ARTICLE pubs.acs.org/OPRD
Process Research on the Asymmetric Hydrogenation of a Benzophenone for Developing the Manufacturing Process of the Squalene Synthase Inhibitor TAK-475 Mitsutaka Goto,*,† Takahiro Konishi, Shinji Kawaguchi, Masatoshi Yamada, Toshiaki Nagata, and Mitsuhisa Yamano †
Chemical Technology Department, Takeda Pharmaceutical Co. Ltd., 4720, Takeda, Mitsui, Hikari, Yamaguchi 743-8502, Japan Chemical Development Laboratories, CMC center, Takeda Pharmaceutical Co. Ltd., 2-17-85, Juso-Honmachi, Yodogawa-ku, Osaka 532-8686, Japan
bS Supporting Information ABSTRACT: A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene synthase inhibitor TAK-475 (1), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7, employed Noyori’s ruthenium precatalyst of the type [RuCl2(diphosphine)(diamine)]. We focused on tuning of the chiral diphosphine, and have discovered a novel ligand, DADMP-BINAP (18c), for the catalyst that has allowed reduction of the operating pressure in the asymmetric hydrogenation. The precatalyst containing 18c performed effectively at low hydrogen pressure (99
95 90
5
18e
6
6 (R)
6
18f
7
36
7
18g
56
35
8
18h
17
15
Reactions were carried out at 4 MPa of H2 for 24 h at 43 °C using 3 mmol of the substrate 7 with Ru complex25 and (S,S)-DPEN in 2-propanol/THF. Substrate/Ru/(S,S)-DPEN/KOH = 1000:1:10:20. b 13 was prepared in situ by charging (S,S)-DPEN with the Ru complex25 containing the corresponding BINAP analogue (18). c 18a18h was prepared with our method for synthesis of BINAP analogues, which is shown in scheme 4.
13b L: 18
H2 [MPa]
time [h]
% conv.
%ee(S)
1
18b
4
65
>99
94
2
18b
1
65
>99
90
3 4
18c 18c
4 1
48 50
>99 >99
95 96
a Reactions were carried out at 43 °C using 10 mmol of the substrate 7 with Ru complex25 and (S,S)-DPEN in 2-propanol/THF. Substrate/ Ru/(S,S)-DPEN/KOH = 1000:1:10:20. b 13 was prepared in situ by charging (S,S)-DPEN with the Ru complex25 containing the corresponding BINAP analogue (18).
Table 3. Asymmetric hydrogenation of 7 using 13c under low hydrogen pressure; influence of reaction temperaturea
a
We developed an alternative method for the preparation of BINAP analogues in our previous studies (Scheme 4).20c,21 The advantage of our method is that phosphineborane complexes are used as a phosphine source and these are easier to handle because of their greater stability towards oxygen and moisture, compared to other phosphine sources such as diphenylphosphine and diphenylchlorophosphine. A large number of phosphineborane complexes (20) were directly synthesized from the corresponding phosphine oxides (16) using a simple reaction involving treatment with lithium aluminum hydride and sodium borohydride activated by cerium chloride,22 or a reduction in boranetetrahydrofuran solution (Scheme 4).23 More than 30 BINAP analogues, including novel compounds, were prepared using the corresponding phosphineborane complexes, and some of them were synthesized on multihundred gram scale. Screening of BINAP Analogues for Fine-Tuning of the Ru Precatalyst 13. Optimization of the Ru precatalyst 13 for
entry
% conv.
% ee (S)
TOFb [h1]
60
85
96
29.0
50
>99
95
55.4
45 24
>99 >99
93 81
81.7 191.3
entry
temp. [°C]
time [h]
1c
23
2
30
3 4
40 60
a
Reactions were carried out at 1 MPa of H2 using 10 mmol of the substrate 7 with 13c in 2-propanol/THF. Substrate/Ru/KOH = 1000:1:20. b Turnover frequency, which is defined as moles of the product per mole of the catalyst per hour. c Entry 1 using Ru complex25 and (S,S)-DPEN instead of 13c.
asymmetric hydrogenation of the benzophenone 7 has been studied, utilizing the available BINAP ligand diversity. The screening of BINAP analogues was conducted for the asymmetric hydrogenation of 7 using in situ prepared 13, by charging (S,S)-DPEN with the Ru complex25 containing the corresponding BINAP analogues (18). On the first screening, the lower alkyl group substituents (such as methyl and ethyl groups) at the 3,5-positions of the aryl moieties of the BINAPs (18bd) were found to markedly increase the enantioselectivity (Table 1, entries 24). Among the BINAPs, 18b and 18c24 led to the highest enantioselectivity, affording 9495% ee (entries 2, 3). This “3,5dialkyl meta-effect” has been described in several reports,26 and it was supposed to arise from steric and electronic effects on the phosphorus atom. Hence, when the meta substituents were bulkier (such as tert-butyl group; 18e and 18f), both the enantioselectivity 1180
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Table 6. Optimization of other conditions for scale-upa amount of entry
Figure 1. Ru complexes for precursor of 13.
waterb [% v/v] S/C time [h] % conv. % ee (S) TOFc [h1]
1
1000
45
99.9
93
81.7
2
0.35%
1000
45
99.8
91
84.8
3
0.70%
1000
45
99.6
91
64.0
4
2000
65
99.9
90
68.5
5
3000
96
99.3
90
73.5
Reactions were carried out at 1 MPa of H2 at 40 °C using 10 mmol of the substrate 7 with 13c in 2-propanol/THF. Ru/KOH = 1:2030. b To entries 2 and 3 were added 0.35% and 0.70% of water, respectively. c Turnover frequency, which is defined as moles of the product per mole of the catalyst per hour. a
Table 4. Asymmetric hydrogenation of 7; comparison of Ru complexesa entry
Ru complexes
time [h]
% conv.
% ee (S)
TOFb [h1]
1c
13c
39
>99
95
55.4
2
22c
40
86
86
34.6
3
23c
60
>99
96
41.3
Reactions were carried out at 1 MPa of H2 at 30 °C using 10 mmol of the substrate 7 with Ru complex and (S,S)-DPEN in 2-propanol/THF. Substrate/Ru/(S,S)-DPEN/KOH = 1000:1:10:20. b Turnover frequency, which is defined as moles of the product per mole of the catalyst per hour. c (S,S)-DPEN was not added. a
Table 5. Asymmetric hydrogenation of 7 using 13c; influence on the residual amount of 22ca entry
22c/ 13cb
% conv.
% ee (S)
TOFc [h1]
1
99
95
55.4
2
0.05
>99
94
3
0.11
>99
89
37.2
a Reactions were carried out at 1 MPa of H2 at 30 °C using 10 mmol of the substrate 7 with 13c in 2-propanol/THF. Substrate/Ru/KOH = 1000:1:2030. b The ratio was calculated from the integral area of 31 P NMR. c turn over frequency, which is defined as moles of the product per mole of the catalyst per hour.
Scheme 5. Preparation of highly pure 13c
and the conversion rate of this reaction decreased remarkably (entries 5, 6). In the next step, we compared 18b and 18c under the mild conditions that had given the best results on the first screening. Interestingly, hydrogen pressure affected the enantioselectivity in this reaction (Table 2). When the hydrogen pressure was decreased to 1 MPa, 18c gave a slightly increased ee value, up to 96% ee, whereas 18b gave a lower ee at this condition. Moreover, the reaction rate when using 18c was shown to be three times higher than that for 18b. Therefore, it is suggested that increasing the electron density on the phosphorus, which will occur when using aryl substituents with 4-dimethylamino groups, has a desirable effect on the asymmetric hydrogenation of 7.27
Furthermore, we evaluated the influence of reaction temperature for Ru precatalyst 13c containing 18c, and found that it also strongly influenced the enantioselectivity (Table 3). There was a clear tendency for increased enantioselectivity of 8 under milder conditions, similar to that seen for reduced hydrogen pressure. However, the reaction rate decreased at lower temperature. Thus, the optimum reaction temperature was 3040 °C, which gave a balance of both selectivity and productivity. In the case of reacting at higher temperatures, such as 60 °C, the enantioselectivity sharply decreased to 81% ee. Examination of Ru Precatalyst Preparation. To the best of our knowledge, Noyori’s ruthenium precatalyst of the type [RuCl2(diphosphine)(diamine)] is generally synthesized via the Ru complexes, [RuC12(diphosphine)(dmf)n], [NH2(C2H5)2][{RuCl(diphosphine)}2(μ-Cl)3], or [RuC1(diphosphine)(η6-arene)]Cl by treatment with a chiral diamine (Figure 1).28 Some of the Ru precatalysts containing BINAP analogues have been obtained as isolated compounds, while many of them have been prepared in situ.29 In the case of the in situ preparation of Ru precatalyst (13), however, the reaction rate is remarkably decreased compared to that obtained with the isolated ones.28,30 Regarding the asymmetric hydrogenation of 7, we also confirmed that the isolated 13c gave the fastest reaction among these Ru complexes (Table 4). Therefore, we decided to use the isolated 13c as the Ru precatalyst. The synthesis of 13c was conveniently accomplished by the reaction of 22c with (S,S)-DPEN. This reaction was incomplete in 2-propanol at 25 °C, and 1015% of 22c remained (observed by 31P NMR). This incomplete formation of 13c has been recognized as a major problem, as even a slight contamination of 13c by 22c causes a decrease in the enantioselectivity. (Table 4, entry 2) To further study the effect of contamination of 13c by 22c, we confirmed that the presence of 22c adversely affected the enantioselectivity by spike testing the asymmetric hydrogenation with 22c (Table 5). In a bid to complete the conversion to 13c, we found that it was important to select the appropriate reaction conditions of temperature and solvent (Scheme 5), and the reaction went to completion in DMF at 90 °C. After crystallization from 2-propanol, pure 13c was obtained in 79% yield. On the other hand, the precursor 23 was generally synthesized by treatment of [RuCl2(cod)]n with the diphosphine ligand in the presence of triethylamine.31 However, the synthesis of [NH2(C2H5)2][{RuCl[(S)-dadmp-binap]}2(μ-Cl)3] (23c) gave only low yield by the general method. Development of Robust Conditions for Scale-Up. It was found that the asymmetric hydrogenation of 7 could be performed 1181
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Scheme 6. Scale-up synthesis of 8
at high concentration by the addition of THF to the 2-propanol solvent, to improve the solubility of 7. Next, we investigated the effect of water on the reaction, and it was found that it slowed the reaction significantly. This tendency was revealed by the fact that the turnover frequency (TOF) dropped to 64 h1 with a slight presence (0.70%) of water. Thus, the concentration of water in the reaction system must be controlled to less than 0.35% to achieve sufficient reaction rate in scale-up operations (Table 6, entries 2, 3). Therefore, we decided to use dehydrated solvents and careful protocols as to degas and purge on large-scale operations in order to prevent an invasion of water. During our studies for optimization, the reaction could be conducted easily on a preparative scale with a substrate to catalyst (S/C) mole ratio of 1000. We challenged the reduction of catalyst loading, and robust and reproducible conversion could be achieved at a lower loading level up to S/C 3000 (entries 4, 5). However, when the catalyst loading was lower, the reaction rate was slowed significantly, and TOF dropped to 6974 h1. Consequently, we decided to implement scale-up operations at S/C 2000. Subsequently, for the purpose of confirming the robustness and reproducibility on the optimum conditions, we could carry out scaleup reaction in a pilot plant. Under these optimum conditions, we successfully manufactured 8 on a large scale using a catalyst loading of S/C 2000 and a hydrogen pressure of 0.85 MPa (Scheme 6) without any incidents. The reaction gave full-conversion in 94% ee.32 After recrystallization from ethylacetate/n-heptane, the perfectly enantiopure 8 (>99.9% ee) was obtained in 82% yield.
’ CONCLUSION In conclusion, a highly enantioselective synthesis of the chiral benzhydrol 8, which is the key intermediate of TAK-475 (1), was established via asymmetric hydrogenation developed using the fine-tuned Noyori’s ruthenium precatalyst (13c), which consisted of a BINAP analogue 18c as the novel diphosphine ligand. Using the precatalyst, asymmetric hydrogenation of the prochiral benzophenone (7) proceeded with high enantioselectivity under low hydrogen pressure (99.9% ee). 1H NMR (300 MHz, CDCl3): δ 3.30 (1H, m), 3.80 (3H, s), 3.86 (3H, s), 4.17 (2H, s), 6.00 (1H, d, J = 4.9 Hz), 6.54 (1H, d, J = 8.4 Hz), 6.88 (2H, d, J = 8.0 Hz), 6.997.08 (3H, m). 13C NMR (75 MHz, CDCl3): δ 55.8, 61.0, 69.2, 112.3, 117.5, 119.7, 122.8, 124.6, 127.3, 128.2, 129.0, 134.8, 143.4, 146.3, 152.5. IR (KBr), cm1: 3418, 1585, 1039, 789. Anal. Calcd for C15H16NO3Cl: C, 61.33; H, 5.49; N, 4.77; Cl, 12.07. Found: C, 61.32; H, 5.40; N, 4.67; Cl, 12.13. Residual amount of ruthenium: 0.15 ppm.
’ ASSOCIATED CONTENT
bS
Supporting Information. NMR spectra of 8, 13c, 18c, 18d, 18f, and 18h and crystallographic information files for 13c. This material is available free of charge via the Internet at http:// pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Telephone: +81-6-6300-6433. Fax: +81-6-6300-6251. E-mail:
[email protected].
’ ACKNOWLEDGMENT We thank Ms. Keiko Higashikawa and Mr. Yoichi Nagano for X-ray crystallographic analysis, Dr. Masahiro Kajino and 1183
dx.doi.org/10.1021/op2001673 |Org. Process Res. Dev. 2011, 15, 1178–1184
Organic Process Research & Development Dr. Atsuhiko Zanka for their fruitful discussions, Mr. Satoru Oi, Mr. Yuzuru Saito, and Mr. Seiji Tajima for helpful discussions. We also thank Takasago Int. Co. for cordial collaboration on developing asymmetric hydrogenation.
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(14) Abbreviations: (S)-XylBINAP (18b) = (S)-2,20 -bis[bis(3,5dimethylphenyl)phosphino]-1,10 -binaphthhyl. (S)-DAIPEN = (2S)1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine. (S,S)-DPEN = (1S,2S)-1,2-diphenylethylenediamine. (15) This technology has been developed in collaboration with Takasago Int. Co.: Sakaguchi, T; Imai, T.; Miura, T.; Yamazaki, T.; Okada, T. Chem. Abstr. 1997, 127, 262513.JP/09/235255 A 1997. For a large scale preparation of 8 using 13b see: ref 4b. (16) For a review see: Shimizu, H; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405–5432. (17) (a) Schmid, R.; Foricher, J.; Cereghetti, M.; Sch€onholzer, P Helv. Chim. Acta 1991, 74, 370–389. (b) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher, J.; Lalinde, M.; M€uller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996, 68, 131–138. (c) Scalone, M.; Waldmeier, P. Org. Process Res. Dev. 2003, 7, 418–425. (18) Miyashita, A; Yasuda, A; Takaya, H; Toriumi, K; Ito, T; Souchi, T; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932–7934. (19) Ager, D. J.; East, M. B.; Eisenstadt, A.; Laneman, S. A. Chem. Commun. 1997, 2359–2360. (20) (a) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagwa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629–635. (b) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagwa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064–3076. (c) For a review see : Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105, 1801–1836. (21) Goto, M.; Yamano, M. Chem. Abstr. 2003, 139, 36636.WO/ 2003/048174 A1 2003. (22) Imamoto, T.; Kusumoto, T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc. 1985, 107, 5301–5303. (23) Yamano, M.; Goto, M.; Yamada, M. Chem. Abstr. 2004, 142, 6662.WO/2004/101580 A1 2004. (24) Abbreviation: (S)-DADMP-BINAP (18c) = (S)-2,20 -bis[bis(4-dimethylamino-3,5-dimethylphenyl)phosphino]-1,10 -binaphthyl. (25) Ru complex containing [NH2(C2H5)2][{RuCl(diphosphine)}2(μ-Cl)3] was prepared by treatment of [RuCl2(cod)]n with the diphosphine (L) in the presence of triethylamine under toluene reflux. After removing the solvent, the concentrated residue was used for reaction without further purification. (26) (a) Selvakumar, K.; Valentini, M.; Pregosin, P. S.; Albinati, A.; Eisentr€ager, F. Organometallics 2000, 19, 1299–1307. (b) RajanBabu, T. V.; Ayers, T. A.; Halliday, G. A.; Kimberly, K. Y.; Calabrese, J. C. J. Org. Chem. 1997, 62, 6012–6028. (27) (a) Morimoto, T.; Chiba, M.; Achiwa, K. Tetrahedron Lett. 1988, 29, 4755–4758. (b) Toth, I; Hanson, B. E.; Davis, M. E. Tetrahedron: Asymmetry 1990, 1, 913–930. (28) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703–1707. (29) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 1086–1087. (30) Yamano, T.; Oi, S.; Yamashita, M. Chem. Abstr. 2001, 135, 19434.WO/2001/040162 A1 2001. (31) Ikariya, T.; Ishii, Y.; Kawano, H.; Arai, T.; Saburi, M.; Yoshikawa, S.; Akutagawa., S. J. Chem. Soc., Chem. Commn. 1985, 922–924. (32) There was slight unevenness of the ee ratio of 8 for different lots of 13c. We supposed that there could be another potential impurity affecting 13c, e.g. dimethylamine that is generated by thermal decomposition of DMF.
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