Novel and Efficient Debenzylation of N-Benzyltetrazole Derivatives with the Rosenmund Catalyst

Abstract

The Rosenmund catalyst (Pd/BaSO₄) was found to efficiently catalyze debenzylation of N-benzyltetrazole derivatives with ammonium formate by catalytic transfer hydrogenation under mild conditions. The protocol has been applied to functionalized substrates to provide various angiotensin II receptor blockers in excellent yields.

Clean deprotection is quite significant in order to obtain functionalized compounds in high yield with retention of the formed structure and functional groups as such.[1] Even if every required structural motif is already installed in the protected target compound, the efficiency of the entire synthetic process would be remarkably compromised by a poor yield or a lack of success of the final deprotection. Sometimes an unexpected poor yield in the deprotection stage forces the researcher to go back to the initial stage of the synthesis to change the protecting group and thereby improve the later deprotection yield. In the course of our synthetic studies on angiotensin II receptor blockers (ARBs),[2] a facile method for the debenzylation of N-benzyltetrazole derivatives 1 (Figure [1]) was required as the benzyl protecting group is indispensable for permitting formation of the required biphenyl skeleton by ruthenium-catalyzed C–H arylation. Disclosed in this paper is a practical protocol for the debenzylation of N-benzyltetrazole derivatives 1 employing the Rosenmund catalyst (Pd/BaSO_4­) and an application to the synthesis of ARBs.[3]

In our process development on olmesartan medoxomil, a type of ARB, a high-yielding removal of the benzyl protecting group of an intermediate 1a was required (Table [1]). The debenzylated product 2a is an intermediate for olmesartan medoxomil.[4] We have successfully used catalytic transfer hydrogenation (CTH) for the debenzylation of N-benzyltetrazole derivatives.[2d] Hence, the reported conditions were first tested for the deprotection of 1a; however, to our surprise, no reaction took place when palladium on carbon and ammonium formate in aqueous isopropyl alcohol was employed (Table [1], entry 1). To overcome this drawback, we screened other types of catalysts and unexpectedly found that the poisoned supported palladium catalyst Pd/CaCO₃ (Lindlar catalyst) worked well to provide the desired debenzylated product 2a in a high conversion (74%; Table [1], entry 2) and, gratifyingly, that another poisoned catalyst, Pd/BaSO₄ (Rosenmund catalyst), gave exceptional debenzylation to provide 2a both in an excellent conversion and in a high yield (93% conversion, 84% yield; Table [1], entry 3). Both the tertiary hydroxy group and the biphenylmethyl group are inert to the reaction conditions. Any change from the optimal conditions resulted in much inferior outcomes. When the reaction was conducted under hydrogen atmosphere, very poor conversion was obtained (20%; Table [1], entry 4).

Table 1 Debenzylation of Olmesartan Medoxomil Intermediate 1a

Entry	Reductant	Catalyst	Solvent	Tempa (°C)	Timea (h)	Convb (%)
1	HCO2NH4	5% Pd/C	i-PrOH–H2O	55	23	0
2	HCO2NH4	5% Pd/CaCO3	i-PrOH–H2O	55 65	4  3	74
3	HCO2NH4	5% Pd/BaSO4	i-PrOH–H2O	55	11	93 (84c)
4	H2 (1 atm)	5% Pd/BaSO4	i-PrOH–H2O	25 40 50	2  6  5	20
5	NaH2PO2·xH2O	5% Pd/BaSO4	i-PrOH–H2O	55 60 70	3  3  6	0
6	cyclohexene	5% Pd/BaSO4	i-PrOH–H2O	55	5	0
7	CO2NH4	5% Pd/BaSO4	EtOAc–H2O	55 70	15 15	0
8	CO2NH4	5% Pd/BaSO4	n-BuOH–H2O	55 70	15 15	0

^a The reaction was conducted by sequential elevation of the temperature, as shown in the table.

^b Conversion as determined by HPLC and shown as % of the consumed substrate.

^c Isolated yield.

The use of other reductants (such as NaH₂PO₂·xH₂O and cyclohexene) and other combinations of aqueous solvent (such as aq EtOAc and aq n-BuOH) resulted in no conversion at all (Table [1], entries 5–8). The better results with isopropyl alcohol might be because of its ability to act as a reductant. The reason as to why the Rosenmund catalyst is so active for the debenzylation is not clear.[5] Indeed, all attempts to use various palladium on carbon catalysts for the debenzylation of this particular substrate 1a failed.

The scope of the new protocol was examined for the debenzylation of various N-benzyltetrazole derivatives, including final intermediates of ARBs. First, the debenzylation of N-benzyllosartan (1b) was tested. The reaction proceeded smoothly and selectively without accompanying undesirable dechlorination (97% conversion, 71% yield; Table [2], entry 1). It should be noted that in our previous synthesis of losartan, a 4-methoxybenzyl protecting group was employed in place of the benzyl group for protection of the tetrazole moiety; the deprotection yield using trifluoroacetic acid was low because of considerable side reactions initiated by benzyl cation generated by the acid treatment.[2a] In contrast, the present deprotection worked well because the reaction proceeds under neutral conditions (pH 7.0). Then, deprotection of N-benzylvalsartan benzyl ester (1c) was tested. Very rapid cleavage of the benzyl ester followed by removal of the N-benzyl group took place to furnish valsartan in a high yield (71%; Table [2], entry 2). Both N-benzylcandesartan cilexetil[2d] (1d) and N-benzylirbesartan (1e) were debenzylated smoothly to provide the corresponding active pharmaceutical ingredients (APIs) in high yield (80% and quantitative, respectively; Table [2], entries 3 and 4). A simple N-benzyltetrazole derivative 1f [2] was subjected to the reaction conditions which also gave the desired product in high yield (86%; Table [2], entry 5). In all cases listed in Table [2], products of excellent quality were obtained due to the very mild reaction conditions employed in the new protocol.

Table 2 Debenzylation of N-Benzyltetrazole Derivatives 1b–f

Entry	Substrate		Temp (°C)	Time (h)	Conva (%)	Yieldb (%)
1	1b		60	8	97	71
2	1c		65	11	99	71
3	1d		25	14	93	80
4	1e		55	3.5	100	100
5	1f		60–65	22	100	86

^a Conversion as determined by HPLC.

^b Isolated yield.

The substrates for the debenzylations (1a, 1b, 1c, 1d,[2d] 1e) were prepared from 1-benzyl-5-phenyl-1H-tetrazole (1f) by alkylation of functionalized side chains with a bromide which was synthesized by means of C–H arylation of 1f (Scheme [1]). The bromide 3 is regarded as a common intermediate for ARBs. Hence, by combining the present facile deprotection, ARBs (losartan, valsartan, candesartan cilexetil, olmesartan medoxomil and irbesartan) have become accessible in a highly convergent and practical manner.

Tetrazole is an important structural motif as an aromatic carboxylic acid surrogate in medicinal chemistry and many pharmaceuticals contain this unit.[6] For the synthesis of tetrazole derivatives, proper selection of the N-protecting group has been a significant challenge. For instance, most of the syntheses of ARBs have been conducted by using a labile and easy-to-remove trityl group as the protecting group.[6] However, the trityl group is quite bulky and is not resistant to strong acidic conditions which has limited its practical use in the synthesis of tetrazole derivatives. The present efficient debenzylation protocol allows the stable and comparatively small benzyl group as the protecting group, and thus would considerably improve the atom economy and expand the scope of the reactions in the synthesis of tetrazole derivatives.

In conclusion, a novel and efficient method for the debenzylation of N-benzyltetrazole derivatives employing the Rosenmund catalyst has been developed. The ease of operation and low price of the reagents, as well as the high yield and selectivity of the reaction, would permit ready access to functionalized tetrazole derivatives of pharmaceutical importance.

Melting points were determined on a Veego VMP-PM melting point apparatus and are uncorrected. ¹H and ¹³C NMR spectra were recorded on a Bruker 400 MHz spectrometer with TMS as an internal standard. IR spectra were recorded on an ABB FTLA-2000-104 FT-IR spectrophotometer. HRMS was conducted by ESI-TOF on a Shimadzu 8030 LC mass spectrometer. Silica gel column chromatography was performed using Kieselgel 60 (E. Merck). TLC was carried out on 0.25-mm precoated glass-backed plates (E. Merck, silica gel 60 F₂₅₄) and developed using 5% phosphomolybdic acid in EtOH with heating or visualized by UV light where feasible.

Ethyl 1-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate (1a)

Into a 100-mL two-neck flask were sequentially added imidazole 4 (5 g, 21.0 mmol), bromide 3 (9.05 g, 22.3 mmol), K₂CO₃ (5.1 g, 37.4 mmol) and MeCN (50 mL) at 25 °C. The reaction mixture was heated at 84 °C until completion of the reaction (18 h). Then, the mixture was cooled to 25 °C and filtered through Celite^®. The Celite^® bed was washed with EtOAc (2 × 10 mL). To the combined EtOAc layer was added H₂O (100 mL). The resulting two layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with 2% aq HCl (30 mL) followed by brine (150 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give 1a; yield: 9.78 g (83%); mp 88–91 °C.

IR (KBr): 3416, 2967, 1702, 1466, 1218, 1172 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.64 (dt, J = 7.6, 1.2 Hz, 1 H), 7.50 (dd, J = 7.6, 1.2 Hz, 1 H), 7.43 (dt, J = 7.6, 1.2 Hz, 1 H), 7.31 (dd, J = 7.6, 1.2 Hz, 1 H), 7.27–7.20 (m, 1 H), 7.08 (d, J = 8.2 Hz, 4 H), 6.83 (d, J = 8.2 Hz, 2 H), 6.78 (d, J = 8.0 Hz, 2 H), 5.42 (s, 2 H), 4.82 (s, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 2.63 (t, J = 7.6 Hz, 2 H), 1.75–1.64 (m, 2 H), 1.61 (s, 6 H), 1.15 (t, J = 7.2 Hz, 3 H), 0.97 (t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.5, 158.9, 154.3, 151.3, 141.2, 138.0, 137.1, 132.9, 131.5, 131.0, 130.2, 129.0, 128.7, 128.6, 127.9, 127.8, 125.9, 122.7, 116.8, 70.3, 61.2, 50.8, 48.6, 29.3, 29.2, 21.3, 13.9, 13.8.

MS: m/z = 565 [M + H]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₆N₆O₃Na: 587.2747; found: 587.2750.

Ethyl 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (2a)

Into a 10-mL single-neck flask were sequentially added 1a (0.3 g, 0.53 mmol), ammonium formate (0.16 g, 2.58 mmol), 5% Pd/BaSO₄ (0.057 g, 5 mol%), i-PrOH (3 mL) and H₂O (1.8 mL) at 25 °C. The reaction mixture was heated at 55 °C until completion (11 h). Then, the mixture was cooled to 25 °C and filtered through Celite^®. The filtrate was concentrated under reduced pressure. The crude product was column chromatographed (2–3% MeOH in CH₂Cl₂) to provide 2a; yield: 0.212 g (84%); mp 150.3 °C.

IR (KBr): 1706, 1604, 1273 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 7.6 Hz, 1 H), 7.60–7.52 (m, 2 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.12 (d, J = 8.75 Hz, 2 H), 6.81 (d, J = 8.0 Hz, 2 H), 5.40 (s, 2 H), 4.18 (q, J = 7.2 Hz, 2 H), 2.38 (t, J = 7.2 Hz, 2 H), 1.70–1.65 (m, 2 H), 1.45 (s, 6 H), 1.25 (s, 1 H), 1.13 (t, J = 7.2 Hz, 3 H), 0.91 (t, J = 7.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.6, 158.5, 155.5, 151.6, 140.8, 138.9, 136.4, 131.2, 130.8, 130.5, 129.5, 128.1, 125.3, 123.5, 117.1, 70.5, 61.7, 48.9, 29.0, 28.7, 21.7, 13.8.

MS: m/z = 475 [M + H]⁺.

HPLC conditions: Cadenza CD-C-18 column (3 μm × 4.6 mm × 180 mm); mobile phase A: 0.03 M KH₂PO₄–MeCN, 95:5; mobile phase B: 0.03 M KH₂PO₄–MeCN, 40:60; gradient program (% B/time): 60/0, 60/5, 90/15, 90/30, 60/35, 60/40; flow rate: 1.0 mL/min; injection volume: 10 μL; column oven temperature: 40 °C.

1-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (6)

Into a 25-mL two-neck flask were sequentially added 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (5; 0.2 g, 1.11 mmol), bromide 3 (0.48 g, 1.18 mmol), K₂CO₃ (0.25 g, 1.82 mmol) and MeCN (5 mL) under nitrogen atmosphere at 25 °C. The reaction mixture was heated at 80–85 °C until completion (20 h). The mixture was cooled to 25 °C, then filtered through a sintered funnel and washed with MeCN (10 mL). The resulting mixture was concentrated under reduced pressure. The obtained crude product was purified using column chromatography (18–20% EtOAc in hexane) to give 6; yield: 0.419 g (74%); mp 103.8 °C.

IR (KBr): 1665, 1517, 1459, 1275 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.76 (s, 1 H), 7.65–7.61 (m, 1 H), 7.53 (dd, J = 8.0, 1.2 Hz, 1 H), 7.44 (dt, J = 7.6, 1.2 Hz, 1 H), 7.33 (dd, J = 7.6, 1.2 Hz, 1 H), 7.24–7.14 (m, 3 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.78 (d, J = 7.6 Hz, 2 H), 5.52 (s, 2 H), 4.80 (s, 2 H), 2.61 (t, J = 7.6 Hz, 2 H), 1.72–1.64 (m, 2 H), 1.40–1.31 (m, 2 H), 0.90 (t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.2, 140.9, 138.6, 135.5, 132.9, 131.6, 131.2, 130.2, 129.2, 128.7, 128.6, 128.0, 127.8, 126.9, 124.2, 122.6, 50.8, 47.8, 29.2, 26.4, 22.3, 13.6.

MS: m/z = 511 [M + H]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₂₉H₂₇ClN₆ONa: 533.1833; found: 533.1832.

(1-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-2-butyl-4-chloro-1H-imidazol-5-yl)methanol (N-Benzyllosartan, 1b)

Into a 25-mL two-neck flask were sequentially added aldehyde 6 (0.38 g, 0.74 mmol), MeOH (1.8 mL) and toluene (0.76 mL) under nitrogen atmosphere at 25 °C. The mixture was cooled to 0–5 °C, which was followed by the addition of NaBH₄ (0.028 g, 0.73 mmol) and stirring for 5 min at 0–5 °C. The reaction mixture was slowly warmed to 25 °C and stirred for a further 0.5 h. Then, the mixture was cooled to 10 °C, and H₂O (1 mL) and EtOAc (5 mL) were sequentially added. The two layers were separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with H₂O (2 × 10 mL) and brine (10 mL), and concentrated under reduced pressure. The obtained crude product was purified using silica gel column chromatography (EtOAc–hexane, 3:7) to give 1b; yield: 0.30 g (79%); mp 144.8 °C.

IR (KBr): 2935, 1725, 1577, 1256 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.51 (t, J = 7.6 Hz, 1 H), 7.40 (d, J = 6.8 Hz, 1 H), 7.32 (t, J = 5.8 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.10–7.00 (m, 3 H), 6.95 (d, J = 8.0 Hz, 2 H), 6.79 (d, J = 8.0 Hz, 2 H), 6.66 (d, J = 8.0 Hz, 2 H), 5.05 (s, 2 H), 4.71 (s, 2 H), 4.36 (s, 2 H), 2.42 (t, J = 8.0 Hz, 2 H), 1.57–1.50 (m, 2 H), 1.25–1.15 (m, 2 H), 0.92–0.83 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.3, 148.4, 141.0, 138.4, 136.1, 132.9, 131.6, 131.1, 130.2, 129.2, 128.7, 128.7, 128.0, 127.8, 127.2, 126.5, 124.9, 122.5, 52.9, 50.9, 47.0, 29.6, 26.7, 22.3, 13.7.

MS: m/z = 513 [M + H]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₂₉H₂₉ClN₆ONa: 535.1989; found: 535.1989.

(2-Butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol (Losartan, 2b)

Into a 5-mL one-neck flask were sequentially added 1b (0.1 g, 0.195 mmol), ammonium formate (0.06 g, 0.95 mmol), 5% Pd/BaSO₄ (0.033 g, 8 mol%), i-PrOH (1.0 mL) and H₂O (0.6 mL) at 25 °C. The reaction mixture was heated at 60 °C until completion (8 h). The mixture was cooled to 25 °C then filtered through Celite^® and the Celite^® was washed with i-PrOH (2 × 5 mL). The filtrate was concentrated under reduced pressure to give a residue. To the residue were added EtOAc (5 mL) and H₂O (5 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layer was concentrated under reduced pressure and the crude residue was purified using column chromatography (MeOH–CH₂Cl₂, 6:94) to give 2b; yield: 0.057 g (71%); mp 161–164 °C.

IR (KBr): 1469, 1256, 1021, 756 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.70–7.50 (m, 4 H), 7.12–7.00 (m, 4 H), 5.23 (s, 2 H), 4.32 (s, 2 H), 2.45 (t, J = 7.6 Hz, 2 H), 1.46–1.42 (m, 2 H), 1.25–1.20 (m, 2 H), 0.79 (t, J = 8 Hz, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ =146.9, 140.5, 138.0, 136.2, 135.4, 130.6, 130.1, 128.6, 127.3, 125.8, 125.5, 50.8, 46.1, 28.4, 25.1, 21.1, 13.0.

MS: m/z = 423 [M + H]⁺.

HPLC conditions: Inertsil C-18 column (5 μm × 4.6 mm × 250 mm); mobile phase A: H₃PO₄ (1 mL) in H₂O (1.0 L); mobile phase B: MeCN; gradient program (% B/time): 25/0, 90/25, 90/35; flow rate: 1.0 mL/min; injection volume: 10 μL; column oven temperature: 25 °C.

Benzyl N-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-l-valinate (8)

Into a 25-mL two-neck flask were sequentially added 7 (2 g, 5.27 mmol), bromide 3 (2.35 g, 5.8 mmol), DIPEA (2.18 mL, 13.8 mmol) and MeCN (20 mL) under nitrogen atmosphere at 25 °C. The reaction mixture was heated to 78 °C and stirred until completion (8 h). Then, the mixture was cooled to 25 °C and concentrated under reduced pressure. To the crude product was added EtOAc (10 mL). The organic layer was washed with H₂O (2 × 20 mL) followed by brine (20 mL). The EtOAc layer was concentrated under reduced pressure. The crude product was purified using neutral alumina column chromatography (25–30% EtOAc in hexane) to give 8 as an amorphous solid; yield: 2.4 g (86%).

IR (KBr): 2957, 1729, 1469, 1175 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.62 (m, 1 H), 7.61 (dd, J = 14.0, 1.6 Hz, 1 H), 7.57–7.06 (m, 14 H), 6.75 (d, J = 1.6 Hz, 2 H), 5.19 (d, J = 1.2 Hz, 2 H), 4.76 (s, 2 H), 3.81 (d, J = 13.6 Hz, 1 H), 3.55 (d, J = 13.6 Hz, 1 H), 3.01 (d, J = 6.0 Hz, 1 H), 1.98–1.93 (m, 1 H), 0.95–0.92 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.8, 154.5, 141.3, 140.0, 137.3, 135.6, 132.9, 131.4, 131.1, 130.1, 128.5, 128.4, 128.4, 128.3, 127.6, 127.5, 122.5, 66.5, 66.2, 51.7, 50.6, 31.5, 19.2, 18.4.

MS: m/z = 532 [M + H]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₃N₅O₂Na: 554.2532; found: 554.2536.

Benzyl N-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-N-pentanoyl-l-valinate (N-benzylvalsartan Benzyl Ester, 1c)

Into a 25-mL two-neck flask were sequentially added amine 8 (0.4 g, 0.75 mmol), DIPEA (0.44 mL, 2.65 mmol) and toluene (4 mL) under nitrogen atmosphere at 25 °C. The reaction mixture was cooled to 0–5 °C and stirred for 0.5 h. Valeroyl chloride (0.18 g, 1.5 mmol) was added dropwise and the reaction mixture was stirred for 10 min, then warmed to r.t. and stirred until completion (2 h). The reaction mixture was cooled to –10 °C and quenched with H₂O (2 mL), and then stirred for 1 h at r.t. The two layers were separated and the organic layer was washed sequentially with H₂O (2 × 10 mL), 0.2 N aq NaOH (2 × 10 mL), H₂O (2 × 10 mL) and brine (10 mL). The organic layer was concentrated under reduced pressure and the crude product was purified using column chromatography (20–22% EtOAc in hexane) to give 1c as a viscous oil; yield: 0.38 g (83%).

IR (KBr): 2961, 1739, 1652, 1467, 1407, 1262, 1188, 1003, 759, 665 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ (mixture of rotomers) = 7.80–6.90 �(m, 16 H),� 6.80–6.70 �(m, 2 H), 5.11 (d, J = 7.6 Hz, 0.4 H), 5.03 (s, 1 H), 4.84 (q, J = 13.2 Hz, 1.6 H), 4.64 (d, J = 7.0 Hz, 0.8 H), 4.45 (d, J = 9.8 Hz, 0.7 H), 4.27 (d, J = 10.5 Hz, 0.7 H), 2.60–2.55 (m, 1 H), 2.30–2.08 (m, 2 H), 1.54–1.39 (m, 2 H), 1.28–1.11 (m, 3 H), 0.92 (d, J = 6.5 Hz, 2 H), 0.87–0.83 (m, 5 H).

¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotomers) = 174.3, 138.6, 137.6, 135.5, 131.5, 131.3, 130.2, 128.9, 128.8, 128.5, 128.2, 127.9, 126.8, 122.8, 77.5, 77.2, 77.0, 76.6, 66.9, 66.5, 62.7, 50.8, 48.9, 45.6, 33.4, 28.3, 27.9, 27.4, 22.4, 20.0, 18.9, 14.0, 13.8.

MS: m/z = 638 [M + Na]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₃₈H₄₁N₅O₃Na: 638.3107; found: 638.3104.

N-Pentanoyl-N-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-l-valine (Valsartan, 2c)

Into a 5-mL one-neck flask were sequentially added 1c (0.1 g, 0.16 mmol), ammonium formate (0.1 g, 1.58 mmol), 5% Pd/BaSO₄ (0.035 g, 10 mol%), i-PrOH (1 mL) and H₂O (0.6 mL) at 25 °C. The reaction mixture was heated at 65 °C for 8 h. Then, the reaction mixture was cooled to 25 °C and 5% Pd/BaSO₄ (0.007 g, 2 mol%) was added. The reaction mixture was heated at 65 °C until completion (3 h). The mixture was cooled to 25 °C then filtered through Celite^® and the Celite^® was washed with i-PrOH (3 × 5 mL). The filtrate was concentrated under reduced pressure to give a crude product which was column chromatographed (MeOH–CH₂Cl₂, 5:95) to provide 2c; yield: 0.049 g (71%); mp 70–95 °C.

IR (KBr): 2961, 1738, 1649, 1457, 1219, 1003 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ (mixture of rotomers) = 7.70 (d, J = 4.0 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.47–7.36 (m, 5 H), 7.19 (dd, J = 16.8, 8.8 Hz, 4 H), 6.99 (dd, J = 9.2, 7.6 Hz, 2 H), 4.60 (s, 2 H), 4.50–4.44 (m, 2 H), 4.13 (s, 1 H), 4.08 (d, J = 10.4 Hz, 0.7 H), 2.25–2.04 (m, 4 H), 1.43 (t, J = 6.8 Hz, 1 H), 1.39–1.11 (m, 12 H), 0.91–0.72 (m, 18 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ (mixture of rotomers) = 173.9, 173.8, 172.4, 167.4, 159.2, 140.9, 139.9, 139.1, 137.2, 132.2, 132.0, 131.0, 130.7, 129.7, 129.4, 129.1, 128.8, 127.4, 126.8, 126.1, 79.6, 67.9, 63.4, 49.0, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.3, 38.5, 33.0, 32.9, 30.2, 28.8, 27.5, 23.7, 22.8, 22.3, 22.1, 20.6, 19.9, 19.2, 14.3, 14.2, 11.2.

MS: m/z = 436 [M + H]⁺.

HPLC conditions: Inertsil C-18 column (5 μm × 4.6 mm × 150 mm); mobile phase: H₂O–MeCN–AcOH, 500:500:1; flow rate: 1 mL/min; injection volume: 10 μL; column oven temperature: 40 °C.

1-(Cyclohexyloxycarbonyloxy)ethyl 2-Ethoxy-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (Candesartan Cilexetil, 2d)

Into a 5-mL one-neck flask were sequentially added 1d [2d] (0.1 g, 0.14 mmol), ammonium formate (0.044 g, 0.69 mmol), 5% Pd/BaSO₄ (0.0152 g, 5 mol%), i-PrOH (1 mL) and H₂O (0.6 mL) at 25 °C. After completion of the reaction (14 h), EtOAc (10 mL) was added to the mixture. The mixture was filtered through Celite^®, the filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane–EtOAc, 15:85) to give 2d as a colorless solid; yield: 0.068 g (80%); mp 161.8 °C.

IR (KBr): 1753 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.08–8.06 (m, 1 H), 7.63–7.53 (m, 2 H), 7.53–7.48 (m, 1 H), 7.35–7.28 (m, 1 H), 7.05–6.93 (m, 2 H), 6.92–6.85 (m, 2 H), 6.72–6.70 (m, 2 H), 6.70–6.65 (m, 1 H), 5.70–5.55 (m, 2 H), 4.45–4.40 (m, 2 H), 4.30–4.15 (m, 1 H), 1.85–1.72 (m, 2 H), 1.68–1.55 (m, 2 H), 1.49–1.14 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.5, 158.2, 152.5, 140.1, 138.0, 137.0, 131.3, 131.1, 130.6, 129.4, 128.3, 125.6, 124.3, 121.2, 115.1, 92.0, 67.5, 47.0, 31.3, 31.2, 25.0, 23.5, 19.3, 14.6.

MS: m/z = 611 [M + H]⁺.

HPLC conditions: Cadenza CD-C-18 (3 μm × 4.6 mm × 180 mm); mobile phase A: 0.03 M KH₂PO₄–MeCN, 95:5; mobile phase B: MeCN–H₂O, 90:10; gradient program (% B/time): 50/0, 50/5, 90/15, 90/20, 50/30, 90/35; flow rate: 1.0 mL/min; injection volume: 10 μL; column oven temperature: 40 °C.

3-{[2′-(1-Benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (N-Benzylirbesartan, 1e)

Into a 25-mL two-neck flask were sequentially added 9 (0.2 g, 0.87 mmol), bromide 3 (0.39 g, 0.95 mmol), K₂CO₃ (0.2 g, 1.47 mmol) and MeCN (5.0 mL) under nitrogen atmosphere at 25 °C. The reaction mixture was heated at 80–85 °C for 20 h. After reaction completion, the mixture was cooled to 25 °C, then filtered through a sintered funnel and washed with MeCN (5 mL). The filtrate was concentrated under reduced pressure and purified using column chromatography (MeOH–CH₂Cl₂, 1:99) to give 1e as a viscous oil; yield: 0.216 g (48%).

IR (KBr): 2957, 1723, 1347, 1216 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.6 (dt, J = 1.6, 7.6 Hz, 1 H), 7.5 (dd, J = 0.8, 7.6 Hz, 1 H), 7.4 (dt, J = 1.2, 7.6 Hz, 1 H), 7.3 (dd, J = 1.2, 7.6 Hz, 1 H), 7.2 (d, J = 7.2 Hz, 1 H), 7.16–7.13 (m, 2 H), 7.11–7.05 (m, 4 H), 6.7 (d, J = 7.2 Hz, 2 H), 4.8 (s, 2 H), 4.6 (s, 2 H), 2.3 (t, J = 7.6 Hz, 2 H), 2.0–1.91 (m, 4 H), 1.83–1.81 (m, 4 H), 1.61–1.53 (m, 2 H), 1.37–1.25 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 186.7, 161.4, 154.4, 141.1, 138.3, 136.5, 133.0, 131.5, 131.2, 130.2, 129.2, 128.7, 128.6, 128.0, 127.8, 127.1, 122.7, 77.2, 76.5, 50.9, 43.1, 37.4, 29.7, 28.7, 27.7, 26.1, 22.3, 13.7.

MS: m/z = 519 [M + H]⁺.

HRMS: m/z [M + H]⁺ calcd for C₃₂H₃₅N₆O: 519.2872; found: 519.2870.

2-Butyl-3-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1,3-diazaspiro[4.4]non-1-en-4-one (Irbesartan, 2e)

Into a 5-mL one-neck flask were sequentially added 1e (0.1 g, 0.19 mmol), ammonium formate (0.059 g, 0.94 mmol), 5% Pd/BaSO₄ (0.021 g, 5 mol%), i-PrOH (1.0 mL) and H₂O (0.6 mL) at 25 °C. The reaction mixture was heated at 55 °C until completion (3.5 h). The mixture was cooled to 25 °C then filtered through Celite^® and the Celite^® was washed with i-PrOH (2 × 5 mL). The filtrate was concentrated under reduced pressure to give 2e; yield: 0.081 g (quant.); mp 181–182 °C.

IR (KBr): 1732, 1616 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.77–7.50 (m, 4 H), 7.10 (s, 4 H), 4.70–4.68 (m, 2 H), 2.35–2.28 (m, 2 H), 1.90–1.60 (m, 8 H), 1.55–1.42 (m, 2 H), 1.32–1.20 (m, 2 H), 0.85–0.75 (m, 3 H).

MS: m/z = 429 [M + H]⁺.

HPLC conditions: Hypersil BDS C-18 (5 μm × 4.6 mm × 250 mm); mobile phase A: H₃PO₄ (5.5 mL) in H₂O (950 mL) adjusted to pH 3.2 with Et₃N; mobile phase B: MeCN; gradient program (% B/time): 10/0, 10/5, 90/15, 90/20, 10/30, 10/35; flow rate: 1.0 mL/min; injection volume: 10 μL; column oven temperature: 25 °C.

5-Phenyl-1H-tetrazole (2f)

Into a 1-L three-neck flask were sequentially added i-PrOH (250 mL), H₂O (150 mL), ammonium formate (64.99 g, 1.03 mol) and 1f (50.0 g, 212 mmol). The reaction mixture was heated to 50–55 °C and 5% Pd/BaSO₄ (9.04 g, 2 mol%) was added in one portion under stirring. Stirring was continued, and the temperature of the reaction mixture was raised to 60–65 °C and kept at that temperature for 17 h. Another lot of 5% Pd/BaSO₄ (4.52 g, 1 mol%) was added in one portion under stirring to the reaction mixture which was further kept at 60–65 °C for 5 h. After this, the mixture was cooled to 25 °C then filtered through a Celite^® bed and the Celite^® bed was washed with i-PrOH (50 mL). The i-PrOH and H₂O were removed by distillation under reduced pressure. Sat. aq NaHCO₃ solution (50 mL) and EtOAc­ (100 mL) were added and the mixture was stirred for 10 min. The separated aqueous layer was extracted with EtOAc (25 mL). The aqueous layer was transferred to a 1-L two-neck flask and the pH of the aqueous layer was adjusted to 3–4 by using 30% aq HCl solution. The solid product was collected by filtration through a sintered funnel and washed with H₂O (100 mL). The solid was dried in vacuo at 45 °C to give 2f; yield: 26.6 g (86%); mp 216 °C.

IR (KBr): 1753 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.05 (m, 2 H), 7.61 (s, 3 H).

MS: m/z = 147 [M + H]⁺.

HPLC conditions: Cadenza CD-C-18 (3 μm × 4.6 mm × 180 mm); mobile phase A: 0.03 M KH₂PO₄–MeCN, 95:5; mobile phase B: MeCN–H₂O, 95:5; gradient program (% B/time): 55/0, 55/5, 85/20, 85/25, 55/30, 55/35; flow rate: 1.0 mL/min; injection volume: 10 μL; column oven temperature: 40 °C.

• References

• 1a Anderson NG. Practical Process Research & Development . Academic Press; Oxford: 2000
  Search in Google Scholar
• 1b Green Chemistry in the Pharmaceutical Industry . Dunn P, Wells A, Williams MT. Wiley-VCH; Weinheim: 2010
  CrossrefSearch in Google Scholar
• 1c The Art of Process Chemistry . Yasuda N. Wiley-VCH; Weinheim: 2011
  CrossrefSearch in Google Scholar

For the importance of deprotection in the synthesis of carbapenems, see:
• 1d Seki M, Kondo K, Kuroda T, Yamanaka T, Iwasaki T. Synlett 1995; 609
  Thieme Connect
• 2a Seki M. WO 2011061996, 2010
• 2b Seki M. ACS Catal. 2011; 1: 607
  CrossrefSearch in Google Scholar
• 2c Seki M, Nagahama M. J. Org. Chem. 2011; 76: 10198
  CrossrefSearch in Google Scholar
• 2d Seki M. Synthesis 2012; 44: 3231
  Thieme ConnectSearch in Google Scholar
• 2e Seki M. J. Synth. Org. Chem., Jpn. 2012; 70: 1295
  CrossrefSearch in Google Scholar
• 2f Kocienski P. Synfacts 2013; 9: 6
  Search in Google Scholar
• 2g Seki M In Science of Synthesis: Catalytic Transformations via C–H Activation. Yu J.-Q. Thieme; Stuttgart: in press
• 2h Seki M. WO 2014034868, 2014
• 3 Seki M. WO 2014051008, 2014
• 4 Graul A, Leeson P, Castaner J. Drugs Future 1997; 22: 1205
  Search in Google Scholar
• 5 For a mechanism of Pd/BaSO₄-catalyzed hydrogenation, see: McEwen AB, Guttieri MJ, Maier WF, Laine RM, Shvo Y. J. Org. Chem. 1983; 48: 4436
  CrossrefSearch in Google Scholar

For example, see:
• 6a Carini DJ, Duncia JV, Aldrich PE, Chiu AT, Johnson AL, Pierce ME, Price WA, Santella III JB, Wells GJ, Wexler RR, Wong PC, Yoo S.-E, Timmermans PB. M. W. M. J. Med. Chem. 1991; 34: 2525
  CrossrefSearch in Google Scholar
• 6b Bernhart CA, Perreaut PM, Ferrari BP, Muneaux YA, Assens J.-LA, Clément J, Haudricourt F, Muneaux CF, Taillades JE, Vignal M.-A, Gougat J, Guiraudou PR, Lacour CA, Roccon A, Cazaubon CF, Brelière J.-C, Le Fur G, Nisato D. J. Med. Chem. 1993; 36: 3371
  CrossrefSearch in Google Scholar
• 6c Kubo K, Kohara Y, Yoshimura Y, Inada Y, Shibouta Y, Furukawa Y, Kato T, Nishikawa K, Naka T. J. Med. Chem. 1993; 36: 2343
  CrossrefSearch in Google Scholar
• 6d Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PB. M. W. M. J. Med. Chem. 1996; 39: 625
  CrossrefSearch in Google Scholar
• 6e Kurup A, Garg R, Carini DJ, Hansch C. Chem. Rev. 2001; 101: 2727
  CrossrefSearch in Google Scholar

• References

• 1a Anderson NG. Practical Process Research & Development . Academic Press; Oxford: 2000
  Search in Google Scholar
• 1b Green Chemistry in the Pharmaceutical Industry . Dunn P, Wells A, Williams MT. Wiley-VCH; Weinheim: 2010
  CrossrefSearch in Google Scholar
• 1c The Art of Process Chemistry . Yasuda N. Wiley-VCH; Weinheim: 2011
  CrossrefSearch in Google Scholar

For the importance of deprotection in the synthesis of carbapenems, see:
• 1d Seki M, Kondo K, Kuroda T, Yamanaka T, Iwasaki T. Synlett 1995; 609
  Thieme Connect
• 2a Seki M. WO 2011061996, 2010
• 2b Seki M. ACS Catal. 2011; 1: 607
  CrossrefSearch in Google Scholar
• 2c Seki M, Nagahama M. J. Org. Chem. 2011; 76: 10198
  CrossrefSearch in Google Scholar
• 2d Seki M. Synthesis 2012; 44: 3231
  Thieme ConnectSearch in Google Scholar
• 2e Seki M. J. Synth. Org. Chem., Jpn. 2012; 70: 1295
  CrossrefSearch in Google Scholar
• 2f Kocienski P. Synfacts 2013; 9: 6
  Search in Google Scholar
• 2g Seki M In Science of Synthesis: Catalytic Transformations via C–H Activation. Yu J.-Q. Thieme; Stuttgart: in press
• 2h Seki M. WO 2014034868, 2014
• 3 Seki M. WO 2014051008, 2014
• 4 Graul A, Leeson P, Castaner J. Drugs Future 1997; 22: 1205
  Search in Google Scholar
• 5 For a mechanism of Pd/BaSO₄-catalyzed hydrogenation, see: McEwen AB, Guttieri MJ, Maier WF, Laine RM, Shvo Y. J. Org. Chem. 1983; 48: 4436
  CrossrefSearch in Google Scholar

For example, see:
• 6a Carini DJ, Duncia JV, Aldrich PE, Chiu AT, Johnson AL, Pierce ME, Price WA, Santella III JB, Wells GJ, Wexler RR, Wong PC, Yoo S.-E, Timmermans PB. M. W. M. J. Med. Chem. 1991; 34: 2525
  CrossrefSearch in Google Scholar
• 6b Bernhart CA, Perreaut PM, Ferrari BP, Muneaux YA, Assens J.-LA, Clément J, Haudricourt F, Muneaux CF, Taillades JE, Vignal M.-A, Gougat J, Guiraudou PR, Lacour CA, Roccon A, Cazaubon CF, Brelière J.-C, Le Fur G, Nisato D. J. Med. Chem. 1993; 36: 3371
  CrossrefSearch in Google Scholar
• 6c Kubo K, Kohara Y, Yoshimura Y, Inada Y, Shibouta Y, Furukawa Y, Kato T, Nishikawa K, Naka T. J. Med. Chem. 1993; 36: 2343
  CrossrefSearch in Google Scholar
• 6d Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PB. M. W. M. J. Med. Chem. 1996; 39: 625
  CrossrefSearch in Google Scholar
• 6e Kurup A, Garg R, Carini DJ, Hansch C. Chem. Rev. 2001; 101: 2727
  CrossrefSearch in Google Scholar

• Supplementary Material