Improved synthesis of tadalafil using dimethyl carbonate and ionic liquids

Abstract

An improved synthesis of tadalafil, a drug for the treatment of male erectile dysfunction, involves the use of safer solvents and reagents as well as a reduced number of steps.

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Introduction

PDE-5 (phosphodiesterase type 5) inhibitors (Fig. 1) such as Viagra™ (sildenafil citrate), Levitra™ (vardenafil) and Cialis™ (tadalafil) are successful in the treatment of male erectile dysfunction (MED),¹ and are highly profitable.

Fig. 1 Structures of three PDE-5 inhibitors in their non-protonated form.

These compounds operate by increasing the level of the cyclic guanosine-3,5-monophosphate (cGMP), which is an important secondary messenger that controls many physiological processes. The level of intracellular cGMP is determined by the activities of the cyclase enzyme which produces it, and the type-V phosphodiesterase (PDE-5) that degrades it. The inhibition of PDE-5 increases the level of cGMP, and therefore can be used in a therapeutic strategy for male erectile dysfunction, and also for the treatment of cardiovascular diseases.²

Recently the synthesis of tadalafil (Cialis™, Icos/Lilly; (6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione) and related compounds have gathered much interest from synthetic and medicinal chemists,^1–3 because it is a specific PDE-5 inhibitor with an improved PDE5/PDE6 selectivity compared with sildenafil (Viagra™, Pfizer) and vardenafil (Levitra™, Bayer/GlaxoSmithKline). The improved selectivity for the PDE-5 enzyme can prevent a series of side effects related to inhibition of other PDE enzymes. Furthermore, tadalafil has a longer half-life (17 h) than sildenafil and vardenafil (5 h and 4 h, respectively).³

State of the art: process details

The reported synthesis of tadalafil⁴ requires four steps and a number of different reagents and solvents (Scheme 1).

Scheme 1 Literature synthesis of tadalafil.⁴

It starts with the esterification of D-tryptophan (the unnatural enantiomer) with thionyl chloride (sulfurous chloride; SOCl₂) in methanol to obtain the methyl ester hydrochloride salt, 1·HCl, followed by reaction with piperonal (benzo[d][1,3]dioxole-5-carbaldehyde) in a Pictet–Spengler reaction⁵ to give 2·HCl. Intermediate 3 is obtained by the reaction of 2 with 2-chloroethanoyl chloride under basic conditions in an aprotic solvent. Finally reaction of 3 with methylamine (in a polar solvent) proceeds by a nucleophilic displacement followed by cyclisation, to afford tadalafil, 4.

This synthetic route presents a number of drawbacks. Thionyl chloride, for example, is hazardous and produces two major pollutants (SO₂ and HCl): in addition, it is also poorly atom economic,⁶ since none of its atoms end up in the final product. Solvents are also an issue in the synthesis, since up to six different organic solvents are needed (methanol, ethanenitrile, toluene, dichloromethane, N,N-dimethylformamide and dimethyl sulfoxide), most of which are undesirable. Efforts to avoid the use of these solvents were reported. In fact, the large scale process, patented by Lilly^4d makes use of 2-propanol for the Pictet–Spengler reaction, while the replacement of dichloromethane in the third step with ethyl ethanoate is also described.⁷

However the procedure reported by Shi et al.⁸ in 2008 was selected as benchmark in the present case since it was the most recent and efficient procedure for a lab scale preparation of tadalafil available in the open literature.

A comparison with the commercial process developed by Orme et al.^4d that operates on multi-kilogram scale is inappropriate in this context as it would imply comparing laboratory scale with industrial scale, where efficiency is intrinsically much higher due to the mass involved.

Diastereoselectivity: the CIAT process

Product stereochemistry is of vital importance, since only the enantiomerically pure (R,R)-stereoisomer of tadalafil is therapeutically active,³ and so a highly diastereoselective synthesis is needed in the formation of the second stereocentre during the Pictet–Spengler reaction of 1.⁹ The diastereoselectivity of this reaction depends dramatically on the solvent.⁸

By using ethanenitrile or nitromethane as the solvent, in which both the product and the reagent are insoluble, excellent yields and very high diastereoselectivity towards the desired cis-compound can be attained. In contrast, by using more polar solvents like methanol or dimethyl sulfoxide, where reagent and product are both solubilised, little or no diastereoselectivity was observed. Better diastereoselectivity was observed in solvents where the product is insoluble, since the cis-diastereoisomer is less soluble than the trans-form. In solution, the diastereoisomers can interconvert via an acid-catalysed mechanism (Scheme 2), and, since the cis-compound is less soluble, the equilibrium is driven towards this particular diastereoisomer.

Scheme 2 Compound 2 epimerisation under acidic conditions.^8,10

It is therefore possible to enrich the mixture in the cis-isomer simply by heating (80–100 °C) in an appropriate solvent for the optimal time (4–10 h). This process is named Crystallisation Induced Asymmetric Transformation (CIAT).¹⁰

Aim of this work

The goals of the present work were the reduction of the number of steps, and the use of more acceptable solvents as reaction media in as many of the steps as possible. The following is a breakdown of the improvements proposed for each step. In the first step, a thionyl chloride free procedure for the esterification of D-tryptophan is described. In the highly atom economic (AE = 100%) second step, the use of ethanenitrile or nitromethane represents a serious drawback, and both these solvents can be replaced. In the last step, dimethyl sulfoxide and N,N-dimethylformamide can be avoided, e.g. by using an ionic liquid, where amine alkylation has been reported to be accelerated.¹¹ The initial approach focussed on finding a solvent where two or more reaction steps could be conducted without the need of intermediate isolation and purification. Subsequently, we tried to revise every single step of this drug synthesis, to develop an improved overall process.

Results and discussion

Synthesis of tadalafil

1. Esterification of tryptophan with dimethyl carbonate (step 1). Both the first and the second steps require acid catalysis, thus acidic ionic liquids [C₄mim][HSO₄], [C₄mim][H₂PO₄] and [P_{6 6 6 14}][HSO₄] ([C₄mim]⁺ = 1-butyl-3-methylimidazolium; [P_{6 6 6 14}]⁺ = trihexyl(tetradecyl)phosphonium) were tested as solvents/catalysts. No reaction was observed, so this approach was abandoned. A literature review revealed that is possible to obtain methyl esters of amino acids using dimethyl carbonate (DMC) and an equimolar amount of sulfuric acid. A recent patent¹² claims that DMC can act as a dehydrating agent (see Scheme 3), driving the esterification reaction to completion.

Scheme 3 The dehydration reaction of dimethyl carbonate.¹²

In our case, the reaction proceeded smoothly, yielding O-Me-tryptophan hydrogensulfate almost quantitatively (Scheme 4). Screening of the experimental conditions was carried out with L-tryptophan (the natural enantiomer) and then applied to D-tryptophan.

Scheme 4 The methylation of tryptophan with dimethyl carbonate.

The final reaction mixture consisted of two separate phases: the upper was dimethyl carbonate, and the lower was mainly the product in which some dimethyl carbonate was dissolved. The product was an ionic liquid at the reaction temperature.

Evaporation of DMC yielded the crude methyl ester hydrogensulfate salt 1·H₂SO₄ as an amorphous, amber-coloured solid, which was impossible to use in the second step. To overcome this drawback, different procedures were studied in order to obtain a crystalline product. In particular, by using phosphoric instead of sulfuric acid, it was possible to obtain O-Me-tryptophan dihydrogenphosphate as depicted in Scheme 5.

Scheme 5 The methylation of tryptophan with dimethyl carbonate.

A 4 : 1 mixture of dimethyl carbonate and methanol led to complete conversion after 48 h at the reflux temperature (ca. 80 °C). Isolation of the O-Me-tryptophan dihydrogenphosphate salt by filtration afforded a white, microcrystalline solid. The use of methanol was unavoidable, as in its absence the dihydrogenphosphate salt was insoluble to the point of inhibiting the reaction.

Treatment of the D-tryptophan methyl ester phosphate salt with aqueous sodium hydrogencarbonate yielded the free base D-tryptophan 1, which could be isolated by extraction with the same dimethyl carbonate used as reaction medium. The solvent was removed under reduced pressure, and the product isolated as a pale yellow solid. Different salts of the D-tryptophan methyl ester with various anions (Cl⁻, [HSO₄]⁻, or [CH₃COO]⁻) were prepared simply by adding the appropriate amount of acid to the free D-tryptophan methyl ester, 1, and then used as starting materials in the second step.

2. Pictet–Spengler reaction in ionic liquids (step 2). The Pictet–Spengler reaction is hardly ever reported in ionic liquids. Only one paper¹³ describes this reaction, using [C₂mim][BF₄] as a solvent in the absence of an added acid catalyst, operating at a relatively high temperature (100 °C). However, the authors failed to recognise that tetrafluoroborate ionic liquids decompose at high temperature releasing HF,¹⁴ which explains why under those conditions no added acid catalyst was needed. This was substantiated by our tests that indicated that the analogous ionic liquid, [C₄dmim][NTf₂] ([NTf₂]⁻ = bis{(trifluoromethyl)sulfonyl}amide), is not by itself able to promote the reaction at 100 °C after 18 h: under such conditions, the Schiff base (Fig. 2) was the sole product, as usually observed in an aprotic medium and in the presence of a dehydrating agent.¹⁵ As anticipated previously, the second step in the synthesis of tadalafil is stereoselective through a crystallisation induced asymmetric transformation that causes precipitation of the desired diastereoisomer.

Fig. 2 The Schiff base product from the reaction of R-(O-methyl) tryptophan and piperonal in ionic liquids.

The caveat in applying this strategy to ionic liquids is that it is difficult to find an ionic liquid in which the Pictet–Spengler adduct is insoluble, since this is obtained as a salt. Therefore, an ionic liquid with a strong interaction with the cis-adduct would be needed in order to disfavour the trans-adduct. To this end, three ionic liquids were investigated: 1-butyl-2,3-dimethylimidazolium bis{(trifluoromethyl)sulfonyl}amide ([C₄dmim][NTf₂]), 1-ethyl-3-methylimidazolium trifluoroethanoate ([C₂mim][CF₃CO₂]), and 1-ethyl-3-methylimidazolium hydrogensulfate ([C₂mim][HSO₄]). A series of reactions were carried out varying tryptophan salt, anion, HX, acid catalyst, and reaction temperature and times. The mixtures were analysed by ¹H-NMR spectroscopy for conversion, selectivity towards the Pictet–Spengler adduct, and the diastereoselectivity as the cis- to trans-ratio. Selected results are summarised in Table 1, complete data are presented in the SI section. At 80 °C, the product formed in moderate to good yields after 24 h; however, at this temperature, no diastereoselectivity was observed (Table 1, entries 1 and 2). At 20 °C, albeit with low conversion, a cis : trans ratio of 80 : 20 could be reached (Table 1, entry 3). Trifluoroethanoic acid, commonly used as a catalyst in this kind of reaction,¹⁶ was then tested; unfortunately mainly mixtures of diastereoisomers were obtained. The best selectivity toward the desired cis-product was only 80% for prolonged reaction times (Table 1, entry 4), so no competition with the established procedure was possible.

Table 1 The reaction of tryptophan methyl ester with piperonal in different ionic liquids^a

Entry	HX	Ionic liquid	Catalyst	T (°C)	Time (h)	Conv. (%NMR)	Schiff base (%NMR)	cis + trans (%NMR)	cis/trans (NMR)
a All reactions were carried out using 1.25 g of ionic liquid as the solvent. The molar ratio tryptophan methyl ester : piperonal was 1.1. b CF3CO2H : tryptophan methyl ester molar ratio was 2.0.
1	HCl	[C2mim][HSO4]	None	80	6	70	—	70	60/40
2	HCl	[C4dmim][NTf2]	None	80	24	>80	—	>80	50/50
3	CF3CO2H	[C2mim][CF3CO2]	None	20	23	21	13	5	80/20
4	None	[C4dmim][NTf2]	CF3CO2H^b	20	288	>80	—	>80	80/20

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3. Pictet–Spengler reaction in dimethyl carbonate (step 2). A CIAT approach to the Pictet–Spengler adduct was then investigated by using dimethyl carbonate as solvent, in order to use the same solvent in more than one step. The properties of dimethyl carbonate seemed promising, since hydrochloride salts are largely insoluble in this solvent, and its boiling point (90 °C) is just 10 °C lower than that of nitromethane, which was used in the reported procedure.⁴ Dimethyl carbonate is water immiscible, as opposed to nitromethane and ethanenitrile, allowing it to be used as the solvent without having to dry it. This reaction was first conducted directly on the crude mixture of 1·HCl obtained in step 1 by addition of piperonal (benzo[d][1,3]dioxole-5-carbaldehyde) directly in to the reaction flask at the end of the esterification with H₂SO₄ or H₃PO₄ in dimethyl carbonate: both attempts resulted in the formation of a dark oil composed by unreacted O-Me-tryptophan, and the Pictet–Spengler adduct (approximately 30% by ¹H NMR spectroscopy). In an improved procedure, treating crystalline O-methyl-tryptophan hydrochloride in dimethyl carbonate with piperonal (Scheme 6) gave the desired Pictet–Spengler adduct in very good yield (95%) and with excellent diastereoselectivity (98%). Moreover, dimethyl carbonate is known as a “green” alternative to common solvents,¹⁷ such as nitromethane and ethanenitrile.

Scheme 6 The Pictet–Spengler reaction of 1 with piperonal in dimethyl carbonate.

4. Ethanoylation in ionic liquids (step 3). The third step is a simple ethanoylation of the amine functionality with 2-chloroethanoyl chloride, after neutralisation of the 2·HCl. This reaction was performed in [C₄dmim][NTf₂] as the solvent by using 2 equivalents of triethylamine, necessary to free the starting amine function, and to later neutralise the HCl (Scheme 7).

Scheme 7 2-Chloroethanoylation of 2 in an ionic liquid.

5. Amination and cyclisation (step 4). In order to test its reactivity, pure 3 was synthesised using a reported procedure.⁸ It was then suspended in [C₄dmim][NTf₂] and, taking advantage of our experience in multiphase reactions, we carried out the amination/cyclisation step in the biphasic system obtained by adding aqueous methylamine. This allowed us to combine the advantage of using cheap and easy to handle aqueous methylamine, with the easy removal of the water soluble methylammonium chloride by-product. The reaction proceeds with very high yield towards tadalafil (91%, Scheme 8).

Scheme 8 The amination and cyclisation of 3 in [C₄dmim][NTf₂].

Tadalafil was obtained as a white solid, which could be simply filtered from the biphasic suspension at the end of the reaction and washed.

6. Integrated procedure (steps 3 + 4). As shown above, a biphasic system can be used to remove salt by-products from the organic phase. For each mole of reagent, step 3 produces two moles of salt, that can be therefore removed by integrating steps 3 and 4 in a single procedure in which two reactions are performed in the same flask using [C₄mim][NTf₂] as the solvent. In the first stage hydrochloride 2 was reacted with 2-chloroethanoyl chloride in the presence of triethylamine, as described earlier. At the end of the ethanoylation step aqueous methylamine was simply added to the reaction mixture to form the biphasic system. At this stage product 3 is dissolved in the ionic liquid, tadalafil precipitates out of solution as a white solid, and the salt by-products remain in the aqueous phase. Remarkably reaction times during the last step are significantly lower using this procedure (5 h) than in N,N-dimethylformamide (16–18 h).¹⁰ Tadalafil was obtained in very good yield (88% considering both steps) and with good optical purity (96%). ¹H-NMR and ¹³C-NMR spectra confirmed the product identity, and revealed no traces of ionic liquid in the final product.

7. Ionic liquid recycling. In order to verify the recyclability of the ionic liquid, the mother liquor (comprised of water, methanol, ionic liquid and salt by-product) was concentrated at reduced pressure. Once volatile materials (methanol and water) were removed, ethyl ethanoate was added to the mixture. The organic phase was collected and washed with 5% hydrochloric acid, then with water. The ionic liquid containing organic phase was separated and dried by heating at 70 °C in vacuum. The ionic liquid recovery was around 90%.

Recovered [C₄mim][NTf₂] was then used to carry out the integrated procedure. By using the recycled ionic liquid tadalafil was obtained in 85% yield, confirming that the ionic liquid can be recycled using a simple purification procedure, employing only dilute hydrochloric acid, water and ethyl ethanoate.

However it must be underlined that the removal of water from the recycled ionic liquid (see Experimental section) is somewhat energy intensive. This aspect could represent a serious drawback at industrial scale.

Processes comparison

All the experiments here described can be summarised by two different processes (A and B in Scheme 9). Both procedures represent improvements in terms of raw material reduction and process simplification with respect to those reported in the literature.

Scheme 9 Reagent and conditions; Process A: (a₁) DMC, reflux, 24 h; (a₂) Na₂CO_3(aq); (a₃) HCl in DMC, RT; Process B: (b) SOCl₂/CH₃OH, 40 °C, 4 h. (c) DMC, reflux, 10 h; (d) 2-chloroethanoyl chloride, NEt₃, [C₄dmim][NTf₂], 5 °C, 2 h; (e) CH₃NH₂₍aq₎, [C₄dmim][NTf₂], RT, 6 h.

In Process A, tryptophan esterification is achieved by using dimethyl carbonate with phosphoric acid. In this case the advantage of avoiding SOCl₂ is balanced by the added steps and reagents: aqueous Na₂CO₃, HCl and solvent for extraction are needed for the unavoidable anion exchange, causing an increment in wastes.

In Process B, O-Me-tryptophan hydrochloride is obtained using SOCl₂ and methanol, without added anion exchange steps, simply by removal of solvent and excess reactant under vacuum.

A simple calculation of the mass indices¹⁸ allows comparison of the reported literature process with our two processes (A and B). As is clear in Fig. 3, both our processes are characterised by better performance in terms of raw material usage with respect to the previously reported procedure. This is thanks to the integrated procedure replacing steps 3 and 4: by avoiding isolation of the intermediate 3 (Scheme 1) and by using the same solvent ([C₄dmim][NTf₂]) for both the last two steps, it is possible to cut the mass index by over 50%, from 66.3 to 30.3 (Fig. 3).

Fig. 3 Mass indices of the three different processes for tadalafil preparation.

Comparison of processes A and B highlights what we already stated: purely from a mass index point of view, the thionyl chloride route (B) seems globally more acceptable than the DMC process involving hydrogensulfate or phosphate followed by anion exchange (A).

However, if material toxicity is instead considered, the DMC route avoids the use of corrosive and toxic materials, and might be considered more environmental compatible.¹⁹ Atom economy⁶ (AE), and mass efficiency²⁰ (ME) are summarised in Table 2 and in Fig. 4. For all three processes the reaction mass efficiency (ME) is low (<0.033), as expected based of the high mass indices (30.3–66.3). However, if the solvents were to be recovered and recycled, the ME value of Process B would raise to a theoretical 0.196 (more than three times greater than the literature reported process). The generally low values of ME should not be a surprise, since these processes involve at least three synthetic steps. Remarkably, the two final steps can be integrated and carried out in a single flask.

Table 2 Process comparison using green chemistry metrics

Parameter^a	Literature^21	Process A	Process B
a Calculated following the work of Andraos.^22
AE	0.542	0.531	0.542
Yield	0.818	0.769	0.811
ME	0.015	0.027	0.033
ME (with solvent reclamation)	0.058	0.084	0.196

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Fig. 4 Processes comparison using common green chemistry metrics.

Other metrics, such as atom economy (AE) and reaction yield indicate that the three processes perform similarly. Atom economy is identical for the published method and Process B (0.542), and only slightly lower for Process A (0.531) due to the anion exchange steps. This small 2% decrease indicates that the DMC route to obtain tryptophan methyl ester, does not affect AE significantly. In terms of reaction yield, the literature process remains the best (81.8%), followed by Process B (81.1%), while for Process A this value is 6% lower (76.9%).

Conclusions

Each step of the published synthesis of tadalafil was investigated in view of the design of an improved process. Two alternative processes A and B were developed (Scheme 9). The principal improvements of processes A and B compared to the published synthesis is that they both do without solvents such as CH₃CN, toluene, CH₂Cl₂, N,N-dimethylformamide and dimethyl sulfoxide, and both combine the final two steps of Scheme 1 by using an ionic liquid as solvent.

Processes A and B are identical in the last two steps, but differ in the first step, i.e. the esterification of tryptophan to yield its methyl ester hydrochloride salt 1·HCl. Process A requires 5 steps, one more than the 4 of the published synthesis, and it uses dimethyl carbonate as reagent and solvent, thus avoiding thionyl chloride. The dimethyl carbonate Process A, produces the hydrogensulfate or hydrogenphosphate methyl ester salt, which must be then ion-exchanged with chloride in order for the second step in the preparation of tadalafil to be stereoselective. Process B requires 3 steps, and is the most efficient with respect to mass. However, as in the published method, it still uses noxious thionyl chloride for esterification, and since mass flow should not be the only aspect considered, the use of a safer reagent in Process A should also be considered as an improvement to the chemistry of the process, even if the overall mass flow is higher.

Dimethyl carbonate proved to be a good alternative to traditional solvents (i.e. nitromethane or ethanenitrile) for the diastereoselective Pictet–Spengler reaction. Both its lower toxicity and the water immiscibility contribute to process' efficiency. The acetylation of 2 to 3, as well as the last step with methylamine, could be carried out stepwise in the same reactor by using [C₄dmim][NTf₂] (an ionic liquid) as the solvent. Intermediate 3 dissolves better in the ionic liquid using the integrated procedure, and the reaction with methylamine proved much faster than in the traditional solvent systems.

In summary, process A and B are high-yielding methods for the preparation of tadalafil using only [C₄mim][NTf₂] (an ionic liquid) and dimethyl carbonate as reaction media. Both have better mass indices, MRP and RME than the published process, and the ionic liquid can be recycled.

Experimental

General

Reagents were ACS grade and used as received. ¹H and ¹³C{¹H} NMR spectra were recorded on a Bruker Avance spectrometer DPX 300; chemical shifts were reported in δ values downfield from TMS. Optical rotation measurements were performed on a Perkin Elmer 241 polarimeter.

The tryptophan methyl esters salts were characterised after basic treatment to obtain the neutral methyl ester. Properties and NMR data were in agreement with those reported in the literature.²³

All the ionic liquids used in this work ([C₄dmim][NTf₂], [C₄mim][HSO₄], and [C₂mim][CF₃CO₂]) were prepared following reported procedures.²⁴

1·H₂SO₄ by esterification of tryptophan using dimethyl carbonate and H₂SO₄. In a round-bottomed flask, D-tryptophan (2.00 g, 9.79 mmol) was suspended in dimethyl carbonate (7 cm³). To the stirred suspension, concentrated sulfuric acid (0.53 cm³, 10.6 mmol) was slowly added and the resulting mixture was heated to reflux temperature (92 °C) for 18 h. At the end of that time, two liquid phases were observed. Both phases were slowly added to a solution of aqueous Na₂CO₃ {10% (w/w); 20 cm³}, with vigorous stirring. The organic phase was then separated and the aqueous phase extracted with dimethyl carbonate (2 × 5 cm³). Extracts were collected and dried over anhydrous Na₂SO₄: the solvent was then removed at reduced pressure, yielding compound 1 (2.00 g, 9.16 mmol, 94%) as an oil that slowly crystallised into an off-white solid.

1·H₃PO₄ by esterification of tryptophan using dimethyl carbonate and H₃PO₄. In a round-bottomed flask, L-tryptophan (2.00 g, 9.79 mmol) was suspended in a mixture of dimethyl carbonate (7 cm³) and methanol (2 cm³). To the stirred suspension, phosphoric acid (1.04 g, 10.6 mmol) was added and the resulting mixture was heated to reflux temperature (ca. 85 °C) for 24 h. The resulting suspension was then filtered yielding compound 1·H₃PO₄ (2.88 g, 9.10 mmol, 93%) as a white solid.

1·HCl by esterification of tryptophan using MeOH and thionyl chloride. Method A: The title compound, 1·HCl, was prepared according to a reported procedure,²³ which was slightly modified. To a cooled (ice bath), stirred suspension of D-tryptophan (2.00 g, 9.79 mmol) in methanol (30 cm³), thionyl chloride (1.0 cm³, 13.7 mmol) was slowly added. The resulting clear solution was then heated to 40 °C and kept at that temperature for 4 h. Excess of thionyl chloride, HCl and SO₂, and the solvent were removed at reduced pressure. The resulting white solid 1·HCl (2.41 g, 9.46 mmol, 97%) was pure enough to use without further purification.

Method B: To the mixture at the end of the reaction of tryptophan with dimethyl carbonate in presence of phosphoric acid (see previous paragraph), an aqueous solution of Na₂CO₃ {10% (w/w); 20 cm³} was slowly added. The organic phase was then separated and the aqueous phase extracted with dimethyl carbonate (2 × 5 cm³). Extracts were collected, then a solution prepared by bubbling gaseous HCl (365 mg, 10 mmol) into dimethyl carbonate (5 cm³) was slowly added to the stirred solution. The resulting suspension was then filtered and the solid washed with dimethyl carbonate. The white solid was dried at 70 °C for 10 h, yielding compound 1·HCl (2.29 g, 8.99 mmol, 92%).

2·HCl by Pictet–Spengler reaction in dimethyl carbonate. Solid 1·HCl (2.00 g 9.16 mmol) was added into a solution of benzo[d][1,3]dioxole-5-carbaldehyde (1.650 g, 10.99 mmol) in dimethyl carbonate (20 cm³). The suspension was heated to reflux and kept at that temperature with stirring for 18 h. After the reaction was complete (monitored by TLC), the mixture was gradually cooled to room temperature. The pale yellow solid was collected by filtration (Buchner funnel), washed with small amounts of dimethyl carbonate, and dried at 70 °C for 10 h to yield 2·HCl as a pale yellow solid (3.658 g, 10.44 mmol, 95%).

Tadalafil, 4. Method A: To a suspension of 3 (ref. 25) (427 mg, 1.00 mmol) in [C₄dmim][NTf₂] (2.00 g), aqueous methylamine (40%; 0.8 cm³, 9.2 mmol) was added. The resulting mixture was stirred for 20 h and then filtered and washed with methanol to remove the ionic liquid. The white solid was dried at 70 °C for 6 h, yielding pure tadalafil, 4 (355 mg, 0.912 mmol, 91%).

Method B: In a round-bottomed flask sealed with a septum, compound 2·HCl (194 mg, 0.500 mmol) was suspended in [C₄dmim][NTf₂] (1.5 g), triethylamine (109 mg, 1.08 mmol) was added, and the resulting mixture was stirred for 1 h until a clear solution was obtained. Then the mixture was cooled to 0 °C by means of an ice bath, and 2-chloroethanoyl chloride (113 mg, 1.00 mmol) was slowly added through the septum with a syringe. The mixture was kept at 0 °C for 1 h, and then allowed to warm to room temperature. After an additional hour, aqueous methylamine (40%; 0.4 cm³, 4.6 mmol) was added. After 6 h, using the procedure described in method A, tadalafil, 4, was isolated as a white solid (171 mg, 0.439 mmol, 88%).

Ionic liquid recycling. The mother liquor from the preparation of tadalafil, 4, using method B and methanol used for washing, were collected in a flask. Methanol was removed under reduced pressure (rotary evaporation). The resulting mixture was constituted by two phases: the upper was [C₄dmim][NTf₂], the lower an aqueous solution of by-product salts formed during the integrated procedure. Ethyl ethanoate (5 cm³) was added to the mixture, and the resulting biphasic system was stirred for ten minutes; the organic phase was separated and the aqueous phase was washed with additional ethyl ethanoate (2 × 3 cm³). Extracts were collected, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure yielding crude [C₄dmim][NTf₂], which was purified from traces of water by heating at 70 °C under vacuum for 6 h.

Characterisation data

O-Me D-tryptophan, 1. ¹H NMR (300 MHz, CDCl₃) δ/ppm. 8.26 (br s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.09–7.22 (m, 2H), 7.05 (d, J = 2.2 Hz, 1H), 3.84 (dd, J = 4.8 Hz, J = 7.7 Hz, 1H), 3.71 (s, 3H), 3.29 (dd, J = 4.8 Hz, J = 14.4 Hz, 1H), 3.06 (dd, J = 7.7 Hz, J = 14.4 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ/ppm. 176.2, 136.7, 127.8, 123.4, 122.5, 119.9, 119.1, 111.6, 111.5, 55.4, 52.4, 31.2.

(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahidro-9H-pyrido[3,4-b]indole-3-carboxylic methyl ester hydrochloride, 2-cis ·HCl. [α]²⁰_D = −81.1 (c 1.0, MeOH). ¹H NMR (300 MHz, dmso-d₆) δ/ppm. 10.83 (s, 1H), 10.59 (s, 1H), 10.13 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.15–6.95 (m, 4H), 6.10 (s, 2H), 5.86 (brs, 1H), 4.70–4.80 (m, 1H), 3.85 (s, 3H), 3.36–3.19 (m, 2H). ¹³C NMR (75 MHz, dmso-d₆) δ/ppm. 168.5, 148.4, 147.1, 136.7, 128.8, 125.4, 124.8, 122.0, 119.1, 118.1, 111.5, 110.2, 108.2, 106.2, 101.5, 57.5, 55.1, 53.0, 22.1.

(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahidro-9H-pyrido[3,4-b]indole-3-carboxylic methyl ester, 2-cis. ¹H NMR (300 MHz, CDCl₃), 7.52 (dd, J = 7.7 Hz, J = 9.6 Hz, 2H), 7.09–7.29 (m, 3H), 6.78–6.90 (m, 3H), 5.95 (s, 2H), 5.17 (s, 1H), 3.95 (dd, J = 4.2 Hz, J = 11.1 Hz, 1H), 3.82 (s, 3H), 3.21 (ddd, J = 1.7 Hz, J = 4.1 Hz, J = 14.9 Hz, 1H), 2.94–3.04 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ/ppm. 173.0, 148.1, 147.7, 136.0, 134.6, 127.0, 121.9, 119.5, 118.1, 110.8, 108.7, 108.2, 101.1, 58.3, 56.8, 52.2, 25.6.

(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic methyl ester, 3. [α]²⁰_D = 109.9 (c 1.0, CHCl₃). ¹H NMR (300 MHz, dmso-d₆) δ/ppm. 10.88 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.0–7.14 (m, 2H), 6.81 (d, J = 8.1 Hz, 1H), 6.76 (s, 1H), 6.64 (s, 1H), 6.46 (d, J = 7.7 Hz, 1H), 5.98 (d, J = 5.9 Hz, 2H), 5.20 (d, J = 6.5 Hz, 1H), 4.84 (d, J = 13.9 Hz, 1H), 4.45 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 16.0 Hz, 1H), 3.08 (dd, J = 16.0 Hz, 6.9 Hz, 1H), 3.04 (s, 3H). ¹³C NMR (75 MHz, dmso-d₆) δ/ppm. 170.3, 166.7, 146.8, 146.5, 136.3, 133.4, 129.8, 125.72, 122.3, 121.5, 118.6, 118.0, 111.1, 109.0, 107.5, 106.1, 100.9, 52.2, 51.7, 51.2, 43.1, 20.9.

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione, 4. [α]²⁰_D = 68.2 (c 1.0, CHCl₃). ¹H NMR (300 MHz, dmso-d₆) δ/ppm. 11.03 (s, 1H), 7.54 (d, 1H, J = 7.6 Hz), 7.30 (d, 1H, J = 7.7 Hz), 7.02 (td, J = 6.9 Hz, J = 18.3 Hz, 2H), 6.87 (s, 1H), 6.78 (s, 2H), 6.13 (s, 1H), 5.92 (s, 2H), 4.40 (dd, J = 3.7 Hz, J = 11.1 Hz, 1H), 4.18 (d, J = 17.2 Hz, 1H), 3.95 (d, J = 17.2 Hz, 1H), 3.52 (dd, J = 4.3 Hz, J = 15.7 Hz, 1H), 2.97 (m, dd, J = 11.3 Hz, J = 15.5 Hz, 1H), 2.93 (s, 1H). ¹³C NMR (75 MHz, dmso-d₆) δ/ppm. 166.7, 166.4, 146.9, 145.9, 136.8, 136.0, 133.8, 125.6, 121.1, 119.1, 118.7, 117.9, 111.1, 107.8, 106.8, 104.6, 100.7, 55.4, 55.1, 51.3, 32.7, 23.0.

Notes and references

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25. Compound 3 was prepared from compound 2·HCl and chloroethanoyl chloride using the method reported in ref. 8.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, and results of the Pictet–Spengler reaction in ionic liquids, selected NMR spectra and calculation of mass indices. See DOI: 10.1039/c3ra45982a

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