The Synthesis of Fexofenadine: The Conversion of Ethyl Isonipecotate to Amino Alcohol 4, and Subsequent Addition to Lactol 3a

Nicole Bernstein and Mike BuchananThe Pennsylvania State University, CHEM 213H

Introduction The Boc-Protection of Ethyl Isonipecotate Synthesis of Grignard Reagent 6

• Fexofenadine is an antihistamine used in the treatment of seasonal allergies ; it works by blocking the H1-histamine receptor.1

• This common drug can be synthesized from ethyl p-tolylacetate and ethyl isonipecotate, commercially-available reagents1.

• The goal of this study was to examine the three-step synthesis of amino alcohol 4 in depth, and subsequently combine the resulting product with Lactol 3a created by Sub-Team 1 to complete the synthesis of fexofenadine.

The Complete Synthesis of Fexofenadine

O

OCH3

CH3 O

O

CH3

CH3

CH3

CH3

89

O

O

CH3

CH3

Br

CH3O

O

CH3

CH3

O

CH3

10 7

NH

OHPh

Ph

O

O

CH3

CH3

CH3

N

OH Ph

Ph

OH

2

OH

O

CH3

CH3

N

OH Ph

Ph

OH

1

4

6

O

O

MgBr

O

O

CH3

CH3

CH3

OH

O

O

5

O

O

CH3

CH3

CH3

O

OH

3a

• The ten-step synthesis of fexofenadine (1) involves the synthesis of lactol 3a from ethyl p-tolylacetate (8)

• Amino alcohol 4, synthesized from ethyl isonipecotate, is added to lactol 3a to complete the synthesis of fexofenadine

• The first step in the synthesis of amino alcohol 4 involves the installation of a t-butyl carbamoyl protecting group on the amine nitrogen

• This N-Boc group is highly tolerant of basic Grignard addition, and is easily removed by acid.

NH

O CH3O

O CH3O

N

Boc

11 12

B o c 2 O , D M A P

C H 2 C l2 , 0 °C

The Grignard Addition to 12

N

Boc

OHPh

Ph

O CH3O

N

Boc

P h M g B r

T H F , re flu x

12 13

• The bis-alkylation of 12 is achieved through nucleophilic attack of the Grignard reagent phenylmagnesium bromide on the ester moiety.

• Low yield could be due to the unwanted presence of water, neutralizing the Grignard reagent.

Deprotection of N-Boc Amino Alcohol 13

• Initial spectral data indicated that instead of the desired product, an elimination reaction had occurred, producing 15 through an intermediate carbocation 15’.

• The Boc cleavage was attempted a second time, adding water to the reaction mixture to prevent the initial alkene-producing side reaction, but only starting material was recovered.

• The deprotection of N-Boc Amino Alcohol 13 was attempted using trifluoroacetic acid at room temperature.

• Grignard reagent 6 is used to convert the aldehyde functionality of 7 into an alcohol product.

• The reaction was conducted in closed conditions under nitrogen, due to the extreme sensitivity of Grignard reagents to the presence of water.

O

O

MgBr

7

O

O

BrM g o t u rn in g s

T H F , < 5 0 °C

14

Discussion

Conclusion

• The conversion of ethyl isonipecotate to amino alcohol 4 was ultimately unsuccessful. The final deprotection of the N-Boc amino alcohol resulted largely in the creating of an alkene due to the extreme stability of a carbocation located next to two benzyl groups.

• The goal of combining amino alcohol 4 with lactol 3a was not achieved.• Future experiments would include other attempts to remove the Boc group from N-Boc

amino alcohol 13, using basic conditions rather than acid.• Other syntheses of amino alcohol 4 would be explored, removing the use of a

protecting group to reduce time and waste.

Acknowledgements

References

The authors of this poster would like to thank the Penn State Chemistry Department and Dr. Katherine Masters for administering the course CHEM 213 H. They would also like to thank Jerry Feng and Anthony Nocket, the teaching assistants for the course, for all of their support and guidance.

1. Masters, K. M. Chem 213H Team Project. Spring 2013 Edition

• The Boc-protection of ethyl-isonipecotate was a necessary step in order to convert the ester functionality to an alcohol. It was successful and produced a 73.7% yield

• The Grignard addition to N-Boc ethyl isonipecotate was successful, as indicated by the presence of two phenyl rings in the H NMR spectrum, though at low yield.

• The Boc deprotecting step was ultimately unsuccessful, and impeded the overall completion of the synthesis. The formation of an alkene was preferred, as a favorable elimination occurred.

• Grignard Reagent 6 was synthesized correctly, and was ultimately reacted with ester aldehyde 7 to form alcohol 5.

N

Boc

OHPh

Ph

NH

OHPh

Ph

13 4

• Additional attempts to synthesize amino alcohol 4 resulted in the failure to remove the Boc group, ultimately preventing the completion of the synthesis of fexofenadine.

• All structures were confirmed using a 400 MHz Bruker AVANCE spectrometer.

1 . N a H M D S , T H F

2 . M e I

N B S , P H 2 (C O O ) 2

C C l4 , r e flu x

E tO H /H 2 O

NN

N

N

p -T sO H , T H F

re flu x1 . M e O H , re flu x

2. NaBH 4, 5 °C

1 . N a O H , M e O H /H 2 Ore flu x

2 . H O A c (p H 5 -6 )

NH

OHPh

Ph

4

O CH3O

N

Boc

12

NH

O CH3O

11

73.7% yield

39.1% yield

N

Boc

OHPh

Ph

13

N+

C+ PhPh

HH

15'

N+

PhPh

H H

15

T F A

C H 2 C l2 , r t .

N

Boc

OHPh

Ph

13

52.3% yield