Process for producing 4'-thio-5-aza-2'-deoxycytidine

Abstract

The present invention relates to a method for producing 4'-thio-5-aza-2'-deoxycytidine which exhibits DNMT1 inhibitory activity. The production method of the present invention enhances the reaction efficiency by developing an efficient process, can stereoselectively produce 4'-thio-5-aza-2'-deoxycytidine, and is economical and suitable for mass production.

Description

Technical Field

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

Background Art

[0002] 4'-Thio-5-aza-2'-deoxycytidine (hereinafter referred to as "5-Aza-T-dCyd") is a new DNMT1 (DNA(cytosine-5)-methyltransferase 1) inhibitor that has been subjected to initial clinical evaluation by the National Cancer Institute (NCI) of the United States, and is currently in clinical trials as a candidate for a therapeutic agent for blood cancer or solid cancer in recent years.

[0003] However, 5-Aza-T-dCyd is a β-anomer as represented by the following formula I, and in order to use this as a raw material for pharmaceuticals, a method for stereoselectively producing it is the most important.

Chemical Formula

[0004] International Publication WO2019 / 152459 discloses a method for producing 5-Aza-T-dCyd. Specifically, International Publication WO2019 / 152459 (Figures 4 and 5) shows a conventional production method, but as shown in the following reaction formula, such a production method has a problem that it is not suitable for mass production because a purification step is essential to obtain the β-anomer.

[0005]

Chemical Formula

[0006] Incidentally, International Publication Gazette WO2019 / 152459 discloses a new manufacturing method for improving the above-mentioned problems (see FIG. 7 below).

[0007] [Chemical formula]

[0008] According to the manufacturing method of the above reaction formula, β-anomer can be predominantly produced, but the ratio of β-anomer and α-anomer is 6:1, and additional steps are still required to obtain 100% β-anomer. That is, since the manufacturing method disclosed in International Publication Gazette WO2019 / 152459 is not entirely suitable for mass production, improvement of the process is still necessary.

[0009] Therefore, it is urgent to develop a new manufacturing method that can improve the above inefficient manufacturing method and stereoselectively produce the β-anomer of 5-Aza-T-dCyd represented by Formula I. [Prior Art Documents] [Patent Documents]

[0010] [Patent Document 1] International Publication No. 2019 / 152459 [Patent Document 2] International Publication No. 2019 / 152459 [Summary of the Invention] [Problems to be Solved by the Invention]

[0011] An object of the present invention is to provide a manufacturing method suitable for mass production with an efficient process step by reducing the production unit price because it can stereoselectively produce 4'-thio-5-aza-2'-deoxycytidine which is a β-anomer. [Means for Solving the Problems]

[0012] The present invention provides a method for stereoselectively producing 4'-thio-5-aza-2'-deoxycytidine. Unless otherwise specified, all terms used in this application have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention pertains. All patent documents and non-patent documents mentioned throughout the disclosure of this application are incorporated by reference in their entirety.

[0013] Specifically, the production method of the present invention includes the following steps (S-1) to (S-3): (S-1) A step of producing a compound represented by the following formula 2 from a compound represented by the following formula 1; (S-2) A step of producing a compound represented by the following formula 3 from the compound represented by the formula 2; and (S-3) A step of producing a compound represented by the following formula I from the compound represented by the formula 3; A method for producing 4'-thio-5-aza-2'-deoxycytidine, comprising:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0014] (S-1) stage In the present invention, the step (S-1) is a step of introducing 5-azacytosine at the 1'-position and introducing a halogen at the 2'-position into the compound represented by the formula 1 having a double bond, as shown in the following reaction formula 1, to produce the compound represented by the formula 2.

[0015] [Chemistry] In the above formula, R is a protecting group for a diol containing one or more Si atoms; X is a halogen.

[0016] In the present invention, since 5-azacytidine is introduced β-selectively at the 1'-position, the target substance, 4'-thio-5-aza-2'-deoxycytidine, can be stereoselectively produced while undergoing the subsequent steps of step (S-2) and step (S-3). Therefore, unlike the conventional production methods, there is an advantage suitable for mass production because a separation step for obtaining the β-anomer is not required.

[0017] According to a specific example of the present invention, the compound represented by the above formula 1 may be a compound represented by the following formula 1a or a compound represented by the following formula 1b: [Chemistry] [Chemistry] In the above formula, R1 to R6 are each independently -C1-C6 alkyl, 3- to 7-membered cycloalkyl, or aryl. For example, R1 to R6 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, but are not limited thereto.

[0018] Also, according to a specific example of the present invention, X may be -bromo (-Br) or -iodo (-I).

[0019] In the present invention, the reaction for introducing 5-azacytidine at the 1'-position involves reacting 5-azacytidine with the compound represented by the above formula 1, and can be carried out in the presence of hexamethyldisilane (HMDS). Further, the reaction can be carried out in the presence of ammonium sulfate. Also, the reaction can be carried out at 90°C to 160°C, more specifically, it can be carried out at 110°C to 130°C, but is not limited thereto. Further, the reaction can be carried out for 8 hours to 26 hours, more specifically, it can be carried out for 15 hours to 20 hours, but is not limited thereto.

[0020] In the present invention, the reaction for introducing a halogen at the 2'-position involves adding N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS), and can be carried out in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf), trifluoromethanesulfonic acid (TfOH), or boron trifluoride diethyl etherate (BF3·OEt2). The reaction can be carried out in an organic solvent. For example, one or more solvents selected from the group consisting of acetonitrile, methylene chloride, ethylene chloride, ethyl acetate, toluene, chlorobenzene, chloroform, isopropyl acetate, tert-butyl acetate, and tetrahydrofuran can be used. Also, the reaction can be carried out at -10°C to 40°C, more specifically, it can be carried out at 0°C to 25°C, but is not limited thereto. Further, the reaction can be carried out for 1 hour to 48 hours, more specifically, it can be carried out for 1 hour to 24 hours, but is not limited thereto.

[0021] According to a specific example of the present invention, the compound represented by the above formula 1 can be produced from the compound represented by the following formula 1c:

Chemical formula

[0022] Also, according to a specific example of the present invention, the compound represented by the formula 1c can be produced from the compound represented by the following formula 1d:

Chemical formula

[0023] Also, according to a specific example of the present invention, the compound represented by the formula 1d can be produced from the compound represented by the following formula 1e:

Chemical formula

[0024] (S-2) stage In the present invention, the step (S-2) is a step of producing the compound represented by the formula 3 by introducing hydrogen instead of halogen at the 2'-position of the compound represented by the formula 2 as shown in the following reaction formula 2.

[0025]

Chemical formula

[0026] According to a specific example of the present invention, the step (S-2) can be carried out by reacting the compound represented by the formula 2 with a radical hydrogen donor in the presence of a radical initiator.

[0027] The radical hydrogen donor may be tributylstannane (Bu3SnH), triphenylstannane (Ph3SnH), or triethylborane (Et3B). However, it is not limited thereto.

[0028] The 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, it is not limited thereto.

[0029] For the reaction, an organic solvent commonly used in radical reactions can be used. For example, as the 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, but it is not limited thereto.

[0030] Also, the reaction can be carried out at 40°C to 120°C, specifically, it can be carried out at 45°C to 115°C, and more specifically, it can be carried out at 60°C to 110°C, but it is not limited thereto. Also, the reaction can be carried out for 1 hour to 48 hours, specifically, it can be carried out for 1 hour to 24 hours, and more specifically, it can be carried out for 1 hour to 4 hours, but it is not limited thereto.

[0031] (S-3) stage In the present invention, the step (S-3) is a step of producing the compound represented by Formula I by a deprotection reaction of the compound represented by Formula 3, as shown in the following Reaction Formula 3.

[0032]

Chemical formula

[0033] According to a specific example 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 trihydrofluoride (TREAT-HF). However, it is not limited thereto.

[0034] For the reaction, an organic solvent commonly used in deprotection reactions can be used. For example, as the 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, but it is not limited thereto. Also, the reaction can be carried out at 0°C to 70°C, more specifically, at 25°C to 65°C, but it is not limited thereto. Also, the reaction can be carried out for 0.5 hours to 12 hours, more specifically, for 2 hours to 5 hours, but it is not limited thereto.

[0035] Also, according to a specific example of the present invention, after the reaction, the step of crystallizing the product can be further included. However, it is not limited thereto.

Advantages of the Invention

[0036] The production method of the present invention can stereoselectively produce 4'-thio-5-aza-2'-deoxycytidine, which is a β-anomer. Therefore, compared with the conventional production method, the production cost is reduced, and it is suitable for mass production due to an efficient process stage.

Modes for Carrying Out the Invention

[0037] Hereinafter, preferred embodiments are presented to assist in the understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the content of the present invention is not limited by the examples.

[0038] Production Example: Production of (6aR,9aS)-2,2,4,4-tetraisopropyl-6a,9a-dihydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin

[0039] (6aR,9R,9aS)-2,2,4,4-Tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol

[0040] (2R,3S,4R)-2-(Hydroxymethyl)tetrahydrothiophene-3,4-diol (1.58 g, 10.52 mmol) was dissolved in pyridine (21 mL), and then 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2, 11.33 mL, 36.3 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, ice was added. After the reaction was completed, ethyl acetate (20 mL) and water (20 mL) were added for extraction. The organic layer was extracted with saturated aqueous sodium hydrogen carbonate solution (20 mL × 2) and saturated aqueous sodium chloride solution (20 mL). It was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. After concentration, methylene chloride was added to the obtained residue to dissolve it. Silica gel was added, and it was concentrated under reduced pressure again. Silica gel column chromatography was performed on the residue adsorbed on silica gel using ethyl acetate:hexane mixed solvent (1:15, v / v) as the developing solvent to obtain the target compound as a colorless syrup (2.07 g, 70%).

[0041] R f = 0.25 (EtOAc / Hexane, 1:10) 1 1H NMR (400 MHz, CDCl3) δ 1.07 - 1.11 (28H, m, TIPDS), 2.65 (1H, s), 2.85 (1H, dd, J = 1.6, 12.1 Hz), 3.03 (1H, ddd, J = 1.0, 4.6, 12.1 Hz), 3.50 (1H, m), 3.91 (1H, dd, J = 4.5, 12.4 Hz), 4.03 (1H, dd, J = 3.3, 12.4 Hz), 4.23 (1H, dd, J = 3.9, 8.5 Hz), 4.34 (1H, m).

[0042] (6aR,9R,9aS)-2,2,4,4-Tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin-9-ylmethanesulfonate

[0043] 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 the mixture was stirred at room temperature for 5 hours. After completion of the reaction, ice was added. After the reaction ended, ethyl acetate (30 mL) and water (20 mL) were added for extraction. The organic layer was extracted with saturated aqueous sodium hydrogen carbonate solution (30 mL × 3) and saturated aqueous sodium chloride solution (30 mL). It was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. After concentration, methylene chloride was added to the obtained residue to dissolve it. Silica gel was added, and it was concentrated under reduced pressure once again. Silica gel column chromatography was performed on the residue adsorbed on the silica gel using an ethyl acetate:hexane mixed solvent (1:10, v / v) as the developing solvent to obtain the target compound as a white solid (1.89 g, 92%).

[0044] R f = 0.1 (EtOAc / Hexane, 1:10) 1 1H NMR (400 MHz, CDCl3) δ 1.00 - 1.10 (28H, m, TIPDS), 3.01 (1H, t, J = 15.3 Hz), 3.11 (1H, s), 3.20 (1H, dd, J = 4.3, 13.0 Hz), 3.51 (1H, dt, J = 2.5, 10.0 Hz), 3.93 (1H, dd, J = 1.7, 12.7 Hz), 4.06 (1H, dd, J = 2.8, 12.7 Hz), 4.27 (1H, dd, J = 3.2, 10.0 Hz), 5.28 (1H, dd, J = 3.6 Hz).

[0045] (6aR,9aS)-2,2,4,4-Tetraisopropyl-6a,9a-dihydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin

[0046] 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, and the temperature was raised to 150 °C and refluxed with stirring for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) was added, and it was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, silica gel column chromatography was performed on the obtained residue using hexane (100%) and a mixed solvent of hexane:ethyl acetate (10:1, v / v) as the developing solvent to obtain the target compound as a colorless syrup (502 mg, 56%).

[0047] R f = 0.2 (Hexane, 100%) 1 1H NMR (400 MHz, CDCl3) δ 1.04 - 1.10 (28H, m, TIPDS), 3.79 (1H, t, J = 11.2 Hz), 3.87 (1H, m), 4.09 (1H, dd, J = 3.7, 11.0 Hz), 5.43 (1H, m), 5.57 (1H, dd, J = 2.6, 5.9 Hz), 6.22 (1H, dd, J = 1.5, 5.9 Hz).

Example

[0048] Example: Production of 4'-thio-5-aza-2'-deoxycytidine

[0049] (6aR,8R,9R,9aR)-9-Iodo-2,2,4,4-tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-1,3,5-triazin-2(1H)-one

[0050] Hexamethyldisilane (HMDS, 8.5 mL) was charged with 5-azacytidine (225 mg, 2.00 mmol) and ammonium sulfate (6 mg, 0.46 mmol), and the suspension was refluxed for 16 hours to obtain a homogeneous solution. After completion of the reaction, the solvent was removed under reduced pressure, and methylene chloride (4 mL) was added to the residue followed by stirring. Then, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.33 mL, 1.80 mmol) was added to the compound at 0 °C, and stirring was continued until the residue was dissolved. The reaction mixture was maintained at 0 °C, the compound obtained in Production Example (450 mg, 1.20 mmol) was dissolved in acetonitrile (8.0 mL) and added, and then N-iodosuccinimide (NIS) (405 mg, 1.80 mmol) was subsequently added, followed by further stirring. After completion of the reaction, methylene chloride and 1N aqueous potassium hydroxide solution were added to the reaction mixture for extraction. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. After concentration, methylene chloride (2.5 mL) was added to the obtained residue to dissolve it, and then hexane (30 mL) was added to precipitate a solid. The solid was filtered to obtain the target compound as an orange solid (383 mg, 75%).

[0051] R f = 0.55 (EtOAc / Hexane, 1:1) 1 1H NMR (400 MHz, CDCl3) δ 0.84 - 1.11 (28H, m, TIPDS), 3.28 (1H, dd, J = 4.5, 9.2 Hz), 3.67 (1H, dd, J = 2.0, 9.2 Hz), 4.03 (1H, d, J = 12.9 Hz), 4.13 (1H, dd, J = 3.0, 12.9 Hz), 4.54 (1H, d, J = 4.4 Hz), 5.54 (1H, br s), 5.97 (1H, s), 6.25 (1H, br s), 9.13 (1H, s).

[0052] (6aR,8R,9aS)-2,2,4,4-Tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-1,3,5-triazin-2(1H)-one

[0053] To the toluene (2 mL), the compound obtained in Step 1 (200 mg, 0.326 mmol) and azobisisobutyronitrile (AIBN) (20 mg, 10 wt% of the starting material) were added, and the mixture was stirred to be uniformly mixed. Under a nitrogen atmosphere, tributylstannane (Bu3SnH) (0.26 mL, 0.98 mmol) was dissolved in toluene (6 mL) and added dropwise over 20 minutes at 45 °C, the temperature was raised to 60 °C, and the mixture was stirred for 1 hour and 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (10 mL) was added, 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 then concentrated under reduced pressure. Hexane was added to the concentrated residue to precipitate a solid. The solid was filtered to obtain the target compound as a white solid (34 mg, 50%).

[0054] R f = 0.1 (DCM / MeOH, 10:1) 1 1H NMR (400 MHz, CDCl3) δ 0.87 - 1.13 (28H, m, TIPDS), 2.34 (1H, dd, J = 5.4, 13.5 Hz), 2.52 (1H, m), 3.36 (1H, m), 3.98 (1H, dd, J = 1.2, 12.7 Hz), 4.14 (1H, dd, J = 3.1, 12.8 Hz), 4.33 (1H, m), 5.45 (1H, br s), 5.90 (1H, br s), 5.97 (1H, dd, J = 6.7 Hz), 9.02 (1H, s).

[0055] (6aR,8R,9aS)-2,2,4,4-Tetraisopropyltetrahydro-6H-thieno[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)-1,3,5-triazin-2(1H)-one

[0056] To methanol (1.47 L), the compound obtained in Step 2 (101.5 g, 0.198 mol) and ammonium fluoride (38.7 g, 1.045 mol) were added, the temperature was raised to 60 °C - 65 °C, and the mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10 °C - 15 °C and then stirred for 30 minutes. The resulting solid was filtered, washed with methanol (60 mL × 2), and the target compound was obtained as a white solid (24.1 g, 60%).

[0057] 11H NMR (400 MHz, DMSO-d6) δ 2.18 - 2.31 (2H, m), 3.28 (1H, td, J = 3.5, 5.9 Hz), 3.54 (1H, dt, J = 5.4, 11.2 Hz), 3.63 (1H, dt, J = 5.9, 11.7 Hz), 4.33 (1H, q, J = 4.1 Hz), 5.15 (1H, t, J = 5.4 Hz), 5.26 (1H, d, J = 4.0 Hz), 6.08 (1H, t, J = 7.1 Hz), 7.55 (2H, d, J = 3.3 Hz), 8.70 (1H, s).

[0058] As described in detail above for the specific part of the present invention, it will be apparent to those with ordinary knowledge in the art that such specific techniques are merely preferred embodiments and do not limit the scope of the present invention thereby. Therefore, it can be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. The step of producing a compound represented by the following formula 2 from a compound represented by the following formula 1 of (S-1); The step of producing a compound represented by the following formula 3 from the compound represented by the formula 2 of (S-2); and The step of producing a compound represented by the following formula I from the compound represented by the formula 3 of (S-3); A method for producing 4'-thio-5-aza-2'-deoxycytidine, comprising: 【Chemical Formula 1】 【Chemical Formula 2】 【Chemical Formula 3】 【Chemical Formula 4】 In the above formula, R is a protecting group of a diol containing one or more Si atoms; X is a halogen.

2. The production method according to claim 1, wherein the compound represented by the formula 1 is a compound represented by the following formula 1a or a compound represented by the following formula 1b: 【Chemical Formula 5】 【Chemical Formula 6】 In the above formula, R １ ~R ６ are each independently -C １ -C ６ alkyl, 3- to 7-membered cycloalkyl, or aryl.

3. The production method according to claim 1, wherein X is -bromo or -iodo.

4. The production method according to claim 1, wherein the step of (S-1) is performed by reacting 5-azacytidine with the compound represented by the formula 1 and adding N-iodosuccinimide or N-bromosuccinimide.

5. The reaction of the compound represented by the formula 1 and 5-azacytidine is carried out in the presence of hexamethyldisilane (HMDS). The manufacturing method according to claim 4.

6. The reaction of the compound represented by the formula 1 and 5-azacytidine is carried out in the presence of ammonium sulfate. The manufacturing method according to claim 4.

7. The 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 etherate (BF ３ ・OEt ２ ) The manufacturing method according to claim 4.

8. The compound represented by the formula 1 is produced from the compound represented by the following formula 1c. The manufacturing method according to claim 1: 【Chemical formula 7】 In the above formula, Y is methanesulfonate (-OMs), trifluoromethanesulfonate (-OTf), or toluenesulfonate (-OTs).

9. The compound represented by the formula 1c is produced from the compound represented by the following formula 1d. The manufacturing method according to claim 8: 【Chemical formula 8】

10. The compound represented by the formula 1d is produced from the compound represented by the following formula 1e. The manufacturing method according to claim 9: 【Chemical formula 9】

11. The step (S-2) is to react the compound represented by the formula 2 and a radical hydrogen donor in the presence of a radical initiator. The manufacturing method according to claim 1.

12. The radical hydrogen donor is tributyltin hydride (Bu ３ SnH), triphenyltin hydride triphenylstannane (Ph ３ SnH) or triethylborane (Et ３ B), and the production method according to claim 11.

13. The 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), and the production method according to claim 11.

14. The step (S-3) is carried out by a deprotection reaction, and the production method according to claim 1.

15. In the step (S-3), ammonium fluoride (NH ４ F), tetra-N-butylammonium fluoride (TBAF), hydrogen fluoride-pyridine (1:1), or triethylamine trihydrofluoride (TREAT-HF) is added and carried out, and the production method according to claim 14.

16. The step (S-3) further includes a crystallization step, and the production method according to claim 1.

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