Improved preparation of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol

Chinese Chemical Letters 24 (2013) 131–133

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Original article

Improved preparation of (1S,30 R,40 S,50 S,60 R)-5-chloro-6-[(4-ethylphenyl)methyl]30 ,40 ,50 ,60 -tetrahydro-60 -(hydroxymethyl)-spiro[isobenzofuran-1(3H),20 [2H]pyran]-30 ,40 ,50 -triol Yong-Hai Liu, Ting-Ming Fu, Chun-Yan Ou, Wen-Ling Fan, Guo-Ping Peng * School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 9 November 2012 Received in revised form 23 November 2012 Accepted 3 December 2012 Available online 29 January 2013

A convenient approach for the preparation of (1S,30 R,40 S,50 S,60 R)-5-chloro-6-[(4-ethylphenyl)methyl]30 ,40 ,50 ,60 -tetrahydro-60 -(hydroxymethyl)-spiro[isobenzofuran-1(3H), 20 -[2H]pyran]-30 ,40 ,50 -triol is developed. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and the isomers of undesired ortho-products were avoided during the preparation. ß 2013 Guo-Ping Peng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Type 2 diabetes Sodium glucose co-transporter 2 Inhibitor Preparation

1. Introduction Sodium glucose co-transporter 2 (SGLT2) plays a key role in maintaining glucose equilibrium in the human body [1]. Much attention has been given to SGLT2 as a molecular target to directly enhance glucose excretion and to safely normalize plasma glucose in the treatment of type 2 diabetes [2]. A promising subset of SGLT2 inhibitors explored was the carbon glycosides in which the bond between the glucose and aglycone is a carbon–carbon bond [3]. It was reported that (1S,30 R,40 R,50 S,60 R)-5-chloro-6-[(4-ethylphenyl)methyl]-30 ,40 ,50 ,60 -tetrahydro-60 -(hydroxymethyl)-spiro [isobenzofuran-1(3H),20 -[2H]pyran]-30 ,40 ,50 -triol 1 may be advancing to clinical development to directly increase glucose excretion and to safely normalize plasma glucose in the treatment of type 2 diabetes [4–6]. Two synthetic routes have been used to synthesize 1. One method is shown in Scheme 1. The key intermediate 16 was prepared by a Fridel-Crafts reaction, but the selectivity for the paraposition over the ortho-position was low. In addition, compound 19 was synthesized by a coupling reaction between 18 and 20 in an unsatisfactory yield and the synthetic route required eleven steps, which was unsuitable for a large scale production [4,5]. The other reported procedure was described by Sato Tsutomu et al. [6]. The target compound was synthesized from 1-bromo-4-chloro-2,5-

* Corresponding author. E-mail address: [email protected] (G.-P. Peng).

dimethylbenzene with an unsatisfactory overall yield of 6%. The synthetic sequence needed twelve steps and was not feasible for industrial scale-ups. 2. Experimental As shown in Scheme 2, a convenient synthetic route was developed. Compound 3 was readily prepared by reacting Nchlorosuccinimide (NCS) with the benzoic acid 2 in CCl4. Acid 3 was treated with SOCl2 in MeOH to afford ester 4. The treatment of 4 with N-bromosuccimide (NBS) in the presence of azodiisobutyronitrile (AIBN) in CCl4 gave 5. Compound 6 was produced in a satisfactory yield by a Suzuki crosscoupling reaction between benzylic halide 5 and 4-ethylphenylboronic acid. Ester 6 was treated with NaBH4 in THF to afford alcohol 7. The treatment of 7 with trimethylsilyl chloride in THF gave silyl ether 8, which was transformed to the D-glucopyranoside 9 in an excellent yield. Compound 9 was hydrogenated under 0.1 MPa of hydrogen in the presence of Pd/C at room temperature to produce 1 in about 39% overall yield. 3. Results and discussion Tetra-kis(triphenylphosphine)palladium (0) and palladium acetate (II), as efficient Pd catalyst precursors, have been used in the Suzuki coupling reactions that allow aryl halides or benzylic

1001-8417/$ – see front matter ß 2013 Guo-Ping Peng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. http://dx.doi.org/10.1016/j.cclet.2013.01.013

Y.-H. Liu et al. / Chinese Chemical Letters 24 (2013) 131–133

132

HO2C

NH2

HO2C

NH2

a

b

MeO2C

Br

MeO2C

MeO2C

Cl

Br

15

Cl g

Cl

MOMO

O

TMSO

Br 18

TMSO

14

CO2H

Cl

HO

h

Br

17

7

Cl

Cl

MOMO j

Cl

Br

Cl

Br

16

O

MeO2C

d

3

MeO2C

Br

COCl

Cl

13

f

e

MeO2C c Br

Br 12

11

i

NH2

O O

OH k

HO HO

OTMS 19 OTMS

OH OH

1

Scheme 1. Reagents and conditions: (a) NBS, DMF, 5 8C; (b) SOCl2, MeOH, reflux; (c) NaNO2, HCl, CuCl2, 1,4-dioxane, H2O, 0 8C; (d) KMnO4, t-BuOH, 18-crown-6, H2O, reflux; (e) (COCl)2, DMF, DCM, r.t.; (f) AlCl3, ethylbenzene, DCM, 5 8C; (g) Et3SiH, CF3SO3H, TFA, reflux; (h) NaBH4, MeOH, THF, reflux; (i) MOMCl, DIPEA, DCM, r.t.; (j) n-BuLi, THF, toluene, (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (20), 78 8C; (k) CH3SO3H, MeOH, r.t.

Br

Br

2

a

COOH

Cl

COOH

3

Br

b Cl

Cl

CO2Me

4

Br

c Br 5

d

MeO2C

CO2Me

Br

Cl

e

6

Cl Cl

HO

f Br

Cl

TMSO

g, h BnO Br

7

8

O

Cl

O i OBn

BnO OBn

HO

O O OH

HO

9

OH

1

Scheme 2. Reagents and conditions: (a) CCl4, NCS, 80 8C, 95%; (b) SOCl2, MeOH, reflux, 96%; (c) CCl4, NBS, AIBN, reflux, 76%; (d) toluene, Pd(OAc)2, PPh3, 4-ethylphenylboronic acid, 80 8C, 4 h, 82%; (e) NaBH4, MeOH, THF, reflux, 96%; (f) THF, trimethylchlorosilane, r.t., 95%; (g) THF/toluene, (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydropyran-2-one (10), 78 8C; (h) THF/toluene, MeSO3H, r.t., 79% (two steps); (i) 10% Pd-C, MeOH, H2 (0.1 MPa), 25 8C, 96%.

halides to be effectively coupled with aryl boronic acids [7–9]. Therefore, a set of experiments were performed in order to optimize the reaction conditions in the synthesis of 6. As shown in Table 1, although both types of catalyst precursors gave the expected coupling product, palladium acetate(II) in the presence of triphenylphosphine using toluene as solvent at 80 8C and K3PO4 as base was the most the effective system (Table 1, entry 4) [10]. The reaction can be carried out with a low catalyst loading and under mild conditions.

In addition, in order to study the solvent effect in the deprotection reaction of the benzyl groups in 9, a series of solvents were screened and the results are shown in Table 2. A mixture of 1 and 1a were found when benzene, toluene, chlorobenzene and 1,2-dichlorobenzene were used as solvents in the deprotection reaction. However, when 20 equiv. of 1,2dichlorobenzene was added in the reaction mixture, by-product 1a could not be detected by LC-MS (Table 2, entry 4) [11–13]. Mechanically, it is possible that the chloro-groups in 1,2-

Table 1 Pd-catalyzed Suzuki cross coupling reaction of 5 with phenylboronic acid. Entry

Pd (mol%)

T (8C)

Time (h)

Yieldc (%)

1a 2a 3a 4a 5b 6b 7b 8b

Pd(OAc)2 (5) Pd(OAc)2 (5) Pd(OAc)2 (1) Pd(OAc)2 (1) Pd(PPh3)4 (10) Pd(PPh3)4 (10) Pd(PPh3)4 (5) Pd(PPh3)4 (5)

25 80 80 80 50 Reflux Reflux Reflux

10 10 10 4 48 48 48 24

11 81 82 82 45 72 61 56

a b c

Reaction conditions: benzylic halide 5 (1 mmol), Pd(OAc)2 (1 mol% or 5 mol%), arylboronic acid (1.5 mmol), K3PO4 (2 mmol), Pd(OAc)2/PPh3 ratio = 2, toluene (5 cm3). Reaction conditions: benzylic halide 5 (1 mmol), Pd(PPh3)4 (5 mol% or 10 mol%), arylboronic acid (1.5 mmol), Na2CO3(4 mmol) in dimethoxyethane (12 cm3). Isolated yields.

Y.-H. Liu et al. / Chinese Chemical Letters 24 (2013) 131–133

133

Table 2 Synthesis of compound 1.

Cl

Cl

O

O BnO

O

BnO

HO

H2/Pd OBn

OBn

EtOAc/MeOH,12 h 9

O

O HO

O

+ HO

OH OH

HO

1

1a

OH OH

Entry

Solvent

Equimolar amounts

Compound 1 yield (%)a

By-product 1a yield (%)a

1

Benzene

2

Toluene

3

Chlorobenzene

4

1,2-Dichlorobenzene

10 20 10 20 10 20 10 20

48 47 49 48 71 80 91 99

51 52 50 50 27 19 7 0

a

Determined by HPLC analysis of crude products before purification.

dichlorobenzene can be reduced to produce hydrochloride, which might inhibit the reduction of the chloro-group in 1. 4. Conclusion In conclusion, a more efficient synthetic route for the synthesis 1 was developed. The overall yield of the sequence was about 39% and the undesired ortho-products in the coupling reaction between the two aryl pieces in the previous reports were avoided using the current method. Acknowledgments This work was financially supported by the Open Project Program of National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, PAPD (ysxk-2010). References [1] D. Mathis, L. Vence, C. Benoist, beta-Cell death during progression to diabetes, Nature 414 (2001) 792–798. [2] T. Asano, T. Ogihara, H. Katagiri, Glucose transporter and Na+/glucose cotransporter as molecular targets of anti-diabetic drugs, Curr. Med. Chem. 11 (2004) 2717–2724. [3] J.R.L. Ehrenkranz, N.G. Lewis, C.R. Kahn, J. Roth, Phlorizin: a review, Diabetes Metab. Res. Rev. 21 (2005) 31–38. [4] L. Binhua, X. Baihua, Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, Bioorg. Med. Chem. Lett. 19 (2009) 6877–6881. [5] L. Binhua, X. Baihua, ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, Bioorg. Med. Chem. Lett. 18 (2010) 4422–4432. [6] S. Tsutomu, H. Kiyofumi, et al., EU Patent, EP 2048153A1, 2009. [7] L. Sandrine, A. Mohamed, Selective double Suzuki cross-coupling reactions. Synthesis of unsymmetrical diaryl (or heteroaryl) methanes, Tetrahedron Lett. 44 (2003) 9255–9258. [8] C. Sultan, E.G. Paris, Palladium catalyzed cross-coupling between phenyl or naphthylboronic acids and benzylic bromides, Tetrahedron Lett. 40 (1999) 7599–7603. [9] M.N. Sabrina, L.M. Adriano, Synthesis of diarylmethane derivatives from Pdcatalyzed cross-coupling reactions of benzylic halides with arylboronic acids, Tetrahedron Lett. 45 (2004) 8225–8228.

[10] Typical procedure for the synthesis of 6: To a solution of 4-ethylphenylboronic acid (0.225 g, 1.5 mmol) in toluene (5 mL) was added Pd(OAc)2 (2.3 mg, 0.01 mmol) under an argon atmosphere, and PPh3 (1.5 mg, 0.005 mmol) and K3PO4 (0.4 g, 2 mmol) were added sequentially. The mixture was stirred for 10 min at room temperature, and 5 (0.26 g, 1 mmol) was added. The reaction mixture was stirred for 4 h at 80 8C under an argon atmosphere, cooled to room temperature, and treated with water. The resultant mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow oil (0.3 g, 82%). [11] Typical procedure for the synthesis of 9: To a stirred 78 8C solution of 8 (0.41 g, 1 mmol) in 1:2 anhydrous THF/toluene (10 mL) was slowly added n-BuLi (1 mL, 1.1 mol/L in hexane) to maintain the temperature below 70 8C. After stirring for 30 min, this solution was added to a stirred solution of (3R,4S,5R,6R)-3,4,5tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-pyran-2-one 10 (0.64 g, 1.2 mmol) in toluene (5 mL) to maintain the temperature below 65 8C, then the solution was stirred for 5 h at 78 8C, and the reaction was quenched by a solution of methanesulfonic acid (214 mg, 2.2 mmol) in THF (5 mL). The mixture was stirred for 24 h at room temperature and quenched with saturated NaHCO3. The mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give oil, which was purified by silicon column chromatography to get a colorless oil (0.62 g, 79%). Rf = 0.35 (petroleum ether/EtOAc, 8:1, v/v). [12] Typical procedure for the synthesis of 1: To a solution of 9 (2.6 g, 3.33 mmol) in 2:3 EtOAc/MeOH (30 mL), 0.25 g palladium on carbon and 1,2-dichlorobenzene (10 mL) was added sequentially. The air of the reactor was removed by argon, then the 0.1 MPa H2 was applied for 12 h at 25 8C. The solvent was filtrated, the filter cake was washed by EtOAc, and the filtrate was concentrated in vacuo to give oil. The oil was purified by silicon column chromatography to get a glassy off white solid (1.35 g, 96%). Rf = 0.35 (MeOH/EtOAc, 1:5, v/v). [13] Selected data compounds: 6: 1H NMR: (300 MHz, CDCl3): d 7.96 (s, 1H), 7.54 (s, 1H), 7.32 (d, 2H, J = 7.8 Hz), 7.11 (d, 2H, J = 7.8 Hz), 4.11 (s, 2H), 3.82 (s, 3H), 2.74 (q, 2H, J = 7.8 Hz), 1.26 (t, 3H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3): d 168.9, 150.3, 142.4, 138.9, 134.6, 133.6, 132.8, 130.9, 129.5, 128.7, 121.7, 53.5, 36.3, 28.5, 14.7; MS: m/z 366 [M+]; 389 [M++Na+]; Anal. Calcd. for C17H16BrClO2: C 55.53, H 4.39; Found: C 55.49, H 4.41; 9 1H NMR (300 MHz, CDCl3): d 7.52 (d, 1H, J = 1.5 Hz), 7.38–7.42 (m, 6H), 7.29–7.32 (m, 9H), 7.17–7.21 (m, 4H), 7.11 (d, 4H, J = 1.2 Hz), 7.08 (d, 2H, J = 8.4 Hz), 4.88–4.96 (m, 3H), 4.72 (S, 2H), 4.56–4.67 (m, 3H), 4.46 (d, 1H, J = 10.8 Hz), 4.16–4.22 (m, 2H), 3.88 (d, 1H, J = 8.4 Hz), 3.82 (s, 1H), 3.66–3.77 (m, 4H), 3.36 (d, 1H, J = 9.6 Hz), 2.60 (q, 2H, J = 7.6 Hz), 1.24 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CH3OD): d 139.8, 138.6, 137.6, 130.5, 129.5, 129.1, 129.0, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.4, 101.2, 85.6, 84.9, 79.8, 78.9, 78.5, 77.5, 76.4, 75.6, 74.9, 73.6, 70.2, 62.7, 39.4, 28.8, 16.0; MS: m/ z 780 [M+]; 803 [M++Na+]; Anal. Calcd. for C50H49ClO6: C 76.86, H 6.32; Found: C 76.47, H 6.43; 1: 1H NMR (300 MHz, CH3OD): d 1.19 (t, 3H, J = 7.5 Hz), 2.57 (q, 2H, J = 7.5, 7.8 Hz), 3.41–3.47 (1H, m), 3.64 (dd, 1H, J = 6 Hz), 3.73–3.83 (m, 4H), 3.95 (s, 2H), 5.11 (dd, 2H, J = 7.8, 12.3 Hz), 7.06–7.12 (m, 4H), 7.16–7.23 (m, 3H); 13C NMR (100 MHz, CH3OD): d 143.3, 142.8, 140.8, 139.7, 138.2, 131.6, 130.8, 129.6, 128.8, 127.8, 125.6, 83.6, 77.2, 72.6, 71.4, 66.1, 62.7, 36.8, 28.6, 15.6; MS: m/z 420 [M+]; 443 [M++Na+]; Anal. Calcd. for C22H25ClO6: C 62.78, H 5.99; Found: C 62.71, H 6.02.