Boc-AEA-OH crystal form A and preparation method thereof

Abstract

The invention discloses a Boc-AEA-OH crystal form A and a preparation method thereof, an X-ray diffraction pattern of the Boc-AEA-OH crystal form A has characteristic diffraction peaks when 2 theta values are 7.3 degrees, 14.5 degrees and 23.1 degrees, and the error range of the 2 theta values is + / -0.2 degrees. The Boc-AEA-OH crystal form A provided by the invention not only has high purity, good crystallinity and long-term stability, is beneficial to storage and use, but also has a remarkable benefit for improving the purity of subsequent compound synthesis, for example, the purity of a side chain of semeglutide can be improved. Moreover, the preparation method provided by the invention is simple, convenient and controllable in process, good in reproducibility and high in yield, can efficiently purify and effectively remove impurities, so that the purity of Boc-AEA-OH is increased to 99% or above, the crystallization yield reaches 80% or above, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of Boc-AEEA-OH, and specifically relates to a Boc-AEEA-OH crystal form A and a preparation method thereof. Background Art

[0002] Boc-AEEA-OH, whose full chemical name is 2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxyacetic acid, is a compound with a unique chemical structure. This compound has attracted much attention due to its wide applications in multiple fields such as polypeptide synthesis and material chemistry. Especially in the field of polypeptide synthesis, Boc-AEEA-OH, as a key chemical raw material, is mainly used for the preparation of the side chains of semaglutide, tirzepatide, and long-chain propylene glycol drugs.

[0003] Currently, the synthesis method of Boc-AEEA-OH mainly uses diethanolamine as the raw material. First, through an amino protection strategy, the amino group of diethanolamine is protected with Boc (tert-butoxycarbonyl) to generate Boc-diethanolamine. Subsequently, in the presence of a strong base, Boc-diethanolamine undergoes a condensation reaction with ethyl 2-bromoacetate, and the target product Boc-AEEA-OH is obtained through subsequent hydrolysis. In addition, there are also literature reports on another synthesis route, where Boc-diethanolamine directly undergoes a condensation reaction with sodium 2-chloroacetate under alkaline conditions to also obtain Boc-AEEA-OH.

[0004] However, although these synthesis methods to a certain extent meet the preparation requirements of Boc-AEEA-OH, they still face many challenges in practical applications. First, Boc-AEEA-OH exists in the form of an oil, which makes it impossible to be purified by conventional crystallization methods, thus increasing the difficulty and cost of purification. Second, although the silica gel column chromatography purification method in the prior art has achieved the purification of Boc-AEEA-OH to a certain extent, this method is not only costly but also inefficient, severely restricting the industrial scale-up production of Boc-AEEA-OH. Moreover, Boc-AEEA-OH has poor stability at room temperature and is prone to degradation reactions, generating impurities mainly due to the removal of the Boc protecting group. The generation of these impurities affects the purity and storage of Boc-AEEA-OH.

[0005] Therefore, developing an efficient, low-cost Boc-AEEA-OH purification method suitable for industrial production and improving the purity and stability of Boc-AEEA-OH have become urgent technical problems to be solved. Summary of the Invention

[0006] To solve the above technical problems, the object of the present invention is to provide a Boc-AEEA-OH crystal form A, which has good crystallinity and stability, and is beneficial to the storage and use of this compound.

[0007] Another object of the present invention is to provide a preparation method of Boc-AEEA-OH crystal form A.

[0008] The above object of the present invention is achieved by the following technical solutions:

[0009] A Boc-AEEA-OH crystal form A, the X-ray diffraction pattern of the Boc-AEEA-OH crystal form A has characteristic diffraction peaks at 2θ values of 7.3°, 14.5°, and 23.1°, where the error range of the 2θ value is ±0.2°.

[0010] Further, the X-ray diffraction pattern of the Boc-AEEA-OH crystal form A has characteristic diffraction peaks at 2θ values of 7.3°, 14.5°, 17.1°, 22.3°, and 23.1°, where the error range of the 2θ value is ±0.2°.

[0011] Further, the Boc-AEEA-OH crystal form A contains 5-20% water of crystallization.

[0012] Preferably, the Boc-AEEA-OH crystal form A contains 10-15% water of crystallization.

[0013] Further, when the Boc-AEEA-OH crystal form A contains two water molecules of crystallization, its structural formula is

[0014]

[0015] A preparation method of Boc-AEEA-OH crystal form A, comprising the following steps:

[0016] (1) Add an organic solvent to the Boc-AEEA-OH oil, then add an organic base, a solid precipitates, and the solid is obtained by suction filtration;

[0017] (2) Dissolve the solid obtained in step (1) in an inorganic salt solution, then add an organic acid, and extract with an organic solvent, and an oil is obtained after concentration;

[0018] (3) Add water or an aqueous solution of an organic solvent to the oil obtained in step (2), heat the resulting mixed solution to 40-80 °C, and then cool it to 5-30 °C for crystallization to obtain the Boc-AEEA-OH crystal form A.

[0019] The present invention purifies Boc-AEEA-OH by the way of salification (solid state) to improve its purity, and then obtains the crystal form A of Boc-AEEA-OH by crystallization. The process is simple and controllable, with good reproducibility and high yield.

[0020] Further, in step (1), the organic solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropyl ether, methyl tert-butyl ether and dichloromethane, and is preferably ethyl acetate.

[0021] Further, in step (1), the dosage ratio (w / v, g / mL) of the Boc-AEEA-OH oil to the organic solvent is 1:(1 - 10), and is preferably 1:(3 - 8).

[0022] Further, in step (1), at 10 - 30 °C, an organic solvent is added to the Boc-AEEA-OH oil, and then an organic base is added, and a solid precipitates out, that is, Boc-AEEA-OH precipitates as a salt.

[0023] If the temperature is too low, the slurry is too viscous and not convenient for suction filtration; if the temperature is higher than 30 °C, the solubility of the salt in the organic solvent increases and the yield decreases.

[0024] Preferably, in step (1), at 15 - 25 °C, an organic solvent is added to the Boc-AEEA-OH oil, and then an organic base is added.

[0025] Further, in step (1), the organic base is dicyclohexylamine and / or cyclohexylamine.

[0026] Further, in step (1), the equivalent ratio of the Boc-AEEA-OH oil to the organic base is 1:(1.0 - 1.5).

[0027] Further, in step (2), the inorganic salt solution is an aqueous solution of an inorganic salt.

[0028] Further, in step (2), the inorganic salt in the inorganic salt solution is an inorganic halide.

[0029] Further, in step (2), the inorganic salt in the inorganic salt solution is selected from one or more of NaCl, KCl, NH4Cl, NaBr, KBr and NH4Br.

[0030] Further, in step (2), the concentration of the inorganic salt in the inorganic salt solution is above 10 wt%, and is preferably 15 - 20 wt%.

[0031] Further, in step (2), the dosage ratio (w / v, g / mL) of the solid to the inorganic salt solution is 1:(1.5 - 8), and is preferably 1:(3 - 8).

[0032] Further, in step (2), the organic acid is selected from one or more of citric acid, oxalic acid, and acetic acid, preferably citric acid.

[0033] Further, in step (2), the equivalent ratio of the solid to the organic acid is 1:(1.0 - 1.5), preferably 1:(1.0 - 1.2).

[0034] Further, in step (2), the organic solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, and dichloromethane, preferably ethyl acetate.

[0035] Further, in step (3), the organic solvent is miscible with water and is selected from one or more of methanol, ethanol, isopropanol, and acetone, preferably methanol and / or acetone.

[0036] Further, in step (3), the dosage ratio (w / v, g / mL) of the oil to water or the aqueous solution of the organic solvent is 1:(1 - 10), preferably 1:(4 - 6).

[0037] Preferably, in step (3), the obtained mixed solution is heated to 50 - 60 °C and then cooled to 10 - 20 °C for crystallization.

[0038] Further, in step (3), it is cooled to 5 - 30 °C for heat preservation crystallization, and the time for heat preservation crystallization is not less than 2 hours.

[0039] Further, in step (3), after crystallization, suction filtration is carried out, and the obtained solid is Boc-AEEA-OH crystal form A.

[0040] In a specific embodiment, the preparation method of Boc-AEEA-OH crystal form A includes the following steps:

[0041] (1) Add the Boc-AEEA-OH oil to a reaction vessel, add an organic solvent at 10 - 30 °C, and dropwise add an organic base under stirring to form a salt. Solids precipitate, and suction filtration is carried out to obtain the solid;

[0042] (2) Dissolve the solid obtained in step (1) in an inorganic salt solution, add an organic acid for desalting, extract with an organic solvent, and concentrate to obtain an oil;

[0043] (3) Add water or an aqueous solution of an organic solvent to the oil obtained in step (2), heat the obtained mixed solution to 40 - 80 °C, and then cool to 5 - 30 °C for crystallization to obtain the Boc-AEEA-OH crystal form A.

[0044] Compared with the prior art, the beneficial effects of the present invention are:

[0045] The Boc-AEEA-OH polymorph A provided by the present invention not only has high purity, good crystallinity and long-term stability, which is beneficial to storage and use, but also significantly helps to improve the purity of subsequent compound synthesis, such as being able to improve the purity of the side chain of semaglutide. Moreover, the preparation method provided by the present invention has a simple and controllable process, good reproducibility and high yield, can efficiently purify and effectively remove impurities, improve the purity of Boc-AEEA-OH to more than 99%, and the crystallization yield reaches more than 80%, which is suitable for industrial production. Description of the Drawings

[0046] Figure 1 It is the HPLC chart of the Boc-AEEA-OH oil.

[0047] Figure 2 It is the specific data corresponding to the HPLC chart of the Boc-AEEA-OH oil.

[0048] Figure 3 It is the HPLC chart of the Boc-AEEA-OH polymorph A prepared in Example 1.

[0049] Figure 4 It is the specific data corresponding to the HPLC chart of the Boc-AEEA-OH polymorph A prepared in Example 1.

[0050] Figure 5 It is the HPLC chart of the Boc-AEEA-OH polymorph A prepared in Comparative Example 1.

[0051] Figure 6 It is the specific data corresponding to the HPLC chart of the Boc-AEEA-OH polymorph A prepared in Comparative Example 1.

[0052] Figure 7 It is the XPRD pattern of the Boc-AEEA-OH polymorph A prepared in Example 1.

[0053] Figure 8 It is the specific data corresponding to the XPRD pattern of the Boc-AEEA-OH polymorph A prepared in Example 1.

[0054] Figure 9 It is the TGA pattern of the Boc-AEEA-OH polymorph A prepared in Example 1. Detailed Description of the Invention

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs. The terms used in the description of the present invention herein are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0056] The reaction equations for synthesizing Boc-AEEA-OH using diethanolamine as a raw material and the reaction equation for directly condensing Boc-diethanolamine to obtain Boc-AEEA-OH in the prior art are as follows:

[0057]

[0058] All Boc-AEEA-OH prepared by the prior art is an oily substance of Boc-AEEA-OH.

[0059] A method for preparing crystalline form A of Boc-AEEA-OH according to the present invention comprises the following steps:

[0060] (1) Add an organic solvent to the oily substance of Boc-AEEA-OH, and then add an organic base. A solid precipitates, and the solid is obtained by suction filtration;

[0061] (2) Dissolve the solid obtained in step (1) in an inorganic salt solution, then add an organic acid, and perform extraction with an organic solvent. After concentration, an oily substance is obtained;

[0062] (3) Add water or an aqueous solution of an organic solvent to the oily substance obtained in step (2), heat the resulting mixed solution to 40 - 80 °C, and then cool it to 5 - 30 °C for crystallization to obtain the crystalline form A of Boc-AEEA-OH.

[0063] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the examples given are not intended to limit the present invention.

[0064] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used, unless otherwise specified, can all be obtained from commercial channels.

[0065] The oily substance of Boc-AEEA-OH used in the following examples is commercially available Boc-AEEA-OH, and the high performance liquid chromatography (HPLC) diagram is as Figure 1 shown, and the corresponding specific data is as Figure 2 shown.

[0066] Example 1

[0067] A preparation method of Boc-AEEA-OH crystal form A, comprising the following steps:

[0068] (1) Add 200 g of Boc-AEEA-OH oil (HPLC purity: 94.9%, 0.76 mol, 1.0 equivalent) to a 2 L four-necked flask, add 1 L of ethyl acetate at 25 °C, and dropwise add 85 g of cyclohexylamine (0.86 mol, 1.13 equivalents) with stirring. Solids will precipitate. After the addition is complete, stir at 25 °C for 2 hours, filter by suction, wash the filter cake with ethyl acetate, and dry at 60 °C for 4 h to obtain the ammonium salt of cyclohexylamine of Boc-AEEA-OH, a white solid, 260 g.

[0069] (2) Add 260 g of the ammonium salt of cyclohexylamine of Boc-AEEA-OH to a 2 L four-necked flask, add 500 mL of an aqueous NaCl solution with a concentration of 15 wt%, add 500 mL of an aqueous solution containing 166 g of citric acid monohydrate (0.79 mol, 1.04 equivalents) with stirring, extract twice with ethyl acetate (800 mL × 2), combine the ethyl acetate layers, wash with 5% aqueous citric acid solution (NaCl solid added until saturated, 200 mL × 2), saturated brine (200 mL), dry with magnesium sulfate, filter by suction to remove magnesium sulfate, and concentrate the filtrate to remove ethyl acetate to obtain 170 g of an oil.

[0070] (3) Add 170 g of the above oil to a 1 L four-necked flask, add 170 mL of methanol and 680 mL of purified water, heat the resulting mixed solution to 50 °C, stir for 1 h, slowly cool down, solids will precipitate, cool down to 10 °C, stir at 10 °C for 2 h, filter by suction, wash with a small amount of purified water, and dry in vacuo at 20 °C for 4 h to obtain Boc-AEEA-OH crystal form A: a white crystalline solid (dihydrate), 182 g (0.61 mol, 0.8 equivalent), yield: 80%; water content: 12.3%; HPLC: above 99%. The HPLC chart is as Figure 3 shown, and the corresponding specific data are as Figure 4 shown.

[0071] Example 2

[0072] A preparation method of Boc-AEEA-OH crystal form A, comprising the following steps:

[0073] (1) Add 200 g of Boc-AEEA-OH oil (HPLC purity: 94.9%, 0.76 mol, 1.0 equivalent) to a 2-L four-necked flask. Add 1 L of ethyl acetate at 20 °C, and dropwise add 152 g of dicyclohexylamine (0.83 mol, 1.1 equivalents) with stirring. A solid precipitates. After the addition is complete, stir at 20 °C for 2 hours, filter by suction, wash the filter cake with ethyl acetate, and dry at 60 °C for 4 h to obtain the ammonium salt of dicyclohexylamine of Boc-AEEA-OH, a white solid, 300 g.

[0074] (2) Add 300 g of the ammonium salt of dicyclohexylamine of Boc-AEEA-OH to a 3-L four-necked flask. Add 750 mL of an aqueous NaCl solution with a concentration of 15 wt%, and add 750 mL of an aqueous solution containing 166 g of citric acid monohydrate (0.79 mol, 1.04 equivalents) with stirring. Extract twice with ethyl acetate (1200 mL × 2), combine the ethyl acetate layers, wash with 5% aqueous citric acid solution (NaCl solid added to saturation, 300 mL × 2) and saturated brine (300 mL), dry with magnesium sulfate, filter by suction to remove magnesium sulfate, and concentrate the filtrate to remove ethyl acetate to obtain 180 g of an oil.

[0075] (3) Add 180 g of the above oil to a 2-L four-necked flask, add 180 mL of methanol and 720 mL of purified water. Heat the resulting mixed solution to 50 °C, stir for 1 h, slowly cool down, and a solid precipitates. Cool down to 15 °C, stir at 15 °C for 2 h, filter by suction, wash with a small amount of purified water, and dry in vacuo at 30 °C for 4 h to obtain Boc-AEEA-OH polymorph A: a white crystalline solid (dihydrate), 193 g, yield: 85%; water content: 12.2%; HPLC: above 99%.

[0076] Example 3

[0077] A method for preparing Boc-AEEA-OH polymorph A is basically the same as that in Example 1, except that: methanol in step (3) is replaced by ethanol, and finally Boc-AEEA-OH polymorph A: a white crystalline solid (dihydrate), 175 g, the yield of this step: 90.6%; water content: 11.5%; HPLC: above 99%.

[0078] Example 4

[0079] A method for preparing Boc-AEEA-OH polymorph A is basically the same as that in Example 1, except that: methanol in step (3) is replaced by isopropanol, and finally Boc-AEEA-OH polymorph A: a white crystalline solid (dihydrate), 172 g, the yield of this step: 89%; water content: 11.7%; HPLC: above 99%.

[0080] Example 5

[0081] A method for preparing Boc-AEEA-OH polymorph A is basically the same as that in Example 1, except that: methanol in step (3) is replaced with acetone, and finally Boc-AEEA-OH polymorph A is obtained: a white crystalline solid (dihydrate), 178 g, the yield of this step: 92%; water content: 12.1%; HPLC: more than 99%.

[0082] Comparative Example 1

[0083] A method for preparing Boc-AEEA-OH polymorph A includes the following steps:

[0084] Add 200 g of Boc-AEEA-OH oil (HPLC purity is 94.9%) into a 1 L four-necked flask, add 200 mL of methanol and 800 mL of purified water, heat the obtained mixed solution to 50 °C, stir for 1 h, cool down slowly, solids precipitate, cool down to 10 °C, stir at 10 °C for 2 h, filter by suction, wash with a small amount of purified water, and dry in vacuum at 20 °C for 4 h to obtain Boc-AEEA-OH polymorph A: a white crystalline solid (dihydrate), 205 g, yield: 90.3%; water content: 12.4%; HPLC: 95.7%, and the HPLC chart is as Figure 5 shown, and the corresponding specific data is as Figure 6 shown.

[0085] Test Example 1

[0086] Test the X-ray diffraction (XPRD) pattern of Boc-AEEA-OH polymorph A prepared in Test Example 1, and the test parameters are:

[0087] X-ray reflection parameters: Cu, Kα; Kα1: Kα2: Tube voltage: 40.0 kV; tube current: 40.0 mA; step size: 0.019°; scanning speed: 0.20 s; scanning range: 3.0° to 40.0°.

[0088] The test results are as Figure 7 shown, and the corresponding specific data of the XPRD pattern is as Figure 8 shown, which proves that the X-ray diffraction pattern of Boc-AEEA-OH polymorph A prepared by the present invention has characteristic diffraction peaks at least at 2θ values of 7.3°, 14.5°, and 23.1°.

[0089] Test Example 2

[0090] Thermogravimetric analysis (TGA) spectrum of Boc-AEEA-OH crystal form A prepared in Test Example 1. The test parameters were: scanning rate: 10 K / minute; protective gas: nitrogen. The test results are as Figure 9 shown. The TGA weight loss was 7.46% + 4.88% = 12.34%, indicating the presence of 2 water of crystallization.

[0091] In summary, the preparation method provided by the present invention can efficiently purify and effectively remove impurities. The Boc-AEEA-OH crystal form A prepared has high purity, good crystallinity and long-term stability, with the purity of Boc-AEEA-OH increased to over 99% and the crystallization yield reaching over 80%, which is suitable for industrial production.

[0092] Obviously, the above embodiments of the present invention are only examples for clearly explaining the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art should understand that other different forms of changes or variations can be made on the basis of the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. A Boc-AEEA-OH crystal form A, characterized in that, The X-ray diffraction pattern of Boc-AEEA-OH crystal form A has characteristic diffraction peaks at 2θ values of 7.3°, 14.5°, and 23.1°, where the error range of the 2θ value is ±0.2°.

2. The Boc-AEEA-OH Form A according to claim 1, wherein The X-ray diffraction pattern of Boc-AEEA-OH crystal form A has characteristic diffraction peaks at 2θ values of 7.3°, 14.5°, 17.1°, 22.3°, and 23.1°, where the error range of the 2θ value is ±0.2°.

3. The Boc-AEEA-OH polymorph A according to claim 1 or 2, characterized in that, The Boc-AEEA-OH crystal form A contains 5-20% water of crystallization.

4. A method for preparing Boc-AEEA-OH crystal form A according to any one of claims 1-3, characterized in that, Comprising the following steps: (1) Add an organic solvent to the Boc-AEEA-OH oil, and then add an organic base. A solid precipitates out, and the solid is obtained by suction filtration; (2) Dissolve the solid obtained in step (1) in an inorganic salt solution, then add an organic acid, and perform extraction with an organic solvent. After concentration, an oil is obtained; (3) Add water or an aqueous solution of an organic solvent to the oil obtained in step (2), heat the resulting mixed solution to 40-80 °C, and then cool it to 5-30 °C for crystallization to obtain the Boc-AEEA-OH crystal form A.

5. The preparation method according to claim 4, characterized in that, In step (1), the organic solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, and dichloromethane.

6. The preparation method according to claim 4, characterized in that, In step (1), the organic base is dicyclohexylamine and / or cyclohexylamine.

7. The preparation method according to claim 4, wherein In step (2), the inorganic salt in the inorganic salt solution is selected from one or more of NaCl, KCl, NH4Cl, NaBr, KBr, and NH4Br.

8. The preparation method according to claim 4, wherein In step (2), the concentration of the inorganic salt in the inorganic salt solution is above 10 wt%.

9. The preparation method according to claim 4, wherein In step (2), the organic acid is selected from one or more of citric acid, oxalic acid, and acetic acid.

10. The preparation method according to claim 4, characterized in that, In step (3), the organic solvent is miscible with water, and the organic solvent is selected from one or more of methanol, ethanol, isopropanol, and acetone.

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