Method for preparing 4 '-thio-5-aza-2'-deoxycytidine

Abstract

The present invention relates to a method for preparing 4 '-thio-5-aza-2'-deoxycytidine exhibiting DNMT1 inhibitory activity, and more particularly, to a method for preparing 4 '-thio-5-aza-2'-deoxycytidine exhibiting DNMT1 inhibitory activity, the method for preparing 4 '-thio-5-aza-2'-deoxycytidine according to the present invention can improve reaction efficiency through efficient process development and can stereoselectively prepare 4 '-thio-5-aza-2'-deoxycytidine, thereby being economical and suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a method for preparing 4'-thio-5-aza-2'-deoxycytidine exhibiting DNMT1 inhibitory activity. Specifically, the present invention relates to a method for stereoselectively preparing 4'-thio-5-aza-2'-deoxycytidine. Background Art

[0002] 4'-thio-5-aza-2'-deoxycytidine (hereinafter, referred to as "5-aza-T-deoxycytidine") is a novel DNMT1 (DNA (cytosine-5)-methyltransferase 1) inhibitor, which has been initially clinically evaluated by the National Cancer Institute (NCI) and is currently in clinical use as a candidate drug for the treatment of hematological cancer or solid cancer.

[0003] Meanwhile, 5-aza-T-deoxycytidine is a β-anomer represented by the following Chemical Formula I, and in order to use 5-aza-T-deoxycytidine as a pharmaceutical raw material, a method of stereoselectively preparing 5-aza-T-deoxycytidine is most important.

[0004] [Chemical Formula I]

[0005]

[0006] International Publication No. WO2019 / 152459 discloses a method for preparing 5-aza-T-deoxycytidine. Specifically, International Publication No. WO2019 / 152459 (FIG. 4 and FIG. 5) shows a conventional preparation method, and as shown in the following reaction scheme, the problem with the preparation method is that it is not suitable for large-scale production, because to obtain the β-anomer, the purification process is crucial.

[0007]

[0008]

[0009] At the same time, International Publication No. WO2019 / 152459 discloses a new preparation method for improving the above-mentioned problems (Figure 7 below).

[0010]

[0011] According to the preparation method of the above reaction scheme, β-anomer can be mainly prepared, but the ratio of β-anomer to α-anomer is 6:1, so additional processes are still required to obtain 100% β-anomer. In other words, all the preparation methods disclosed in International Publication No. WO2019 / 152459 are not suitable for large-scale production, so process improvements are still needed.

[0012] Therefore, there is an urgent need to improve the above-mentioned inefficient preparation method and develop a novel preparation method capable of stereoselectively preparing the β-anomer of 5-aza-T-deoxycytidine represented by Chemical Formula I. Summary of the invention [Technical issues]

[0013] The object of the present invention is to provide a method for stereoselectively preparing 4'-thio-5-aza-2'-deoxycytidine as the β-anomer, which method can achieve low production costs and efficient process steps suitable for large-scale production. [Technical solution]

[0014] The present invention provides a method for stereoselectively preparing 4'-thio-5-aza-2'-deoxycytidine. Unless otherwise defined, all terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. All patents and non-patent literatures mentioned throughout the disclosure of this application are incorporated by reference in their entirety.

[0015] Specifically, the preparation method of the present invention comprises the following steps (S-1) to (S-3):

[0016] (S-1) preparing a compound represented by the following Chemical Formula 2 from a compound represented by the following Chemical Formula 1;

[0017] (S-2) preparing a compound represented by the following Chemical Formula 3 from the compound represented by Chemical Formula 2; and

[0018] (S-3) preparing a compound represented by the following Chemical Formula I from the compound represented by Chemical Formula 3;

[0019] A method for preparing 4'-thio-5-aza-2'-deoxycytidine comprising the above steps:

[0020] [Chemical formula 1]

[0021]

[0022] [Chemical formula 2]

[0023]

[0024] [Chemical formula 3]

[0025]

[0026] [Chemical Formula I]

[0027]

[0028] in

[0029] R is a protecting group of a diol comprising one or more Si atoms, and

[0030] X is halogen.

[0031] Hereinafter, each of steps (S-1) to (S-3) will be described separately.

[0032] Step (S-1)

[0033] In the present invention, step (S-1) is a step of preparing a compound represented by Chemical Formula 2 by introducing 5-azacytosine at the 1'-position and halogen at the 2'-position of the compound having a double bond represented by Chemical Formula 1, as shown in the following reaction scheme 1:

[0034] [Reaction Scheme 1]

[0035]

[0036] in

[0037] R is a protecting group of a diol comprising one or more Si atoms, and

[0038] X is halogen.

[0039] In the present invention, since 5-azacytosine is β-selectively introduced at the 1'-position, 4'-thio-5-aza-2'-deoxycytidine as a target material can be stereoselectively prepared through steps (S-2) and (S-3), which adopt the following process. Therefore, unlike the conventional preparation method, the preparation method of the present invention does not require a separation process for obtaining a β-anomer, and is therefore suitable for large-scale production.

[0040] According to an embodiment of the present invention, the compound represented by Chemical Formula 1 may be a compound represented by the following Chemical Formula 1a or a compound represented by the following Chemical Formula 1b:

[0041] [Chemical formula 1a]

[0042]

[0043] [Chemical formula 1b]

[0044]

[0045] in

[0046] R1 to R6 are each independently -C1-C6 alkyl, 3-7 membered cycloalkyl or aryl. For example, R1 to R6 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, but the present invention is not limited thereto.

[0047] Furthermore, according to an embodiment of the present invention, X may be -bromine (-Br) or -iodine (-I).

[0048] In the present invention, the reaction of introducing 5-azacytosine at the 1'-position is to react 5-azacytosine with a compound represented by Chemical Formula 1, which can be carried out in the presence of hexamethyldisilane (HMDS). In addition, the reaction can be carried out in the presence of ammonium sulfate. In addition, the reaction can be carried out at 90 to 160°C, more specifically at 110 to 130°C, but the present invention is not limited thereto. In addition, the reaction can be carried out for 8 to 26 hours, more specifically 15 to 20 hours, but the present invention is not limited thereto.

[0049] In the present invention, the reaction of introducing halogen into the 2'-position is to add N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS), which can be carried out under the condition of trimethylsilyl trifluoromethanesulfonate (TMSOTf), tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf), trifluoromethanesulfonic acid (TfOH) or trifluoroboron diethyl ether (BF3 · OEt2). The reaction can be carried out in an organic solvent, and one or more solvents selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, ethyl acetate, toluene, chlorobenzene, chloroform, isopropyl acetate, tert-butyl acetate and tetrahydrofuran can be used. In addition, the reaction can be carried out at -10 to 40 ° C, more specifically at 0 to 25 ° C, but the present invention is not limited thereto. In addition, the reaction can be carried out for 1 to 48 hours, more specifically 1 to 24 hours, but the present invention is not limited thereto.

[0050] According to an embodiment of the present invention, the compound represented by Chemical Formula 1 can be prepared from the compound represented by the following Chemical Formula 1c:

[0051] [Chemical formula 1c]

[0052]

[0053] in

[0054] Y is mesylate (-OMs), triflate (-OTf) or tosylate (-OTs).

[0055] In addition, according to an embodiment of the present invention, the compound represented by Chemical Formula 1c can be prepared from the compound represented by the following Chemical Formula 1d:

[0056] [Chemical formula 1d]

[0057]

[0058] In addition, according to an embodiment of the present invention, the compound represented by Chemical Formula 1d can be prepared from the compound represented by the following Chemical Formula 1e:

[0059] [Chemical formula 1e]

[0060]

[0061] Step (S-2)

[0062] In the present invention, step (S-2) is a step of preparing the compound represented by Chemical Formula 3 by introducing hydrogen instead of halogen at the 2'-position of the compound represented by Chemical Formula 2, as shown in the following Reaction Scheme 2:

[0063] [Reaction Scheme 2]

[0064]

[0065] wherein R is as defined above.

[0066] According to an embodiment of the present invention, step (S-2) may be performed by reacting the compound represented by Chemical Formula 2 with a radical hydrogen donor in the presence of a radical initiator.

[0067] The radical hydrogen donor may be tributyltin hydride (Bu3SnH), triphenyltin hydride (Ph3SnH) or triethylborane (Et3B). However, the present invention is not limited thereto.

[0068] The free radical initiator may be 2,2'-azobisisobutyronitrile (AIBN), 1,1'-azobis(cyclohexanecarbonitrile)isobutyronitrile (ABCN), 2,2'-azobis-2,4-dimethylvaleronitrile (ADMVN) or 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70). However, the present invention is not limited thereto.

[0069] The reaction can use an organic solvent commonly used in free radical reactions. For example, as a solvent, one or more solvents selected from the group consisting of toluene, xylene, benzene, chlorobenzene, chloroform, 1,4-dioxane and tetrahydrofuran can be used. Specifically, toluene can be used as a solvent, but the present invention is not limited thereto.

[0070] In addition, the reaction can be carried out at 40 to 120° C., specifically 45 to 115° C., more specifically 60 to 110° C., but the present invention is not limited thereto. In addition, the reaction can be carried out for 1 to 48 hours, specifically 1 to 24 hours, more specifically 1 to 4 hours, but the present invention is not limited thereto.

[0071] Step (S-3)

[0072] In the present invention, step (S-3) is a step of preparing a compound represented by chemical formula I by a deprotection reaction of a compound represented by chemical formula 3, as shown in the following reaction scheme 3:

[0073] [Reaction Scheme 3]

[0074]

[0075] wherein R is as defined above.

[0076] According to an embodiment of the present invention, the reaction can be carried out by adding ammonium fluoride (NH4F), tetra-n-butylammonium fluoride (TBAF), hydrogen fluoride-pyridine (1:1) or triethylamine trihydrogen fluoride (TREAT-HF). However, the present invention is not limited thereto.

[0077] The reaction can use an organic solvent commonly used in a deprotection reaction. For example, as a solvent, one or more solvents selected from the group consisting of methanol, 1,4-dioxane, tetrahydrofuran, and acetonitrile can be used. Specifically, methanol can be used as a solvent, but the present invention is not limited thereto.

[0078] In addition, the reaction may be performed at 0 to 70° C., more specifically 25 to 65° C., but the present invention is not limited thereto. In addition, the reaction may be performed for 0.5 to 12 hours, more specifically 2 to 5 hours, but the present invention is not limited thereto.

[0079] In addition, according to an embodiment of the present invention, a method of crystallizing the product after the reaction may be further included. However, the present invention is not limited thereto. [Beneficial Effects]

[0080] Compared with conventional preparation methods, by stereoselectively preparing 4'-thio-5-aza-2'-deoxycytidine (which is a β-anomer), the preparation method of the present invention can reduce production costs through efficient process steps and is suitable for large-scale production. DETAILED DESCRIPTION

[0081] Hereinafter, preferred embodiments are given to help understand the present invention. However, the following embodiments are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by the embodiments.

[0082] Preparation Example: (6aR,9aS)-2,2,4,4-tetraisopropyl-6a,9a-dihydro-6H-thieno[3,2-f][1, Preparation of 3,5,2,4]trioxadisiloxane

[0083] Step 1: (6aR,9R,9aS)-2,2,4,4-tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]triazine Preparation of 9-oxadisiloxane

[0084] (2R, 3S, 4R) -2- (hydroxymethyl) tetrahydrothiophene -3, 4- diol (1.58g, 10.52mmol) was dissolved in pyridine (21mL), and then 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2, 11.33mL, 36.3mmol) was added thereto at 0°C, followed by stirring at room temperature for 12 hours. After the reaction was completed, ice was added to the reaction product to terminate the reaction, and ethyl acetate (20mL) and water (20mL) were added to the resulting product, followed by extraction. The organic layer was extracted with saturated sodium bicarbonate aqueous solution (20mL × 2) and saturated sodium chloride aqueous solution (20mL). The extracted solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane was added to dissolve the residue obtained after concentration. Silica gel was added, and then concentrated under reduced pressure again. The residue adsorbed on silica gel was subjected to silica gel column chromatography using a mixed solvent of ethyl acetate:hexane (1:15, v / v) as a developing solvent to obtain the target compound (2.07 g, 70%) as a colorless syrup.

[0085] R f =0.25 (ethyl acetate / hexane, 1:10).

[0086] 1 H NMR (400MHz, CDCl3) δ1.07-1.11(28H,m,TIPDS),2.65(1H,s),2.85(1H,dd,J=1.6,12.1Hz),3.03(1H,ddd,J=1.0,4.6,12 .1Hz), 3.50(1H,m), 3.91(1H,dd,J=4.5,12.4Hz), 4.03(1H,dd,J=3.3,12.4Hz), 4.23(1H,dd,J=3.9,8.5Hz), 4.34(1H,m).

[0087] Step 2: (6aR,9R,9aS)-2,2,4,4-tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]triazine Preparation of 9-oxadisiloxane-1-methanesulfonate

[0088] The compound obtained in step 1 (1.71 g, 4.35 mmol) was dissolved in pyridine (22 mL). Methanesulfonyl chloride (0.44 mL, 5.66 mmol) was added at 0 ° C, and then stirred at room temperature for 5 hours. After the reaction was completed, ice was added to the reaction product to terminate the reaction, and ethyl acetate (30 mL) and water (20 mL) were added to the resulting product, followed by extraction. The organic layer was extracted with saturated sodium bicarbonate aqueous solution (30 mL × 3) and saturated sodium chloride aqueous solution (30 mL). The extracted solution was dried with sodium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane was added to dissolve the residue obtained after concentration. Silica gel was added and then concentrated under reduced pressure again. The residue adsorbed on silica gel was subjected to silica gel column chromatography, and a mixed solvent of ethyl acetate: hexane (1: 10, v / v) was used as a developing solvent to obtain the target compound (1.89 g, 92%) as a white solid.

[0089] R f =0.1 (ethyl acetate / hexane, 1:10).

[0090] 1 H NMR(400MHz, CDCl3) δ1.00-1.10(28H,m,TIPDS),3.01(1H,t,J=15.3Hz),3.11(1H,s),3.20(1H,dd,J=4.3,13.0Hz),3.51(1H,dt,J=2.5,10.0 Hz),3.93(1H,dd,J=1.7, 12.7Hz),4.06(1H,dd,J=2.8,12.7Hz),4.27(1H,dd, J=3.2,10.0Hz),5.28(1H,dd,J=3.6Hz).

[0091] Step 3: (6aR,9aS)-2,2,4,4-tetraisopropyl-6a,9a-dihydro-6H-thieno[3,2-f][1,3,5,2, 4] Preparation of trioxadisiloxane

[0092] The compound obtained in step 2 (1.13 g, 2.4 mmol) was dissolved in dimethylformamide (10 mL). 1,5-diazabicyclo (4.3.0) non-5-ene (DBN, 2 mL, 16.8 mmol) was added to the obtained product, heated to 150°C, and stirred under reflux for 30 minutes. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) was added thereto, and the resulting mixture was washed with saturated sodium bicarbonate aqueous solution (20 mL×3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained after concentration was subjected to silica gel column chromatography, and a mixed solvent of hexane (100%) and hexane: ethyl acetate (10:1, v / v) was used as a developing solvent to obtain the target compound (502 mg, 56%) as a colorless syrup.

[0093] R f =0.2 (hexane, 100%).

[0094] 1 H NMR(400MHz, CDCl3) δ1.04-1.10(28H,m,TIPDS),3.79(1H,t,J=11.2Hz),3.87(1H,m),4.09(1 H,dd,J=3.7,11.0Hz), 5.43(1H,m),5.57(1H,dd,J=2.6,5.9Hz), 6.22(1H,dd,J=1.5,5.9Hz).

[0095] Example: Preparation of 4'-thio-5-aza-2'-deoxycytidine

[0096] Step 1: 4-amino-1-((6aR,8R,9R,9aR)-9-iodo-2,2,4,4-tetraisopropyltetrahydro-6H-thienoyl)- Preparation of [3,2-f][1,3,5,2,4]trioxadisiloxane-8-yl)-1,3,5-triazine-2(1H)-one

[0097] 5-azacytosine (225mg, 2.00mmol) and ammonium sulfate (6mg, 0.46mmol) are added to hexamethyldisilane (HMDS, 8.5mL), and the suspension is refluxed for 16 hours to obtain a uniform solution. After the reaction is completed, the solvent is removed under reduced pressure, and dichloromethane (4mL) is added to the residue and then stirred. Thereafter, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.33mL, 1.80mmol) is added to the compound at 0°C, and then stirred until the residue is dissolved. The reaction mixture is maintained at 0°C, and the compound (450mg, 1.20mmol) obtained in the preparation example is dissolved in acetonitrile (8.0mL) and added thereto, and then N-iodosuccinimide (NIS) (405mg, 1.80mmol) is added, and stirring is continued. After the reaction is completed, dichloromethane and 1N potassium hydroxide aqueous solution are added to the reaction mixture, and then extracted. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane (2.5 mL) was added to dissolve the residue obtained after concentration, and then hexane (30 mL) was added to the obtained product to precipitate a solid. The solid was filtered to obtain the target compound (383 mg, 75%) as an orange solid.

[0098] R f =0.55 (ethyl acetate / hexane, 1:1).

[0099] 1H NMR (400MHz, CDCl3) δ0.84 -1.11(28H,m,TIPDS),3.28(1H,dd,J=4.5,9.2Hz),3.67(1H,dd,J=2.0,9.2Hz),4.0 3(1H,d,J=12.9Hz),4.13(1H,dd,J=3.0,12.9Hz),4.54(1H,d,J=4.4Hz),5.54(1H,br s),5.97(1H,s),6.25(1H,br s),9.13(1H,s).

[0100] Step 2: 4-amino-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyltetrahydro-6H-thieno[3,2-f][1, Preparation of 3,5,2,4]trioxadisiloxane-8-yl)-1,3,5-triazine-2(1H)-one

[0101] The compound obtained in step 1 (200 mg, 0.326 mmol) and azobisisobutyronitrile (AIBN) (20 mg, 10 wt% starting material) were added to toluene (2 mL) and stirred to mix evenly. Tributyltin hydride (Bu3SnH) (0.26 mL, 0.98 mmol) was dissolved in toluene (6 mL) at 45 ° C under a nitrogen atmosphere, added dropwise for 20 minutes, heated to 60 ° C, and stirred for 1 hour and 30 minutes. After the reaction was completed, the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (10 mL) was added thereto, and the aqueous layer was extracted with ethyl acetate (10 mL×3). The organic layer was extracted with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Hexane was added to the concentrated residue to precipitate a solid. The solid was filtered to obtain the target compound (34 mg, 50%) as a white solid.

[0102] R f =0.1 (DCM / MeOH, 10:1).

[0103] 1 H NMR (400MHz, CDCl3) δ0.87-1.13 (28H, m, TIPDS), 2.34 (1H, dd, J = 5.4, 13.5Hz), 2.52 (1H, m), 3. 36(1H,m),3.98(1H,dd,J=1.2,12.7Hz),4.14(1H,dd,J=3.1,12.8Hz),4.33(1H,m),5.45(1H,br s), 5.90 (1H, br s), 5.97 (1H, dd, J = 6.7Hz), 9.02 (1H, s).

[0104] Step 3: Preparation of 4'-thio-5-aza-2'-deoxycytidine

[0105] The compound obtained in step 2 (101.5 g, 0.198 mol) and ammonium fluoride (38.7 g, 1.045 mol) were added to methanol (1.47 L), heated to 60 to 65 ° C, and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to 10 to 15 ° C and stirred for 30 minutes. The solid was filtered and washed with methanol (60 mL × 2) to obtain the target compound (24.1 g, 60%) as a white solid.

[0106] 1 H NMR (400MHz, DMSO-d6) δ2.18-2.31(2H,m),3.28(1H,td,J=3.5,5.9Hz),3.54(1H,dt,J=5.4,11.2Hz),3.63(1H,dt,J=5.9,11.7Hz ), 4.33 (1H, q, J = 4.1Hz), 5.15 (1H, t, J = 5.4Hz), 5.26 (1H, d, J = 4.0Hz), 6.08 (1H, t, J = 7.1Hz), 7.55 (2H, d, J = 3.3Hz), 8.70 (1H, s).

[0107] Although the present invention has been described in detail with reference to specific features, it is obvious to those skilled in the art that this description is only an illustration of a preferred embodiment and is not intended to limit the scope of the present invention. Therefore, the actual scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 4'-thio-5-aza-2'-deoxycytidine, the method comprising: (S-1) preparing a compound represented by the following Chemical Formula 2 from a compound represented by the following Chemical Formula 1; (S-2) preparing a compound represented by the following Chemical Formula 3 from the compound represented by the Chemical Formula 2; as well as (S-3) preparing the compound represented by the following chemical formula I from the compound represented by the chemical formula 3: [Chemical formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical Formula I] wherein R is a protecting group of a diol comprising one or more Si atoms, and X is halogen.

2. The method according to claim 1, wherein the compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 1a or a compound represented by the following Chemical Formula 1b: [Chemical formula 1a] [Chemical formula 1b] wherein R1 to R6 are each independently -C1-C6 alkyl, 3-7 membered cycloalkyl or aryl.

3. The method of claim 1, wherein X is -bromo or -iodo. 4 . The method according to claim 1 , wherein the step (S-1) is performed by reacting the compound represented by Chemical Formula 1 with 5-azacytosine and adding N-iodosuccinimide or N-bromosuccinimide thereto. 5 . The method according to claim 4 , wherein the reaction between the compound represented by Chemical Formula 1 and 5-azacytosine is performed in the presence of hexamethyldisilane (HMDS). 6 . The method of claim 4 , wherein the reaction between the compound represented by Chemical Formula 1 and 5-azacytosine is performed in the presence of ammonium sulfate.

7. The method of claim 4, wherein N-iodosuccinimide or N-bromosuccinimide is added in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf), trifluoromethanesulfonic acid (TfOH) or boron trifluoride diethyl ether (BF3.OEt2).

8. The method of claim 1, wherein the compound represented by Chemical Formula 1 is prepared from a compound represented by the following Chemical Formula 1c: [Chemical formula 1c] wherein Y is mesylate (-OMs), triflate (-OTf) or tosylate (-OTs).

9. The method of claim 8, wherein the compound represented by Chemical Formula 1c is prepared from the compound represented by the following Chemical Formula 1d: [Chemical formula 1d] 10. The method according to claim 9, wherein the compound represented by Chemical Formula 1d is prepared from the compound represented by the following Chemical Formula 1e: [Chemical formula 1e] 11. The method of claim 1, wherein the step (S-2) comprises reacting the compound represented by Chemical Formula 2 with a radical hydrogen donor in the presence of a radical initiator.

12. The method of claim 11, wherein the radical hydrogen donor is tributyltin hydride (Bu3SnH), triphenyltin hydride (Ph3SnH) or triethylborane (Et3B).

13. The method of claim 11, wherein the free radical initiator is 2,2'-azobisisobutyronitrile (AIBN), 1,1'-azobis(cyclohexanecarbonitrile)isobutyronitrile (ABCN), 2,2'-azobis-2,4-dimethylvaleronitrile (ADMVN) or 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70).

14. The method according to claim 1, wherein the step (S-3) is performed by a deprotection reaction.

15. The method of claim 14, wherein the step (S-3) is performed by adding ammonium fluoride (NH4F), tetra-n-butylammonium fluoride (TBAF), hydrogen fluoride-pyridine (1:1) or triethylamine trihydrogen fluoride (TREAT-HF).

16. The method of claim 1, wherein the step (S-3) further comprises a crystallization process.

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