METHOD FOR PREPARING INTERMEDIATE FOR SYNTHESIS OF SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONIST

Abstract

The present invention relates to a novel method for producing an intermediate expressed by chemical formula 5 that can be effectively used in synthesis of sphingosine-1-phosphate receptor agonist.

Claims

1. A method for preparing an intermediate compound of the following Formula 5 comprising the following steps of: i) a step of preparing a compound of Formula 3 by reacting a compound of Formula 2 with an acetylating agent and a base in an organic solvent, ii) a step of preparing a compound of Formula 4 by Vilsmeier-Haack reaction of the compound of Formula 3, and iii) a step of preparing a compound of Formula 5 by removing an acetyl group from the compound of Formula 4: ##STR00011## wherein, R1 and R2 are each independently hydrogen, alkyl, halogen, haloalkyl or alkoxyalkyl.

2. The method according to claim 1, wherein R1 and R2 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, halogen, halo-C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkyl.

3. The method according to claim 2, wherein R1 and R2 are each independently hydrogen or C.sub.1-C.sub.4 alkyl.

4. The method according to claim 1, wherein the organic solvent of step (i) is selected from dichloromethane, dichloroethane, toluene, acetonitrile, or a mixture thereof.

5. The method according to claim 1, wherein the acetylating agent of step (i) is acetyl chloride or acetic anhydride.

6. The method according to claim 1, wherein the base of step (i) is selected from N,N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, sodium hydroxide, potassium carbonate, sodium carbonate, or a mixture thereof.

7. The method according to claim 1, wherein the Vilsmeier-Haack reaction of step (ii) is carried out at a temperature of 30 C. or below.

8. The method according to claim 7, wherein the Vilsmeier-Haack reaction is carried out at a temperature of 20 to 25 C.

9. The method according to claim 1, wherein the removal of acetyl group in step (iii) is carried out with K.sub.2CO.sub.3.

10. The method according to claim 1, wherein the reaction of step (iii) is carried out at room temperature.

11. The method according to claim 1, wherein the compound of Formula 5 prepared in step (iii) is directly crystallized.

Description

MODE FOR THE INVENTION

[0046] Hereinafter, the present invention is explained in more detail with the following examples. However, it must be understood that the protection scope of the present invention is not limited to the examples.

Example 1-1: Synthesis of acetic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester

[0047] 6-Hydroxy-3,4-dihydro-2H-naphthalen-1-one (3.9 kg, 24.07 mol) and dichloromethane (DCM, 25.88 kg) were added to a reactor, and the internal temperature was cooled to 0 C. Acetyl chloride (AcCl, 2.08 kg, 26.47 mol) was slowly added dropwise at 10 C. or below, and when the addition was completed, triethylamine (TEA, 2.92 kg, 28.88 mol) was added dropwise at 10 C. or below to proceed with the reaction. The internal temperature was raised to room temperature, and the reaction was carried out for 1 hour. Ion-pair chromatography (IPC) was carried out by HPLC, and the reaction was completed (6-hydroxy-3,4-dihydro-2H-naphthalen-1-one <1%). The reaction was terminated by adding 19.5 kg of purified water to the reaction product. Layer separation was carried out to remove water from the upper layer, and the organic layer was additionally washed with 19.5 kg of purified water and distilled under reduced pressure to obtain the title compound (4.66 kg, net yield: 95%).

[0048] .sup.1H NMR (400 MHz, CDCl.sub.3): 2.10 (m, 2H), 2.30 (s, 3H), 2.60 (t, 2H), 2.95 (t, 2H), 7.00 (s, 1H), 7.05 (d, 1H), 8.05 (d, 1H)

Example 1-2: Synthesis of 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde

[0049] Phosphoryl chloride (POCl.sub.3, 10.5 kg, 68.45 mol) was added to a reactor, and the internal temperature was cooled to 0 C. Dimethylformamide (DMF, 8.34 kg, 114.09 mol) was slowly added dropwise at 10 C. or below, followed by stirring for 30 minutes. 4.66 Kg of 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester was slowly added dropwise to the reactor at 30 C. or below, and when the addition was completed, the reaction was carried out for 3 hours. IPC was carried out by HPLC, and the reaction was completed (acetic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester <2%). 46.60 Kg of purified water and 29.42 kg of ethyl acetate (EtOAc) were added to another reactor, and the internal temperature was cooled to 0 C. The above solution was slowly added dropwise to carry out quenching by decomposing the remaining POCl.sub.3. After layer separation, the organic layer was collected in another reactor, and the aqueous layer was further extracted with 12.61 kg of EtOAc. The aqueous layer was removed, and the organic layer in another reactor was added. The collected organic layers were washed with 23.30 kg of purified water and then distilled under reduced pressure to remove the solvent. Methanol (MeOH, 22.95 kg) and K.sub.2CO.sub.3 (2.68 kg, 19.39 mol) were added to the residue, and the reaction was carried out at room temperature for about 2 hours. IPC was carried out by HPLC, and when the reaction was completed (5-chloro-6-formyl-7,8-dihydronaphthalen-2-yl acetate <1%), 19.39 kg of 3 N HCl was added dropwise to proceed with crystallization. When crystals were formed, the crystals were kept for 30 minutes, filtered, washed with 24.31 kg of purified water and dried with nitrogen to obtain the title compound (4.31 kg, net yield: 90.5%).

[0050] .sup.1H NMR (500 MHz, CDCl.sub.3): 2.30 (s, 3H), 2.65 (t, 2H), 2.85 (t, 2H), 7.00 (s, 1H), 7.05 (m, 1H), 7.90 (d, 1H), 10.40 (s, 1H)