Process for synthesizing (S)-edelfosine or (R)-edelfosine

Abstract

The present invention relates to an improved method for synthesizing (S)-edelfosine or (R)-edelfosine ((S)-CP201 ​​or (R)-CP201).

Description

[Technical Field]

[0001] The present invention relates to an improved method for synthesizing (S)-edelfosine or (R)-edelfosine ((S)-CP201 ​​or (R)-CP201). [Background technology]

[0002] CP201, or edelfosine, is a synthetic alkyl lysophospholipid (ALP) with antitumor (anticancer), neuroprotective, and anti-inflammatory properties. Summary of the Invention

[0003] The present invention provides a method for synthesizing (S)-edelfosine ((S)-CP201), comprising the steps of: [ka]

[0004] The present invention further provides a method for synthesizing (R)-edelfosine ((R)-CP201), comprising the steps of: [ka]

[0005] The present invention further provides a method for synthesizing (R)-edelfosine ((R)-CP201), comprising the steps of: [ka]

[0006] The present invention further provides a method for synthesizing (S)-edelfosine ((S)-CP201), comprising the steps of: [ka]

[0007] According to a preferred embodiment, step 2 is carried out in the presence of ethyl vinyl ether, p-toluenesulfonic acid, and optionally a solvent.

[0008] The optional solvent in step 2 is preferably THF or toluene.

[0009] According to a further preferred embodiment, step 3 is carried out in the presence of benzyl alcohol, t-BuOK, and optionally a solvent, followed by the addition of methyl iodide.

[0010] The optional solvent in step 3 is preferably THF or toluene.

[0011] According to a further preferred embodiment, step 4 is carried out in the presence of hydrogen, Pd / C, and EtOH.

[0012] According to a further preferred embodiment, step 5 is carried out in the presence of toluene and t-BuOK.

[0013] According to a further preferred embodiment, step 6 is carried out in the presence of methanol and methanesulfonic acid.

[0014] According to a further preferred embodiment, step 7 is carried out in the presence of pyridine / toluene and 2-chloro-1,3,2-dioxaphospholane-2-oxide.

[0015] According to a further preferred embodiment, step 8 is carried out in the presence of trimethylamine and acetonitrile.

[0016] According to a further preferred embodiment, compound 6 is prepared according to the following reaction: [ka]

[0017] According to a particularly preferred embodiment, step 1 is carried out in the presence of triethylamine, methanesulfonyl chloride, and optionally a solvent such as THF.

[0018] According to a further preferred embodiment, the following by-products are obtained in step 3: [ka]

[0019] According to a further preferred embodiment, the following by-products are obtained in step 4: [ka]

[0020] According to a further preferred embodiment, step 4' is carried out in the presence of acetic acid and a solvent, such as a mixture of butanol and water.

[0021] According to a further preferred embodiment, step 5' is carried out in the presence of toluene and t-BuOK.

[0022] According to a more preferred embodiment, step 6' is carried out in the presence of hydrogen, Pd / C, and EtOH.

[0023] The present invention further provides an improved method for synthesizing compound 7a', comprising the steps of: [ka]

[0024] Step 9 is preferably carried out in the presence of a solvent. In particular, the solvent is preferably toluene, and the reaction is optionally carried out under an inert atmosphere, particularly an argon atmosphere. In step 9, potassium tert-butoxide is preferably added. [ka]

[0025] The present invention further provides an improved method for synthesizing compound 7', comprising the steps of: [ka]

[0026] Step 9' is preferably carried out in the presence of a solvent. In particular, the solvent is preferably toluene, and the reaction is optionally carried out under an inert atmosphere, in particular an argon atmosphere. In step 9', potassium tert-butoxide is preferably added. [ka]

[0027] According to a further preferred embodiment, compound 11' is reacted with methyl iodide (MeI). A further preferred step, step 10', is carried out in a solvent and NaH can be added.

[0028] Preferably, the solvent is anhydrous DMF.

[0029] The above reactions (Steps 9 and 10, and Steps 9' and 10') facilitate the formation of intermediates 7a' and 7', respectively. This eliminates the need for the EVE protecting group. Consequently, these modifications significantly reduce the number of steps required and streamline the overall synthetic process. The starting material, (S)-2-((benzyloxy)methyl)oxirane, is commercially available from companies such as Sigma-Aldrich and abcr GmbH, and is preferred over volatile glycidol, an IARC Group 2A carcinogen. Its enantiomer, (R)-2-((benzyloxy)methyl)oxirane, is also commercially available from the same source.

[0030] Furthermore, these two reaction steps 9 and 10, and reaction steps 9' and 10' can each be combined into one step, similar to step 3 above.

[0031] Accordingly, the present invention further provides an improved method for synthesizing (S)-edelfosine ((S)-CP201), comprising the steps of: [ka]

[0032] The reaction conditions and preferred reaction conditions are as disclosed above.

[0033] Accordingly, the present invention further provides an improved method for synthesizing (R)-edelfosine ((R)-CP201), comprising the steps of: [ka]

[0034] The reaction conditions and preferred reaction conditions are as disclosed above.

[0035] According to a further embodiment, the present invention relates to (S)-edelfosine ((S)-CP201) obtainable by the process according to the invention.

[0036] According to a further embodiment, the present invention relates to (R)-edelfosine ((R)-CP201) obtainable by the process according to the invention.

[0037] According to a particularly preferred embodiment, ethyl vinyl ether is used as a protecting group in the synthesis of edelfosine (CP201).

[0038] According to further embodiments, the present invention provides a compound selected from the following compounds: [ka]

[0039] According to further embodiments, the present invention provides a compound selected from the following compounds: [ka]

[0040] According to further embodiments, the present invention provides a compound selected from the following compounds: [ka] DETAILED DESCRIPTION OF THE INVENTION

[0041] Table 1 compares the yields of the conventionally applied synthesis process and the process of the present invention. [Table 1]

[0042] According to the conventional procedure, (S)-CP201 ​​was synthesized in eight steps. In the conventional procedure, MOMCl was used as an intermediate protecting group between steps 2 and 6. In contrast, in the present invention, EVE (ethyl vinyl ether) is used as the intermediate protecting group.

[0043] The use of different protecting groups increased the overall yield (steps 2-8) from 11% to 21%.

[0044] According to a more preferred embodiment, (S)-CP201 ​​and (R)-CP201 ​​were synthesized in five steps, which further improved the process of the present invention and increased the overall yield to 63%.

[0045] In the process according to the invention, the following by-products were produced: [ka]

[0046] The by-product was separated from the crude reaction product of step 8 by a two-step MPLC method: the first step was performed using a cyano column, and the second step was performed using a HILIC column. The product was identified by LC-MS, NMR, and MS / MS and was obtained with a purity of >95%.

[0047] The present invention can be applied to drug-eluting stents and can be suitably used to prevent restenosis of coronary arteries in cardiac interventional procedures. In particular, the present invention can be used to assist cardiologists in treating patients with coronary artery disease.

[0048] Synthesis procedure 1. Preparation of Compound 2 A three-necked round-bottom flask equipped with a mechanical stirrer, nitrogen inlet, and thermometer socket was charged with (R)-glycidol (90 g, 1.215 mol) and p-toluenesulfonic acid (2.09 g, 0.012 mol) in ethyl vinyl ether (450 mL, 5 volumes). The reaction mixture was stirred at room temperature for 2.5 hours. After completion of the reaction (monitored by GC), 5% NaHCO3 (180 mL) was slowly added to the reaction mixture. The temperature of the reaction mixture was maintained below 25 °C. The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 90 mL). The combined organic layers were washed with water (90 mL), dried over MgSO4, and then concentrated under reduced pressure (below 30 torr) at 30 °C to give crude compound 2 as a tan oil. The crude compound 2 was purified by distillation under reduced pressure at 50 to 60°C using a high vacuum pump (about 5 torr) to obtain compound 2 (154.14 g, yield: 86.8%). 1 H-NMR (300MHz, CDCl3) δ4.77(qd, J=5.4Hz, 1H), 3.85~3.38(m, 4H), 3.19~3.12(m, 1H), 2.81(ddd, J= 5.1, 4.1, 1.0Hz, 1H), 2.63 (ddd, J=5.1Hz, 1H), 1.33 (dd, J=5.4, 4.1Hz, 3H), 1.21 (td, J=1.0Hz, 3H). 13C-NMR (75MHz, CDCl3) δ99.68, 99.66, 65.75, 65.08, 60.94, 60.89, 50.91, 50.80, 44.63, 44.57, 19.75, 19.63, 15.26.

[0049] 2. Preparation of Compound 2 A four-neck round-bottom flask equipped with a stirrer, condenser, nitrogen inlet, and thermometer socket was charged with benzyl alcohol (110.961 g, 1.026 mol) in THF (500 mL, 10.0 vol) at room temperature. t-BuOK (134.327 g, 1.197 mol) was added over 10 min, and the reaction mixture was heated to 60-65 °C and stirred for 60 min. Compound 2 (50 g, 0.342 mol) in THF (250 mL, 5 vol) was added dropwise to the reaction mixture at 60-65 °C over 90 min, followed by stirring at 60-65 °C for 2 h. The reaction mixture was cooled to 25-30 °C. Methyl iodide (194.191 g, 1.368 mol) was added dropwise to the reaction mixture at 25-40 °C, and the mixture was then stirred at 25-30 °C overnight. The progress of the reaction was monitored by GC. Analysis indicated that unreacted BnOH was still present. Additional t-BuOK (0.5 equiv.) and MeI (0.5 equiv.) were added dropwise to the reaction mixture at room temperature. Stirring of the reaction mixture was continued at room temperature. After completion of the reaction (monitored by GC), the reaction mixture was diluted with water (250 mL) and extracted with MTBE (2 × 250 mL). The combined organic layers were washed with brine (250 mL) and concentrated under reduced pressure (<30 torr) at 45–50 °C to give compound 3 as an oil. The benzyl methyl ether impurity was removed by vacuum distillation under high vacuum (approximately 5 torr) at 60–65 °C to give compound 3 (80.99 g, yield: 88.2%).

[0050] 3. Preparation of Compound 4 A three-necked round-bottom flask equipped with a mechanical stirrer and a hydrogen inlet tube was charged with compound 3 (87.62 g, 0.327 mol) and 10% Pd / C (26.29 g, 30% w / w) in 95% EtOH (613.34 mL, 7.0 volumes). The reaction mixture was stirred overnight at room temperature under a H2 gas atmosphere (1 atm) and protected from light. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with 95% EtOH. (If compound 3 is still present on TLC, 10% Pd / C (5% w / w) should be added and stirred overnight again.) The organic layer was concentrated under reduced pressure (<30 torr) at 45 °C. Crude compound 4 (57.31 g, 98.4% yield) was obtained as a tan oil. Crude compound 4 was azeotroped several times with toluene before use in the next step. 1 H-NMR (300MHz, CDCl3) δ4.72 (qd, J=5.3Hz, 1H), 3.84~3.38 (m, 10H), 2.21~2.08 (m, 1H), 1.32 (d, J=5.3Hz, 3H), 1.21 (td, 3H). 13 C-NMR (75MHz, CDCl3) δ99.92, 80.10, 77.22, 63.88, 62.33, 61.20, 57.74, 19.69, 15.26.

[0051] 4. Preparation of Compound 6 A three-necked round-bottom flask equipped with a stirrer, condenser, nitrogen inlet, and thermometer socket was charged with compound 5 (60 g, 0.222 mol), THF (600 mL, 10 volumes), and triethylamine (29.180 g, 0.288 mol) at 20-25 °C. Methanesulfonyl chloride (30.494 g, 0.266 mol) was added dropwise to the reaction mixture below 30 °C. The reaction mixture was stirred at 25-30 °C for 4 h. After completion of the reaction (monitored by HPLC), the reaction mixture was diluted with MTBE (300 mL) and washed with HCl (2 N) (300 mL). The MTBE layer was separated, and the aqueous layer was extracted with MTBE (300 mL). The combined organic layers were washed with water (300 mL) and aqueous sodium bicarbonate (300 mL), dried over MgSO4, and then concentrated under reduced pressure (less than 20 torr) at 35-40°C to give compound 6 (74.35 g, yield: 96.0%) as an off-white solid.1 H-NMR (300MHz, CDCl3) δ4.22(t, J=6.6Hz, 2H), 3.00(s, 3H), 1.75(dq, J=6.6Hz, 2H), 1.26(s, 30H), 0.92~0.84(m, 3H). 13 C-NMR (75MHz, CDCl3) δ70.21, 37.38, 31.94, 29.71, 29.67, 29.62, 29.53, 29.44, 29.37, 29.14, 29.05, 25.43, 22.70, 14.13.

[0052] 5. Preparation of Compound 7 A four-neck round-bottom flask equipped with a stirrer, condenser, nitrogen inlet, and thermometer socket was charged with compound 4 (53 g, 0.297 mol), toluene (530 mL, 10 volumes), and t-BuOK (36.7 g, 0.327 mol) at room temperature. The reaction mixture was stirred at 70-75 °C for 60 min. The reaction mixture was cooled to 30-35 °C. Compound 6 (83 g, 0.238 mol) was added to the reaction mixture at 30-35 °C. The reaction mixture was stirred at 100-105 °C for 2 h. After completion of the reaction (monitored by HPLC), the reaction mixture was cooled to 25-30 °C and extracted with EA (1060 mL) and 10% aqueous NaCl (530 mL). The aqueous layer was extracted with EA (530 mL), and the organic layer was filtered through a Celite pad and then collected. MgSO4 was added to the combined organic layers, and the organic layer was concentrated under reduced pressure to give crude compound 7 (140.53 g). The crude product was taken up in methanol (215 mL, 4 volumes) and stirred for 30 minutes. The precipitated solid was filtered through a pad of Celite and washed with methanol. The methanol solution was used directly in the next step.

[0053] 6. Preparation of Compound 8 A four-neck round-bottom flask equipped with a stirrer, condenser, nitrogen inlet, and thermometer socket was charged with compound 7 (114.72 g, 0.266 mmol) in methanol (265 mL, 2.31 volumes), followed by methanesulfonic acid (2.56 g, 26.64 mmol). The reaction mixture was heated to reflux at 65-70 °C for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature. The pH of the reaction mixture was adjusted to approximately 7 with saturated aqueous sodium bicarbonate (175 mL). The reaction mixture was concentrated, and the residue was diluted with MTBE (575 mL). The solution was extracted with saturated aqueous sodium bicarbonate (115 mL) and purified water (115 mL). MgSO4 was added to the organic layer, and the organic layer was concentrated under reduced pressure (less than 30 torr) at 35 °C to give crude compound 8 (83.27 g). The crude compound 8 was purified by column chromatography: silica gel (1 kg), mobile phase: EA / hexane = 1 / 5 to 1 / 3. Compound 8 was recovered by TLC and concentrated under reduced pressure (less than 40 torr) at 35 °C to give compound 8 (59.73 g, 56%). Before using compound 8 in the next step, it was azeotroped with toluene several times. 1 H-NMR (300MHz, CDCl3) δ3.82~3.20(m, 10H), 2.16(dd, 1H), 1.57(d, 2H), 1.25(s, 30H), 0.91~0.84(m, 3H). 13 C-NMR (75MHz, CDCl3) δ79.82, 71.96, 70.66, 62.73, 57.79, 31.94, 29.71, 26.09, 22.70, 14.13.

[0054] 7. Preparation of Compound 9 A three-necked round-bottom flask equipped with a stirrer, nitrogen inlet, and thermometer socket was charged with compound 8 (30 g, 0.084 mol) and toluene (300 mL, 10 volumes). The reaction mixture was cooled to 5 °C, and pyridine (9.926 g, 0.125 mol) was added. 2-Chloro-1,3,2-dioxaphospholane-2-oxide (17.878 g, 0.125 mol) dissolved in toluene (60 mL, 2 volumes) was then added dropwise at 5–10 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by HPLC), the solid was filtered under a nitrogen bag. The toluene layer was then concentrated under reduced pressure until 6 volumes remained. The resulting compound 9 was used directly in the next step.

[0055] 8. Preparation of crude (S)-CP201 In a serum bottle, trimethylamine (74.177 g, 1.255 mol) in acetonitrile (485.45 mL, 15 volumes) was added to compound 9 (38.87 g, 0.084 mol) in toluene (97.55 mL) at room temperature. The reaction mixture was stirred at 65-70 °C for 24 h and then cooled to room temperature. The precipitate was filtered under a nitrogen atmosphere and washed with acetonitrile. The solid was dried under reduced pressure to give crude (S)-CP201 ​​(21.05 g, yield: 96.1%). 1 H-NMR (300MHz, CDCl3) δ4.31(s, 1H), 4.08~3.71(m, 4H), 3.59~3.11(m, 16H), 2.49(s, 7H), 1.53(d, 2H), 1.25(s, 28H), 0.95~0.81(m, 3H). 13 C-NMR (75MHz, CDCl3) δ77.22, 71.81, 57.81, 54.45, 31.94, 29.73, 29.69, 29.58, 29.38, 26.11, 22.70, 14.13.

[0056] 9. Purification Procedure of (S)-CP201 Stage 1 (Removal of TMA and insoluble materials) A mixture of crude (S)-CP201 ​​(38.25 g, purity: 92-94%) and EA (10 volumes) was stirred at 70 °C for 30 min. The reaction mixture was cooled to room temperature. The solid was filtered and dried under high vacuum for 1 h to obtain solid (S)-CP201 ​​(37.84 g). IPA (9 volumes) was added to the resulting solid and stirred at room temperature for 1 h. The cloudy solution was filtered several times through filter paper. The filtrate was further filtered through a 0.2 μm membrane to obtain a clear solution. The solvent was removed under reduced pressure and dried under high vacuum overnight to obtain solid (S)-CP201 ​​(36.95 g, yield: 60%).

[0057] Phase 2: (Improving the purity level of (S)-CP201) A mixture of solid (S)-CP201 ​​(53.6 g) and 95% EtOH (1.2 volumes) was stirred at 70°C. EA was added to the reaction solution, and the temperature was maintained at 70°C for 5-10 minutes. The reaction mixture was rapidly cooled to 40-45°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and stirred for 1 hour. The reaction mixture was further cooled to 0-5°C and stirred for 2 hours. The solid was filtered and dried under high vacuum overnight to obtain solid (S)-CP201 ​​(46.91 g, yield: 87.5%).

[0058] Step 3: (Removing excess IPA) A mixture of solid (S)-CP201 ​​(59.24 g) and EA (10 volumes) was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 3-4 hours. The reaction mixture was further cooled to 0-5°C and stirred for 1 hour. The solid was filtered and dried overnight at 33-35°C to give (S)-CP201 ​​(57.24 g, yield: 96.62%) as a white powder.

[0059] Synthesis of (R)-edelfosine (R)-Edelfosine (i.e., (R)-CP201) can be prepared in a similar manner to (S)-CP201, using (S)-glycidol as the starting material.

[0060] 10. Preparation of Compound 4' Compound 3 (0.54 g, 1 equiv.) was reacted with acetic acid (1.4 mL, 14 equiv.) in a mixture of butanol and HO (3.2:1.9 mL). The reaction was stirred at room temperature for 6 h. The solution was quenched with 1 M NaOH (a few drops) and extracted with 2 × 10 mL of AE, followed by washing with brine (19 mL). The crude product was purified by column chromatography. 0.26 g of the desired product was recovered (76% yield, 99% purity).

[0061] 11. Preparation of Compound 7' A three-necked round-bottom flask was charged with t-BuOK (1.14 g, 1.1 equiv.), compound 4' (1.787 g, 1 equiv.), and toluene (10 mL, 1 M) at room temperature. The reaction mixture was stirred at 70-75 °C for 60 min. Compound 6 (3.46 g, 1.1 equiv.) was added to the reaction mixture at 70-75 °C. The reaction mixture was stirred at 100-105 °C for 3.5 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature. AcOEt (10 mL) and water (10 mL) were added to the reaction mixture. The layers were separated. The aqueous layer was extracted with AcOEt (5 × 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO3, filtered, and concentrated under reduced pressure. The crude product (3.8 g) was purified by column chromatography (0-30% EA in heptane, 10 min gradient, then 30% for 20 min). 3.48 g of pure product was recovered (85% yield, 97% purity).

[0062] 12. Preparation of Compound 8a To a stirred solution of compound 7' (2.336 g) in ethanol A15 5% IPA (15 mL, 7 volumes), 10% Pd / C (Thermoscientific, 0.236 g, 10% wt) was charged in an autoclave. The reaction mixture was stirred at room temperature under a H atmosphere (2 bar) for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOH (2 × 10 mL). The organic layer was concentrated under reduced pressure at 45 °C to give compound 8a (m = 1.884 g, 89% yield, 89% purity by qNMR) as a gray solid. This product was used directly in the next step.

[0063] 13. Preparation of Compound 11 A purged and dried round-bottom flask containing octadecanol (330 mg, 1.218 mmol) was charged with anhydrous toluene (20 mL) under an argon atmosphere. To the resulting suspension was then added a solution of potassium tert-butoxide in tetrahydrofuran (1.3 mL of a 1.0 M solution, 1.3 mmol), and the mixture was heated to 50 °C. After 30 min, (S)-2-((benzyloxy)methyl)oxirane was added in one portion. The mixture was then heated to reflux for 1 h. After concentration under reduced pressure, flash column chromatography (0–10% EtOAc in DCM) afforded compound 11 (115 mg, 0.265 mmol, 43%) as a white solid.

[0064] 14. Preparation of Compound 7a' To a magnetically stirred solution of compound 11 (20 mg, 0.046 mmol) in anhydrous DMF (0.7 mL) was added NaH (29 mg, 0.72 mmol), followed by methyl iodide (26 mg, 0.18 mmol). The resulting solution was stirred overnight. The reaction was then quenched with a few drops of methanol, and 20 mL of water was added to the mixture. The aqueous layer was extracted with DCM (3 × 20 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure. The resulting mixture was subjected to flash column chromatography (0–4% EtOAc in cyclohexane) to afford product 7a' (13 mg, 0.029 mmol, 63%) as a white solid.

[0065] The structures of the intermediate and product are: 1 H-NMR, 13 This was confirmed by C-NMR and mass spectrometry.

Claims

1. A process for synthesizing (S)-edelfosine ((S)-CP201), comprising the steps of: 【Chemistry 1】

2. A process for synthesizing (R)-edelfosine ((R)-CP201), comprising the steps of: 【Chemistry 2】

3. A process for synthesizing (R)-edelfosine ((R)-CP201), comprising the steps of: 【Transformation 3】

4. A process for synthesizing (S)-edelfosine ((S)-CP201), comprising the steps of: 【Chemistry 4】

5. Step 2 is carried out in the presence of ethyl vinyl ether, p-toluenesulfonic acid, and optionally a solvent; and / or Step 3 is carried out in the presence of benzyl alcohol, t-BuOK, and optionally a solvent, followed by the addition of methyl iodide, and / or Step 4 is carried out in the presence of hydrogen, Pd / C, and EtOH, and / or Step 5 is carried out in the presence of toluene and t-BuOK, and / or Step 6 is carried out in the presence of methanol and methanesulfonic acid, and / or Step 7 is carried out in the presence of pyridine / toluene and 2-chloro-1,3,2-dioxaphospholane-2-oxide, and / or 3. The process of claim 1 or 2, wherein step 8 is carried out in the presence of trimethylamine and acetonitrile.

6. Step 2 is carried out in the presence of ethyl vinyl ether, p-toluenesulfonic acid, and optionally a solvent; and / or Step 3 is carried out in the presence of benzyl alcohol, t-BuOK, and optionally a solvent, followed by the addition of methyl iodide, and / or Step 4' is carried out in the presence of acetic acid and a solvent, and / or Step 5' is carried out in the presence of toluene and t-BuOK, and / or Step 6' is carried out in the presence of hydrogen, Pd / C, and EtOH, and / or Step 7 is carried out in the presence of pyridine / toluene and 2-chloro-1,3,2-dioxaphospholane-2-oxide, and / or 5. The process of claim 3 or 4, wherein step 8 is carried out in the presence of trimethylamine and acetonitrile.

7. 3. The process of claim 1 or 2, wherein the following by-products are obtained in step 3: 【Transformation 6】

8. 3. The process of claim 1 or 2, wherein the following by-products are obtained in step 4: 【Transformation 7】

9. The process of any one of claims 1 to 8, wherein compound 6 is prepared according to the following reaction: 【Transformation 5】

10. 10. The process of claim 9, wherein step 1 is carried out in the presence of triethylamine, methanesulfonyl chloride, and optionally a solvent.

11. Use of ethyl vinyl ether as a protecting group in the synthesis of edelfosine (CP201).

12. A process for synthesizing compound 11, comprising the steps of: 【Transformation 8】

13. A process for synthesizing compound 7a', comprising the steps of: 【Chemistry 9】

14. A process for synthesizing (S)-edelfosine ((S)-CP201), comprising the steps of: 【Chemistry 12】

15. 15. The process of claim 12 or 14, wherein step 9 is carried out in the presence of a solvent, preferably toluene.

16. 16. The process of claim 12, 14, or 15, wherein step 9 is carried out in the presence of potassium tert-butoxide under an inert atmosphere, preferably under an argon atmosphere.

17. 15. The process of claim 13 or 14, wherein compound 11 is reacted with methyl iodide.

18. 18. The process of claim 13, 14, or 17, wherein step 10 is carried out in a solvent, preferably anhydrous DMF, and NaH is added.

19. A process for synthesizing compound 11', comprising the steps of: [Chemistry 18]

20. A process for synthesizing compound 7', comprising the steps of: 【Chemistry 11】

21. A process for synthesizing (R)-edelfosine ((S)-CP201), comprising the steps of: 【Chemistry 13】

22. 22. The process of claim 19 or 21, wherein step 9' is carried out in the presence of a solvent, preferably toluene.

23. 23. The process of claim 19, 21, or 22, wherein step 9' is carried out in the presence of potassium tert-butoxide under an inert atmosphere, preferably under an argon atmosphere.

24. 22. The process of claim 20 or 21, wherein compound 11' is reacted with methyl iodide.

25. 25. The process of claim 20, 21, or 24, wherein step 10' is carried out in a solvent, preferably anhydrous DMF, and NaH is added.

26. A compound selected from the following compounds: 【Chemistry 19】

27. A compound selected from the following compounds: 【Chemistry 20】

28. A compound selected from the following compounds: 【Chemistry 16】

29. A compound represented by the formula: 【Chemistry 17】

Images