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Intermediates of Sitagliptin and preparation method thereof

A technology of sitagliptin and intermediates, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problem of less catalysts, etc., and achieve the effects of improving purity, reducing dosage, and reducing production costs

Active Publication Date: 2011-07-20
JIANGSU SENRAN CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this scheme only discloses amide-substituted aniline derivatives, and technicians have found that using alkyl or alkoxy-substituted aniline derivatives, the performance of the obtained intermediate is more superior, and the amount of catalyst used is less

Method used

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  • Intermediates of Sitagliptin and preparation method thereof
  • Intermediates of Sitagliptin and preparation method thereof
  • Intermediates of Sitagliptin and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Sitagliptin Intermediate II 1 Synthesis

[0034]

[0035] Using existing methods to prepare I 1 Compound is used as raw material, then the 200g reactant I 1 (0.81mol) and 98g (0.81mol) of (R)-1-phenylethylamine were added to 2.8L of methanol, the temperature was raised to 40°C, 49mL of AcOH was added, the temperature was raised to 48°C, kept for 15min and dropped to within 1h 40°C. After aging for 5 hours, 0.4% seed crystals were added, and the mixture was aged for 1 hour to form a slurry. The mixture was aged for 1 h, 2.8 L of heptane was added over 3 h, the mixture was aged at 40 °C for 3.5 h, and slowly cooled to room temperature over 5.5 h. After a total reaction time of 21 h, the slurry was rapidly filtered and washed with 800 mL of a 1:1 isopropanol / heptane mixture. solid in N 2 258g target product II was produced after drying for 24h 1 , The yield is 90%.

Embodiment 2

[0036] Example 2 Sitagliptin II 2 compound synthesis

[0037]

[0038] Using existing methods to prepare I 2 Compound is used as raw material, then the 200g (0.77mol) reactant I 2 Add 93.1g (0.77mol) of (R)-1-phenylethylamine into 2.8L of isopropanol, raise the temperature to 40°C, add 49mL of AcOH, raise the temperature to 48°C, keep it for 15min and drop it to within 1h 40°C. After aging for 5 hours, 0.4% seed crystals were added, and the mixture was aged for 1 hour to form a slurry. The mixture was aged for 1 h, 2.8 L of heptane was added over 3 h, the mixture was aged at 40 °C for 3.5 h, and slowly cooled to room temperature over 5.5 h. After a total reaction time of 21 h, the slurry was rapidly filtered and washed with 800 mL of 1:1 isopropanol / heptane. The solid was dried under N2 for 24h to produce 243g of the target product II 2 , The yield was 87%.

Embodiment 3

[0039] Example 3 Sitagliptin Intermediate III 1 Synthesis

[0040]

[0041] in N 2 Under protection, add 200g reactant II in 2L autoclave 1 (0.57mol), dissolved in 1.2L of MeOH, added 4g of 5% Pt / Al 2 o 3 (2%) as a catalyst, followed by 16atm of H 2 , heated to 35°C for 15h, TLC detected the reaction and removed the solvent under reduced pressure to obtain 197g of product III 1 , the yield was 98%, ee (enantiomeric excess) > 98%.

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Abstract

The invention mainly relates to intermediates of Sitagliptin and a preparation method thereof. The intermediates of the Sitagliptin have chemical structures shown as II and III, wherein definitions of Ar, R1 and R2 are shown in the specifications. The compounds shown as the II and the III are prepared by reacting a compound shown as a formula I with a substituent of phenylethylamine, which serve as raw materials, under hydrogen pressure. The intermediates are used for synthetizing the Sitagliptin, so synthetic difficulty is reduced, purity of a product is improved, the using amount of a high-price catalyst is reduced, production cost is effectively reduced, and the intermediates and the method are suitable for industrialized production.

Description

technical field [0001] The invention mainly relates to the field of intermediate synthesis of medicines, in particular to an intermediate of sitagliptin, a medicine for treating type 2 diabetes, and a preparation method thereof. Background technique [0002] Sitagliptin (sitagliptin) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor developed by Merck in the United States, and its chemical name is (3R)-3-amino-1-[3-(trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) Butan-1-one, the structural formula is shown in the following formula. [0003] [0004] In October 2006, sitagliptin phosphate (trade name Januvia) as the first DPP-IV inhibitor was approved by the US FDA for clinical use in the treatment of type 2 diabetes. a product. Dipeptidyl peptidase IV inhibitors inhibit DPP-4, reduce the degradation of glucagon-like peptide-I (GLP-1), increase the plasma concentration of GLP-1, and improve postprandial blood glucose cont...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C227/08C07C227/16
Inventor 袁建栋徐安佗
Owner JIANGSU SENRAN CHEM
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