1

Work Presentation

Synthesis of Pimprinine and Oxaprozin

from Enamides

Yunhui Zheng 2013.3.15

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Pimprinine

NH

1) POCl3, DMF, rt, then KOH(aq.), rt

2) TsCl, DMAP, Et3N, DCM, rt NTs

CHO

74%(over two steps)

PPh3, CBr4

CH2Cl2, 0 oC NTs

Br

Br

97%1 2 3

3Pd(OAc)2, PPh3

Bu3SnH, toluene, rt NTs

Br

4

K2CO3, NH2COR, toluene NTs

NH

5

R

O

95%

5

NTs6

NO

R

NH

NO

R

7

Pimprinine (R = Me)

NH HNCuI

68%

PIDA

3

entry oxidant additive (equiv) solvent temp(OC) yield(%)

1 PIDA BF3.Et2O (2.0) DCE reflux decomposed

2 PIDA BF3.Et2O (2.0) DCM -78 decomposed

3 PIDA BF3.Et2O (0.1) DCM -78 decomposed

4 PIDA ̶� DCE 0 NR

5 PIDA BF3.Et2O (0.1) DCE 0 decomposed

6 PIDA ̶� DCE rt decomposed

7 PIDA ̶� DCE reflux ND

8 PIDA AgCO3(2.0) DCE reflux decomposed

9 PIDA ̶� ACN reflux decomposed

10 PIDA ̶� 1,4-dioxane reflux decomposed

11 PIDA ̶� TFE reflux decomposed

NTs

NH R

O

NTs

NO

R

PIDA

R = Me

4

NTs

NH R

O

NTs

NO

R

PIDA

R = Me

NTs

NH R

O

NPG

NH R

O

PG = Boc, Bn, H

NTs

NH R

O

Mg turnings

MeOH, 0 oC-rt

yield = 55%

NH

NH R

O

R = Me

5

NH

O

Boc2O, DMAP

MeCN, rt

NaH, DMF

BnBr, rtNBn

O

NBoc

O

90% 92%

NBoc

O

NBoc

Br

Br

PPh3, CBr4

CH2Cl2, 0 oCquant. N

Bn

O

NBn

Br

Br

PPh3, CBr4

CH2Cl2, 0 oC

NBn

O

NBn

COOH

CH2(COOH)2

pridine, piperidine

reflux

TBAB, DMP

DCM,rt

90%NBn

Br

6

Oxaprozin

N

O COOH

It is a non-steroidal anti-inflammatory drug, used to relieve the inflammation, swelling,

stiffness, and joint pain associated with osteoarthritis and rheumatoid arthritis.

OH

OO OO

pyridine

O

O

ONHOAc/HOAc

H2O N

O COOH

HOOC

Previous work

This work

HN

COOR

O

N

O COOR

N

O COOH

7

COOEt CN NaH

THF

CN

O O

HBr(>40%, aq.)

yield = 52% (over two steps)

Route A

O1) HCl.NH2-OH, CH3COONa, MeOH

2) CuI, NaHSO3, succinic anhydride, DCE

yield: 15%(over two steps)

HN COOH

O

1

1PIDA, BF3

.OEt2, DCE NO

COOH

2

8

O1) HCl.NH2-OH, CH3COONa, MeOH

2) CuI, NaHSO3, (MeOOCCH2CH2CO)2O, DCE

yield: 77%(over two steps)

HN COOMe

O

1

1PIDA, BF3

.OEt2, DCE 1N NaOH(aq.)/MeOH

yield: 73%

NO

COOMe

yield: 90%

NO

COOH

2 3

Route B

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COOEtCN NaH

THF

CN

O O

HBr(>40%, aq.)

BrOMe

Br OMe BrOMe

56%

1) HCl.NH2-OH, CH3COONa, MeOH

2) CuI, NaHSO3, (MeOOCCH2CH2CO)2O, DCE

yield: 61%(over two steps)

NH

PIDA, BF3.OEt2, DCE 1N NaOH(aq.)/MeOH

yield: 72%

NO

COOMe

yield: 95%

NO

COOH

O

OMeCF3

OMe COOMeO

OMe

MeO

F3C

OMe

MeO

OMe

MeO

F3C F3C

O

OMeCF3

OMeOMe

OMe CF3

COClAlCl3

DCM

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Thank you!