METHOD FOR SYNTHESIZING C-NUCLEOSIDE COMPOUND

Abstract

Disclosed is a method for preparing a C-nucleoside compound represented by Formula (III) or salt thereof. The present method has a high reaction yield, is simple to operate, uses a single metal reagent, has stable reaction temperature conditions, does not require frequent changes to the reaction system during the operation process, is suitable for scale-up synthesis, is suitable for large-scale production of Remdesivir, and has low costs.

##STR00001##

Claims

1. A method for preparing a C-nucleoside compound represented by Formula III or salt thereof, comprising: a) providing a compound represented by Formula II; b) in a solvent, in the presence of a secondary amine represented by Formula 4, a metal lithium reagent and 1,2-bis(chlorodimethylsilyl)ethane, allowing a compound represented by Formula 1 to react with the compound represented by Formula II to generate the C-nucleoside compound represented by Formula III, ##STR00021## in the compound represented by Formula 1, X is halogen; in the secondary amine represented by Formula 4, each R is independently C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or trimethylsilyl, or two Rs and the nitrogen atom to which they are attached together form a substituted or unsubstituted piperidine or pyrrolidine; in the compound represented by Formula II or Formula III, R.sup.a, R.sup.b and R.sup.c are each independently methyl, benzyl, p-methoxybenzyl, trityl, tert-butyl or allyl; in the compound represented by the Formula III, “” indicates that the structural formula can represent the α configuration or the β configuration of the compound, or a mixture of the α configuration and the β configuration in any ratio.

2. The method for preparing C-nucleoside compound according to claim 1, wherein X is a bromine atom or an iodine atom.

3. The method for preparing C-nucleoside compound according to claim 1, wherein each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or trimethylsilyl, or two Rs and the nitrogen atom to which they are attached together form piperidine, pyrrolidine or 2,2,6,6-tetramethylpiperidine.

4. The method for preparing C-nucleoside compound according to claim 1, wherein R.sup.a, R.sup.b, and R.sup.c are each independently benzyl group.

5. The method for preparing C-nucleoside compound according to claim 1, wherein the solvent is an organic solvent.

6. The method for preparing C-nucleoside compound according to claim 1, wherein the metal lithium reagent is methyllithium, n-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium bis(trifluoromethanesulfonimide), lithium triethylborohydride, lithium borohydride, lithium amide or lithium hydride.

7. The method for preparing C-nucleoside compound according to claim 1, wherein step b) comprises: b1) dissolving the compound represented by Formula 1 and 1,2-bis(chlorodimethylsilyl)ethane in the solvent, and adding the secondary amine represented by Formula 4 to obtain a mixture; b2) sequentially adding the metal lithium reagent and the compound represented by Formula II to the mixture obtained in b1), and allowing the compound represented by Formula 1 to react with the compound represented by Formula II to obtain the compound represented by Formula III.

8. The method for preparing C-nucleoside compound according to claim 1, wherein the compound represented by Formula 1 is reacted with the compound represented by Formula II, and the initial concentration of the compound represented by Formula 1 is 0.06 to 0.3 mol/L.

9. The method for preparing C-nucleoside compound according to claim 1, wherein the compound represented by Formula 1 is reacted with the compound represented by Formula II at a temperature of 0° C. to −80° C.

10. The method for preparing C-nucleoside compound according to claim 1, wherein the feeding molar ratio of the compound represented by Formula 1 to the compound represented by Formula II is 1:1.5˜-3.

11. The method for preparing C-nucleoside compound according to claim 1, wherein step b) is carried out under anhydrous and anaerobic conditions.

12. The method for preparing C-nucleoside compound according to claim 1, wherein the reaction between the compound represented by Formula 1 and the compound represented by Formula II comprises: under the action of the secondary amine represented by Formula 4 and the metal lithium reagent, allowing the 4-position amino group in the compound represented by Formula 1 to undergo a bis-silicon protection by using 1,2-bis(chlorodimethylsilyl)ethane to generate a compound represented by the intermediate Formula 5; ##STR00022## under the action of the secondary amine represented by Formula 4 and the metal lithium reagent, the compound represented by Formula 5 undergoing a lithium-halogen exchange to generate a compound represented by the intermediate Formula 6, wherein M is Li; the compound represented by the Formula 6 undergoing an addition reaction with the compound represented by the Formula II to generate the C-nucleoside compound represented by the Formula III.

13. A method for preparing a C-nucleoside compound, comprising: 1) in a solvent, under the action of a secondary amine represented by Formula 4 and a metal lithium reagent, allowing the 4-position amino group in the compound represented by Formula 1 to undergo a bis-silicon protection by using 1,2-bis(chlorodimethylsilyl)ethane to generate a compound represented by the intermediate Formula 5; ##STR00023## 2) under the action of the secondary amine represented by Formula 4 and the metal lithium reagent, the compound represented by Formula 5 undergoing lithium-halogen exchange to generate a compound represented by the intermediate Formula 6, wherein M is Li; 3) the compound represented by Formula 6 undergoing an addition reaction with a compound represented by Formula II to generate a C-nucleoside compound represented by Formula III, wherein, the definitions of the solvent, X, R, R.sup.a, R.sup.b, R.sup.c, are as described in claim 1.

14. The method for preparing C-nucleoside compound according to claim 2, wherein X is a bromine atom.

15. The method for preparing C-nucleoside compound according to claim 3, wherein the secondary amine represented by Formula 4 is diisopropylamine, diisobutylamine, dicyclohexylamine, 2,2,6,6-tetramethylpiperidine or hexamethyldisilazane.

16. The method for preparing C-nucleoside compound according to claim 5, wherein the solvent is tetrahydrofuran.

17. The method for preparing C-nucleoside compound according to claim 6, wherein the metal lithium reagent is n-butyllithium.

18. The method for preparing C-nucleoside compound according to claim 1, wherein the feeding molar ratio of the compound represented by Formula 1 to the lithium metal reagent is 1:3.5˜4.5.

19. The method for preparing C-nucleoside compound according to claim 1, wherein the feeding molar ratio of the compound represented by Formula 1 to 1,2-bis(chlorodimethylsilyl)ethane is 1:1˜1.5.

20. The method for preparing C-nucleoside compound according to claim 1, wherein the feeding molar ratio of the compound represented by Formula 1 to the secondary amine represented by Formula 4 is 1:1˜1.5.

Description

SPECIFIC MODELS FOR CARRYING OUT THE INVENTION

[0114] The technical solutions of the present application are described in further detail below, but the protection scope of the present application is not limited to the following description.

Example 1

Synthesis of Chiral C-Nucleoside Compound Represented by Formula 3

[0115] ##STR00010##

[0116] Under anhydrous and anaerobic conditions, Compound 1a (10.0 g, 46.94 mmol) and 1,2-bis(chlorodimethylsilyl)ethane (11.1 g, 51.63 mmol) were dissolved in THF (100 mL), then diisopropylamine represented by Formula 4 (7.3 mL, 51.63 mmol) was added. N-butyllithium (81 mL, 201.8 mmol) and ribonolactone (39.3 g, 93.88 mmol) represented by Formula 2 in THF solution (50 mL) were sequentially added to the reaction solution at −78° C. The reaction solution reacted at −78° C. for 2 hours, then citric acid in aqueous solution (1M, 200 mL) was added to quench the reaction, the reaction solution was warmed to room temperature, and the aqueous layer was extracted with ethyl acetate (3×200 mL), and the organic layers were combined, washed sequentially with water (1×250 mL), saturated NaHCO.sub.3 solution (1×250 mL), and saturated NaCl solution (1×250 mL). The organic layer was dried with anhydrous magnesium sulfate, and filtered, and the solvent was removed under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (developing solvent: firstly gradient eluted with petroleum ether:ethyl acetate=1:1 to pure ethyl acetate, then eluted with methanol/ethyl acetate=10%) to obtain a white foamy solid compound (19.2 g), which was the chiral C-nucleoside compound represented by Formula 3, with a yield of 74%. .sup.1H-NMR (400 MHz, DMSO-d6): δ 8.06 (br s, 2H), 7.99 (s, 1H), 7.37-7.22 (m, 11H), 7.19-7.10 (m, 3H), 7.03-6.97 (m, 2H), 6.95 (d, J=4.8 Hz, 1H), 5.39 (d, J=5.9 Hz, 1H), 5.05 (d, J=5.2 Hz, 1H), 4.61-4.54 (m, 2H), 4.52-4.42 (m, 4H), 4.06-3.98 (m, 1H), 3.93 (dd, J=5.9, 4.4 Hz, 1H), 3.69 (dd, J=10.1, 3.4 Hz, 1H), 3.47 (dd, J=10.0, 6.4 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6): δ 187.98, 155.88, 148.96, 138.63, 138.43, 138.14, 128.67, 128.14, 128.12, 127.82, 127.54, 127.44, 127.26, 127.21, 127.09, 118.60, 117.51, 103.15, 102.30, 81.91, 80.92, 72.50, 72.33, 71.74, 71.44, 69.42; HRMS calcd for C.sub.32H.sub.32N.sub.4O.sub.5 552.2373, found 552.2362.

Example 2

[0117] According to the method described in Example 1, Compound 1a and the ribonolactone represented by Formula 2 were used as substrates, the yields of synthesis of the chiral C-nucleoside compound represented by Formula 3 under the action of different secondary amines represented by Formula 4 were compared, and the data obtained were shown in the table below.

##STR00011##

TABLE-US-00001 Item Amine (4) Product 3 (yield) 1 [00012] 41% 2 [00013] 74% 3 [00014] 45% 4 [00015] 54% 5 [00016] 71% 6 [00017] 70% 7 [00018] 57% 8 [00019] 74%

Example 3

[0118] According to the method described in Example 1, Compound 1a was reacted on a scale of 10 grams, other reaction conditions remained unchanged, and only the concentration of Compound 1a in the reaction solution and the equivalent number of ribonolactone represented by Formula 2 were changed, the obtained data of synthesis yields of the chiral C-nucleoside compounds represented by Formula 3 were shown in the table below.

TABLE-US-00002 Compound 2 Concentration of Compuond 1a Product 3 No. (equivalent) (mol/L) (yield) 1 2.0 0.08 75% 2 2.0 0.20 74% 3 2.0 0.25 70% 4 1.8 0.20 62% 5 1.6 0.20 59%

Example 4

[0119] According to the method described in Example 1, Compound 1a and Compound 1b were used as substrates, respectively, and other reaction conditions unchanged, 1 equivalent of Compound 1 was subjected to an addition reaction with 2.5 equivalents of ribonolactone represented by Formula 2, and the reaction was carried out in the presence of different amines or bases. The synthesis yield data of the chiral C-nucleoside compound represented by the Formula 3 obtained under the conditions of different amine or base were shown in the following table.

##STR00020##

TABLE-US-00003 Amine or base n-BuLi Product 3 No. Compound 1 (equivalent) (equivalent) Reaction temperature (yield) 1 1a i-Pr.sub.2NH 4.3 −78° C. 74% (1.1) 2 1a NaH 3.3 Room temperature/−78° C. 42% (2.5) 3 1b i-Pr.sub.2NH 4.3 −78° C. 59% (1.1) 4 1b No amine added 3.3 −78° C. 24% i-Pr.sub.2NH

[0120] The above are only preferred embodiments of the present application, and it should be understood that the present application is not limited to the form disclosed herein, and they should not be regarded as an exclusion of other embodiments, but may be used in various other combinations, modifications and environments, and can be modified within the scope of the concepts described herein according to the above teachings or skill or knowledge in the relevant field. However, the modifications and changes made by one skilled in the art do not depart from the spirit and scope of the present application, and should be within the scope of protection of the appended claims of the present application.