1-Boc-3-(cyanomethylene)azetidine Chemical Properties

Boiling point:

309.7±35.0 °C(Predicted)

Density 

1.215

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

form 

powder to crystal

pka

-1.88±0.20(Predicted)

color 

White to Orange to Green

InChI

InChI=1S/C10H14N2O2/c1-10(2,3)14-9(13)12-6-8(7-12)4-5-11/h4H,6-7H2,1-3H3

InChIKey

BESFCRTTXQYNBW-UHFFFAOYSA-N

SMILES

N1(C(OC(C)(C)C)=O)C/C(=C\C#N)/C1

Safety Information

RIDADR 

UN 3439 6.1/PG III

HazardClass 

6.1

PackingGroup 

III

HS Code 

2933998090

1-Boc-3-(cyanomethylene)azetidine Usage And Synthesis

Uses

1-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidine is used in the synthesis of baricitinib via Horner-Emmons reaction of tert-butyl-oxoazetidine-carboxylate followed by sulfonamidation, nucleophilic addition. and subsequent Suzuki-coupling reaction.

Description

1-Boc-3-(cyanomethylene)azacyclobutane is an important pharmaceutical intermediate and a multifunctional structural unit, primarily used as a key intermediate in the synthesis of baricitinib, a JAK inhibitor used to treat rheumatoid arthritis and alopecia areata. The synthesis of baricitinib typically involves the Horner-Emmons reaction of this intermediate.

Uses

1-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidine is used in the synthesis of baricitinib via Horner-Emmons reaction of tert-butyl-oxoazetidine-carboxylate followed by sulfonamidation, nucleophilic addition. and subsequent Suzuki-coupling reaction.

Synthesis

Under nitrogen protection, 24.8 g of cyanomethyl diethyl phosphate and 300 mL of anhydrous tetrahydrofuran were added to a 1000 mL four-necked flask. The reaction mixture was cooled to -15 to -10 °C under nitrogen protection and 128.5 mL of 1.0 M potassium tert-butanolate in tetrahydrofuran solution was slowly added while controlling the temperature below -5 °C. After addition, the reaction continued to be stirred at -10 to -5 °C for 3 hours. Subsequently, keeping the temperature below -5 °C, a tetrahydrofuran solution of 1-Boc-3-azetidinone was added slowly and dropwise (20.0 g 1-Boc-3-azetidinone dissolved in 67 mL of tetrahydrofuran). After dropwise addition, the reaction temperature was maintained at -10 to -5°C with continued stirring for 2 hours. Next, the reaction mixture was slowly warmed to 25 to 30 °C and stirred at this temperature for 16 hours. Upon completion of the reaction, the layers were separated by slowly adding 300 mL of 12.5% aqueous sodium chloride solution. The aqueous phase was extracted with 300 mL of ethyl acetate. The organic phases were combined and washed with 200 mL of brine. A final 20.65 g white solid product tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate was obtained in 91% yield.

References

[1] Patent: CN108752254, 2018, A. Location in patent: Paragraph 0097-0099
[2] Patent: WO2013/36611, 2013, A1. Location in patent: Page/Page column 28; 29
[3] Patent: US2016/333015, 2016, A1. Location in patent: Paragraph 0055; 0056; 0081; 0082; 0105; 0106; 0134; 0135

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