A Facile, Six-Step Process for the Synthesis of (3S,5S)-3-Isopropyl-5

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A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5((2S,4S)-4-isopropyl-5 -oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1carboxylic acid tert-butyl ester, the key synthetic intermediate of aliskiren Xianhua Pan, Siyao Xu, Rui Huang, Wansheng Yu, and Feng Liu Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 21 May 2015 Downloaded from http://pubs.acs.org on May 21, 2015

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Organic Process Research & Development

A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5 -oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-car boxylic acid tert-butyl ester, the key synthetic intermediate of aliskiren Xianhua Pan,‡ Siyao Xu,‡ Rui Huang,† Wansheng Yu and Feng Liu* School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100 Haiquan Rd, Shanghai, 201418, P.R. China. *E-mail: [email protected].

ACS Paragon Plus Environment 1


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Table of contents graphic


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ABSTRACT: A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester from (S)-4-benzyloxazolidin-2-one 2 in an overall 50% yield is reported. The key transformations include: a highly efficient diastereoselective epoxidation, Lewis acid-catalyzed ring-opening with bromide, an SN2 reaction using NaN3 and a tandem reduction-cyclization reaction. KEYWORDS: aliskiren, diastereoselective, epoxidation, Lewis acid, azidation, tandem



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INTRODUCTION: Aliskiren (1) is the first of a new class of orally effective direct renin inhibitors, which was approved by ®

®

the U.S. Food and Drug Administration (FDA) in 2007 and marketed by Novartis AG (Rasilez , Enviage , ®

® 1-4

Sprimeo and Tekturna ).

Although it has received a warning and contraindication from the U.S. FDA in

2012 because of the potential risk of renal failure and angioedema, its superior blood pressure-lowering efficacy and unique chemical structure still captures the interest of pharmaceutical companies and synthetic chemists. The difficulty and challenge of synthesizing aliskiren lies in the construction of its four chiral centers (Scheme 1). Lots of effort and several synthetic approaches towards the synthesis of aliskiren have been 5

reported in the recent literature. Göschke etc. provided a protocol that the core 4,5-(S)-amino-hydroxy was introduced by halo-lactonization and the following azidation.

5a

Rüeger etc. reported in 2000 a

convergent synthetic route, the key reaction employed the coupling of Grignard reagent with the diastereomeric pure γ-lactone and enantioselective reduction.

5b

The linchpin of Sandham’s

5c

synthesis

routes was the enantioselective Grignard addition to the amide spiroacetal, which was introduced by the pseudoephedrine chiral auxiliary. Dondoni and colleagues synthesized the core chiral β-amino alcohol segment via the Grignard addition to the pseudoephedrine spiroanellated γ-butyolactone derivative. Göschke etc. reported another convergent synthesis of aliskiren in 2003,

5e

5d

in which the key chiral amine

was introduced by the alkylation of the chiral Schöllkopf dihydropyrazine. Ma’s synthetic route was based 5f

on the approach reported by Göschke along with modifications. Hanessian devised a “macrocycle route”


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toward aliskiren, include a chllenging RCM reaction to produce a nine-membered unsaturated lactone, a highly enantioselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring opening to a vicinal amino alcohol.

5g

Prasad etc. described a 12-step synthesis of aliskiren that features a

Curtius rearrangement to transform carboxylic acid to the benzyl carbamate via the isocyanate.

5h

Ko

reported a total synthesis of aliskiren, in there route they used the symmetric trans-cisoid-trans-bis latone as a key precursor.

5i

Scheme 1. A convergent synthetic route towards aliskiren. Among the synthetic approaches reported, the convergent routes that disconnect aliskiren into three independent segments are the most effective and convenient (Scheme 1).

5a, j, m

As part of our continuing interest in developing efficient and practical processes for the synthesis of active 6

pharmaceutical ingredients (API) and intermediates, we now report a facile and convergent six-step approach towards the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-



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2-yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (Segment B), the key synthetic intermediate of aliskiren (Scheme 2).

Scheme 2. Original retrosynthetic analysis of Segment B. RESULTS AND DISCUSSION: Choice of Synthetic Strategy Our original synthetic strategy was based on the approaches reported by Göschke, Mickel and Kidemet respectively.

5a, j, m

In order to simplify the reaction steps and optimize the work-up procedures, we have

suggested an alternative synthetic route (Scheme 2). We found that 2,7-(S)-isopropyl and 1,8-dicarbonyl groups of Segment B could be easily prepared using the Evans chiral auxillary 4 and (Z)-1,4-dibromo-but-2-ene 5a. The adjacent 4-(S)-amino and 5-(S)-hydroxyl groups could be introduced in one step by the nucleophilic NaN3 ring-opening at the C4-position of (4R,5S)-epoxide 7a. As 6a is a C2


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symmetrical chiral compound, epoxidation on either face of the alkene will produce the same enantiomer,, (4R,5S)-epoxide 7a. However, there is not much regio-selectivity of C4- and C5- position of 7a in the epoxide opening reaction we did not expect high diastereoelectivity for this direct azidation (Scheme 3). Epoxidation on either face of the alkene produces same enantiomer

C2 axis in the plane of the paper

Bn

(S)

5

4

2

O

7

(S)

N

O

(S)

O

N

O

O

(S)

epoxidation Bn

Bn

O 5 4 (R) (S)

2 (S)

O (S) N

O

NaN3

7 (S)

N (S)

O

O

O

O

O

+

O 4 5 (S) (R)

7 (S)

O

(S) N Bn Bn

O

O

N O

(S) 2

k attac

O

(S) Bn

O (S) 5 (S) 4 N3

N (S) Bn O

7a

C 4-

O

O

O

O

7a

6a

NaN3

2 (S)

(S) 7

9

C5attac k

O

O 2 (S)

O

Bn (S) N

4 (R) (R) 5 N3

O

(S) 7

O

9'

Scheme 3. The nucleophilic ring-opening reaction of (4R,5S)-epoxide 7a with NaN3. Since the direct azidation of 7a was not feasible, we have designed a double inversion strategy (Scheme 4). We envisaged that azide 9 could be prepared via a ring-opening reaction of 7 with bromide and the following nucleophilic azidation. The absolute configuration of the chiral center would undergo a double inversion to form the (4S)-amino and (5S)-hydroxy functionality in compound 9. Therefore, epoxide 7a was replaced by (4S,5S)-epoxide 7. No matter which position (C4- or C5-) of 7 was attacked, the axis symmetry of 7 could guarantee the formation of a same enantiomer 8 bearing the required (4S)-amino and (5R)-bromide. Compound 9 with the anticipated (4S)-amino and (5S)-hydroxy functionality would be easily



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formed after the SN-2 azidation.. And the desired (4S, 5S)-epoxide 7 could be constructed by the 7

epoxidation of the related unsaturated dicarbonyl compound 6, which could be prepared from the Evans chiral auxillary 4 and (E)-1,4-dibromobut-2-ene 5. O (S)

3

2

4

NBoc

1

O

8

O (S) (S)

O

O O

5 7 (S) 6

O

Bn

O

(S)

2

4

O

(S)

2

4

(S)

N O

7

Bn (S)

O

(R)

(S)

(S)

Br 8

9

O

O (S) 5

7

O

N

O (S)

Bn

(S)

Br

Bn

N

O

6 (S)

(S)

(S)

Br

6

N

(S)

6

Br

5

4

+

O

(S)

4

O

O 7 C2 axis preserved perpendicular to the plane of paper. Epoxide opening at either position produce same result.

5

3 (E)

O Bn

5

(S)

O

(S)

N3

(S)

N

O

(S)

Segment B O

O

(S)

N

O

Bn

O

C2 axis perpendicular to the plane of paper.

O

O 2,7

N O

1,8 (S)

Bn 4

Scheme 4. Modified retrosynthetic analysis of Segment B. Synthesis of (4S,5S)-epoxide 7. Our synthesis begins from (S)-4-benzyloxazolidin-2-one 2 (Scheme 5). Upon treatment with n-BuLi and isoamyl chloride 3, the Evans chiral auxillary 4 was formed in 94% yield. Then, an alkylation reaction using 2 eq. of oxazolidinone 4 and 1 eq. of 1,4-dibromo-but-2-ene 5 in the presence of lithium hexamethyldisilazide (LiHMDS) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at -40 °C gave alkene 6 in 88% yield with the expected (2S,7S)-diisopropyl configuration.


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Scheme 5. Synthesis of 7 We were pleased to find out that the following epoxidation reaction of 6 could be carried out smoothly 1

and gave 7 in 91% yield with excellent diastereoselectivity (d.e. >99%, as ascertained by H NMR 7

spectroscopy). We envisioned that the high steric hindrance of 6 should facilitate the diastereospecific 8

epoxidation at the top-face of the paper plane to form the (4S,5S)-epoxide 7. With the chiral epoxide 7 in hand, the desired SN2 ring-opening reaction of (4S,5S)-epoxide 7 with bromide was thoroughly studied and the reaction conditions optimised. The SN2 ring-opening reaction of (4S,5S)-epoxide 7 We have investigated the ring-opening reaction of (4S,5S)-epoxide 7 with respect to the following four key variables: (1) bromide, (2) additive (loading), (3) solvent and (4) temperature. The bromination of (4S,5S)-epoxide 7 using sodium bromide in DMF/H2O was initially attempted, but only the starting material was recovered even after heating to 120 °C for 24 h (Table 1, entry 1). We then examined some other sources of bromide such as KBr, LiBr and even the more reactive and nucleophilic KI. Unfortunately, neither produced the desired product (Table 1, entry 2-4). An enhancement in the conversion to 8 was



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9

achieved with the use of 2 eq. of HBr as the bromide source (Table 1, entry 5), revealing that an acidic environment could promote the desired ring-opening reaction. Therefore, a series of acids such as Brφnstded acids (Table 1, entry 6-8), acidic resin (Table 1, entry 9) 10

and Lewis acid (Table 1, entry 10) were used as an acidic additive. Mg(ClO4)2 proved to be the best acidic additive (Table 1, entry 10). After screening of the solvent and the reaction temperature, THF was finally chosen as the reaction solvent at 80 ºC (Table 1, entry 16). We then found that an increased amount of LiBr and Mg(ClO4)2 could further improve the yield. Consequently, 5 equiv of LiBr / 10 equiv of Mg(ClO4)2 was used (Table 1, entry 18), considering the cost and the fact that adding more LiBr and Mg(ClO4)2 made the reaction mixture too viscous to be stirred smoothly (Table 1, entry 19). With the optimized conditions, enantiopure compound 8 was obtained in 82% yield and 99% d.e. after simple work-up.

a

Table 1. The ring-opening reaction of (4S,5S)-epoxide 7 to give bromide 8.

Bromide

Additive

(eq.)

(eq.)

1

NaBr (2)

-

DMF/H2O

2

KBr (2)

-

Entry

3 4

LiBr (2)

d

KI (2) e

b

Temp.

Yield

(°C)

%

c

120

-

DMF/H2O

c

120

-

DMF/H2O

c

120

-

-

DMF/H2O

c

120

-

-

DCM

20

12

-

solvent

5

HBr (2)

6

LiBr (2)

H2SO4 (2)

DCM

20

trace

7

LiBr( 2)

HCl (3)

DCM

20

6


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8

LiBr (2)

H3PO4 (3)

DCM

20

10

9

LiBr (2)

Amberlyst 15 (3)

DCM

20

15

10

LiBr (2)

Mg(ClO4)2 (3)

DCM

20

21

11

LiBr (2)

Mg(ClO4)2 (3)

CH3CN

20

28

12

LiBr (2)

Mg(ClO4)2 (3)

CH3CN

80

35

13

LiBr (2)

Mg(ClO4)2 (3)

DMF

80

A Facile, Six-Step Process for the Synthesis of (3S,5S)-3-Isopropyl-5

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