The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban.

The human drugs - the antibiotic linezolid (1) and the anticoagulant rivaroxaban (2) - belong among modern pharmaceutics, which contain an oxazolidine-2-one moiety bearing a stereogenic center. The chirality of these drugs is a fundamental attribute for their biological activity. Herein, one of the efficient asymmetric syntheses of these drugs was studied in detail. Highly enantioselective catalysts were tested in the key step of the synthetic procedure, i.e., the asymmetric Henry reaction, under different reaction conditions, using several starting aldehydes. The corresponding nitroaldols as chiral intermediates in the syntheses of these drugs were obtained in high yields and enantiomeric excesses of up to 91% ee.

Introduction

Oxazolidine-2-one derivatives represent an important branch of pharmaceutical substances [1-3]. This class includes for instance oxazolidine-type antibiotics [3], e.g., linezolid (1) [4] (sold under the trade name Zyvox® (Figure 1) or tedizolid [5] (sold under the trade name Sivextro®), and the anticoagulant rivaroxaban (2) [6-7] (Figure 1), a member of DOACs (direct oral anticoagulants). All these human drugs can be considered as modern medicaments, which were developed and approved during the past three decades [8]. The chirality of the mentioned oxazolidine-2-ones is a crucial factor for their therapeutic effect, because only a single enantiomer affords the desired biological activity. Hence, only the S-enantiomer of rivaroxaban (2) (sold under trade name Xarelto®) exhibits a strong inhibitory activity against coagulant factor Xa, whereas the R-enantiomer is almost inactive (IC50 = 0.7 nM for S vs 2300 nM for R) [7]. Similarly, in the case of the oxazolidine-2-one antibiotics only the S-enantiomers are able to block bacterial ribosomes, which leads to the prevention of translation processes in bacteria [9-10]. With regards to these facts, a high enantiomeric purity is one of the fundamental requirements in the production of such pharmaceutical substances, because the reduction of the amount of the undesirable stereoisomer to a minimum can suppress possible side effects.

Figure 1

The structure of the oxazolidine-2-one-containing drugs linezolid (1) and rivaroxaban (2).

The oxazolidine-2-one-type drugs are usually prepared following synthetic methods that utilize available chiral building blocks (e.g., epichlorohydrine, glycidol, 3-chloropropane-1,2-diol, etc.) [11]. Beside this, approaches in which asymmetric synthesis is included are also applicable. Recently, the utilization of an asymmetric Henry reaction for the preparation of two oxazolidine-type drugs, namely linezolid (1) and rivaroxaban (2), has been described [12-13]. These published papers confirmed that the application of the asymmetric Henry reaction represents a promising alternative route for the feasible production of these compounds. Nevertheless, the studies provided only preliminary results, because they included only one enantioselective catalyst in the preparation of rivaroxaban (1) [12] and the study of the linezolid (2) synthesis used only commercially unavailable and poorly enantioselective catalysts (max 72% ee) [13].

In this paper, we focused on the application of the asymmetric Henry reaction for the preparation of the oxazolidine-2-one-type drugs linezolid (1) and rivaroxaban (2). The main aim of this study was the evaluation of the catalytic activity and enantioselectivity of several established enantioselective catalysts applicable to the asymmetric Henry reaction, which were used for the preparation of chiral intermediates of these drugs. Various highly efficient catalysts based on copper complexes of different types of chiral ligands, 2-(pyridin-2-yl)imidazolidine-4-ones (I–III), bis-oxazolines (IV–VII), or diamine (VIII) were chosen for the study (Figure 2). Furthermore, the modification of the structure of the prochiral aldehyde intermediates 15 and 19 was also performed with the aim to increase the enantiomeric purity of the corresponding nitroaldol products 21–26. The structural modification consisted in the introduction of different alkyl moieties to the carbamate functional group of the aldehyde intermediates 15–20. As bulky and/or chiral alkyl groups we considered tert-butyl, ʟ-menthyl, and (−)-bornyl in this study.

Figure 2

Overview of the chiral ligands that were used for the study of the asymmetric Henry reaction.

Results and Discussion

The aldehydes 15–20 were prepared by analogous methods, which were described previously [12-13]. The starting ʟ-menthyl (7) and (−)-bornyl chloroformate (8) were obtained according to the modified synthetic procedure [14]. Here, it was included the chromatographic purification of the final chloroformates, which led to removing of corresponding alkyl chlorides formed as byproducts. The aldehyde 17 was prepared by a different way, because the acid-catalyzed hydrolysis of its acetal intermediate 11 was accompanied with simultaneous cleavage of the Boc group. However, attempts of achieving a selective deacetalation of 11 by the treatment with several reagents (e.g., I2/acetone [15], FeCl3·6H2O/acetaldehyde [16], Ce(OTf)3 [17]) were unsuccessful. Therefore, an alternative synthesis [18] was utilized, which consisted of alkylation of aniline 3 by methyl bromoacetate, followed by introduction of the Boc group into intermediate Int-17a, and final reduction of Int-17b with DIBAL-H (Scheme 1).

Scheme 1

Syntheses of aldehydes 15–20.

For the study of the asymmetric Henry reaction aldehydes 15–20, nitromethane, and highly enantioselective catalysts based on copper(II) complexes with chiral nitrogen ligands were chosen. Generally, chiral copper complexes possess many advantages valuable for the pharmaceutical industry. They exhibit low toxicity (compared to other metal-based complexes) and many of them exist in forms suitable for recycling [19]. Therefore, they represent a very useful tool for diverse asymmetric transformations, including the Henry reaction. The pilot study of the synthesis of rivaroxaban through an asymmetric Henry reaction [12] described the application of only one copper complex with a 2-(pyridin-2-yl)imidazolidin-4-one derivative. Here, we extended the series of catalysts to include copper complexes with another six 2-(pyridin-2-yl)imidazolidin-4-ones Ia,b–IIIa,b [20-22], four bisoxazolines IV–VII [23-24], and as chiral diamine, the alkaloid (+)-sparteine VIII [25] (Figure 2). All Henry reactions were performed on sub-millimolar scales in isopropyl alcohol (IPA). The obtained products 21–26 were separated from the starting aldehydes 15–20 by column chromatography. The reaction conditions (i.e., temperature, reaction time, amount of catalyst, and solvent) were adopted from the pilot study [12] for relevant comparison of the catalysts’ characteristics. Subsequently, the reaction temperature and loading of the catalyst were tuned using aldehyde 15 to achieve a satisfactory chemical yield and ee for the nitroaldol product 21 (Table 1).

Table 1

Asymmetric Henry reactions of aldehyde 15 with nitromethane under various conditions.

Ligand	Cat. loading [mol %]	Temp. [°C]	Conversiona [%](yieldb [%])	eec [%]
Ia	5	20	94 (83)	85 (R)
Ia	5	6	55 (51)	88 (R)
Ia	10	6	78 (72)	88 (R)
Ib	5	20	65 (49)	68 (S)
IIa	5	20	69 (65)	68 (R)
IIa	5	6	37 (33)	80 (R)
IIa	10	6	47 (40)	86 (R)
IIb	5	20	67 (65)	66 (S)
IIb	5	6	24 (20)	71 (S)
IIb	10	6	26 (19)	69 (S)
IIIa	5	20	87 (85)	81 (R)
IIIa	5	6	52 (44)	80 (R)
IIIa	10	6	70 (63)	86 (R)
IIIb	5	20	31 (26)	38 (S)
IV	5	20	86 (78)	88 (R)
IV	5	6	59 (54)	85 (R)
IV	10	6	71 (62)	89 (R)
V	5	20	29 (23)	45 (R)
V	5	6	10 (–)	–
VI	5	20	82 (78)	78 (S)
VI	5	6	40 (36)	80 (S)
VII	5	20	46 (36)	46 (S)
VII	5	6	43 (35)	54 (S)
VIII	5	20	40 (38)	9 (S)

aThe yield was determined by 1H NMR analysis of the crude product. bIsolated yield after column chromatography. cThe enantiomeric excess was determined by chiral HPLC.

As can be seen from the results summarized in Table 1, the highest enantioselectivity was achieved with the copper(II) complexes of ligands Ia, IIa, IIIa, and IV. Fortunately, these catalysts provided the R-enantiomer of nitroaldol 21 as the major product, which can be subsequently transformed to S-linezolid (1) (the active stereoisomer). On the other hand, the catalysts derived from 2-(pyridin-2-yl)imidazolidine-4-ones Ib–IIIb, bisoxazoline ligands V–VII, and (+)-sparteine (VIII) showed only insufficient enantioselectivity and therefore, they were excluded from further studies. A higher catalyst loading (10 mol %) slightly increased the enantioselectivity in some cases (i.e., with ligands IIa, IIIa, and IV) and, expectedly, it enabled the achievement of a higher chemical yield. Performing of the reaction at room temperature also increased the chemical yield, however, a certain drop of the ee was observed, especially in the case of catalysts derived from ligands IIa and VII. From these results, 10 mol % of the catalyst derived from ligands Ia, IIa, IIIa, and IV and a reaction temperature of 6 °C were identified as the optimal reaction conditions for the studied asymmetric Henry reaction.

Further, the asymmetric Henry reaction of the other aldehydes 16–20 was studied (Table 2). The bulky (R2 = t-Bu) or chiral (R2 = ʟ-menthyl or (−)-bornyl) alkoxy groups (derived from relatively inexpensive and readily available alcohols) were introduced into the carbamate moiety instead of an ethyl group as in aldehydes 15 and 19. Here, the influence of this structural modification of the starting aldehydes on the enantioselectivity of the Henry reaction was examined. Moreover, the resulting nitroaldols 22, 24, and 26 were formed as a pair of epimers, and therefore, a possible separation of the individual stereoisomers of these compounds was assumed. Hence, it should be noted that the R2O- part of the carbamate group does not modify the structure of linezolid (1), because this molecular moiety is cleaved during the intramolecular nucleophilic substitution in the final reaction step (Scheme 2). The catalysts derived from ligands Ia, IIa, IIIa, and IV were also tested in the asymmetric Henry reaction using the substrates 19 and 20, which afforded the chiral intermediates 25 and 26 that are applicable for the rivaroxaban (2) synthesis.

Table 2

Asymmetric Henry reactions of aldehydes 16–20 with nitromethane catalyzed by copper(II) complexes of Ia, IIa, IIIa, and IV.

Nitroaldol R2		Ligand	Conversiona [%](yieldb [%])	ee or dec,d [%]
22	ʟ-menthyl	Ia	63 (60)	89 (R)
22		IIa	49 (41)	87 (R)
22		IIIa	38 (27)	83 (R)
22		IV	72 (65)	89 (R)
23	t-Bu	Ia	80 (77)	85 (R)
23		IIa	62 (54)	85 (R)
23		IIIa	72 (59)	86 (R)
23		IV	73 (62)	87 (R)
24	(−)-bornyl	Ia	70 (66)	87 (R)
24		IIa	63 (58)	88 (R)
24		IIIa	62 (55)	88 (R)
24		IV	79 (74)	90 (R)
25	Et	Ia	91 (88)	86 (R)
25		IIa	72 (60)	83 (R)
25		IIIa	55 (47)	86 (R)
25		IV	80 (69)	90 (R)
26	(−)-bornyl	Ia	65 (47)	86 (R)
26		IIa	44 (38)	83 (R)
26		IIIa	44 (34)	88 (R)
26		IV	67 (63)	91 (R)

aThe yield was determined by 1H NMR analysis of the crude product. bIsolated yield after column chromatography. cThe ee or de values were determined by chiral HPLC. dThe configuration at the newly formed stereocenter of the prevailing stereoisomer.

Scheme 2

Synthesis of linezolid (1) and rivaroxaban (2) from nitroaldols 24 or 26.

From the results summarized in Table 2 it follows that the carbamate substituents in the aldehydes 16–20 do not affect the enantioselectivity or diastereoselectivity. All nitroaldol products 22–26 were obtained with ee (or de) values in the range of 83–91%. This observation was confirmed in a separate experiment, where the aldehyde 16 bearing the substituent R2 = ᴅ-menthyl (opposite sense of chirality) was applied. This substrate was transformed to the corresponding nitroaldol 22 by the action of the complex Cu(OAc)2/Ia with practically identical de of 88%. On the other hand, the interpretation of chemical yields is rather indistinct. Generally, the copper(II) complexes of ligands Ia and IV exhibited a higher catalytic activity than the catalysts derived from IIa and IIIa. Thus, the yields achieved by catalysts derived from Ia and IV can be considered as satisfactory for almost all nitroaldols 21–26. The influence of the substituent R2 differed in the type of the substrate. In the cases of nitroaldols 21–24 leading to linezolid (1) we found higher chemical yields for derivatives 23 (R2 = t-Bu) and 24 (R2 = (−)-bornyl) (62–80%) than for derivatives 21 (R2 = Et) and 22 (R2 = ʟ-menthyl) (38–78%). However, in the cases of nitroaldols 25 and 26, affording subsequently rivaroxaban (2), we obtained higher chemical yields for derivative 25 (R2 = Et, 55–91%) than for 26 (R2 = (−)-bornyl, 44–67%). For these findings we do not have any reliable explanation.

Next, the synthetic method [12-13] for the preparation of the target oxazolidine-2-one drugs 1 and 2 from the new chiral intermediates was verified (Scheme 2). For this study, the bornyl derivatives 24 and 26 were chosen. The reduction of the nitro groups in 24 and 26 via the hydrogenation procedure proceeded smoothly with almost quantitative yields; the amine intermediates were immediately used in the next step. Hence, the N-acylation reactions were performed by the action of the corresponding acylating reagent (1.0 equiv) in DCM and in the presence of TEA (1.1 equiv). The amides 27 and 28 were obtained with moderate yields (78% for 27 and 65% for 28) – values that are comparable to those previously described for the analogous ethyl derivatives [12-13]. Finally, the base-catalyzed intramolecular transesterification (cyclization) led to the desired products 1 and 2. In the case of amides 27 and 28, the reaction conditions for the cyclization were slightly modified, i.e., the reaction time was prolonged to 24 h and the precipitated product was washed with hexane to remove traces of borneol. No changes in the de were observed and the presence of the major S-enantiomer in the products 1 and 2 was confirmed by chiral HPLC analysis.

Moreover, an enhancement of the abundance of the major epimer in the nitroaldols 22, 24, and 26 as well as the amides 27 and 28 was examined. Generally, epimers represent pairs of stereoisomers that are easier to separate by standard techniques than enantiomers. In particular, an exploration of convenient chromatographic conditions was performed. Unfortunately, none of the conditions was successful even though all derivatives were tested. Subsequently, the separation of the epimers by recrystallization was tested. For this purpose, the nitroaldols 24 and 26 were prepared at a 10 mmol scale (ca. 4 g) using 10 mol % of the catalyst Cu(OAc)2/IV at 20 °C to achieve high yields of the products (24: 92% and 26: 84%). The nitroaldols 24 and 26 were obtained in these scale-up experiments with de values of 84% and 88%, respectively. Hence, the higher temperature led to a slight drop of the de, nevertheless, the higher amount of the undesired diastereomer was considered as convenient here, in terms of the study of its separation. The nitroaldols 24 and 26 were isolated as an oil/waxy solid material, what made the attempts of recrystallization impossible. On the other hand, the corresponding amides 27 and 28 were obtained as fine crystalline solids. Their crystallization was successfully performed from several solvents. However, the de values of the isolated recrystallized material were practically the same as the one of the starting material in all cases. Further, the separation via kinetic resolution in the final reaction step was also examined. The course of the re-esterification was stopped at a conversion of ca 50% and the de values were determined. Unfortunately, no difference between the de values of the starting amides 27 and 28 and the final drugs 1 and 2 was found.

Conclusion

In conclusion, the synthetic approach to the preparation of the antibiotic linezolid (1) and the anticoagulant rivaroxaban (2) based on the asymmetric Henry reaction was studied in detail. A series of 11 efficient enantioselective catalysts was tested to obtain the corresponding nitroaldol 21 in an enantiomeric excess as high as possible. Four of them based on the chiral ligands Ia, IIa, IIIa, and IV were identified as the most effective catalysts. They exhibited mutually comparable enantioselectivities in the range of 83–91% ee. It was found, that the enantioselectivity does not vary with the substitution in the carbamate group of the used aldehydes 15–20. However, all nitroaldols 21–24 prepared as chiral intermediates suitable for the linezolid (1) synthesis were obtained with higher ee (or de) values (83–90%) than in the previously published study (up to 72% ee) [13]. The introduction of a chiral moiety into the structure of aldehydes 16, 18 and 20 led to the formation of nitroaldols 22, 24, and 26 as pairs of epimers. Unfortunately, the attempts of separating the minor epimer were unsuccessful. From this point of view, further efforts on the separation of the remaining minor (5–8%) inactive (R)-stereomer in the final linezolid (1) or rivaroxaban (2) should be continued to make this synthetic approach commercially viable.

General information and experimental data of all isolated products, copies of 1H and 13C NMR spectra for products and HPLC chromatograms.