Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin

Our plain-English summary of Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin, by I. Gill, R. Patel (Bioorganic & Medicinal Chemistry Letters, 2006).

The study

• Authors: I. Gill, R. Patel
• Journal: Bioorganic & Medicinal Chemistry Letters
• Published: 2006;16(3):705-9
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.

In plain English

This article does not report research on asbestos or on human health. It is a laboratory chemistry study from Bristol-Myers Squibb on a method for making a chemical intermediate (an amide) used to produce the diabetes drug Saxagliptin. The authors screened many commercial enzymes. Only Candida antartica lipase B (CALB) and two immobilized forms of it gave useful amounts of the amide (69%, 43% and 40%); all other enzymes gave less than 5%. The authors then tested different ammonia sources, temperatures, and amounts of enzyme and ammonium carbamate. Adding calcium chloride raised the amide yield to 79%. Placing Ascarite above the reaction mixture, where it was presumed to absorb carbon dioxide, raised the yield to 95%. Using both together gave 98%. In a larger preparative run, the amide was isolated in 81% yield. The authors concluded that they had developed an efficient process for this conversion. They noted that the side products were not further characterized.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory chemistry (biocatalysis) experiment developing an enzyme-based chemical synthesis step; not a study of asbestos or of people
• Who was studied: No people or animals. The study tested commercial enzymes (lipases, proteases and esterases) on a chemical starting material (an ethyl ester, compound 1) dissolved in toluene.
• Exposure: None. No asbestos or other health exposure was studied. The experimental variables were the enzyme, the ammonia source, the temperature, and additives such as calcium chloride and Ascarite.
• Main results:
  • In the enzyme screen, CALB and its immobilized forms Novozym 435 and Chirazyme L2 gave amide yields of 69%, 43% and 40%, respectively. All other enzymes gave less than 5%.
  • The amide yield was highest at 50 to 60 degrees C.
  • Adding calcium chloride at 100 g/L gave 79% amide and 13% side products.
  • Ascarite at 200 g/L in the reaction headspace raised the amide yield to 95%. Combining Ascarite with calcium chloride raised it further, to 98%.
  • In the preparative-scale run, the amide was isolated in 81% yield, at 98% potency and greater than 99.9% ee.
• The authors' conclusion: The authors concluded that they had developed an efficient biocatalytic process for converting ester 1 into amide 2, and that it was economic and scalable for industrial use.
• Limitations the authors state:
  • The side products were not further characterized.
  • The exact origins of the trends seen when varying enzyme and ammonium carbamate amounts were unclear.

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