A concise synthesis of the HCV protease inhibitor BILN 2061 and its P3 modified analogs

FULL PAPER

A Concise Synthesis of the HCV Protease Inhibitor BILN 2061

and Its P3 Modified Analogs

Liu, Dejun(刘德军)

Dong, Jingchao*(董径超)

Yin, Yunxing(尹云星)

Ma, Rujian(马汝建)

Shi, Yifeng(施一峰)

Wu, Hao(吴颢)

Chen, Shuhui*(陈曙辉)

Li, Ge(李革)

WuXi AppTech Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China

A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4-quinoline moiety

via S_N2 displacement of the β-OBs group located on the 4-hydroxyl proline intermediate, which was prepared from

4-α-hydroxyl proline analog via Mitsunobu reaction with inversion of stereochemistry. In addition, a short and

practical synthesis for P3 unit is also described herein. Final assembly of four fragments for BILN 2061 was

achieved with an overall yield of 58% in 4 steps from P1 to 15a. Furthermore several analogs of BILN 2061

(WX-1— WX-5) containing modifications on P3 unit were synthesized successfully using the same synthetic route

as described for the parent inhibitor BILN 2061.

Keywords hepatitis C virus (HCV), BILN 2061, synthesis

say.⁵This molecule features a 15-membered ring bear-

ing a (Z)-1,2-disubstituted alkene subunit, as well as

five stereocenters. Despite the fact that there have been

successful synthetic approaches reported in the literature,

preparation of above building blocks requisite for such

assembly still presents considerable synthetic challenges

such as lengthy synthetic sequence and low overall

yield.⁶In this article, we present a more concise and

higher yielding synthesis of BILN 2061. Further appli-

cation of this synthetic methodology allows for the effi-

cient preparation of several BILN 2061 like HCV pro-

tease inhibitors with heteroatom incorporated in the P3

macrocyclic ring subunit.

As highlighted in Figure 1, retro-synthetic analysis

of BILN 2061 suggests that this macrocyclic tripeptidyl

inhibitor can be built in a convergent manner using four

building blocks including three non-natural amino acids

(P1, P2 and P3 shown in Figure 1) and a 4-quinoline

containing moiety. The typical disconnections suggest

Introduction

Hepatitis C virus (HCV) is a major cause of chronic

liver disease worldwide, with approximately 170 mil-

lion people being infected.^1,3The severity of the disease

varies widely from mild chronic hepatitis to cirrhosis

and hepatocellular carcinoma.^1-4The current standard

treatment calls for the combination of pegylated inter-

feron and ribavirin.^2,3A significant population of the

patients does not respond well to this treatment regiment

(especially HCV genotype 1). Furthermore, the existing

therapies are associated with considerable side effects

requiring discontinuation of treatment in certain patient

populations. The high prevalence of infection together

with the side effects and the limited efficacy of current

therapies necessitate the need for new therapeutics pref-

erably targeting HCV virus directly. Thanks to the great

efforts of virologists working at pharmaceutical com-

panies and academic institutions, several viral specific

molecular targets have been identified including

NS3-NS4A protease, NS5B polymerase, and etc. Sub-

sequently, medicinal chemistry programs were launched

aiming at discovery of small-molecule inhibitors of viral

enzymes such as HCV protease as potential new thera-

pies against HCV infections.

that its 15-memberering can be formed by

a

Ru-catalyzed ring-closing olefin metathesis reaction

linking the P1 and P3 terminal olefin moieties. Indeed,

this synthetic strategy has been used widely for such

macrocyclic ring formation in recent years.⁷In this arti-

cle, we report herein a concise process for ether forma-

tion between P2 and 4-quinoline moiety connection

along with a practical approach for P3 preparation as

exemplified for the synthesis of BILN 2061 and its

analogs (WX-1 through WX-5).

The first HCV protease inhibitor to enter clinical

development, BILN 2061, is a macrocyclic tripeptide

discovered by Boehringer Ingelheim with high potency

in the enzyme assay as well as in the HCV replicon as-

*

E-mail: dong_jinchao@wuxiapptec.com; chen_shuhui@wuxiapptec.com

Received November 10, 2010; revised January 30, 2011; accepted March 2, 2011.

Project supported by Shanghai Rising-Star Program (B type).

Chin. J. Chem. 2011, 29, 1489— 1502

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Figure 1 Retrosynthetic analysis of BILN 2061 and its analogs.

Synthesis of P3 terminal olefin bearing α-amino acid

Results and discussion

For the synthesis of P3 building block with optically

pure terminal olefin bearing long chain α-amino acid, a

6-step synthetic route was reported by Faucher et al.⁹

The key step in this methodology involves a catalytic

enantioselective hydrogenation of an enamine using the

DUPHOS system.¹⁰Such lengthy sequence and usage of

Ru catalyst for the catalytic enantioselective hydroge-

nation prompted us to investigate alternative route. Af-

ter careful experimentation, we discovered a very

straightforward and scalable method for the preparation

of this optically pure α-amino acid precursor 36 with

very good overall yield (50%) and high ee value

(＞99% ee) via the following two-step sequence starting

from readily available (S)-N-Boc-2-pyrrolidone-5-car-

boxylic acid: (1) opening of the γ-lactam ring by an or-

ganometallic reagent; (2) ketone reduction (Scheme

1).¹¹

As documented in the synthetic route published by

Yee et al.,⁸for the ether formation to introduce the qui-

noline moiety onto the C-4 position of the P2 proline

subunit, a double inversion sequence was required

starting from 4α-hydroxyproline in order to retain the

desired (R)-configuration at the C-4 position of proline.

The synthetic sequence started with a Mitsunobu reac-

tion on commercially available 4-α-hydroxyproline 9

using p-nitrobenzoic acid (PNBA) as the nucleophile,

then followed by hydrolyzing the C-4 ester PNBA in 8

to afford its 4β-hydroxyproline 7. This intermediate was

caped via brosylation to form the intermediate 6, which

was then used as the substrate for S_N2 displacement

with 4-hydroxyquinoline fragment. Such 4-step se-

quence would add considerable amount of workload

into the already lengthy synthesis of BILN 2061 (Figure

2).

Figure 2 Retro-synthesis analysis on installation of P2 ether functionality.

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Chin. J. Chem. 2011, 29, 1489— 1502

Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

Synthesis of BILN 2061

In summary, a more concise route for the synthesis

of BILN 2061 as outlined in Scheme 2 is accomplished

through an efficient P2 ester formation sequence in

comparison to that reported in the literature. The syn-

thesis is based on the preparation and assembly of four

fragments with an overall yield of 58% in 4 steps from

P1 to 15a, which represents a reduction of three linear

synthetic steps from the 7-step sequence reported in the

literature.⁸

The 15-membered macrocyclic ring in BILN 2061

was elaborated from the brosylated intermediate 12

(P1-P2 subunit prepared via coupling of the 4β-Bs

proline 11 with the P1 cyclopropyl bearing α-amino

acid) and 3a (P3 and P3 cap) via standard solution pep-

tide coupling procedures¹²to afford the acyclic tripep-

tide 14a. The latter was then subjected to ring-closing

olefin metathesis by using Hoveyda’s catalyst¹³to af-

ford the macrocycle 15a. Final S_N2 displacement of Bs

group with the 4-quinoline piece 4 as shown in Figure 1

Rationale for the synthesis of WX-1 through WX-5

Upon completion of BILN 2061 total synthesis, we

turned our attention to synthesis of several P3 modified

analogs of HCV protease inhibitor, namely WX-1

through WX-5 as shown in Figure 1. These analogs

were designed as bioisosters of BILN 2061 with hetero

(prepared via

a

known 4-step sequence from

3-methoxy-phenylamine¹⁴) thus afforded the ester ana-

log 16a, thereafter BILN 2061 upon LiOH mediated

ester hydrolysis.

Scheme 1 Synthesis of P3 amino acid 3a

Scheme 2 Expedient assembly of BILN 2061

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atom (O, or S, or N) incorporated on the P3 side chain

while maintaining same macrocycle ring size as BILN

2061. These newly designed molecules should have

improved aqueous solubility, metabolic stability, and

bioavailability due to the presence of hetero atom lo-

cated on P3 linkage. Furthermore, these new analogs

(WX-1 — WX-5) may create new IP position if

anti-viral activity could be detected with these P3 modi-

fied analogues

success of this approach hinged upon the preparation of

the requisite hetero atoms (O, S, and N) incorporated P3

intermediates 3b—3f as shown in Schemes 3 through

Scheme 5, respectively.

As depicted in Scheme 3, the O- inserted P3 inter-

mediate 3b was prepared in 5 steps from N-Boc serine

17. The O-alkylated amino ester 19 was prepared fol-

lowing the literature procedure via a two-step sequence

from 17.¹⁵Compound 19 was then subjected to N-Boc

deprotection followed by N-cyclopentyl carbamate for-

mation to yield methylester 21, which was then hydro-

lyzed to provide the desired intermediate 3b in an over-

all good yield.

Preparation of novel P3 amino acids 3b—3f

Based on the successfully developed approach for

BILN 2061 as shown in Scheme 2, a similar synthetic

strategy could be envisioned for synthesizing these

BILN 2061 analogs (WX-1—WX-5). The key to the

For the S-inserted P3 intermediate 3c, unprotected

L-cysteine ethyl ester 22 was subjected to selective

Scheme 3 Preparation of intermediate 3b

Scheme 4 Preparation of intermediate 3c

Scheme 5 Preparation of intermediates 3d, 3e and 3f

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Chin. J. Chem. 2011, 29, 1489— 1502

Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

S-alkylation to afford the desired product 23 in very

high yield (95%), which was further treated with

cyclopentyl chloroformate to yield the N-cyclopentyl

carbamate ester 24, thereafter the free acid 3c via LiOH

mediated ester hydrolysis. The overall three-step yield

for the synthesis of compound 3c was 88%.

tive P3 subunit 3b—3f in moderate to good conversion

as that obtained with 14a depicted in Scheme 2. The

resulting dienes 14b—14f were then further taken as the

precursors for RCM reactions to form 15-membered

macrocyclic ring by using Hoveyda’s catalyst. The cy-

clization yields were found to be quite variable depend-

ing on the nature of hetero atom incorporated (O, S, or

N). When 14b and 14c were used as the substrates, the

desired products 15b (X＝O) and 15c (X＝S) were ob-

tained in 80% and 74% yields, respectively. However,

when N-incorporated intermediates 14d—14f (X＝NNs

or NAc or NMe) were subjected to RCM reactions,

lower yields of final products 15d—15f were obtained

(ranged between 15%—40%). Although the exact rea-

son for the variable yields mentioned here is not known

with certainty, we speculate that spatial distance be-

tween two terminal olefins may be too far for 14d—14f.

The next set of key S_N2 reactions were attempted with

these 15-membered macrocycles 15b—15f. To our sat-

isfaction, all desired products 16b—16f were obtained

with correct stereochemistry at the 4-position on proline

subunit (with S_N2 inversion) in moderate yields except

for 16e (X＝NAc). The protecting group in 16d (X＝

NNs) was then removed to afford 16d' (X＝NH) under

mild basic condition. Subjection of these ester interme-

diates (16b—16c, 16d', 16e—16f) to LiOH

The syntheses of three N-incorporated P3 side chain

intermediates 3d, 3e, and 3f are outlined in Scheme 5.

The key β-N-alkylated intermediate 28 was prepared in

three steps via ester formation, N-Ns protection and se-

lective N-alkylation according to literature protocol.¹⁵

Compound 28 was then subjected to N-de-Boc and the

resulting free amino moiety was capped with cyclo-

pentyl carbamate to yield 30, en route to the final inter-

mediate 3d, upon LiOH mediated ester hydrolysis. Al-

ternatively, subjection of 30 to N-de-Ns reaction thus

afforded 31, which was further derivatized to the corre-

sponding N-Ac and N-Me P3 side chains 3e and 3f.

With all five requisite hetero atom (O, S, and N) in-

corporated P3 intermediates in hand (3b—3f), we

started final assembly of the target molecules (WX-1—

WX-5 as shown in Figure 1) employing the concise

route developed for the synthesis of BILN 2061 (see

Scheme 6). Towards this end, acyclic tripeptidyl inter-

mediates 14b—14f were prepared by the similar cou-

pling procedure between P1—P2 unit 13b with respec-

Scheme 6 Expedient assembly of WX-1— WX-5

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mediated hydrolysis afforded five respective P3 side

chain modified BILN 2061 analogs (WX-1—WX-5).

In summary, we described a highly convergent route

for the synthesis of BILN 2061. A shorter process was

reported for the construction of the C-4 ether function-

ality in desired stereochemistry between P2 unit and

4-quinoline moiety with only one Mitsunobu reaction.

In addition, a concise and practical approach for the

preparation of P3 subunit was outlined also. And the

final assembly of four fragments needed for BILN 2061

was achieved with an overall yield of 58% in 4 steps

from P1 to 15a. Furthermore, the generality of this con-

cise synthetic route was demonstrated via successful

syntheses of several P3 side chain hetero-atom contain-

ing analogs of BILN 2061 (WX-1—WX-5).

formed. The solid was collected by filtration and dried

to give compound 11 (13 g, 57.7% yield after 2 steps).

¹H NMR (CDCl₃, 400 MHz) δ: 12.66 (br, 1H), 7.89 (d,

J＝7.0 Hz, 2H), 7.84 (d, J＝7.0 Hz, 2H), 5.12—5.13 (m,

1H), 4.21—4.22 (m, 1H), 3.55—3.61 (m, 1H), 3.25—

3.40 (m, 1H), 2.07—2.12 (m, 1H), 1.34—1.37 (m,

10H).

4-(4-Bromo-benzenesulfonyloxy)-2-(1-ethoxycar-

bonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidine-1-

carboxylic acid tert-butyl ester (12b) To a stirred

solution of compound 11 (11.6 g, 0.0258 mol) in

anhydrous CH₂Cl₂(180 mL) was added N,N-diso-

propylethylamine (3.3 g, 0.0258 mol) and compound 2

(4.0 g, 0.0258 mol). The mixture was cooled to 10—15

℃, then O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetrame-

thyluronium hexafluorophosphate (10.2 g, 0.0258 mol)

was added portionwise. After addition, the mixture was

stirred overnight at room temperature. TLC (ethyl ace-

tate∶petrol ether＝1∶1, volume ratio) showed the

material was consumed completely. The mixture was

poured into water and the organic layer was purified via

column chromatography (ethyl acetate ∶ petroleum

ether＝1∶5, volume ratio) to afford compound 12b (15

g, 95%) as brown gum. [α]²_D⁰－19.8 (c 1.12, CH₃OH);

¹H NMR (CDCl₃, 400 MHz) δ: 7.65 (d, J＝8.4 Hz, 2H),

7.55 (d, J＝8.4 Hz, 2H), 5.59—5.66 (m, 1H), 5.16 (d,

J＝17.2 Hz, 1H), 4.99 (d, J＝10.0 Hz, 1H), 4.92 (br,

1H), 4.18 (br, 1H), 3.97—4.04 (m, 2H), 3.56 (s, 2H),

1.90—1.95 (m, 1H), 1.69—1.72 (m, 2H), 1.32—1.40

(m, 11H), 1.07 (t, J＝6.2 Hz, 3H); ¹³C NMR (CDCl₃,

100 MHz,) δ: 171.5, 169.7, 154.3, 135.4, 133.5, 132.7,

129.3, 128.7, 117.8, 81.5, 79.2, 61.3, 59.3, 53.1, 39.7,

38.5, 33.9, 28.2, 22.8, 14.2; IR (KBr) ν: 3314, 2983,

1725, 1698, 1660, 1574, 1515, 1471, 1390, 1370, 1320,

Experimental section

4-(4-Bromo-benzenesulfonyloxy)-pyrrolidine-1,2-

dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10)

The reactor was fitted with a Dean-Stark apparatus and

condenser and charged with the 4-bromobenzenesul-

fonic acid monohydrate (15.3 g, 60 mmol) and toluene

(100 mL). The mixture was refluxed under nitrogen un-

til water removal was complete and evaporated to dry-

ness. To the flask was added triphenylphosphine (16.3 g,

62.5 mmol) in 125 mL of dry toluene and was cooled to

about 20 ℃, and diisopropyl azodicarboxylate (13.5 g,

70 mmol) was added, keeping the temperature below 35

℃. Then the alcohol 5 (50 mmol) in 20 mL of dry tolu-

ene was added, followed by triethylamine (2.75 mL, 20

mmol). The slurry was heated to 60—70 ℃ for about 4

h until the formation of the sulfonate was complete by

HPLC. The reaction was cooled to about room tem-

perature for work up. 200 mL water was added into the

flask and stirred for 30 min. The solid was removed by

filtration. The filtrate was extracted with ethyl acetate

(100 mL×3), dried over anhydrous Na₂SO₄, evaporated

to give the crude product, which was purified with

column chromatography (ethyl acetate ∶ petroleum

ether＝1∶10, volume ratio) to afford 26 g of a 1∶1

mixture of the desired product and diisopropyl hydra-

zinedicarboxylate. An analytic sample was purified by

preparative TLC. ¹H NMR (CDCl₃, 400 MHz) δ: 7.70—

7.75 (m, 4H), 5.09—5.12 (m, 1H), 4.33—4.46 (m, 1H),

3.69 (s, 3H), 3.60—3.69 (m, 2H), 2.39—2.46 (m, 1H),

1.40—1.44 (m, 10H).

^－1

1186, 1158, 1121, 1092, 1068, 1022, 1001, 892 cm .

1-{[4-(4-Bromo-benzenesulfonyloxy)-pyrrolidine-

2-carbonyl]-amino}-2-vinyl-cyclopropane-carboxylic

acid ethyl ester hydrogen chloride salt (13b) To a

stirred solution of compound 12b (0.9 g, 0.0016 mol) in

di_－oxane (5 mL) was added HCl/dioxane (2 mL, 4 mol•

L

¹) at room temperature. The mixture was stirred

overnight. TLC (ethyl acetate∶petrol ether＝1∶1,

volume ratio) showed the material was consumed com-

pleted. The solvent was removed under reduced pres-

sure with temperature below 30 ℃ and CH₂Cl₂(10 mL

×3) was added to the residue, the solvent was removed

under reduced pressure with temperature below 30 ℃

to afforded compound 13 (0.8 g, 98%) as brown solid,

which was used in the next step without further workup.

2-tert-Butoxycarbonylamino-3-pent-4-enyloxy-

propionic acid methyl ester (19) To a solution of 7.4

g (36.1 mmol, 1 equiv.) of N-tert-butoxycarbonyl-L-

serine in 500 mL of anhydrous dimethylsulfoxide at

room temperature was added 1.44 g (36 mmol, 1.0

equiv.) of 60% sodium hydride in mineral oil. This

mixture was stirred at room temperature for 0.5 h until

the evolution of gas had ceased. To the resulting solu-

tion was added 5.3 g (36 mmol, 1.0 equiv.) of 5-

4-(4-Bromo-benzenesulfonyloxy)-pyrrolidine-1,2-

dicarboxylic acid 1-tert-butyl ester (11) To 1∶1

mixture of the compound 10 and diisopropyl hydrazine-

dicarboxylate (26 g) in 190 mL of THF was added

^－1

dropwise LiOH (1.4 mol•L , 60 mL, 84 mmol), main-

taining the temperature between 0—5 ℃, then stirred at

25 ℃ for 8 h until TLC indicated the starting material

was consumed completely. The water phase was ex-

tracted with ether (50 mL×3) to remove the diisopropyl

hydrazinedicarboxylate. The water phase was acidified

by HOAc to pH to 4—5, at which the precipitate was

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Chin. J. Chem. 2011, 29, 1489— 1502

Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

bromo-1-pentene followed immediately by another 1.4

g (36 mmol, 1.0 equiv.) of 60% sodium hydride in min-

eral oil. The reaction mixture then was stirred at room

temperature for 16 h. The mixture was diluted with

2000 mL of water, adjusted pH to 3—4 by the addition

of 50 mL of 1.00 mol/L hydrochloride acid, and ex-

tracted with ethyl acetate. The organic phase was

washed with water (200 mL×3) and brine, dried over

anhydrous sodium sulphate, filtrate, and concentrated

under vacuum to afford the crude compound, which

could be used directly for the next step. To a solution of

above crude compound in 100 mL of anhydrous di-

methylsulfoxide, was added 7.8 g (56 mmol) of potas-

sium carbonate and 3.5 mL (56 mmol) of iodomethane,

and the resulting mixture was stirred at room tempera-

ture for 24 h. The reaction mixture was diluted with

water and extracted with ethyl acetate. The combined

extracts were washed with water (100 mL) and brine,

dried over anhydrous sodium sulphate, filtrated, and

concentrated under vacuum to afford the crude com-

pound, which was purified by column chromatography

(elution: 10% ethyl acetate/petrol ether) to afford 3.4 g

was consumed completely. The mixture was extracted

with ethyl acetate (15 mL×3), dried over anhydrous

Na₂SO₄, evaporated to afford 2.0 g of the desired prod-

1

uct in 98% yield; [α]²_D⁰－1.6 (c 1.57, CH₃OH); H

NMR (CDCl₃, 400 MHz) δ: 5.75—5.85 (m, 1H), 5.45 (d,

J＝8.0 Hz, 1H), 5.12 (s, 1H), 4.97—5.05 (m, 2H),

4.46—4.49 (m, 1H), 3.85 (dd, J＝9.2, 3.2 Hz, 1H), 3.78

(s, 3H), 3.65 (dd, J＝9.6, 3.2 Hz, 1H), 3.40—3.50 (m,

2H), 2.08 (q, J＝7.2 Hz, 2H), 1.68—1.80 (m, 4H),

1.54—1.68 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ:

171.3, 156.4, 138.2, 115.0, 71.0, 70.7, 54.5, 52.6, 32.9,

30.3, 28.7, 23.8; IR (KBr) ν: 3333, 2951, 2870, 1748,

1716, 1640, 1505, 1436, 1339, 1290, 1204, 1166, 111_＋8,

^－1

1051 cm ; HRMS calcd for C₁₅H₂₅NO₅([M＋H] )

300.18055, found 300.17917.

With similar procedure, 24 and 30 were prepared.

2-Cyclopentyloxycarbonylamino-3-pent-4-enylsul-

fanyl-propionic acid ethyl ester (24) 8.7 g, 98%

1

yield; [α]²_D⁰－14.8 (c 1.83, CH₃OH); H NMR (CDCl₃,

400 MHz) δ: 5.71—5.80 (m, 1H), 5.43 (d, J＝7.2 Hz,

1H), 5.09 (br, 1H), 4.95—5.06 (m, 2H), 4.51—4.58 (m,

1H), 4.21 (q, J＝7.2 Hz, 2H), 2.95—3.00 (m, 2H), 2.53

(t, J＝7.6 Hz, 2H), 2.13 (q, J＝6.8 Hz, 2H), 1.78—1.88

(m, 2H), 1.52—1.77 (m, 8H), 1.29 (t, J＝7.2 Hz, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ: 170.9, 155.8, 137.5,

115.4, 78.4, 61.7, 53.6, 34.5, 32.7, 32.6, 32.1, 28.6, 23.6,

14.1; IR (KBr) ν: 2968, 1713, 1504, 1337, 1258, 1198,

of

N-tert-butoxycarbonate-O-(4-pentenyl)-L-serine,

methyl ester as a colorless oil (33% yield two steps).

1

[α]²_D⁰－1.8 (c 1.66, CH₃OH); H NMR (CDCl₃, 400

MHz) δ: 5.72—5.82 (m, 1H), 5.34 (br, d, J＝7.6 Hz,

1H), 4.93—5.01 (m, 2H), 4.38—4.41 (m, 1H), 3.80 (dd,

J＝9.2, 2.4 Hz, 1H), 3.74 (s, 3H), 3.61 (dd, J＝9.2, 3.2

Hz, 1H), 3.36—3.46 (m, 2H), 2.06 (q, J＝7.2 Hz, 2H),

1.61 (quint, J＝7.2 Hz, 2H), 1.44 (s, 9H); ¹³C NMR

(CDCl₃, 100 MHz,) δ: 171.5, 155.7, 138.3, 115.1, 70.9,

70.8, 54.2, 52.6, 30.3, 28.7, 28.5; IR (KBr) ν: 2975,

2933, 2870, 1750, 1713, 1498, 143_－6, 1365, 1347, 1246,

^－1

1166, 1030, 912 cm ; HRMS calcd for C₁₆H₂₇NO₄S

([M＋H]^＋) 330.17336, found 330.17267.

2-Cyclopentyloxycarbonylamino-3-[(2-nitro-ben-

zenesulfonyl)-pent-4-enyl-amino]-propionic

acid

methyl ester (30) 2.8 g, 88% yield; [α]²_D⁰＋5 (c 2.1,

1

CH₃OH); H NMR (CDCl₃, 300 MHz) δ: 8.01 (dd, J＝

1

1207, 1161, 1118, 1059, 1023 cm ; HRMS calcd for

6.9, 2.1 Hz, 1H), 7.64—7.70 (m, 3H), 5.60—5.70 (m,

1H), 5.33 (d, J＝8.4 Hz, 1H), 5.04 (s, 1H), 4.91—4.96

(m, 2H), 4.49 (q, J＝7.5 Hz, 1H), 3.70 (s, 3H), 3.54—

3.65 (m, 2H), 3.27 (t, J＝7.8 Hz, 2H), 1.89 (q, J＝6.6

Hz, 2H), 1.41—1.80 (m, 10H); ¹³C NMR (CDCl₃, 100

MHz) δ: 170.9, 156.2, 148.1, 137.1, 133.9, 133.6, 131.9,

131.3, 124.5, 115.8, 78.5, 52.9, 52.3, 48.5, 47.1, 32.9,

30.6, 26.6, 23.8; IR (KBr) ν: 2955, 2919, 1743, 1705,

1540, 1507, 1436, 1370, 1339, 1294, 1211, 1159, 1124,

C₁₄H₂₅NO₅( [M＋Na]^＋) 310.16249, found 310.16183.

2-Amino-3-pent-4-enyloxy-propionic acid methyl

ester (20) A solution of compound 19 (3.75 g, 13.1

mmol) in CH₂Cl₂(50 mL) was added TFA (20 mL),

keeping the temperature below 10 ℃, then stirred at

ambient temperature for 1 h until TLC indicated the

starting material was consumed completely. The solvent

was removed in vacuum to afford the desired product as

1

^－1

the form of TFA salt (3.7 g, 99% yied). H NMR

1057, 971 cm ; HRMS calcd for C₂₁H₂₉N₃O₈S ([M＋

(CDCl₃, 400 MHz) δ: 8.0 (br, 3 H), 5.70—5.80 (m, 1H),

4.94—5.00 (m, 2H), 4.29 (s, 1H), 3.86—3.92 (m, 2H),

3.83 (s, 3H), 3.41—3.53 (m, 2H), 2.03 (q, J＝7.2 Hz,

2H), 1.62 (q, J＝7.2 Hz, 2H); ¹³C NMR (CDCl₃, 100

MHz) δ: 168.1, 161.5 (q, J＝30.3 Hz, C＝O-TFA),

137.9, 115.7 (q, J＝230 Hz, CF₃-TFA), 115.2, 71.3,

67.1, 53.9, 53.8, 30.0, 28.3; HRMS calcd for C₉H₁₇NO₃

([M＋H]^＋) 188.12812, found 188.12822.

Na]^＋) 506.15676, found 506.15692.

2-Cyclopentyloxycarbonylamino-3-pent-4-enyl-

oxy-propionic acid (3b) A solution of compound 21

(1.4 g, 6.02 mmol) in THF (_－26 mL) was added 13 mL of

1

aqueous LiOH (1.4 mol•L , 18 mmol) at 0 ℃ and

stirred at that temperature for about 2 h until TLC indi-

cated the starting material was consumed completely.

The pH was adjusted to about 5 with 1 mol/L HCl, then

extracted with ethyl acetate (20 mL×3), dried over an-

hydrous Na₂SO₄, evaporated in vacuum to afford the

desired product (1.4 g, 82% yield). [α]²_D⁰＋9 (c 1.69,

2-Cyclopentyloxycarbonylamino-3-pent-4-enyl-

oxy-propionic acid methyl ester (21) A solution of

compound 20 (1.9 g, 6.5 mmol) in THF (20 mL) and

H₂O (20 mL) was added sodium bicarbonate (1.68 g, 20

mmol) and cyclopentyl chloroformate (1.06 g, 7.1 mmol)

at ambient temperature. The resulting mixture was

stirred for 2 h until TLC indicated the starting material

1

CH₃OH); H NMR (CDCl₃, 400 MHz) δ: 7.20 (br, 1H),

5.77—5.84 (m, 1H), 5.50 (d, J＝8.4 Hz, 1H), 5.13 (s,

1H), 5.03 (dd, J＝17.2, 1.6 Hz, 1H), 4.98 (dd, J＝9.2,

1.6 Hz, 1H), 4.49—4.51 (m, 1H), 3.91 (dd, J＝9.0, 2.0

Chin. J. Chem. 2011, 29, 1489— 1502

www.cjc.wiley-vch.de

1495

Liu et al.

FULL PAPER

Hz, 1H), 3.69 (dd, J＝13.2, 3.6 Hz, 1H), 3.49 (t, J＝6.4

Hz, 2H), 2.11 (q, J＝7.6 Hz, 2H), 1.87—1.89 (m, 2H),

1.59—1.86 (m, 8 H); ¹³C NMR (CDCl₃, 100 MHz,) δ:

174.8, 156.6, 138.2, 115.1, 71.1, 70.4, 54.2, 32.9, 30.3,

28.7, 23.8; IR (KBr) ν: 2941, 2871, 1715, 1513, 1415,

mmol) and potassium carbonate (19.2 g, 0.14 mol) in

DMF (74 mL) was added dropwise 5-bromo-1-pentene

at 0 ℃, then stirred at ambient temperature overnight

until TLC indicated the starting material was consumed

completely. The solid was removed by suction filtration.

The filtrate was evaporated to remove the solvent. To

the residue was added petrol ether, and the solid was

washed by petrol ether to afford pure product (8.6 g,

^－1

1336, 1205, 1165, 11_＋18, 1053 cm ; HRMS calcd for

C₁₄H₂₃NO₅([M＋Na] ) 308.14684, found 308.14603.

With similar procedure of 3b, 3c, 3d, 3e and 3f were

prepared.

1

95% yield). H NMR (CDCl₃, 400 MHz) δ: 5.72—5.82

2-Cyclopentyloxycarbonylamino-3-pent-4-enylsul-

fanyl-propionic acid (3c) 3.1 g, 95% yield; [α]_D²⁰

－13.6 (c 1.02, CH₃OH); ¹H NMR (CDCl₃, 300 MHz) δ:

5.69—5.83 (m, 1H), 5.48 (d, J＝7.5 Hz, 1H), 5.10 (br,

1H), 4.96—5.05 (m, 2H), 4.52—4.62 (m, 1H), 2.90—

3.01 (m, 2H), 2.55 (t, J＝7.2 Hz, 2H), 2.13 (q, J＝7.5

Hz, 2H), 1.52—1.90 (m, 10H); ¹³C NMR (CDCl₃, 100

MHz) δ: 174.8, 156.2, 137.5, 115.4, 78.4, 53.4, 34.5,

32.7, 32.6, 32.1, 28.6, 23.6; IR (KBr) ν: 3324, 3075,

2960, 2872, 1694, 1510, 1410, 1336, 1305, 1214, 116_＋7,

(m, 1H), 5.02 (dd, J＝16.8, 1.2 Hz, 1H), 4.97 (dd, J＝

10, 1.2 Hz, 1H), 4.19 (q, J＝7.2 Hz, 2H), 3.61 (dd, J＝

7.2, 4.8 Hz, 1H), 2.87—2.94 (m, 1H), 2.73—2.78 (m,

1H), 2.53 (t, J＝7.6 Hz, 2H), 2.14 (q, J＝6.8 Hz, 2H),

1.63—1.71 (m, 2H), 1.28 (t, J＝7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 100 MHz,) δ: 174.0, 137.5, 115.3, 61.1, 54.2,

37.2, 32.6, 31.9, 28.7, 14.1.

3-Amino-2-tert-butoxycarbonylamino-propionic

acid methyl ester (26) To a mixture of 25 (18.7 g,

91.6 mmol) in 300 mL of CH₂Cl₂was added 30 mL of

methanol. To this solution was slowly added (trimethyl-

^－1

1048 cm ; HRMS calcd for C₁₄H₂₃NO₄S ([M＋H] )

^－1

302.14206, found 302.14145.

silyl) diazomethane (2 mol•L in hexane, 49 mL, 98

2-Cyclopentyloxycarbonylamino-3-[(2-nitro-ben-

zenesulfonyl)-pent-4-enyl-amino]-propionic acid (3d)

mmol). The mixture was stirred at r.t. overnight until

most of the solid dissolved and the solution turned light

yellow. The solid was removed by filtration and the fil-

trate was then concerntraed to yield 17.8 g (89%) of

compound 26 as a colorless oil. [α]²_D⁰－14.0 (c 1.02,

1

2.0 g, 89% yield; H NMR (CDCl₃, 300 MHz) δ: 8.04

(dd, J＝6.6, 2.1 Hz, 1H), 7.61—7.76 (m, 3H), 5.61—

5.75 (m, 1H), 5.51 (d, J＝8.4 Hz, 1H), 5.08 (br, 1H),

4.93—4.99 (m, 2H), 4.55—4.65 (m, 1H), 3.66—3.87

(m, 2H), 3.38 (t, J＝7.5 Hz, 2H), 1.98 (q, J＝6.6 Hz,

2H), 1.48—1.88 (m, 10H).

1

CH₃OH); H NMR (CDCl₃, 300 MHz) δ: 5.42 (br, 1H),

4.29 (br, 1H), 3.75 (s, 3H), 3.02 (d, J＝4.5 Hz, 2H),

1.49 (br, 2H), 1.43 (s, 9H); IR (KBr) ν: 3301, 2970,

2925, 1707, 1642, 1511, 1364, 1254, 1155, 1021, 841

3-(Acetyl-pent-4-enyl-amino)-2-cyclopentyloxycar-

bonylamino-propionic acid (3e) 1.05 g, 90% yield;

^－1

cm .

1

[α]²_D⁰－24 (c 1.77, CH₃OH); H NMR (CDCl₃, 400

2-tert-Butoxycarbonylamino-3-(2-nitro-benzene-

sulfonylamino)-propionic acid methyl ester (27) To

a mixture of compound 26 (17 g, 78 mmol) in CH₂Cl₂

(500 mL) was added diisopropylethylamine (13 g, 101

mmol) and 2-nitrobezenesulfonyl chloride (17.2 g, 78

mmol). The mixture was stirred at r.t. for 2 h. It was

then washed with citric acid, sat. sodium bicarbonate,

brine and dried over sodium sulfate. It was then filtered,

concentrated to yield 26 g (84%) of compound 27 as a

MHz) δ: 6.00 (br, 1H), 5.73—5.83 (m, 1H), 5.02—5.09

(m, 3H), 4.27 (q, J＝5.2 Hz, 1H), 3.86 (dd, J＝14.4 Hz,

4.8 Hz, 1H), 3.47—3.55 (m, 2H), 3.36—3.44 (m, 1H),

2.16 (s, 3H), 2.08 (q, J＝7.2 Hz, 2H), 1.78—1.88 (m,

2H), 1.52—1.76 (m, 8H); ¹³C NMR (CDCl₃, 100 MHz)

δ: 173.9, 172.2, 156.8, 137.1, 116.4, 78.7, 60.8, 55.0,

50.2, 33.1, 31.3, 31.0, 28.0, 24.0, 21.5; IR (KBr) ν: 3330,

2957, 2867, 1729, 1690, 1611, 1597, 1537, 1484, 1432,

1416, 1374, 1335, 13161277, 1233, 1199, 1051, 103_＋7,

1

yellow foam. [α]_D²⁰－6.3 (c 2.81, CH₃OH); H NMR

^－1

899 cm ; HRMS calcd for C₁₆H₂₆N₂O₅([M＋H] )

(CDCl₃, 400 MHz) δ: 8.12 (d, J＝9.2 Hz, 1H), 7.88 (d,

J＝9.2 Hz, 1H), 7.74—7.77 (m, 2H), 5.81 (t, J＝6.4 Hz,

1H), 5.33 (br, 1H), 4.36 (br, 1H), 3.78 (s, 3H), 3.48—

3.55 (m, 2H), 1.42 (s, 9H); IR (KBr) ν: 3342, 3101,

2978, 1744, 16_－99, 1557, 1438, 1340, 1301, 1244, 1176,

327.19145, found 327.19047.

2-Cyclopentyloxycarbonylamino-3-(methyl-pent-

4-enyl-amino)-propionic acid (3f) 0.8 g, 94% yield;

[α]²_D⁰＋1.3 (c 0.5, CH₃OH); ¹H NMR (CDCl₃, 400 MHz)

δ: 11.45 (br, 1H), 6.31 (d, J＝5.2 Hz, 1H), 5.65—5.74

(m, 1H), 4.96—5.04 (m, 3H), 4.38 (q, J＝6.4 Hz, 1H),

3.43 (d, J＝6.0 Hz, 2H), 3.06—3.13 (m, 2H), 2.88 (s,

3H), 2.08 (q, J＝7.2 Hz, 2H), 1.73—1.89 (m, 4H),

1.57—1.70 (m, 4H), 1.44—1.52 (m, 2H); ¹³C NMR

(CDCl₃, 100 MHz) δ: 171.8, 156.5, 136.0, 116.4, 78.1,

56.3, 56.1, 50.1, 41.2, 32.7, 30.4, 23.6, 22.7; IR (KBr) ν:

3397, 2962, 2871, 1703, 1613, 1469, 1392, 1338, 1258,

1

1058, 1022 cm ; HRMS calcd for C₁₅H₂₁N₃O₈S ([M＋

Na]^＋) 426.09416, found 426.09372.

2-tert-Butoxycarbonylamino-3-[(2-nitro-benzene-

sulfonyl)-pent-4-enyl-amino]-propionic acid methyl

ester (28) To a mixture of compound 27 (26 g, 64.5

mmol) in 480 mL of DMF was added potassium

carbonate (17.8 g, 129 mmol). This mixture was stirred

at r.t. for 20 min followed by the addition of

5-bromo-1-pentene (14 g, 96.8 mmol). The reaction

mixture was stirred at r.t. for 2 d. It was then filtered,

concentrated and purified by silica gel chromatography

(eluting with 25% ethyl acetate in petrol ether) to give

^－1

1167, 1046, 914 cm ; HRMS calcd for C₁₅H₂₆N₂O₄

([M＋H]^＋) 299.19653, found 299.19635.

2-Amino-3-pent-4-enylsulfanyl-propionic

ethyl ester (23) A solution of compound 22 (7.4 g, 40

acid

1496

www.cjc.wiley-vch.de

Chin. J. Chem. 2011, 29, 1489— 1502

Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

17.3 g (57%) of compound 28 as a yellow solid. [α]_D²⁰

171_－7, 1625, 1513, 1431, 1368, 1250, 1176, 1094, 8_＋92

)

299.19653, found 299.19571.

1

＋1.1 (c 2.4, CH₃OH); H NMR (CDCl₃, 400 MHz) δ:

cm ¹; HRMS calcd for C₁₅H₂₆N₂O₄([M ＋ H]

8.02 (dd, J＝6.8, 2.0 Hz, 1H), 7. 63—7.70 (m, 3H),

5.62—5.69 (m, 1H), 5.27 (d, J＝8.4 Hz, 1H), 4.95 (d,

J＝5.6 Hz, 1H), 4.92 (s, 1H), 4.51 (q, J＝8.0 Hz, 1H),

3.76 (s, 3H), 3.62—3.70 (m, 2H), 3.33 (t, J＝8.0 Hz,

2H), 1.95 (q, J＝7.2 Hz, 2H), 1.56—1.65 (m, 2H), 1.42

(s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 170.8, 155.2,

147.8, 136.8, 133.6, 133.4, 131.7, 131.0, 124.3, 115.5,

80.2, 52.6, 51.9, 48.2, 46.9, 30.4, 28.2, 26.4; IR (KBr) ν:

3364, 2976, 2931, 1741, 1688, 1541, 1522, 1457, 1436,

1369, 1300, 1269, 1246, 1158, 1123, 1078, 1057, 102_＋6,

3-(Acetyl-pent-4-enyl-amino)-2-cyclopentyloxycar-

bonylamino-propionic acid methyl ester (32) To a

solution of compound 31 (1.1 g, 3.69 mmol) in

CH₂Cl₂(20 mL) was added Et₃N (0.6 mL, 4.4 mmol)

and acetyl chloride (0.3 mL, 4 mmol) and stirred at r.t.

overnight. The reaction mixture was washed with citric

acid, dried and evaporated to give compound 32 (1.25 g,

99%). [α]²_D⁰－22.3 (c 1.46, CH₃OH); ¹H NMR (CDCl₃,

400 MHz) δ: 5.72—5.82 (m, 2H), 4.95—5.08 (m, 3H),

4.42 (dd, J＝12.4, 7.6 Hz, 1H), 3.89 (dd, J＝14, 8.4 Hz,

1H), 3.74 (s, 3H), 3.49 (dd, J＝13.6, 4.8 Hz, 1H), 3.26

(t, J＝8.0 Hz, 2H), 2.08 (s, 3H), 2.02—2.07 (m, 2H),

1.75—1.87 (m, 2H), 1.50—1.75 (m, 8H); ¹³C NMR

(CDCl₃, 100 MHz,) δ: 172.0, 171.0, 156.2, 136.8, 115.8,

77.8, 53.5, 52.5, 48.7, 46.4, 32.7, 30.6, 27.5, 23.5, 21.2;

IR (KBr) ν: 2954, 2871, 1694, 1639, 1524, 1484, 1416,

^－1

988 cm ; HRMS calcd for C₂₀H₂₉N₃O₈S ([M＋Na] )

494.15676, found 494.15762.

2-Amino-3-[(2-nitro-benzenesulfonyl)-pent-4-enyl-

amino]-propionic acid methyl ester (29) To a stirred

solution of compound 28 (13 g, 27.6 mmol) in dioxane

(80 mL) was added HCl/dioxane (80 mL, 4.8 N) at

room temperature. The mixture was stirred overnight.

TLC (ethyl acetate∶petrol ether＝1∶3, volume ratio)

showed the material was consumed completed. The

solvent was removed under reduced pressure with tem-

perature below 30 ℃ and CH₂Cl₂(50 mL×3) was

added to the residue, the solvent was removed under

reduced pressure with temperature below 30 ℃ to af-

forded compound 29 (11.2 g, 98%) as brown solid,

which was used in the next step without further workup.

[α]²_D⁰＋5.5 (c 0.4, CH₃OH); ¹H NMR (CDCl₃, 400 MHz)

δ: 8.80 (br, 3H), 8.10 (d, J＝6.8 Hz, 1H), 7.58—7.68 (m,

2H), 7.50 (d, J＝7.6 Hz, 1H), 5.54—5.64 (m, 1H),

4.80—4.87 (m, 2H), 4.42 (br, 1H), 4.01—4.16 (m, 2H),

3.71 (s, 3H), 3.30—3.36 (m, 2H), 1.90 (q, J＝6.8 Hz,

2H), 1.46—1.68 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz,)

δ: 168.5, 148.1, 137.3, 134.1, 132.7, 132.6, 131.4, 124.3,

115.7, 67.3, 54.0, 52.3, 48.7, 30.7, 26.8; IR (KBr) ν:

2920, 2850, 1733, 1540, 1507, 1437, 1341, 1296, 1228,

^－1

1339, 1230, 1169, 1052, 907 cm ; HRMS calcd for

C₁₇H₂₈N₂O₅([M＋H]^＋) 341.20710, found 341.20724.

2-Cyclopentyloxycarbonylamino-3-(methyl-pent-

4-enyl-amino)-propionic acid methyl ester (33) To a

solution of compound 31 (1.6 g, 5.37 mmol) in acetoni-

trile (16 mL) was added potassium carbonate (1.48 g,

10.7 mmol). Then MeI (0.84 g, 5.9 mmol) was added to

the mixture and stirred at r.t. overnight. The solid was

removed by filtration and the filtrate was evaporated in

vacuum to afford the crude product, which was purified

by silica gel chromatography (eluting with 20% ethyl

acetate in petrol ether) to afford 0.9 g of compound 33

1

(54% yield). [α]_D²⁰＋1.2 (c 0.48, CH₃OH); H NMR

(CDCl₃, 400 MHz) δ: 5.73—5.83 (m, 1H), 5.44 (br, 1H),

5.08 (br, 1H), 5.00 (dd, J＝17.2, 2.0 Hz, 1H), 4.95 (d,

J＝10 Hz, 1H), 4.26—4.30 (m, 1H), 3.73 (s, 3H), 2.70

(br, 2H), 2.31—2.43 (m, 2H), 2.21 (s, 3H), 2.02 (dd,

J＝7.2, 8.0 Hz, 2H), 1.77—1.82 (m, 2H), 1.63—1.76

(m, 4H), 1.48—1.59 (m, 4H); ¹³C NMR (CDCl₃, 100

MHz,) δ: 172.6, 156.1, 138.3, 114.7, 77.8, 60.3, 58.3,

57.3, 52.7, 52.2, 42.2, 32.7, 31.2, 26.3, 23.6; IR (KBr) ν:

3392, 2958, 2849, 1702, 1613, 1467, 1394, 1337, 1258,

^－1

1158, 1123, 1059 cm ; HRMS calcd for C₁₅H₂₁N₃O₆S

([M＋H]^＋) 372.12238, found 372.12274.

2-Cyclopentyloxycarbonylamino-3-pent-4-enyl-

aminopropionic acid methyl ester (31) To a solution

of compound 30 (2.88 g, 5.96 mmol) in acetonitrile (60

mL) was added potassium carbonate (1.23 g, 9 mmol).

Then PhSH (1.3 g, 12 mmol) was added to the mixture

and stirred at r.t. overnight. The reaction mixture was

added ether (20 mL) and partitioned with citric acid (9%,

20 mL) until the desired product was completely

washed into water phase and discard the ether phase.

basified the water phase with K₂CO₃to pH＝10, ex-

tracted with ether, the organic phase was dried and

evaporated to give 1.2 g of compound 31 as an oil (70%

^－1

1168, 1046, 911 cm ; HRMS calcd for C₁₆H₂₈N₂O₄

([M＋H]^＋) 313.21218, found 313.21161.

1-{[4-(4-Bromo-benzenesulfonyloxy)-1-(2-cyclo-

pentyloxycarbonylamino-non-8-enoyl)-pyrrolidine-

2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic

acid methyl ester (14a) To a stirred solution of com-

pound 3a (22.2 g, 0.071 mol) in DMA (230 mL) was

added

O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-

uronium tetrafluoroborate (20.83 g, 0.065 mol) at room

temperature, which was stirred for 30 min and com-

pound 17 (33 g, 0.065 mol) in DMA (400 mL) was

added. Then, Et₃N was added dropwise to the above

mixture with the temperature below 30 ℃. The mixture

was stirred until TLC (ethyl acetate∶petroleum ether＝

1∶1, volume ratio) showed the material was consumed

completely. The mixture was poured into saturated aq.

NaHCO₃solution (1000 mL) and the mixture was ex-

1

yield). [α]²_D⁰＋7.8 (c 0.99, CH₃OH); H NMR (CDCl₃,

400 MHz) δ: 5.66—5.76 (m, 1H), 5.49 (br, 1H), 5.01

(br, 1H), 4.93 (dd, J＝17.2, 1.6 Hz, 1H), 4.87 (d, J＝10

Hz, 1H), 4.33 (s, 1H), 3.67 (s, 3H), 2.85—2.97 (m, 2H),

2.54 (t, J＝7.2 Hz, 2H), 1.99 (q, J＝7.2 Hz, 2H), 1.58—

1.80 (m, 8H), 1.44—1.52 (m, 4H); ¹³C NMR (CDCl₃,

100 MHz) δ: 172.2, 156.7, 138.3, 115.5, 78.5, 53.6, 53.0,

50.4, 49.1, 33.1, 31.6, 28.5, 24.0; IR (KBr) ν: 3292,

Chin. J. Chem. 2011, 29, 1489— 1502

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1497

Liu et al.

FULL PAPER

tracted with tert-butyl methyl ether (300 mL×3), the

combined organic layers were washed with water (400

mL) and brine (300 mL), dried over anhydrous Na₂SO₄

and the solvent was removed under reduced pressure.

The residue was purified via column chromatography

(ethyl acetate∶petroleum ether＝1∶8—1∶2, volume

ratio) to afford compound 14a (39 g, 81%) as yellow

gum.

1H), 5.14 (s, 1H), 5.05—5.08 (m, 1H), 5.00 (s, 1H),

4.91 (d, J＝12 Hz, 2H), 4.48—4.67 (m, 2H), 4.00—4.16

(m, 2H), 3.78—3.93 (m, 1H), 3.45—3.68 (m, 2H),

3.08—3.36 (m, 3 H), 2.30—2.55 (m, 2H), 1.86—1.94

(m, 2H), 1.45—1.80 (m, 11H), 1.38—1.42 (m, 1H),

1.15—1.20 (m, 3 H); ¹³C NMR (CDCl₃, 100 MHz) δ:

170.5, 170.0, 169.9, 169.8, 155.9, 148.0, 136.7, 135.3,

134.2, 133.7, 132.7, 131.0, 130.9, 129.4, 124.4, 117.8,

117.7, 115.8, 78.8, 78.5, 61.3, 59.6, 53.4, 52.6, 49.4,

48.7, 39.9, 34.4, 33.7, 32.7, 30.3, 26.5, 23.5, 22.6, 14.2;

IR (KBr) ν: 2958, 2933, 1716, 1704, 1652, 1540, 1520,

1506, 1369, 1340, 1159 cm_＋^－¹; HRMS calcd for

C₃₉H₄₈BrN₅O₁₃S₂([M ＋ H] ) 938.19462, found

938.19537.

With similar procedure, 14b, 14c, 14d, 14e and 14f

were prepared.

1-{[4-(4-Bromo-benzenesulfonyloxy)-1-(2-cyclo-

pentyloxycarbonylamino-3-pent-4-enyloxy-propio-

nyl)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclo-

propanecarboxylic acid ethyl ester (14b) (1.5 g,

1

44% yield); [α]²_D⁰－15.9 (c 0.64, CH₃OH); H NMR

1-{[1-[3-(Acetyl-pent-4-enyl-amino)-2-cyclopentyl-

oxycarbonylamino-propionyl]-4-(4-bromo-benzene-

sulfonyloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-

cyclopropanecarboxylic acid ethyl ester (14e) 1.5 g,

(CDCl₃, 400 MHz) δ: 7.77 (d, J＝8.8 Hz, 2H), 7.71 (d,

J＝8.8 Hz, 2H), 7.28 (s, 1H), 5.67—5.88 (m, 2H), 5.39

(d, J＝8.0 Hz, 1H), 5.21—5.32 (m, 1H), 4.94—5.15 (m,

4H), 4.68—4.82 (m, 1H), 4.47—4.66 (m, 1H), 4.04—

4.16 (m, 3H), 3.69—3.95 (m, 1H), 3.33—3.60 (m, 3 H),

2.97 (br, 2H), 2.40—2.70 (m, 1H), 2.14—2.28 (m, 1H),

1.95—2.09 (m, 3H), 1.79—1.85 (m, 2H), 1.55—1.72

(m, 7H), 1.43 (q, J＝5.2 Hz, 1H), 1.21 (t, J＝7.2 Hz,

3H); ¹³C NMR (CDCl₃, 100 MHz,) δ: 171.2, 170.3,

169.8, 156.2, 137.7, 135.7, 134.1, 133.8, 133.0, 129.6,

117.8, 115.5, 79.4, 78.6, 71.9, 71.6, 71.2, 61.6, 59.2,

53.7, 52.9, 39.9, 34.4, 32.9, 30.2, 28.5, 23.8, 23.2, 22.8,

14.4; IR (KBr) ν: 3308, 2918, 2849, 1651, 1518, 1435,

1

77% yield; [α]²_D⁰－20.6 (c 0.32, CH₃OH); H NMR

(400 MHz, CDCl₃, contained rotamers) δ: 8.02 (br, 1H),

7.78 (d, J＝8.4 Hz, 2H), 7.68 (d, J＝8.4 Hz, 2H),

5.69—5.84 (m, 3H), 5.24 (dd, J＝17.2, 1.6 Hz, 1H),

4.98—5.12 (m, 5H), 4.61 (dd, J＝9.2, 2.4 Hz, 1H), 4.45

(q, J＝5.6 Hz, 1H), 4.04—4.14 (m, 2H), 3.96—4.03 (m,

1H), 3.85—3.91 (m, 1H), 3.58—3.70 (m, 2H), 3.20—

3.42 (m, 2H), 2.46—2.63 (m, 1H), 2.16—2.23 (m, 2H),

1.99—2.08 (m, 6H), 1.51—1.83 (m, 10H), 1.44—1.48

(m, 1H), 1.18 (t, J＝7.2 Hz, 3H); ¹³C NMR (CDCl₃, 100

MHz) δ: 172.5, 170.9, 170.8, 170.5, 169.7, 156.2, 137.1,

135.6, 134.6, 133.1, 129.7, 117.8, 116.4, 79.6, 78.6,

61.5, 60.1, 53.6, 52.9, 50.2, 47.8, 40.2, 34.4, 33.8, 33.2,

30.9, 28.0, 24.0, 23.0, 21.6, 14.6; IR (KBr) ν: 2965,

2868, 1_－702, 1636, 1521, 1435, 1368, 1320, 1175, 100_＋0,

^－1

1369, 1319, 1260, 1175, 1094, 890 cm ; HRMS calcd

for C₃₁H₄₀BrN₃O₁₀S ([M ＋ H] ^＋) 754.20035, found

754.20117.

1-{[4-(4-Bromo-benzenesulfonyloxy)-1-(2-cyclo-

pentyloxycarbonylamino-3-pent-4-enylsulfanyl-pro-

pionyl)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-

cyclopropanecarboxylic acid ethyl ester (14c) (2.4 g,

1

891 cm ; HRMS calcd for C₃₅H₄₇BrN₄O₁₀S ([M＋H] )

795.22690, found 795.22717.

1

47% yield); [α]²_D⁰－18.9 (c 1.15, CH₃OH); H NMR

1-({4-(4-Bromo-benzenesulfonyloxy)-1-[2-cyclo-

pentyloxycarbonylamino-3-(methyl-pent-4-enyl-ami-

no)-propionyl]-pyrrolidine-2-carbonyl}-amino)-2-

vinyl-cyclopropanecarboxylic acid ethyl ester (14f)

1.68 g, 76% yield; HRMS calcd for C₃₄H₄₇BrN₄O₉S

([M＋H]^＋) 767.23194, found 767.23285.

(CDCl₃, 300 MHz) δ: 7.69—7.80 (m, 4H), 5.70—5.84

(m, 2H), 5.22—5.34 (m, 2H), 4.96—5.18 (m, 5H), 4.74

(dd, J＝7.5, 2.1 Hz, 1H), 4.22—4.61 (m, 1H), 4.12 (q,

J＝7.2 Hz, 2H), 4.00—4.06 (m, 1H), 2.81—2.90 (m,

1H), 2.48—2.74 (m, 3H), 2.07—2.27 (m, 4H), 1.50—

1.88 (m, 14H), 1.41—1.48 (m, 2H), 1.25 (t, J＝7.2 Hz,

3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 171.2, 170.8,

169.7, 155.7, 137.2, 135.2, 133.7, 132.7, 129.5, 129.4,

117.7, 115.7, 79.3, 78.5, 61.3, 60.4, 59.2, 53.9, 51.6,

39.6, 34.0, 32.8, 32.7, 32.5, 32.2, 28.5, 23.6, 22.7 14.3;

IR (KBr) ν: 3292, 2956, 2872, 1699, 1633, 1519, 1435,

18-(4-Bromo-benzenesulfonyloxy)-14-cyclopentyl-

oxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo-

[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid methyl

ester (15a) To a stirred solution of compound 14a (15

g, 0.020 mol) in anhydrous toluene (1800 mL) was

added Hoveyda’s catalyst (0.518 g, 0.0094 mol) and the

mixture was degassed with nitrogen. The mixture was

heated to 70—80 ℃ overnight, LC-MS showed 90%

of compound 14a had been converted into compound

15a. The reaction was heated for another 6 h, and

LC-MS showed the reaction has no progress. The sol-

vent was removed under reduced pressure and the resi-

due was purified via column chromatography to afford

compound 15a (11.2 g, 77.2%) as brown gum.

^－1

1391, 1369, 1320, 1239, 1176, 1001, 1032, 1001 cm_＋;

HRMS calcd for C₃₃H₄₄BrN₃O₉S₂([M ＋ H]

)

770.17751, found 770.17859.

1-[(4-(4-Bromo-benzenesulfonyloxy)-1-{2-cyclo-

pentyloxycarbonylamino-3-[(2-nitro-benzenesulfon-

yl)-pent-4-enyl-amino]-propionyl}-pyrrolidine-2-car-

bonyl)-amino]-2-vinyl-cyclopropanecarboxylic acid

ethyl ester (14d) 4.0 g, 71% yield; [α]²_D⁰－14.0 (c

1

0.85, CH₃OH); H NMR (400 MHz, CDCl₃, contained

18-(4-Bromo-benzenesulfonyloxy)-14-cyclopentyl-

oxycarbonylamino-2,15-dioxo-12-oxa-3,16-diazatri-

rotamers) δ: 7.98 (d, J＝8.0 Hz, 1H), 7.60—7.79 (m,

7H), 7.34 (s, 1H), 5.55—5.81 (m, 3H), 5.20—5.29 (m,

cyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic

acid

1498

www.cjc.wiley-vch.de

Chin. J. Chem. 2011, 29, 1489— 1502

Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

ethyl ester (15b) To a stirred solution of compound

14b (1.5 g, 1.86 mmol) in anhydrous toluene (150 mL)

was added Grubbs 2nd catalyst (0.16 g, 0.186 mol) and

the mixture was degassed with nitrogen. The mixture

was heated to 70—80 ℃ for 3 h and LC-MS showed

90% of compound 14b had been converted into com-

pound 15b. The solvent was removed under reduced

pressure and the residue was purified via column chro-

matography to afford compound 15b (1.1 g, 80% yield)

as brown gum. [α]_D²⁰＋29.3 (c 1.03, CH₃OH); ¹H NMR

(CDCl₃, 300 MHz) δ: 7.74 (d, J＝8.7 Hz, 2H), 7.64 (d,

J＝8.7 Hz, 2H), 7.38 (s, 1H), 5.46—5.55 (m, 2H), 5.23

—5.33 (m, 1H), 5.10 (br, 1H), 4.99 (br, 1H), 4.65 (dd,

J＝9.3, 2.7 Hz, 1H), 4.58 (br, 1H), 3.90—4.16 (m, 4H),

3.54—3.76 (m, 3H), 3.32—3.35 (m, 1H), 2.48 (s, 1H),

1.41—2.21 (m, 14H), 1.18—1.27 (m, 1H), 1.13 (t, J＝

7.2 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 170.0,

169.6, 168.6, 156.0, 135.3, 132.6, 132.5, 129.4, 129.3,

127.3, 78.8, 78.2, 70.5, 69.4, 61.1, 58.6, 53.0, 52.0, 40.2,

33.3, 32.7, 29.7, 27.9, 23.6, 23.0, 22.4, 14.4; IR (KBr) ν:

3338, 2929, 2869, 1707, 1659, 1574, 1525, 1431, 1391,

(m, 2H), 1.41—1.87 (m, 11H), 1.21 (t, J＝7.2 Hz, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ: 172.4, 169.7, 169.2,

158.7, 155.7, 148.1, 135.2, 134.0, 132.7, 132.6, 132.0,

131.2, 129.5, 129.4, 127.0, 124.3, 78.8, 78.1, 61.8, 59.2,

53.2, 50.9, 49.8, 47.2, 41.2, 32.7, 32.3, 28.9, 26.9, 25.3,

23.5, 22.3, 14.2; IR (KBr) ν: 2968, 1698, 1641, 1541,

1438, 1370, 1186, 1160 cm_＋^－¹; HRMS calcd for

C₃₇H₄₄BrN₅O₁₃S₂([M ＋ H] ) 910.16332, found

910.16241.

12-Acetyl-18-(4-bromo-benzenesulfonyloxy)-14-

cyclopentyloxycarbonylamino-2,15-dioxo-3,12,16-tri-

aza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic

acid ethyl ester (15e) 0.2 g, 15% yield; [α]²_D⁰＋23.0

1

(c 0.18, CH₃OH); H NMR (CDCl₃, 400 MHz) δ: 7.80

(d, J＝8.4 Hz, 2H), 7.69 (d, J＝8.4 Hz, 2H), 7.32 (br,

1H), 5.57—5.72 (m, 1H), 5.29—5.46 (m, 1H), 4.94—

5.16 (m, 3 H), 4.36—4.92 (m, 2H), 4.09 (q, J＝6.8 Hz,

2H), 3.97 (d, J＝11.2 Hz, 1H), 3.69 (d, J＝11.6 Hz, 1H),

3.51—3.64 (m, 1H), 3.20 (t, J＝11.2 Hz, 1H), 2.95 (t,

J＝12.6 Hz, 1H), 2.64—2.77 (m, 1H), 2.02—2.35 (m,

7H), 1.43—1.98 (m, 13H), 1.21 (t, J＝7.2 Hz, 3H); ¹³C

NMR (CDCl₃, 100 MHz) δ: 174.4, 172.7, 170.8, 169.6,

159.6, 156.1, 135.6, 133.0, 131.2, 129.9, 129.4, 128.3,

116.8, 113.9, 79.3, 78.6, 62.2, 59.6, 53.6, 51.9, 49.5,

^－1

1369, 1316, 1176, 1094, 1067, 1010, 887 cm ; HRMS

calcd for C₃₁H₄₀BrN₃O₁₀S ([M＋H]^＋) 726.16905, found

726.16870.

With similar procedure, 15c, 15d, 15e and 15f were

prepared.

48.7, 41.6, 33.2, 29.3, 26.8, 25.8, 23.9, 22.4, 20.7, 14.6;

＋

HRMS calcd for C₃₃H₄₃BrN₄O₁₀S ([M ＋ H]

)

18-(4-Bromo-benzenesulfonyloxy)-14-cyclopentyl-

oxycarbonylamino-2,15-dioxo-12-thia-3,16-diazatri-

767.19560, found 767.19586.

18-(4-Bromo-benzenesulfonyloxy)-14-cyclopentyl-

oxycarbonylamino-12-methyl-2,15-dioxo-3,12,16-tria-

za-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic

acid ethyl ester (15f) 0.4 g, 40% yield [α]²_D⁰＋37.0 (c

cyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic

acid

ethyl ester (15c) 1.6 g, 74% yield; [α]²_D⁰＋52.0 (c

1

0.48, CH₃OH); H NMR (CDCl₃, 300 MHz) δ: 7.80 (d,

1

J＝8.7 Hz, 2H), 7.69 (d, J＝8.7 Hz, 2H), 7.55 (s, 1H),

5.48—5.61 (m, 2H), 5.29 (t, J＝9.6 Hz, 1H), 5.18 (br,

1H), 5.04 (br, 1H), 4.82 (d, J＝7.8 Hz, 1H), 4.69—4.76

(m, 1H), 4.10 (q, J＝7.2 Hz, 2H), 2.97—3.07 (m, 2H),

2.64—2.73 (m, 2H), 2.44—2.51 (m, 1H), 2.25—2.38

(m, 1H), 2.05—2.20 (m, 3H), 1.93—1.98 (m, 1H),

1.49—1.86 (m, 13H), 1.24 (t, J＝7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 100 MHz) δ: 170.8, 169.7, 169.5, 155.9, 135.5,

132.8, 132.6, 129.7, 129.6, 127.4, 79.4, 78.5, 61.5, 58.9,

53.5, 51.2, 40.6, 34.8, 33.2, 32.9, 31.6, 28.4, 28.2, 25.7,

23.8, 22.2 14.6; IR (KBr) ν: 3308, 29_－33, 2872, 1687,

0.07, CH₃OH); H NMR (CDCl₃, 400 MHz) δ: 7.76 (d,

J＝8.4 Hz, 2H), 7.66 (d, J＝8.4 Hz, 2H), 7.41 (s, 1H),

5.66 (q, J＝7.6 Hz, 1H ), 5.23—5.29 (m, 1H), 5.16 (s,

1H), 4.98 (s, 1H), 4.77 (d, J＝8.8 Hz, 1H), 4.45—4.56

(m, 2H), 3.90—4.14 (m, 3H), 2.93 (t, J＝11.6 Hz, 1H),

2.60 (d, J＝14.4 Hz, 1H), 2.35—2.44 (m, 2H), 1.95—

2.28 (m, 10H), 1.44—1.84 (m, 11H), 1.32—1.38 (m,

1H), 1.16 (t, J＝7.2 Hz, 3H); ¹³C NMR (CDCl₃, 100

MHz) δ: 172.6, 169.6, 169.1, 156.0, 135.4, 133.1, 132.6,

129.6, 129.2, 127.2, 79.5, 78.3, 61.2, 60.3, 58.8, 58.6,

53.8, 50.1, 42.4, 40.8, 33.4, 32.8, 32.6, 30.1, 28.3, 26.1,

23.5, 22.6, 14.4; IR (KBr) ν: 3291, 2952, 2868, 1685,

1654, 1575, 1522, 1433, 1390, 1368, 1312, 1250, 1176,

1

1654, 1568, 1511, 1429, 1319, 11_＋72 cm ; HRMS calcd

for C₃₁H₄₀BrN₃O₉S₂([M ＋ H] ) 742.14621, found

742.14795.

^－1

1094, 1002, 890 cm ; HRMS calcd for C₃₂H₄₃BrN₄O₉S

18-(4-Bromo-benzenesulfonyloxy)-14-cyclopentyl-

oxycarbonylamino-12-(2-nitro-benzenesulfonyl)-2,15-

dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nonadec-7-

ene-4-carboxylic acid ethyl ester (15d) 0.6 g, 20%

([M＋H]^＋) 739.20069, found 739.20282.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-

ene-4-carboxylic acid methyl ester (16a) A mixture

of compound 15a (55 g, 0.0776 mol), compound 4 (26 g,

0.0815 mol) and Cs₂CO₃(38 g, 0.1166 mol) in

4-methyl-morpholine (800 mL) was heated to 50—60

℃ overnight. TLC (CH₃OH∶CH₂Cl₂＝1∶20, volume

ratio) showed compound 15a was consumed completely,

the mixture was cooled to r.t., poured into water (3000

mL) and stirred for 30 min. The mixture was filtered

and the solid was washed with water (200 mL). The

1

yield; [α]²_D⁰＋21.0 (c 0.38, CH₃OH); H NMR (CDCl₃,

400 MHz) δ: 8.06 (br, 1H), 7.82 (d, J＝8.4 Hz, 2H),

7.70—7.76 (m, 4 H), 7.60—7.68 (m, 1H), 7.39 (br, 1H),

5.60—5.66 (m, 1H), 5.38 (t, J＝9.6 Hz, 2H), 5.20 (d,

J＝7.2 Hz, 1H), 5.15 (s, 1H), 4.97 (s, 1H), 4.61—4.70

(m, 1H), 4.27 (br, 1H), 4.09 (q, J＝7.2 Hz, 2H), 3.70—

3.80 (m, 2H), 3.64 (d, J＝14.4 Hz, 1H), 3.46—3.57 (m,

1H), 3.29—3.40 (m, 1H), 2.65 (d, J＝14.0 Hz, 1H),

2.22—2.30 (m, 1H), 2.02—2.15 (m, 2H), 1.89—2.00

Chin. J. Chem. 2011, 29, 1489— 1502

www.cjc.wiley-vch.de

1499

Liu et al.

FULL PAPER

solid was dissolved in CH₂Cl₂(1500 mL) and filtered,

the filtrate was dried over anhydrous Na₂SO₄and the

solvent was removed under reduced pressure. The resi-

due was purified via column chromatography (CH₂Cl₂),

the crude compound 16a was re-crystalizated with

mixed solvent (ethyl acetate 200 mL; petroleum ether

400 mL) to afford compound 16a (35 g, 57.4%) as

white solid. ¹H NMR (CDCl₃, 300 MHz) δ: 7.98 (d, J＝

9.3 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H),

7.05 (dd, J＝9.0 Hz, 2.4 Hz, 1H), 5.55 (q, J＝7.8 Hz,

1H), 5.36—5.42 (m, 2H), 5.18—5.28 (m, 2H), 5.00—

5.07 (m, 1H), 4.89—4.95 (m, 1H), 4.60—4.69 (m, 1H),

4.28—4.35 (m, 1H), 4.00—4.10 (m, 1H), 3.94 (s, 3H),

3.68—3.74 (m, 4H), 3.05—3.09 (m, 1H), 2.38—2.40

(m, 1H), 2.15—2.24 (m, 3H), 1.32—1.90 (m, 24H).

With similar procedure, 16b, 16c, 16d, 16e and 16f

were prepared.

calcd for C₄₁H₅₂N₆O₈S₂([M＋H]^＋) 821.33608, found

821.33600.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

12-(2-nitro-benzenesulfonyl)-2,15-dioxo-3,12,16-tri-

aza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic

acid ethyl ester (16d) 90 mg, 60% yield; [α]²_D⁰＋51.6

1

(c 0.38, CH₃OH); H NMR (CDCl₃, 400 MHz) δ: 8.74

(s, 1H), 8.06 (d, J＝9.2 Hz, 1H), 8.00 (d, J＝9.6 Hz,

1H), 7.90 (s, 1H), 7.66—7.71 (m, 4H), 7.58—7.60 (m,

1H), 7.44 (s, 1H), 7.19 (d, J＝8.4 Hz, 1H), 5.76 (s, 1H),

5.59 (dd, J＝17.6 Hz, 9.6 Hz, 1H), 5.43 (t, J＝9.6 Hz,

1H), 5.18 (d, J＝8.0 Hz, 1H), 4.81 (t, J＝8.0 Hz, 1H),

4.67 (d, J＝10.0 Hz, 2H), 4.25 (br, 1H), 4.04—4.22 (m,

2H), 3.97 (s, 3 H), 3.62—3.75 (m, 2H), 3.51—3.59 (m,

2H), 3.26—3.38 (m, 1H), 2.93—3.00 (m, 1H), 2.54—

2.63 (m, 1H), 2.19 (q, J＝8.8 Hz, 1H), 1.94—2.09 (m,

2H), 1.82—1.86 (m, 1H), 1.65—1.68 (m, 1H), 1.32—

1.59 (m, 16H), 1.24—1.31 (m, 1H), 1.21 (t, J＝7.2 Hz,

3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 172.7, 170.9,

170.0, 169.7, 167.0, 165.7, 155.8, 148.4, 144.0, 143.8,

134.5, 134.3, 133.1, 132.4, 132.3, 131.5, 127.3, 124.8,

124.7, 122.3, 115.4, 113.6, 100.4, 99.8, 80.3, 78.6, 62.0,

59.1, 56.9, 53.1, 51.9, 51.4, 49.8, 47.4, 41.5, 33.3, 33.0,

32.6, 29.4, 26.8, 25.8, 23.8, 23.4, 22.1, 14.5; IR (KBr) ν:

2968, 16_－91, 1631, 1543, 1446, 1425, 1371, 1269, 124_＋6,

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-12-oxa-3,16-diaza-tricyclo[14.3.0.04,6]-

nonadec-7-ene-4-carboxylic acid ethyl ester (16b)

1

0.28 g, 58% yield; H NMR (CDCl₃, 300 MHz) δ: 7.93

(d, J＝9.0 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.38 (d,

J＝2.1 Hz, 1H), 7.34 (s, 1H), 7.05 (dd, J＝9.0, 2.7 Hz,

1H), 5.68 (d, J＝7.8 Hz, 1H), 5.54—5.63 (m, 1H),

5.37—5.44 (m, 3H), 5.00—5.07 (m, 1H), 4.90—4.97

(m, 1H), 4.70—4.79 (m, 1H), 4.08—4.21 (m, 3H), 3.92

(s, 3H), 3.80—3.87 (m, 1H), 3.51—3.74 (m, 3H), 3.33

—3.41 (m, 2H), 2.85—2.94 (m, 1H), 2.40—2.60 (m,

2H), 2.35 (t, J＝8.1 Hz, 1H), 2.20 (q, J＝8.7 Hz, 1H),

1.91—2.11 (m, 3H), 1.42—1.86 (m, 10H), 1.31 (d, J＝

6.6 Hz, 6H), 1.21 (t, J＝7.2 Hz, 3H); ¹³C NMR (CDCl₃,

100 MHz) δ: 170.5, 170.3, 170.0, 169.0, 161.3, 160.0,

156.0, 155.9, 154.1, 151.1, 132.7, 127.3, 122.8, 118.1,

115.2, 107.1, 106.3, 98.5, 70.6, 69.4, 61.2, 59.0, 55.4,

52.4, 52.1, 49.4, 48.2, 40.4, 33.6, 32.7, 30.6, 29.3, 28.1,

23.6, 23.2, 22.8, 14.4; HRMS calcd for C₄₁H₅₂N₆O₉S

([M＋H]^＋) 805.35892, found 805.35944.

1

1166 cm ; HRMS calcd for C₄₇H₅₆N₈O₁₂S₂([M＋H] )

989.35319, found 989.35358.

12-Acetyl-14-cyclopentyloxycarbonylamino-18-[2-

(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-

4-yloxy]-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,

6]nonadec-7-ene-4-carboxylic acid ethyl ester (16e)

1

34 mg, 20% yield; [α]²_D⁰＋20.0 (c 0.6, CH₃OH); H

NMR (CDCl₃, 400 MHz) δ: 10.81 (br, 1H), 9.17 (br,

1H), 8.78 (s, 1H), 8.08 (d, J＝9.6 Hz, 1H), 7.98 (s, 1H),

7.70 (s, 1H), 7.20 (d, J＝8.4 Hz, 2H), 5.73 (s, 1H),

5.54—5.67 (m, 2H), 4.77—4.93 (m, 3H), 4.11—4.22

(m, 3H), 3.99 (s, 3H), 3.85—3.94 (m, 2H), 3.50—3.61

(m, 2H), 3.11 (t, J＝11.6 Hz, 1H), 2.88—3.02 (m, 2H),

2.56—2.63 (m, 1H), 2.11—2.30 (m, 4H), 2.07 (s, 3H),

1.85 (t, J＝6.8 Hz, 1H), 1.32—1.65 (m, 18H), 1.23 (t,

J＝7.2 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 172.8,

172.5, 171.9, 169.9, 169.7, 167.0, 165.5, 155.6, 144.3,

135.4, 131.1, 128.0, 124.8, 121.9, 115.5, 113.3, 100.8,

99.9, 80.3, 78.4, 61.9, 58.9, 56.9, 53.0, 51.7, 51.6, 49.4,

48.4, 41.5, 33.4, 33.0, 32.6, 31.3, 29.9, 27.0, 26.0, 23.8,

23.7, 23.2, 22.2, 2_＋1.2, 14.5; HRMS calcd for

C₄₃H₅₅N₇O₉S ([M＋H] ) 846.38547, found 846.38562.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

12-methyl-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.

04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (16f)

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-12-thia-3,16-diaza-tricyclo[14.3.0.04,6]-

nonadec-7-ene-4-carboxylic acid ethyl ester (16c)

1

135 mg, 55% yield; H NMR (CDCl₃, 300 MHz) δ:

10.56 (br, 1H), 8.58 (s, 1H), 8.09 (d, J＝9.2 Hz, 1H),

7.91 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.24 (d, J＝9.2

Hz, 1H), 5.69 (s, 1H), 5.59—5.66 (m, 2H), 5.40 (t, J＝

9.2 Hz, 1H), 5.04 (t, J＝8.0 Hz, 1H), 4.70—4.80 (br,

2H), 4.46 (d, J＝12.4 Hz, 1H), 4.18 (q, J＝7.2 Hz, 2H),

4.08—4.13 (m, 1H), 4.02 (s, 3H), 3.58—3.66 (m, 1H),

3.02—3.11 (m, 2H), 2.93—2.99 (m, 1H), 2.65—2.76

(m, 2H), 2.55—2.61 (m, 1H), 2.25—2.36 (m, 2H),

2.15—2.23 (m, 1H), 1.93—2.02 (m, 1H), 1.51—1.84

(m, 11H), 1.46 (d, J＝6.4 Hz, 6H), 1.24 (t, J＝7.2 Hz,

3H); ¹³C NMR (CDCl₃, 75 MHz) δ: 171.2, 170.4, 169.9,

169.2, 164.9, 164.6, 155.7, 145.3, 145.1, 145.0, 132.6,

127.1, 124.0, 121.4, 115.0, 111.5, 101.7, 98.8, 78.9,

78.2, 61.4, 58.6, 56.3, 52.7, 51.1, 40.6, 34.6, 33.7, 32.6,

31.9, 28.1, 27.8, 25.7, 23.5, 22.7, 21.8, 14.3; HRMS

1

100 mg, 56% yield; [α]²_D⁰＋63.0 (c 0.69, CH₃OH); H

NMR (CDCl₃, 400 MHz) δ: 9.4 (br, 3 H), 8.22 (s, 1H),

7.91 (d, J＝9.6 Hz, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.07

(d, J＝7.6 Hz, 1H), 5.44—5.64 (m, 3H), 4.81 (br, 3H),

3.96—4.40 (m, 2H), 4.11 (q, J＝7.2 Hz, 2H), 3.88 (s,

3H), 3.72—3.80 (m, 1H), 3.53—3.60 (m, 1H), 3.40—

1500

www.cjc.wiley-vch.de

Chin. J. Chem. 2011, 29, 1489— 1502

Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

3.48 (m, 1H), 3.22 (br, 2H), 2.93 (br, 3 H), 2.43 (br, 1H),

2.22 (br, 2H), 2.04—2.12 (m, 1H), 1.84—1.92 (m, 1H),

1.28—1.80 (m, 18H), 1.20 (t, J＝7.2 Hz, 3H); ¹³C NMR

(CDCl₃, 100 MHz) δ: 172.4, 169.9, 169.1, 164.1, 163.9,

155.9, 146.6, 144.7, 139.5, 130.3, 127.9, 123.8, 120.4,

117.9, 115.0, 114.6, 101.9, 98.1, 79.0, 78.7, 61.2, 59.8,

55.9, 52.9, 50.0, 49.4, 42.3, 40.3, 34.3, 32.4, 31.1, 25.1,

24.4, 23.3, 23.0, 21.9, 13.9; IR (KBr) ν: 2969, 1664,

1634, 1599,1447, 1422, 1390, 1269, 1246, 1172, 112_＋4,

J＝7.2 Hz, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 7.13 (d, J＝

7.2 Hz, 1H), 7.01 (d, J＝9.0 Hz, 1H), 5.35—5.42 (m,

3H), 4.65—4.70 (m, 1H), 4.40—4.47 (m, 2H), 4.17—

4.22 (m, 1H), 3.94—4.00 (m, 1H), 3.88 (s, 3H), 3.72—

3.84 (m, 1H), 2.25—2.49 (m, 3H), 1.85—1.94 (m, 2H),

1.15—1.69 (m, 24 H).

With similar procedure, WX-1, WX-2, WX-3,

WX-4 and WX-5 were prepared.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-12-oxa-3,16-diaza-tricyclo[14.3.0.04,6]nona-

dec-7-ene-4-carboxylic acid (WX-1) 0.15 g, 68%

^－1

1022 cm ; HRMS calcd for C₄₂H₅₅N₇O₈S ([M＋H] )

818.39055, found 818.39172.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nona-

dec-7-ene-4-carboxylic acid ethyl ester (16d') To a

solution of compound 16d (330 mg, 0.334 mmol) in

acetonitrile (7 mL) was added potassium carbonate (69

mg). Then PhSH (74 mg, 0.668 mmol) was added to the

mixture and stirred at r.t. overnight. The solid was re-

moved by filtration. The filtrate was concentrated in

vacuum. The residue was switched with hexane to re-

move the excess PhSH, to afford compound 16d' (250

mg, 80% yield). [α]²_D⁰＋56.6 (c 0.12, CH₃OH); ¹H

NMR (CDCl₃, 400 MHz) δ: 10.46 (br, 1H), 9.03 (br,

1H), 8.47 (s, 1H), 7.96 (d, J＝8.4 Hz, 1H), 7.66 (s, 1H),

7.56 (s, 1H), 7.10 (d, J＝8.4 Hz, 1H), 6.79 (br, 1H),

5.62 (s, 1H), 5.43—5.54 (m, 3H), 5.10 (t, J＝8.0 Hz,

1H), 4.82—4.91 (m, 2H), 4.31 (d, J＝11.6 Hz, 1H),

4.07—4.17 (m, 4H), 3.92 (s, 3H), 3.59 (t, J＝6.0 Hz,

1H), 3.43 (d, J＝12.8 Hz, 2H), 3.18 (s, 1H), 3.10 (s, 1H),

2.96—3.01 (m, 1H), 2.60—2.63 (m, 1H), 2.44—2.53

(m, 1H), 2.35 (q, J＝8.4 Hz, 1H), 1.93—2.09 (m, 2H),

1.79—1.90 (m, 1H), 1.37—1.76 (m, 16H), 1.33 (d, J＝

7.2 Hz, 1H), 1.22 (t, J＝7.2 Hz, 3H); ¹³C NMR (CDCl₃,

100 MHz) δ: 173.2, 169.7, 169.2, 169.0, 164.3, 164.1,

155.9, 131.4, 131.1, 127.2, 123.6, 120.9, 117.8, 114.9,

114.7, 110.6, 102.4, 98.1, 79.3, 78.3, 61.3, 59.4, 56.1,

52.5, 51.1, 50.3, 49.8, 47.8, 40.4, 34.3, 32.5, 32.3, 29.7,

26.6, 23.9, 23.3, 22.6, 21.7, 14.0; HRMS calcd for

C₄₁H₅₃N₇O₈S ([M＋H]^＋) 804.37491, found 804.37494.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-

ene-4-carboxylic acid (BILN 2061) To a stirred solu-

tion of compound 16a (53 g, 0.067 mol) in a mixed so-

lution (H₂O 400 mL; THF 400 mL) was added

LiOH•H₂O (23 g, 0.548 mol). The mixture was stirred

overnight at room temperature. TLC (CH₃OH ∶

CH₂Cl₂＝1∶20, volume ratio) showed compound 16a

was consumed completely. The solvent was removed

under reduced pressure and the mixture was acidified to

pH 5—6 and the off-yellow gum was grinded to yellow

grain, which was filtered, the solid was dissolved in

mixed solution (CH₃OH 600 mL; CH₂Cl₂＝2000 mL)

and dried over anhydrous Na₂SO₄. The solvent was re-

moved under reduced pressure to afford BILN 2061 (43

1

yield; [α]²_D⁰＋21.0 (c 0.78, CH₃OH); H NMR (CDCl₃,

300 MHz) δ: 8.61 (s, 1H), 8.03 (d, J＝9.1 Hz, 1H), 7.98

(d, J＝1.8 Hz, 1H), 7.50 (s, 1H), 7.25 (dd, J＝9.0, 2.1

Hz, 1H), 5.84—5.93 (m, 1H), 5.60—5.70 (m, 1H), 5.50

(t, J＝9.0 Hz, 1H), 5.04 (s, 1H), 4.37 (t, J＝8.4 Hz, 1H),

4.00 (s, 3H), 3.91—3.96 (m, 1H), 3.72—3.85 (m, 3H),

3.48—3.58 (m, 1H), 3.45 (t, J＝6.6 Hz, 2H), 2.88—

2.95 (m, 1H), 2.28—2.56 (m, 3H), 1.52—1.88 (m, 9H),

1.88—2.13 (m, 3H), 1.32 (d, J＝6.6 Hz, 6H); ¹³C NMR

(CDCl₃, 100 MHz) δ: 171.3, 170.3, 169.8, 166.5, 165.3,

155.9, 147.6, 143.7, 139.9, 132.3, 127.1, 123.6, 121.6,

114.4, 114.0, 100.4, 98.8, 78.5, 75.4, 71.0, 70.7, 58.7,

56.5, 50.8, 49.7, 40.1, 34.2, 32.7, 29.4, 27.8, 23.7, 23.5,

22.9, 22.1; IR (KBr) ν: 3308, 3094, 2960, 2872, 1666,

1630, 1600, 1557, 1448, 1422, 1269, 1246, 1198, 117_＋6,

^－1

1126 cm ; HRMS calcd for C₃₉H₄₈N₆O₉S ([M＋H] )

777.32763, found 777.32926.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-12-thia-3,16-diaza-tricyclo[14.3.0.04,6]-

nonadec-7-ene-4-carboxylic acid (WX-2) 150 mg,

1

68% yield; [α]²_D⁰＋29.4 (c 0.68, CH₃OH); H NMR

(CDCl₃, 300 MHz) δ: 8.31 (d, J＝9.0 Hz, 1H), 8.19 (s,

1H), 8.76 (s, 2H), 7.35 (d, J＝9.0 Hz, 1H), 5.78—5.85

(m, 1H), 5.64—5.75 (m, 2H), 5.47—5.56 (m, 1H),

4.73—4.78 (m, 1H), 4.38—4.49 (m, 2H), 4.14—4.22

(m, 2H), 4.05 (s, 3H), 2.80—2.97 (m, 3H), 2.59—2.74

(m, 3H), 2.34—2.48 (m, 2H), 2.09—2.20 (m, 1H), 1.41

—1.75 (m, 12H), 1.35 (d, J＝6.3 Hz, 6H); ¹³C NMR

(CDCl₃, 75 MHz) δ: 171.2, 170.7, 170.3, 166.2, 165.1,

155.7, 147.6, 146.8, 143.5, 140.2, 132.6, 126.4, 123.6,

121.4, 114.5, 114.0, 100.3, 98.6, 78.4, 75.7, 58.7, 56.5,

51.0, 49.9, 49.5, 40.2, 34.8, 33.6, 32.7, 32.6, 29.1, 28.4,

25.9, 23.5, 22.1, 22.0; IR (KBr) ν: 3308, 1668, 1631,

160_－0, 1557, 1448, 1422, 1269, 1246, 1198, 1177, 1131

cm ¹; HRMS calcd for C₃₉H₄₈N₆O₈S₂([M＋H]^＋)

793.30478, found 793.30686.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nona-

dec-7-ene-4-carboxylic acid (WX-3) 60 mg, 30%

1

yield; [α]²_D⁰＋56.3 (c 0.55, CH₃OH); H NMR (CDCl₃,

400 MHz) δ: 9.76 (br, 1H), 9.50 (br, 1H), 8.76 (s, 1H),

8.49 (s, 1H), 7.87 (d, J＝9.6 Hz, 1H), 7.77 (s, 1H), 7.10

(d, J＝8.4 Hz, 2H), 6.19 (br, 1H), 5.34—5.55 (m, 3H),

4.99 (br, 3H), 4.54 (s, 1H), 3.87 (s, 4H), 3.62—3.78 (m,

1

g, 82.9%) as yellow power. H NMR (DMSO-d₆, 300

MHz) δ: 8.25 (s, 1H), 8.00 (d, J＝9.0 Hz, 1H), 7.66 (d,

Chin. J. Chem. 2011, 29, 1489— 1502

www.cjc.wiley-vch.de

1501

Liu et al.

FULL PAPER

1H), 3.22—3.36 (m, 3H), 3.10—3.19 (m, 1H), 2.91—

3.05 (m, 1H), 2.53—2.64 (m, 1H), 2.38—2.47 (m, 1H),

2.15—2.28 (m, 1H), 1.39—2.07 (m, 14H), 1.22—1.26

(m, 6H); ¹³C NMR (MeOD-d₃, 100 MHz) δ: 175.7,

173.8, 171.5, 171.1, 167.6, 167.0, 150.8, 144.0, 143.3,

132.6, 128.9, 126.6, 121.9, 121.3, 117.3, 116.8, 101.5,

99.8, 81.7, 80.1, 61.1, 57.5, 54.4, 51.9, 50.6, 41.8, , 36.0,

34.1, 32.0, 31.9, 28.4, 26.1, 25.0, 24.0, 23.4; IR (KBr) ν:

2967, 1666, 1629, 1599, 1557, 1447, 1421, 1269, 1246,

References

1

(a) Proceedings of the European Association for the Study

of the Liver International Consensus Conference on Hepati-

tis C, Paris, France, February 26, 27, 1999.

(b) Pol, S.; Couzigou, P.; Bourliere, M.; Abergel, A.; Com-

bis, J.; Laney, D.; Fran, A.; Moussalli, J.; Roupon, R.;

Berthelot, P.; Brechot, C. J. Hepatol. 1999, 31, 1.

Stefan, W.; Thomas, L.; Stephan, G.; Patrick, G. Hepatol-

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Dhumeaux, D.; Marcellin, P.; Lerebours, E. Gut 2003, 52,

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Marcellin, P.; Asselah, T.; Boyer, N. Hepatology 2002, 36,

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Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.;

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M.; Cordingley, M. G.; Faucher, A.-M.; Goudreau, N.;

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nas-Brunet, M. Nature 2003, 426, 186.

2

3

4

5

^－1

1173, 1127, 1049, 1021, 829 cm ; HRMS calcd for

C₃₉H₄₉N₇O₈S ([M＋H]^＋) 776.34361, found 776.34393.

12-Acetyl-14-cyclopentyloxycarbonylamino-18-[2-

(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-

4-yloxy]-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,

6]nonadec-7-ene-4-carboxylic acid (WX-4) 20 mg,

67% yield; [α]²_D⁰＋5.0 (c 0.4, CH₃OH); ¹H NMR

(CDCl₃, 400 MHz) δ: 8.49 (br, 1H), 8.35 (br, 1H),

7.95—7.98 (m, 1H), 7.88 (s, 1H), 7.81 (br, 1H), 7.31 (s,

1H), 7.13—7.22 (m, 2H), 5.65—5.74 (m, 1H), 5.50—

5.63 (m, 2H), 5.12—5.22 (m, 1H), 4.81—4.94 (m, 2H),

4.22—4.23 (m, 1H), 4.09—4.21 (m, 1H), 3.98 (s, 3H),

3.85 (d, J＝11.6 Hz, 1H), 3.48—3.61 (m, 1H), 3.33—

3.45 (m, 1H), 2.87—3.07 (m, 2H), 2.17—2.29 (m, 2H),

1.95—2.16 (m, 5H), 1.44—1.90 (m, 11H), 1.30—1.33

(m, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ: 173.4, 172.6,

172.1, 170.2, 164.8, 155.7, 147.3, 143.4, 140.1, 131.0,

126.9, 123.9, 120.9, 117.9, 114.3, 113.8, 100.7, 99.9,

98.2, 78.2, 58.6, 56.4, 50.8, 49.6, 46.6, 41.5, 32.7, 32.5,

30.8, 26.7, 25.2, 23.5, 22.4, 22.1, 22.0, 20.9; HRMS

calcd for C₄₁H₅₁N₇O₉S ([M＋H]^＋) 818.35417, found

818.35474.

6

(a) Beaulieu, P. L.; Gillard, J.; Bailey, M. D.; Boucher, C.;

Ducepee, J. S.; Simoneau, B.; Wang, X. J.; Zhang, L.;

Grozinger, K.; Houpis, I.; Farina, V.; Heimroth, H.; Krueger,

T.; Schnaubelt, J. J. Org. Chem. 2005, 70, 5869.

(b) Wang, X. J.; Zhang, L.; Smith-Keenan, L. L.; Houpis, I.;

Farina, V. Org. Process Res. Dev. 2007, 11, 60.

7

8

Grubbs, R. H. Handbook of Metathesis, Wiley-VCH,

Weinheim, Germany, 2003.

Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R.

P.; Gallou, F.; Wang, X.; Wei, X.; Simpson, R. D.; Feng, X.;

Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan,

L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.

J. Org. Chem. 2006, 71, 7133.

14-Cyclopentyloxycarbonylamino-18-[2-(2-isopro-

pylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-

12-methyl-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.

04,6]nonadec-7-ene-4-carboxylic acid (WX-5) 34

mg, 50% yield; [α]_D²⁰＋41.0 (c 0.19, CH₃OH); ¹H NMR

(MeOD-d₃, 400 MHz) δ: 8.20 (d, J＝9.2 Hz, 1H), 8.18

(s, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 7.34 (dd, J＝9.2 Hz,

2.4 Hz, 1H), 5.87 (s, 1H), 5.50—5.64 (m, 2H), 4.64—

4.72 (m, 2H), 4.48—4.54 (m, 1H), 4.09—4.17 (m, 2H),

4.02 (s, 3H), 3.65—3.75 (m, 1H), 3.32—3.40 (m, 1H),

3.04 (s, 3H), 2.87—2.99 (m, 2H), 2.50—2.58 (m, 1H),

2.16—2.43 (m, 3H), 1.94—2.07 (m, 1H), 1.36—1.77

(m, 12H), 1.31 (d, J＝6.0 Hz, 6H), 1.16—1.23 (m, 1H);

¹³C NMR (CDCl₃, 100 MHz) δ: 175.1, 173.5, 170.6,

170.1, 167.0, 166.4, 157.8, 150.2, 143.4, 142.7, 131.7,

128.9, 125.9, 121.4, 116.8, 116.3, 110.9, 99.4, 81.3,

79.6, 61.8, 60.9, 58.5, 56.9, 53.8, 50.8, 43.6, 41.3, 35.4,

33.5, 33.4, 31.8, 26.2, 25.6, 24.4, 23.9, 22.8; IR (KBr) ν:

3236, 2967, 1663, 1629, 1599, 1560, 1447, 1420, 1268,

9

Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.;

Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.; Hal-

mos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos,

Y. S.; Llinas-Brunet, M. Org. Lett. 2004, 6, 2901.

10 Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J.

Am. Chem. Soc. 1993, 115, 10125.

11 Miao, W.; Jia, L.; Zhang, Z.; Dong, J.; Shi, Y.; Ma, R.;

Tang, S.; Chen, S.; Li, G. Lett. Org. Chem. 2006, 3, 489.

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442066].

^－1

1246, 1172, 1126, 1022, 830 cm ; HRMS calcd for

C₄₀H₅₁N₇O₈S ([M＋H]^＋) 790.35926, found 790.35974.

(E1011102 Cheng, F.; Lu, Z)

1502

www.cjc.wiley-vch.de

Chin. J. Chem. 2011, 29, 1489— 1502

Article Doi

A concise synthesis of the HCV protease inhibitor BILN 2061 and its P3 modified analogs

DOI: 10.1002/cjoc.201180270

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