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

Chemical Properties

white crystalline

Uses

Different sources of media describe the Uses of 654671-77-9 differently. You can refer to the following data:
1. antimuscarinic
2. Sitagliptin Phosphate Monohydrate is a dipeptidyl peptidase-IV (DPPIV) inhibitor.

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 
• 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 
• 763105-70-0 2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide 
• 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 

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.

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.

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.