Patent Application
20230381761
The present disclosure relates to a diastereoselective synthetic process for the preparation of remdesivir (or GS-5734). More particularly, the disclosure invention relates to a one-pot process for diastereoselective synthesis of remdesivir carried out in the presence of a chiral imidazo-cinnamaldehyde-derived carbamate catalyst.
Remdesivir 1 (GS-5734,
The preparation of remdesvir 1 has been explored by Gilead's team. The entire procedure resulted in attributing a high price—$2,340 US dollars for a 5-day course per person in clinic, announced by Gilead on 29 Jun. 2020. Gilead's process is presented in
In view of the above, there exists in this art a need of an improved process for diastereoselective synthesis of remdesivir.
The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the present invention or delineate the scope of the present invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later.
In accordance with a first aspect of this invention, there is provided novel catalysts for the synthesis of the anti-coronavirus drug remdesivir (or GS-5734) by producing a diastereomerically enriched form of compound 8, which is a (Sp)-diasteroisomer.
According to some embodiments of the present disclosure, the catalyst has the structure of formula (1),
wherein,
X is C or N;
n is 0 or 1;
R1 and R2 are independently hydrogen or phenyl;
R3 is tert-butyl, tert-butyldimethylsilyl (TBDMS), phenyl, benzyl, or adamantanyl; and
R4 is hydrogen provided that X is N, or R4 is —OCOCH3 provided that X is C.
The catalyst of formula (1) may be any one of,
According to other embodiments of the present disclosure, the catalyst has the structure of formula (2-1)
wherein, R1 and R2 are independently hydrogen or phenyl.
The catalyst of formula (2-1) may be any one of,
According to further embodiments of the present disclosure, the catalyst has the structure of formula (2-2),
wherein, R1 and R2 are independently hydrogen or phenyl.
The catalyst of formula (2-2) may be any one of,
In accordance with a second aspect of this invention, there is provided a one-pot synthetic process for the preparation of remdesivir, the process comprises:
wherein,
the compound 4 in the step (a) exists in a racemic mixture; and
the steps (a) and (b) are performed in the same vessel without intermediate purification.
According to embodiments of the present disclosure, in the step (a), the catalyst is present in the amount of 10-100 mol % in the reaction mixture; and the reaction is performed at a temperature between −10° C. to −50° C. for a period of 12 to 48 h. Preferably, the catalyst is present in the amount of 20 mol % in the reaction mixture; and the reaction is performed at −20° C. for 24 h and the compound 8 is formed with at least 96% selectivity
According to embodiments of the present disclosure, the step (b) is performed in an acidic solution that comprises p-toluenesulfonic acid (p-TSA) and methanol at a temperature between 20° C. to 60° C. for a period of 4-36 h. Preferably, the step (b) is performed at room temperature for 24 h.
Many of the attendant features and advantages of the present disclosure will becomes better understood with reference to the following detailed description considered in connection with the accompanying drawings.
The present description will be better understood from the following detailed description read in light of the accompanying drawings, where:
The detailed description provided below in connection with the appended drawings is intended as a description of the present examples and is not intended to represent the only forms in which the present example may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.
The singular forms “a”, “and”, and “the” are used herein to include plural referents unless the context clearly dictates otherwise.
This invention relates to a novel process for the synthesis of the anti-coronavirus drug remdesivir (or GS-5734), in which chirality is introduced in the coupling reaction between phosphoramidoyl chloridate and D-ribose-derived 5-alcohol (i.e., compounds 4 and 7 in Gilead's scheme for the preparation of remdesivir as depicted in
Accordingly, it is the objective of the present disclosure to provide a one-pot synthetic process for the preparation of remdesivir (GS-5734). The process comprises steps of:
wherein,
the compound 4 in the step (a) exists in a racemic mixture; and
the steps (a) and (b) are performed in the same vessel without intermediate purification.
According to some embodiments of the present disclosure, the catalyst suitable for use in the step (a) has the structure of formula (1),
wherein,
X is C or N;
n is 0 or 1;
R1 and R2 are independently hydrogen or phenyl;
R3 is tert-butyl, tert-butyldimethylsilyl (TBDMS), phenyl, benzyl, or adamantanyl; and
R4 is hydrogen provided that X is N, or R4 is —OCOCH3 provided that X is C. Examples of the catalyst of formula (1) suitable for use in the one-pot process include, but are not limited to,
Preferably, the catalyst of formula (1) suitable for use in the one-pot process is compound 29.
According to other embodiments of the present disclosure, the catalyst suitable for use in the step (a) has the structure of formula (2-1)
wherein, R1 and R2 are independently hydrogen or phenyl.
Examples of the catalyst of formula (2-1) suitable for use in the one-pot process include, but are not limited to,
According to further embodiments of the present disclosure, the catalyst suitable for use in the step (a) has the structure of formula (2-2),
wherein, R1 and R2 are independently hydrogen or phenyl.
Examples of the catalyst of formula (2-1) suitable for use in the one-pot process include, but are not limited to,
According to embodiments of the present disclosure, the catalyst in the step (a) may be present in the amount of 10-100 mol %, such as 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, and 100 mol %; preferably, the catalyst is present in the amount of 15-50 mol %, such as 15, 20, 25, 30, 35, 40, 45, and 50 mol %; most preferably, the catalyst is present in the amount of 20 mol %. Further, the step (a) is performed at a temperature between −10° C. to −50° C. for a period of 12 to 48 hrs.
According to preferred embodiments of the present disclosure, 20 mol % of the catalyst of formula (1), (2-1) or (2-2) are used to catalyze the coupling reaction between compounds 4 and 7, thereby producing compound 8 in (Sp)-diasetreomerically enriched form, in which the selectivity of (Sp)-diasetreomer over (Rp)-diasetreomer is at least 80%, such as 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99%; preferably, the selectivity of (Sp)-diasetreomer over (Rp)-diasetreomer is at least 90%, such as 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99%; more preferably, at least 95%, such as 95, 96, 97, 98, and 99%. In one embodiment, compounds 4 and 7 are coupled in the presence of 20 mol % of compound 29 at −20° C. for 24 hr, thereby forming compound 8 with 96.1% selectivity (i.e., 96.1% of the product of the step (a) are (Sp)-diastereomers, while the rest of the product are (Rp)-diasetreomer) and 97% yield. In another embodiment, compounds 4 and 7 are coupled in the presence of 20 mol % of compound 31 at −20° C. for 24 hr, thereby forming compound 8 with 89% selectivity (i.e., 89% of the product of the step (a) are (Sp)-diastereomers, while the rest of the product are (Rp)-diasetreomer) and 79% yield. In a further embodiment, compounds 4 and 7 are coupled in the presence of 20 mol % of compound 34 at −20° C. for 24 hr, thereby forming compound 8 with 91.7% selectivity (i.e., 91.7% of the product of the step (a) are (Sp)-diastereomers, while the rest of the product are (Rp)-diasetreomer) and 94% yield. In still a further embodiment, compounds 4 and 7 are coupled in the presence of 20 mol % of compound 38 at −20° C. for 24 hr, thereby forming compound 8 with 84.5% selectivity (i.e., 84.5% of the product of the step (a) are (Sp)-diastereomers, while the rest of the product are (Rp)-diasetreomer) and 93% yield.
The compound 8 thus produced in the step (a) is then subjected to acidic hydrolysis to remove the isopropylidene protective group, thereby producing the desired remdesivir (step (b)). The acidic hydrolysis is conducted in a solution that comprises p-toluenesulfonic acid (p-TSA) and methanol at 40° C. for 6 hrs in the same reaction flask as that of step (a), thereby achieving one-pot synthesis of remdesivir. A typical one-pot synthesis for preparing remdesivir according to the present invention comprises the above mentioned steps (a) to (b), which are performed in the same reaction vessel without intermediate purification.
According to preferred embodiment of the present disclosure, the remdesivir thus produced in the step (b) may be further purified by any suitable means, such as column chromatography. In one specific embodiment, the yield of remdesivir after purification is 73%. In addition, the catalyst may be recycled or recovered as well. In certain embodiments, compound 29, which serves as the catalyst, is recovered at a yield of 82%.
The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the present invention.
In this example, for synthesis of remdesivir 1, series of chiral bicyclic imidazoles (compounds 26-32, and 42-45) and bis bicyclic imidazoles (compounds 33 to 41) serving as chiral catalysts were designed and synthesized to ensure compound 8 would acquire desired (5)-stereochemistry at the phosphorus center. The efficacy of each synthesized catalyst in achieving desired stereo-selectivity was also evaluated.
1.1 Synthesis of the Present Chiral Catalyst
1.1.1 Synthesis of Compounds 26 and 26A
To a solution of trans-isomers (1.0 g, 4.99 mmol) and (+)-O-Acetyl-L-mandelic acid in CH2Cl2, added EDC·HCl (1.43 g, 7.40 mmol) and DMAP (0.61 g, 4.99 mmol) at 0° C. Then, the reaction temperature was gradually warmed up to room temperature and allowed to stir for 3 h. The TLC analysis indicated the complete conversion of starting materials into their respective products. The reaction mixture was concentrated and the crude residue was dissolved in ethyl acetate and washed with sat. NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was subjected to silica gel column chromotography by using ethyl acetate/hexane (1/3) as eluent to afford 26 (820 mg, 44%) as a semi solid and 26A (790 mg, 42%) as a gummy solid.
Compound 26.
1H NMR (600 MHz, CDCl3): δ 7.49 (d, J=4.3 Hz, 2H), 7.44-7.36 (m, 6H), 7.22 (s, 1H), 7.15 (d, J=6.7 Hz, 2H), 6.78 (d, J=0.6 Hz, 1H), 6.10 (d, J=6.5 Hz, 1H), (s, 1H), 5.47 (t, J=6.9 Hz, 1H), 3.11 (dd, J=14.7, 6.8 Hz, 1H), 2.91 (dt, J=13.9, 6.8 Hz, 1H), 2.23 (s, 3H).
13C NMR (150 MHz, CDCl3): δ 171.0, 168.8, 150.3, 139.3, 135.4, 133.0, 129.7, 129.4, 129.1, 128.9, 127.9, 126.5, 115.4, 75.0, 68.9, 59.6, 46.1, 20.9. HRMS m/z (ESI, M+Na+) calcd for C12H12N2ONa+ 399.1315, found 399.1330.
Compound 26 A.
1H NMR (600 MHz, CDCl3): δ 7.44 (dd, J=6.5, 2.9 Hz, 2H), 7.39-7.36 (m, 3H), 7.35-7.29 (m, 3H), 7.20 (s, 1H), 7.05-6.99 (m, 2H), 6.71 (d, J=0.6 Hz, 1H), 6.10 (dd, J=6.5, 1.8 Hz, 1H), 5.15 (t, J=6.9 Hz, 1H), 2.77 (dt, J=13.6, 6.7 Hz, 1H), 2.70 (ddd, J=14.7, 6.9, 1.8 Hz, 1H), 2.15 (s, 3H).
13C NMR (150 MHz, CDCl3): δ 170.3, 168.5, 150.4, 139.1, 135.5, 133.8, 129.6, 129.4, 129.1, 129.0, 128.0, 126.4, 115.4, 74.6, 68.7, 59.5, 45.9, 20.9.
HRMS m/z (ESI, M+Na+) calcd for C12H12N2ONa+ 399.1315, found 399.1329.
1.1.2 General Procedure (A) for the Synthesis of Compounds 27 and 28.
To a solution of an alcohol (50 mg, 0.40 mmol) in THF (1.0 mL) was added sodium hydride (60% in mineral oil, 19 mg, 0.48 mmol) in portions. After 30 min, tert-butylisocyanate (40 mg, 0.40 mmol) was added dropwise. After 16 h the reaction was quenched by the addition of water (2.0 mL) and was then partitioned between water (2.0 mL) and iPAc (4.0 mL). The organic layer was washed with brine (4.0 mL), dried over MgSO4, filtered and concentrated to yield a pale orange semi-solid. The residue was dissolved in MTBE (2.0 mL) with gentle heating, and then heptane (2.0 mL) was added over 10 min. After 2 h the mixture was filtered and washed with 1/1 MTBE/heptane (2 mL) and dried under nitrogen stream to yield desired compound.
Compound 27 was prepared according to the general procedure (A) as a white solid (77 mg, 86%).
1H NMR (600 MHz, CDCl3): δ 7.17 (s, 1H), 6.93 (s, 1H), 5.87 (d, J=4.8 Hz, 1H), 4.75 (s, 1H), 4.04-4.10 (m, 1H), 3.98-3.94 (m, 1H), 3.08-3.02 (m, 1H), 2.61-2.57 (m, 1H), 1.30 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 154.1, 151.8, 135.0, 115.6, 67.3, 50.7, 43.1, 35.6, 29.0.
HRMS m/z (ESI, M+H+) calcd for C11H18N3O2+ 224.1394, found 224.1398.
Compound 28 was prepared according to the general procedure (A) as a white solid (79 mg, 88%).
1H NMR (600 MHz, CDCl3): δ 7.18 (s, 1H), 6.93 (s, 1H), 5.87 (d, J=5.4 Hz, 1H), 4.75 (s, 1H), 4.14-4.10 (m, 1H), 3.98-3.94 (m, 1H), 3.07-3.02 (m, 1H), 2.61-2.57 (m, 1H), 1.30 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 154.1, 151.8, 135.0, 115.6, 67.3, 50.8, 43.1, 35.6, 29.8, 29.0. HRMS m/z (ESI, M+H+) calcd for C11H18N3O2+ 224.1394, found 224.1398.
1.1.3 General Procedure (B) for the Synthesis of Compounds 29-32 and 42.
To a solution of alcohol (50 mg, 0.25 mmol) and tert-butylisocyanate (25 mg, 0.25 mmol) in THF, sodium hydride (60% in mineral oil, 7.2 mg, 0.30 mmol) was added at room temperature. After 30 min, the reaction was quenched by the addition of water (2 mL) and concentrated to give a pale orange semi-solid. The crude residue was purified by using silica gel column chromatography.
Compound 29 was prepared according to the general procedure (B) as a white solid (66 mg, 89%).
1H NMR (600 MHz, CDCl3): δ 7.40-7.36 (m, 3H), 7.24 (s, 1H), 7.14 (d, J=6.1 Hz, 2H), 6.78 (s, 1H), 6.03 (d, J=5.7 Hz, 1H), 5.44 (t, J=6.0 Hz, 1H), 4.81 (s, 1H), 3.08-3.04 (m, 1H), 2.92-2.87 (m, 1H), 1.34 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 153.9, 151.8, 139.6, 135.1, 129.4, 128.8, 126.4, 115.1, 67.2, 59.6, 50.7, 46.6, 29.0.
HRMS m/z (ESI, M+H+) calcd for C17H22N3O2+ 300.1707, found 300.1712.
Compound 30 was prepared according to the general procedure (B) as a white solid (62 mg, 87%).
1H NMR (600 MHz, CDCl3): δ 7.38-7.32 (m, 3H), 7.21 (s, 1H), 7.18 (d, J=6.0 Hz, 2H), 6.77 (s, 1H), 5.98-5.97 (m, 1H), 5.23-5.20 (m, 1H), 4.79 (s, 1H), 3.60-3.55 (m, 1H), 2.49-2.47 (m, 1H), 1.29 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 154.0, 151.8, 140.5, 135.4, 129.3, 128.7, 126.4, 115.0, 67.2, 59.3, 50.8, 45.7, 29.8, 29.0.
HRMS m/z (ESI, M+H+) calcd for C17H22N3O2+ 300.1707, found 300.1706.
Compound 31 was prepared according to the general procedure (B) as a white solid (62 mg, 87%).
1H NMR (600 MHz, CDCl3): δ 7.40-7.36 (m, 3H), 7.24 (s, 1H), 7.14 (d, J=6.0 Hz, 2H), 6.78 (s, 1H), 6.03 (d, J=5.2 Hz, 1H), 5.42 (t, J=6.0 Hz, 1H), 4.80 (s, 1H), 3.08-3.04 (m, 1H), 2.92-2.87 (m, 1H), 1.34 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 153.96, 151.85, 139.70, 135.254, 129.36, 128.79, 126.37, 115.11, 67.23, 59.64, 50.78, 46.66, 29.02.
HRMS m/z (ESI, M+H+) calcd for C17H22N3O2+ 300.1707, found 300.1715.
Compound 32 was prepared according to the general procedure (B) as a white solid (61 mg, 85%).
1H NMR (600 MHz, CDCl3): δ 7.38-7.33 (m, 3H), 7.26 (s, 1H), 7.21-7.17 (m, 2H), 6.77 (s, 1H), 5.97 (dd, J=12.2, 6.8 Hz, 1H), 5.21 (dd, J=12.0, 6.0 Hz, 1H), 4.78 (s, 1H), 3.59-3.56 (m, 1H), 2.48 (dd, J=12.0 Hz, 6.0 Hz, 1H), 1.30 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 154.0, 151.8, 140.5, 135.4, 129.3, 128.7, 126.4, 115.0, 67.3, 59.3, 50.8, 45.7, 29.8, 29.0.
HRMS m/z (ESI, M+H+) calcd for C17H22N3O2+ 300.1707, found 300.1702.
To a solution of alcohol (100 mg, 0.5 mmol) and 1-Adamantyl isocyanate (106 mg, 0.6 mmol) in THF, sodium hydride (60% in mineral oil, 24 mg, 1.0 mmol) was added at room temperature. After 30 min, the reaction was quenched by the addition of water (2 mL) and concentrated to give a pale orange semi-solid. The crude residue was subjected to silica gel column chromatography by using 30%-40% EtOAc in hexane to afford product as foamy solid (167 mg, 89%).
1H NMR (600 MHz, CDCl3): δ 7.38-7.32 (m, 3H), 7.22 (s, 1H), 7.11 (d, J=7.32 Hz, 2H), 6.75 (s, 1H), 5.97 (d, J=6.4 Hz, 2H), 5.4 (t, J=6.8 Hz, 1H), 4.66 (s, 1H), 3.05-3.02 (m, 1H), 2.88-2.83 (m, 1H), 2.07 (s, 3H), 1.92 (s, 6H), 1.66 (s, 6H).
13C NMR (150 MHz, CDCl3): δ 153.5, 151.9, 139.7, 135.3, 129.4, 128.8, 126.4, 115.1, 67.2, 59.6, 51.2, 46.6, 41.9, 36.5, 29.6.
1.1.4 General Procedure (C) for the Synthesis of Compounds 34-39.
4,4′-(1,3-Phenylene)dibutanoic acid (200 mg, 0.80 mmol) and triethylamine (0.25 mL, 1.80 mmol) were dissolved in THF (4.0 mL). After cooling to 0° C., ethyl chloroformate (0.17 mL, 1.80 mmol) was added dropwise and the mixture was stirred for min. To this mixture was added a solution of sodium azide (0.26 g, 4.0 mmol) in water (3.4 mL). After 30 min, toluene (10.0 mL) and water (10.0 mL) were added and the organic layer was separated. The aqueous layer was extracted with toluene (10.0 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated to ˜50% of the original volume. The crude solution of the acyl azide was then heated to 90° C. for min, then concentrated to yield the diisocyanate (195 mg, 90%) as yellow oil which was used in the next step without further purification. THF (4.0 mL) was added to dissolve the residue. Then, the corresponding starting material among (20-25) (1.6 mmol) was added followed by sodium hydride (60% suspension in mineral oil, 14 mg, 0.36 mmol). An additional portion of sodium hydride was added to complete the reaction. After 30 min, a few drops of water were added to quench the reaction and the solvent removed in vacuo. The crude residue was purified by silica gel chromatography by using ethyl acetate/hexane (3/1)
Compound 34 was prepared according to the general procedure (C) as a white solid (299 mg, 76%).
1H NMR (600 MHz, CDCl3): δ 7.17-7.15 (m, 3H), 7.0-6.93 (m, 5H), 5.90-5.87 (m, 2H), 5.17-4.95 (m, 2H), 4.14-4.09 (m, 2H), 3.98-3.95 (m, 2H), 3.24-3.12 (m, 4H), 3.08-3.00 (m, 2H), 2.61-2.57 (m, 6H), 1.83-1.77 (m, 4H).
13C NMR (151 MHz, CDCl3): δ 155.9, 151.7, 142.1, 141.6, 135.0, 134.8, 128.9, 128.8, 126.3, 126.3, 115.6, 67.9, 43.1, 40.7, 39.8, 35.5, 35.4, 33.1, 32.9, 31.9, 31.6, 31.4.
HRMS m/z (ESI, M+H+) calcd for C26H33N6O4+ 493.2558, found 493.2556.
Compound 35 was prepared according to the general procedure (C) as a white solid (295 mg, 75%).
1H NMR (600 MHz, CDCl3): δ 7.20-7.15 (m, 3H), 7.0-6.93 (m, 5H), 5.90-5.89 (m, 2H), 4.97 (bs, 2H), 4.14-4.10 (m, 2H), 3.98-3.94 (m, 2H), 3.25-3.13 (m, 2H), 3.08-3.02 (m, 2H), 2.62-2.57 (m, 6H), 1.84-1.77 (m, 4H).
13C NMR (150 MHz, CDCl3): δ 155.9, 151.7, 141.6, 134.9, 128.8, 126.3, 115.6, 77.4, 77.2, 77.0, 67.9, 43.1, 40.7, 35.5, 33.1, 31.6.
HRMS m/z (ESI, M+H+) calcd for C26H33N6O4+ 493.2558, found 493.2556.
Compound 36 was prepared according to the general procedure (C) as a white solid (278 mg, 54%).
1H NMR (600 MHz, CDCl3): δ 7.38-7.34 (m, 6H), 7.26 (bs, 2H), 7.11 (bs, 4H), 7.01 (bs, Hz, 3H), 6.74 (s, 2H), 6.02 (s, 2H), 5.40 (bs, 1H), 5.04 (bs, 2H), 3.20-3.18 (m, 4H), 3.05-3.02 (m, 2H), 2.89-2.85 (m, 2H), 2.62 (t, J=6.2 Hz, 4H), 2.47 (t, J=5.7 Hz, 4H).
13C NMR (150 MHz, CDCl3): δ 155.8, 151.7, 141.7, 139.7, 135.3, 129.4, 128.8, 128.79, 128.7, 126.4, 126.3, 115.1, 67.9, 59.6, 46.6, 40.8, 33.1, 31.6.
HRMS m/z (ESI, M+H+) calcd for C26H33N6O4+ 645.3184, found 645.3173.
Compound 37 was prepared according to the general procedure (C) as a white solid (288 mg, 56%).
1H NMR (600 MHz, CDCl3): δ 7.38-7.34 (m, 6H), 7.26 (d, J=5.9 Hz, 2H), 7.11 (d, J=6.0 Hz, 4H), 7.01 (d, J=6.0 Hz, 4H), 6.75 (s, 1H), 6.02 (d, J=5.2 Hz, 2H), (t, J=6.1 Hz, 2H), 4.94 (bs, 2H), 3.25-3.18 (m, 4H), 3.05-3.02 (m, 2H), 2.89-2.85 (m, 2H), 2.62 (t, J=6.2 Hz, 4H), 2.47 (t, J=5.7 Hz, 4H).
13C NMR (150 MHz, CDCl3): δ 155.8, 151.7, 141.7, 139.7, 135.3, 129.4, 128.8, 128.8, 128.7, 126.4, 126.3, 115.1, 67.9, 59.6, 46.6, 40.8, 33.1, 31.6.
HRMS m/z (ESI, M+H+) calcd for C26H33N6O4+ 645.3184, found 645.3177.
Compound 38 was prepared according to the general procedure (C) as a white solid (293 mg, 57%).
1H NMR (600 MHz, CDCl3): δ 7.34-7.33 (m, 6H), 7.25 (s, 2H), 7.20-7.15 (m, 5H), 6.96 (bs, 3H), 6.77 (s, 2H), 5.99 (s, 2H), 5.20 (s, 2H), 4.98 (s, 2H), 3.56-3.55 (m, 2H), 3.20-3.14 (m, 4H) 2.58-2.47 (m, 6H), 1.8 (bs, 4H).
13C NMR (150 MHz, CDCl3): δ 155.8, 151.7, 141.7, 139.7, 135.2, 129.4, 128.8, 128.8, 126.4, 126.2, 115.1, 67.8, 59.6, 46.5, 40.8, 33.1, 31.6.
HRMS m/z (ESI, M+H+) calcd for C26H33N6O4+ 645.3184, found 645.3190.
Compound 39 was prepared according to the general procedure (C) as a white solid (283 mg, 55%).
1H NMR (600 MHz, CDCl3): δ 7.34-7.33 (m, 6H), 7.25 (s, 2H), 7.20-7.15 (m, 5H), 6.96 (bs, 3H), 6.77 (s, 2H), 5.99 (s, 2H), 5.20 (s, 2H), 4.98 (s, 2H), 3.56-3.55 (m, 2H), 3.20-3.14 (m, 4H) 2.58-2.47 (m, 6H), 1.8 (bs, 4H).
13C NMR (150 MHz, CDCl3): δ 155.8, 151.7, 141.7, 139.7, 135.2, 129.4, 128.8, 128.8, 126.4, 126.3, 115.1, 67.9, 59.6, 46.5, 40.8, 33.1, 31.6.
HRMS m/z (ESI, M+H+) calcd for C26H33N6O4+ 645.3184, found 645.3176.
1.1.5 Synthesis of Compounds 40-41
To a solution of alcohol 22 (100 mg, 0.51 mmol) and benzyl chloride (104 mg, mmol) in anhydrous DMF (2.0 mL), NaH (9.0 mg, 0.37 mmol) was added. The reaction mixture was allowed to stir at room temperature under N2, and the progress of the reaction was monitored by TLC. After 8 h, the TLC analysis indicates the complete conversion of starting materials into products. The reaction mixture was quenched with ice-cold water and extracted with EtOAc, organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was subjected to silica gel column chromatography to afford benzyl ether 40 (99 mg, 68%) as a colorless oil.
1H NMR (600 MHz, CDCl3): δ 7.41-7.34 (m, 7H), 7.30-7.27 (m, 1H), 7.20 (s, 1H), 7.15-7.13 (s, 2H), 6.74 (s, 1H), 5.46 (dd, J=12.0, 6.0 Hz, 1H), 4.95-4.90 (m, 2H), 4.75-4.73 (m, 1H), 3.06-3.02 (m, 1H), 2.73-2.69 (m, 1H).
13C NMR (150 MHz, CDCl3): δ 153.6, 139.9, 138.0, 134.2, 129.3, 128.7, 128.6, 128.3, 127.9, 126.6, 114.7, 71.5, 71.0, 59.9, 47.0, 29.9.
HRMS m/z (ESI, M+H+) calcd for C19H19N2O+ 291.1492, found 291.1493.
To a solution of alcohol 22 (100 mg, 0.51 mmol) and 2,6-lutidine (80.4 mg, 0.75 mmol) in CH2Cl2 (1.5 mL) was added tert-butyldimethylsilyl chloride (TBDMSCl) (0.11 mL, 0.5 mmol) at 0° C. The mixture was warmed to room temperature and allowed to stir for 12 h. After concentration in vacuo, the residue was subjected to silica gel chromatography by using ethyl acetate in hexane (0→100%) as an eluent to afford desired compound 41 as a colorless liquid (99 mg, 63%).
1H NMR (600 MHz, CDCl3): δ 7.36-7.33 (m, 3H), 7.17 (s, 1H), 7.10 (s, 2H), 6.67 (s, 1H), 5.44 (s, 1H), 5.21 (s, 1H), 2.88-2.86 (m, 1H), 2.71-2.68 (m, 1H), 0.92 (s, 9H), 0.22 (s, 3H), 0.13 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 155.2, 140.4, 134.4, 129.3, 128.6, 126.5, 114.2, 66.3, 59.4, 49.8, 26.1, 18.5, −4.3, −4.6.
HRMS m/z (ESI, M+H+) calcd for C18H27N2OSi+ 315.1887, found 315.1889.
1.2 Characterization of the Catalyst of Example 1.1
In this example, the catalyst prepared in Example 1.1 was used to catalyze the coupling reaction between 1:1 phosphoramidoyl chloridates 4 with the D-ribose-derived 7, thereby forming compounds 8 and 8a. The selectivity and yield of the products 8 and 8a are summarized in Table 1.
1.2.1 General Procedure for the Catalytic Asymmetric Phosphoramidation
In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (10.0 mg, 0.03 mmol) and catalyst (mol % was according to Table 1 below) were co-evaporated with anhydrous toluene (1.0 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH2Cl2 (1.0 mL) and then freshly activated 4 Å molecular sieves (20 mg) followed by 2,6-luditine (7.0 μL, 0.06 mmol) were added. The suspension was then stirred under N2 atmosphere at room temperature for 10 min, and then cooled to −20° C. After 10 min, a solution of phosphochloridate 4 (15.7 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. The whole reaction mixture was filtered through a pad of Celite®, the filtrate was concentrated in vacuo. The crude residue was dissolved in MeOH and filtered off. The filtrate was subjected to HPLC analysis.
aThe ratio was determined by HPLC analysis.
Referring to Table 1, in entry 1, when 20 mol % of the (S)-carbamate 27 was used in the reaction at −20° C. for 24 h, a mixture of the diastereomers 8 and 8a was obtained in 94% yield with a ratio of 93.6/6.4 (determined by HPLC). In contrast, the (R)-carbamate 28 gave 64% yield with a 65.4/34.6 ratio (entry 2). Obviously, the (5)-configuration of 27 favored the formation of (S)—P-diastereomer in both selectivity and yield. We then tested the (S)-carbamate 29 having an extra phenyl group with (R)-configuration under similar conditions (entry 3), and the ratio (96.1/3.9) and yield (97%) were slightly increased in comparison with 27. On the other hand, in entry 5, when the (S)-carbamate 31 attaching an extra (S)-phenyl group was tested, a decrease of the yield (79%) and ratio (89.0/11.0) was observed. The configuration of this extra phenyl group is important for the asymmetric phosphoramidation. We next individually examined the (R)-carbamates 30 [entry 4, (9-Ph] and 32 [entry 6, (R)-Ph], and similar results were found as compared to 28 (entry 2).
Regarding the catalysts of bis-bicyclic imidazoles, the ratios of 8/8a were generated in 91.7/8.3 (entry 7, 94% yield), 96.1/3.9 (entry 9, 96% yield) and 84.5/15.5 (entry 11, 93% yield) by using the dimeric (S)-carbamates 34, 36, and 38, respectively. Interestingly, the dimeric (R)-carbamates 35 (entry 8), 37 (entry 10) and 39 (entry 12) furnished the undesired diastereomer 8a as a major product in much better yields and ratios in comparison with the monomeric (R)-carbamates 28, 30 and 32, respectively. In addition to the carbamate moiety, the (5)-benzyl ether (40, entry 13), (5)-silyl ether (41, entry 14), (5)-adamantyl carbamate (42, entry 15), and (S)-ester (26, entry 16) were further carried out to provide the 8/8a rations in 83.1/16.9 (68%), 80.3/19.7 (61%), 96.8/3.2 (86%) and 75.1/24.9 (67%), respectively.
Since compound 29 provides the best results in the catalyst screening in terms of yield and selectivity, thus, its catalytic properties as well as temperature effect were further investigated. It was found that when the reaction was carried out at −10° C. (entry 17), the yield (90%) and selectivity (94.5/5.5) slightly decreased. Whereas, at a lower temperature −40° C., marginal improvement of the selectivity (96.8/3.2) was observed (entry 18). However, the reaction time required 48 h for completion due to the decrease of catalytic activity. Moreover, no reaction was initiated at −78° C. (entry 19). In entries 19-24, various catalytic concentrations were studied. Reducing the amounts of catalyst 29 to mol % (entry 22), 10 mol % (entry 21) and 2 mol % (entry 20), both selectivity and yield gradually decreased. When 50 mol % of 29 was checked at −20° C. (entry 23), the selectivity slightly increased from 96.1/3.9 to 97.1/2.9 and the reaction was completed in 12 h. By lowering temperature to −40° C. (entry 24), a ratio of 97.3/2.7 was obtained. Similar phenomenon was observed by employing 100 mol % of 29 (entry 25), providing a 97.7/2.3 ratio.
One-pot synthesis of remdesivir 1 was carried out in accordance with steps described in Scheme 2, in which all reactions were carried out in the same flask without intermediate purification until the final product (i.e., remdesivir) was produced. Remdesivir was produced in 73% yield after C18 column purification. The catalyst 29 was recovered in 82% yield.
In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (1.0 g, 3.02 mmol) and catalyst 29 (180 mg, 0.62 mmol) were co-evaporated with anhydrous toluene (20 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH2Cl2 (50 mL) and then freshly activated 4 Å molecular sieves (1.5 g) followed by 2,6-luditine (700 μL, 6.04 mmol) were added. The suspension was then stirred under N2 atmosphere at room temperature for 10 min, and then cooled to −20° C. After 10 min, a solution of phosphochloridate 4 (1.57 g, 4.53 mmol) in dry CH2Cl2 (5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. Then the CH2Cl2 was evaporated by vacuum. Later on, the crude material was treated with 10.0 equiv of p-TSA in MeOH (50 mL). The reaction mixture was allowed to stir for 24 h at room temperature and the TLC analysis indicated the product formation. Then the reaction mixture was filtered through a pad of Celite® to remove 4 Å molecular sieves, quenched by adding Et3N and concentrated in vacuo. The crude residue was dissolved in EtOAc and washed with Saturated NaHCO3, the aqueous layer was back extracted with EtOAc (3×50 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was subjected to silica gel column chromatography by using EtOAc in hexane (0→100%) as an eluent to afford the products as a foamy solid. The diastereomeric mixture was purified by using C18 column to give compound 1 as a foamy solid (1.39 g, 73%).
1H NMR (600 MHz, CD3OD) δ 7.87 (s, 1H), 7.30 (t, J=7.8 Hz, 2H), 7.21-7.14 (m, 3H), 6.91 (d, J=4.6 Hz, 1H), 6.88 (d, J=4.6 Hz, 1H), 4.79 (d, J=5.4 Hz, 1H), 4.42-4.35 (m, 2H), 4.28 (dt, J=10.5, 5.1 Hz, 1H), 4.17 (t, J=5.6 Hz, 1H), 4.02 (dd, J=5.8 Hz, 1H), 3.90 (ddd, J=23.7, 12.7, 6.4 Hz, 2H), 1.45 (dt, J=12.3, 6.2 Hz, 1H), 1.34-1.28 (m, 7H), 0.85 (t, J=7.5 Hz, 6H).
13C NMR (150 MHz, CD3OD) δ 175.15, 175.1, 157.4, 152.3, 152.3, 148.4, 130.9, 126.2, 125.7, 121.51, 121.5, 118.1, 117.7, 112.5, 102.8, 84.44, 81.4, 84.4, 75.9, 71.8, 68.2, 67.3, 67.27, 41.8, 24.4, 24.3, 20.7, 20.6, 11.5, 11.4.
In conclusion, this invention provides an efficient catalyst for stereoselective (S)—P-phosphoramidation in excellent yield and selectivity. The 1/1 racemic mixture of phosphoramidoyl chloridates 4 may be directly used as the coupling reagent for the synthesis of remdesivir, avoiding a waste of the other diastereomer. In addition, a high yielding combination of (S)—P-phosphoramidation and isopropylidene-deprotection successfully provided remdesivir in a one-pot manner. The catalyst may be recovered in good yield, and similar results were obtained with the recycled catalyst. Accordingly, this one-pot cost-down process has a potential being scale-up for industrial production.
It will be understood that the above description of embodiments is given by way of example only and that various modifications may be made by those with ordinary skill in the art. The above specification, examples, and data provide a complete description of the structure and use of exemplary embodiments of the invention. Although various embodiments of the invention have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those with ordinary skill in the art could make numerous alterations to the disclosed embodiments without departing from the spirit or scope of this invention.
This application claims priority and the benefit of U.S. Provisional Patent Application No. 63/089,028, filed Oct. 8, 2020, the entirety of which is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/053886 | 10/7/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63089028 | Oct 2020 | US |
