohydrate;Sitagliptin phosphate mon;Sitagliptin phosphate monohydrate, >=99%;7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate;(R)-3-Amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4;Sitagliptin phosphate monohydrate;Sitagliptin phosphate for research
• CAS NO: 654671-77-9
• Molecular Formula: C₁₆H₁₅F₆N₅O*H₂O*H₃O₄P
• Molecular Weight: 523.3240802
• EINECS: 1806241-263-5
• Product Categories: Inhibitors;API;Inhibitor
• Mol File: 654671-77-9.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 529.9 °C at 760 mmHg
• Flash Point: 274.3℃
• Appearance: White or almost white crystalline powder
• Vapor Pressure: 2.59E-11mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: ≥23.8 mg/mL in DMSO; insoluble in EtOH; ≥30.6 mg/mL in H2O with ultrasonic
• CAS DataBase Reference: Sitagliptin phosphate monohydrate(CAS DataBase Reference)
• NIST Chemistry Reference: Sitagliptin phosphate monohydrate(654671-77-9)
• EPA Substance Registry System: Sitagliptin phosphate monohydrate(654671-77-9)

Safety Data

• Statements: 28-38-41-48-62-63
• Safety Statements: 24/25-26-28-36/37/39
• Hazardous Substances Data: 654671-77-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Sitagliptin phosphate monohydrate is used as an antimuscarinic agent for the treatment of type 2 diabetes. It helps in controlling blood sugar levels by inhibiting the DPP-IV enzyme, which in turn increases the levels of insulin and decreases the production of glucagon, leading to better glucose management in the body.
Used in Diabetes Management:
Sitagliptin phosphate monohydrate is used as an oral antidiabetic drug for managing type 2 diabetes. It aids in improving glycemic control by modulating the actions of incretin hormones, which are responsible for stimulating insulin secretion and suppressing glucagon release, thus maintaining a balanced blood glucose level.

Biological Activity

sitagliptin phosphate monohydrate is the phosphate salt of its active component, sitagliptin, with one molecule of water. sitagliptin is a potent inhibitor of dipeptidyl peptidase 4 (dpp-4), an enzyme catalyzing the cleavage of peptides with an n-terminal alanine or proline amino acid residue, that selectively inhibits dpp-4 with 50% inhibition concentration ic50 value of 18 nm and shows no affinity towards other ddp enzymes (such as ddp-8 and ddp-9). the inhibition of dpp4 by sitagliptin has been found to be mediated by increasing levels of two dpp-4 substrates, including glucagon-like peptide-1 (glp-1) and gastric inhibitory polypeptide (gip). sitagliptin is currently being investigated in the treatment of type ii diabetes.gallwitz b. review of sitagliptin phosphate: a novel treatment for type 2 diabetes. vasc health risk manag. 2007;3(2):203-10.

InChI:InChI=1/C16H15F6N5O.H3O4P.H2O/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);1H2/t9-;;/m1../s1

Synthetic route

sitagliptin (486460-32-6) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
With phosphoric acid In water; isopropyl alcohol at 70 - 80℃; for 2h; Temperature;	97.7%
With phosphoric acid; water In isopropyl alcohol at 20 - 75℃;	95%
With phosphoric acid; water In isopropyl alcohol at 75℃;

1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (764667-65-4) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: isopropyl alcohol; acetic acid / 18 h / 50 °C 2: sodium tetrahydroborate; formic acid / tetrahydrofuran / -30 °C 3: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr 4: phosphoric acid; water / isopropyl alcohol / 20 - 75 °C View Scheme
Multi-step reaction with 4 steps 1: isopropyl alcohol; acetic acid / 18 h / 50 °C 2: sodium tetrahydroborate; acetic acid / tetrahydrofuran / 3 h / 20 °C 3: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr 4: phosphoric acid; water / isopropyl alcohol / 20 - 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux 2.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 2.2: 13 h / 50 °C / 10343.2 Torr 3.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

(R,Z)-3-[(1-phenylethyl)amino]-1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)but-2-en-1-one (1169707-29-2) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; formic acid / tetrahydrofuran / -30 °C 2: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr 3: phosphoric acid; water / isopropyl alcohol / 20 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; acetic acid / tetrahydrofuran / 3 h / 20 °C 2: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr 3: phosphoric acid; water / isopropyl alcohol / 20 - 75 °C View Scheme

(3R)-3-[[(1R)-1-phenylethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (1169707-30-5) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr 2: phosphoric acid; water / isopropyl alcohol / 20 - 75 °C View Scheme

3(S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoic acid (868071-17-4) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: lithium hydroxide; dicyclohexyl-carbodiimide / tetrahydrofuran; water; cis-1,2-Dichloroethylene / 3 h / 20 - 22 °C 1.2: 18.5 h / 10 - 20 °C 2.1: lithium hydroxide / tetrahydrofuran; water / 2.33 h / 20 - 25 °C / pH 3 2.2: 3 h / 0 - 5 °C 3.1: phosphoric acid / isopropyl alcohol / 16 h / 30 °C 4.1: sodium hydroxide / water / 1 h / 0 - 5 °C 5.1: phosphoric acid; water / water; isopropyl alcohol / 0.25 h View Scheme

N-(benzyloxy)-4(R)-[1-methyl-(2,4,5-trifluorophenyl)]-2-oxoazetidine (767352-30-7) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium hydroxide / tetrahydrofuran; water / 2.33 h / 20 - 25 °C / pH 3 1.2: 3 h / 0 - 5 °C 2.1: phosphoric acid / isopropyl alcohol / 16 h / 30 °C 3.1: sodium hydroxide / water / 1 h / 0 - 5 °C 4.1: phosphoric acid; water / water; isopropyl alcohol / 0.25 h View Scheme

3(R)-3-[(benzyloxy)amino]-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (1361389-75-4) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphoric acid / isopropyl alcohol / 16 h / 30 °C 2: sodium hydroxide / water / 1 h / 0 - 5 °C 3: phosphoric acid; water / water; isopropyl alcohol / 0.25 h View Scheme

sitagliptin phosphate → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 1 h / 0 - 5 °C 2: phosphoric acid; water / water; isopropyl alcohol / 0.25 h View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: hydrogen; dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) / methanol; acetic acid / 70 °C / 3620.13 Torr / Inert atmosphere; Autoclave 2.1: lithium hydroxide; dicyclohexyl-carbodiimide / tetrahydrofuran; water; cis-1,2-Dichloroethylene / 3 h / 20 - 22 °C 2.2: 18.5 h / 10 - 20 °C 3.1: lithium hydroxide / tetrahydrofuran; water / 2.33 h / 20 - 25 °C / pH 3 3.2: 3 h / 0 - 5 °C 4.1: phosphoric acid / isopropyl alcohol / 16 h / 30 °C 5.1: sodium hydroxide / water / 1 h / 0 - 5 °C 6.1: phosphoric acid; water / water; isopropyl alcohol / 0.25 h View Scheme

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: triethylamine; magnesium chloride / acetonitrile / 30 - 50 °C / Inert atmosphere 1.2: 5.5 h / 30 °C / Inert atmosphere 2.1: hydrogen; dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) / methanol; acetic acid / 70 °C / 3620.13 Torr / Inert atmosphere; Autoclave 3.1: lithium hydroxide; dicyclohexyl-carbodiimide / tetrahydrofuran; water; cis-1,2-Dichloroethylene / 3 h / 20 - 22 °C 3.2: 18.5 h / 10 - 20 °C 4.1: lithium hydroxide / tetrahydrofuran; water / 2.33 h / 20 - 25 °C / pH 3 4.2: 3 h / 0 - 5 °C 5.1: phosphoric acid / isopropyl alcohol / 16 h / 30 °C 6.1: sodium hydroxide / water / 1 h / 0 - 5 °C 7.1: phosphoric acid; water / water; isopropyl alcohol / 0.25 h View Scheme
Multi-step reaction with 5 steps 1.1: dmap; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 20 - 40 °C 1.2: 2 - 3 h / 0 - 5 °C 2.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 2.2: 3 - 5 h / 20 - 45 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux 4.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 4.2: 13 h / 50 °C / 10343.2 Torr 5.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide (763105-70-0) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: hydrogenchloride / methanol; water / 0.75 h / 55 °C 2.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 2.2: 3 - 5 h / 20 - 45 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux 4.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 4.2: 13 h / 50 °C / 10343.2 Torr 5.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

(Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one (767340-03-4) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 1.2: 13 h / 50 °C / 10343.2 Torr 2.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

C15H13F3O4 → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 1.2: 3 - 5 h / 20 - 45 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux 3.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 3.2: 13 h / 50 °C / 10343.2 Torr 4.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 1.2: 3 - 5 h / 20 - 45 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux 3.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 3.2: 13 h / 50 °C / 10343.2 Torr 4.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 24 h / 0 °C 2: hydrogenchloride / methanol / 3 h / 20 °C 3: phosphoric acid / isopropyl alcohol; water / Reflux View Scheme

(R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid (936630-57-8) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 10 h / 20 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 24 h / 0 °C 3: hydrogenchloride / methanol / 3 h / 20 °C 4: phosphoric acid / isopropyl alcohol; water / Reflux View Scheme

sitagliptin phosphate monohydrate (654671-77-9) → sitagliptin phosphate

Conditions	Yield
In water Purification / work up;
at 58 - 140℃; for 1 - 8h;

Upstream product

• 936630-57-8 (R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid 
• 486460-00-8 (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 
• 209995-38-0 (2,4,5-trifluorophenyl)acetic acid 
• 769195-26-8 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester 
• 654671-78-0 sitagliptin phosphate 
• 1361389-75-4 3(R)-3-[(benzyloxy)amino]-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 767352-30-7 N-(benzyloxy)-4(R)-[1-methyl-(2,4,5-trifluorophenyl)]-2-oxoazetidine 
• 868071-17-4 3(S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoic acid 
• 1169707-30-5 (3R)-3-[[(1R)-1-phenylethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 1169707-29-2 (R,Z)-3-[(1-phenylethyl)amino]-1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)but-2-en-1-one 
• 764667-65-4 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione 
• 486460-32-6 sitagliptin 
• 762240-92-6 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 
• 767340-03-4 (Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one 

Downstream Products

• 654671-78-0 sitagliptin phosphate 

Relevant articles and documents

BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and preparation method thereof

The invention provides a sitagliptin phosphate important intermediate BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and a preparation method and preparation thereof. TheBOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and the preparation method thereof have important significance for the following industrial production of bulk drugs.

A phosphoric acid west geleg sandbank crystal and its preparation and use

The invention provides a crystal-type sitagliptin phosphate monohydrate and a preparation method, pharmaceutical composition and application thereof. The solubility of the sitagliptin phosphate crystal is high and obviously higher than that of a sitagliptin phosphate monohydrate in the prior art, and the sitagliptin phosphate crystal is good in both stability and hygroscopicity under the conditions of high temperature, high humidity and illumination. Compared with the prior art, the crystal-type sitagliptin phosphate monohydrate has the advantages that the solubility is higher, and the great significance for improving the pharmaceutical effect and reducing the pharmaceutical loading capacity is achieved; the preparation method is easy to operate, good in repeatability and beneficial for cost control in industrialized production and has the extremely high economic value; the time period of industrialized mass production is greatly shortened, the production efficiency is improved, the production energy consumption is reduced, and the cost of industrialized mass production is lowered.

SITAGLIPTIN, SALTS AND POLYMORPHS THEREOF

The present invention relates to an improved process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof. The present invention further relates to novel polymorphs of Sitagliptin salts and process for preparation thereof.

Practical and economical approach to synthesize sitagliptin

Economic syntheses of sitagliptin phosphate monohydrate, acknowledged as the first dipeptidyl peptidase 4 (DPP-4) inhibitor, have been achieved in an overall yield of 42.4% in four steps from 1-{3-(trifluoromethyl)-5,6-dihydro-[1, 2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione. The key stereoselective reduction of this process was carried out by NaBH 4/HCOOH instead of expensive and toxic catalysts or ligands. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

AMORPHOUS FORM OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR

The present invention relates to a novel amorphous form of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-a mine as well as a process for its preparation, pharmaceutical compositions containing this novel form, and methods of use of the novel form and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure.

NOVEL CRYSTALLINE FORM OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR

The present invention relates to a novel crystalline anhydrate polymorph of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-a mine as well as a process for their preparation, pharmaceutical compositions containing this novel form, and methods of use of the novel form and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure.