A method for synthesizing 3,3-difluorocyclopentylamine hydrochloride

Abstract

The application discloses a synthesis method of 3,3-difluorocyclopentylamine hydrochloride, and particularly relates to the technical field of chemical synthesis. The synthesis method comprises the following steps: taking 2-cyclopentenone and phthalimide as raw materials, and sequentially performing a Michael addition reaction, deoxygenation fluorination, removal of a phthaloyl protecting group, Boc protection and deprotection and salt formation reaction to obtain 3,3-difluorocyclopentylamine hydrochloride. The synthesis route and process design of the application are reasonable, the starting raw material is 2-cyclopentenone, the required reaction condition is mild, the post-treatment method is simple, the operability is strong, the raw material and reagent are cheap and easy to obtain, and the total yield can reach 43.6%, so the synthesis method has large-scale preparation value.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride. Background Technology

[0002] 3,3-Difluorocyclopentanamine hydrochloride has important applications in the pharmaceutical and new drug development fields. Compounds containing this structural fragment exhibit a wide range of biological activities, and the demand for them in drug development is increasingly strong. Patent CN 102459267A reports the inhibitory activity of compound 8 against JAK for the treatment of diseases involving the immune system and inflammation (including rheumatoid arthritis, hematologic malignancies, and epithelial cancer (i.e., malignant epithelial tumors)); patent CN 114340634A reports compound 9 with CDK kinase inhibitory activity for the treatment of tumors; and patent CN 107001372A reports a method for treating or preventing cancers such as melanoma using compound 10.

[0003]

[0004] The synthetic method for 3,3-difluorocyclopentanamine hydrochloride is reported in the literature as follows:

[0005] 1. Patents CN 102459267 and CN107001372 report a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride with an overall yield of 50.3%. The route is as follows:

[0006]

[0007] The reported synthesis method has the following shortcomings: First, using TMSN3 as the amino source, the method limits its scale-up feasibility due to the significant safety risks associated with low-molecular-weight azide compounds; second, the reduction of azides uses the noble metal palladium and is a pressurized reaction, resulting in poor economic efficiency; third, the product after the second step requires column chromatography, further limiting the possibility of large-scale production. Therefore, these drawbacks make this synthesis method unfeasible for large-scale preparation.

[0008] 2. Patent CN 105111201 reports a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, but does not report the specific yield. Furthermore, the purification method for each reaction product is column chromatography, which does not meet the feasibility for large-scale production. The route is as follows:

[0009]

[0010] 3. Patent CN114340634 reports a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, but does not report the yield. Its starting material, 3-aminocyclopentanol, is expensive, and the synthesis process uses the toxic chromium PCC oxidant and the precious metal palladium, making it economically unfeasible for large-scale production. The synthetic route is as follows:

[0011]

[0012] 4. The literature *Journal of Fluorine Chemistry*, 2017, 199, 60-66, reports a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride with an overall yield of 30.1%. However, the starting material, 3-oxo-1-cyclopentanecarboxylic acid, is expensive, and the final amino source uses TMSN3, increasing the safety risks during production and making large-scale preparation impractical. The synthetic route is as follows:

[0013] Summary of the Invention

[0014] Therefore, the present invention provides a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride to solve the above-mentioned problems.

[0015] To achieve the above objectives, the present invention provides the following technical solution:

[0016] The present invention provides a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, characterized in that 3,3-difluorocyclopentanamine hydrochloride is prepared by sequentially performing Michael addition reaction, deoxyfluorination, phthaloyl protecting group removal, tert-butyloxycarbonyl (Boc) protection and deprotection salt formation reaction using 2-cyclopentenone and phthalimide as raw materials.

[0017] The reaction route is as follows:

[0018]

[0019] Furthermore, the Michael addition reaction is as follows: 2-cyclopentenone (Formula 1) and phthalimide (Formula 2) are dissolved in a solvent, the temperature is controlled at 0-5℃, and then a base is slowly added. After the addition is complete, the temperature is raised to 20-25℃ and the reaction is stirred until complete. Water is added and the mixture is filtered to obtain the compound shown in Formula 3.

[0020] This invention presents a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, particularly focusing on the extensive research into the synthesis of compound 3 using amino source reagents. It was found that under the above reaction conditions, the formation of byproducts can be greatly reduced, which is beneficial for improving yield and simplifying post-processing, making it suitable for industrial production.

[0021] Furthermore, the deoxyfluorination reaction is as follows: the compound of formula 3 is dissolved in a solvent, the system temperature is controlled at 0-5℃, and then the fluorinating reagent diethylaminotrifluoride (DAST) is slowly added. After the reaction is completed, saturated sodium bicarbonate is added, the phases are separated, and the mixture is evaporated to dryness to obtain the compound of formula 4.

[0022] Furthermore, the removal of the phthaloyl protecting group and the tert-butyloxycarbonyl (Boc) is performed as follows: the compound of formula 4 is dissolved in acetic acid, hydrochloric acid is added, the system temperature is controlled at 100-110℃ and stirred, after the reaction is complete, the solvent is evaporated, an alcohol is added to dissolve it, Boc anhydride is added, the solvent is evaporated again to obtain the compound of formula 6.

[0023] Furthermore, the deprotection and salt formation of the tert-butyloxycarbonyl (Boc) is as follows: Compound of Formula 6 is added to a solvent, the temperature is controlled at 0-5°C, and then hydrogen chloride solution is slowly added. The reaction is stirred, and after the reaction is complete, the mixture is filtered, washed, and dried to obtain the pure compound of Formula 7.

[0024] Furthermore, the molar ratio of 2-cyclopentenone of Formula 1: phthalimide of Formula 2: base is 1.0:1.0-1.5:0.1-0.2; and / or,

[0025] The base is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium tert-butoxide, or potassium tert-butoxide; and / or

[0026] The solvent is N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide.

[0027] Studies have found that using DMF as the solvent and sodium carbonate as the alkali is more conducive to improving reaction efficiency and product yield.

[0028] Furthermore, the aforementioned deoxyfluorination reaction is carried out in the presence of a fluorinating agent and a solvent, wherein the molar ratio of the compound of formula 3 to the fluorinating agent is 1.0:2.0–4.0; and / or,

[0029] The fluorinating agent is diethylaminosulfur trifluoride (DAST) or thiomorpholine trifluoride; and / or,

[0030] The solvent is tetrahydrofuran, dichloromethane, or 1,2-dichloroethane; and / or,

[0031] The temperature of the deoxyfluorination reaction is 0–5 °C.

[0032] Further, the phthaloyl protecting group removal and tert-butyloxycarbonyl (Boc) protection are performed as follows: the compound of formula 4 is dissolved in acetic acid, and hydrochloric acid is added for reflux, with the mass-to-volume ratio of the compound of formula 4 to acetic acid to hydrochloric acid being 1.0:5-10:5-10; and / or; an alcohol is added for dissolution, and Boc anhydride is added, with the molar ratio of the compound of formula 5 to Boc anhydride being 1:1.1-1.5;

[0033] The hydrochloric acid concentration is 5N or 10N; and / or,

[0034] The alcohol is methanol or 95% ethanol.

[0035] The removal of phthaloyl groups is more favorable under acidic conditions. Conventional hydrazine hydrate conditions severely affect the purification of intermediates. After protection with tert-butyloxycarbonyl (Boc), the compound of formula 6 is easier to separate and purify.

[0036] Furthermore, the deprotection and salt formation of the tert-butyloxycarbonyl (Boc) is carried out in the presence of the compound of formula 6, a hydrogen chloride solution, and a solvent, wherein the molar ratio of the compound of formula 6 to hydrogen chloride is 1.0:1.5–2.0; and / or,

[0037] The hydrogen chloride solution is an ethanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a dioxane solution of hydrogen chloride, or a tetrahydrofuran solution of hydrogen chloride; and / or,

[0038] The solvent is water, tetrahydrofuran, dioxane, or ethyl acetate.

[0039] Studies have found that using tetrahydrofuran as a solvent and adding hydrogen chloride to dioxane solution produces products with better properties, higher purity, and higher yield.

[0040] The present invention has the following advantages:

[0041] The synthetic route and process design of this invention are reasonable. It uses 2-cyclopentenone as the starting material, requires mild reaction conditions, has simple post-processing methods, is highly operable, and uses inexpensive and readily available raw materials and reagents. Moreover, the overall yield can reach 43.6%, making it a synthetic method with large-scale preparation value. Attached Figure Description

[0042] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are merely exemplary, and those skilled in the art can derive other embodiments based on the provided drawings without creative effort.

[0043] The structures, proportions, sizes, etc. illustrated in this specification are only for the purpose of assisting those skilled in the art in understanding and reading the content disclosed herein, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes in the proportions, or adjustments to the size, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0044] Figure 1 The HPLC purity spectrum of 6-tert-butoxycarbonyl-2-amino-6-azaspiro[3.4]octane provided in Example 1 of this invention;

[0045] Figure 2 MS diagram of 6-tert-butoxycarbonyl-2-amino-6-azaspiro[3.4]octane provided in Example 1 of this invention. Detailed Implementation

[0046] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0047] Example 1

[0048] This embodiment provides a method for synthesizing 6-tert-butoxycarbonyl-2-amino-6-azaspiro[3.4]octane, comprising the following steps:

[0049] (1) Michael addition reaction

[0050]

[0051] Compound 1 (5.0 kg, 60.976 mol, 1.0 eq) was added to a reaction vessel, followed by DMF (50 L) and compound 2 (8.97 kg, 60.976 mol, 1.0 eq). The mixture was cooled to 0 °C, and sodium carbonate solid (646.4 g, 6.098 mol, 0.1 eq) was added in batches. The mixture was stirred for 12 h. UPLC monitoring showed no change in starting material compound 1. Water (100 L) was added, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was washed with water (10 L) and dried to obtain 311.88 kg of compound 311.88 kg, with a yield of 85% (HPLC 90.5%) and LC-MS [M+H] = 230.24. No further purification was required before proceeding to the next step of the reaction.

[0052] (2) Deoxyfluorination reaction

[0053]

[0054] Compound 3 (11.880 kg, 51.823 mol, 1.0 eq) obtained in step (1) was dissolved in dichloromethane (60 L), and the temperature was controlled at 0 °C. Diethylaminotrifluoride (DAST) (20.88 kg, 129.558 mol, 2.5 eq) was added dropwise for at least 1 h, and the mixture was stirred for 3 h. UPLC showed that starting material 3 disappeared. The reaction system was then added to saturated sodium bicarbonate (50 L), and the reaction was quenched by stirring for 1 h. The mixture was washed with water (5 L × 2), saturated sodium chloride (5 L × 2), and concentrated to obtain compound 4 (9.764 kg, yield 75%, HPLC 92.3%), LC-MS: [M+H] = 252.23. No purification was required before proceeding to the next step of the reaction.

[0055] (3) Removal of phthaloyl protecting group and protection of tert-butyloxycarbonyl (Boc) group

[0056]

[0057] Compound 4 (5.0 kg, 19.902 mol) was dissolved in 30 L of glacial acetic acid, slowly heated to reflux for 6 h with 15 L of 10 N hydrochloric acid, concentrated, dissolved in 5 L of 95% ethanol, and concentrated twice to obtain crude hydrochloride of compound 5. This crude hydrochloride was dissolved in 20 L of 95% ethanol, and (Boc)₂O (5.513 kg, 23.882 mol, 1.2 eq) was added in portions. The mixture was stirred at 25 °C for 12 h, and the solvent was evaporated to obtain compound 6 (3.545 kg, HPLC 92%, LC-MS: [M+H] = 222.25, yield 80.5%), which proceeded to the next step of the reaction without further purification.

[0058] (1) Boc protection desalination

[0059]

[0060] Compound 6 (2.0 kg, 9.040 mol) was added to a reaction vessel, dissolved in 10 L of tetrahydrofuran, cooled to 0 °C, and a dioxane solution of hydrogen chloride (4 M, 4.52 L, 2.0 eq) was added dropwise. The mixture was stirred for 8 h, and a large amount of white solid precipitated. After filtration, the solid was washed with 2 L of tetrahydrofuran and dried to obtain compound 7. (1.21 kg, yield 85%, HPLC purity chromatogram as shown) Figure 1 As shown, the purity is 99.42%, and the MS spectrum is as follows. Figure 2 As shown, LC-MS: [M+H] = 121.0).

[0061] Example 2

[0062] This embodiment provides a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, which differs from Example 1 only in the deoxyfluorination reaction conditions.

[0063] The deoxyfluorination reaction in this embodiment is as follows:

[0064] Compound 3 (11.880 kg, 51.823 mol, 1.0 eq) was dissolved in dichloromethane (60 L), and the mixture was kept at 0 °C. Diethylaminosulfur trifluoride (DAST) (18.378 kg, 114.011 mol, 2.2 eq) was added dropwise for at least 1 h, and the mixture was stirred for 3 h. UPLC showed that starting material 3 disappeared. The reaction mixture was then added to saturated sodium bicarbonate (50 L), and the reaction was quenched by stirring for 1 h. The mixture was washed with water (5 L × 2), saturated sodium chloride (5 L × 2), and concentrated to give compound 4 (7.811 kg, yield 60%, HPLC 85%), LC-MS: [M+H] = 252.23. No purification was required before proceeding to the next step of the reaction.

[0065] Comparative Example 1

[0066] This comparative example provides a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, which differs from Example 1 only in the different reaction conditions for the removal of the phthaloyl protecting group and the protection of the tert-butyloxycarbonyl (Boc).

[0067] Compound 4 (5.0 kg, 19.902 mol) was dissolved in 30 L of methanol, and slowly reacted with 3 L of 40% hydrazine hydrate at room temperature with stirring for 12 h. The solid was filtered off, and the filter cake was washed with 5 L of methanol. The filtrate was concentrated to obtain the crude product of compound 5. 20 L of 95% ethanol was added to dissolve the crude product, and (Boc)2O (5.513 kg, 23.882 mol, 1.2 eq) was added in portions. The mixture was stirred at 25 °C for 12 h. The solvent was evaporated, and 10 L of MTBE was added for purification to obtain compound 6 (2.642 kg, HPLC 80%, LC-MS: [M+H] = 222.25, yield 60.0%). No further purification was required before proceeding to the next step of the reaction.

[0068] Comparative Example 2

[0069] This comparative example provides a method for synthesizing 3,3-difluorocyclopentanamine hydrochloride, which differs from Example 1 only in the reaction conditions for deoxyfluorination.

[0070] Compound 3 (11.880 kg, 51.823 mol, 1.0 eq) was dissolved in dichloromethane (60 L), and the mixture was kept at 0 °C. Thiomorpholine trifluoride (MOST) (22.698 kg, 129.58 mol, 2.5 eq) was added dropwise for at least 1 h, and the mixture was stirred for 6 h. UPLC showed that starting material 3 had disappeared. The reaction mixture was then added to saturated sodium bicarbonate (50 L), and the reaction was quenched by stirring for 1 h. The mixture was washed with water (5 L × 2), saturated sodium chloride (5 L × 2), and concentrated to give compound 4 (5.207 kg, yield 40%, HPLC 88%), LC-MS: [M+H] = 252.23. No purification was required before proceeding to the next step of the reaction.

[0071] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A process for the synthesis of 3,3-difluorocyclopentylamine hydrochloride, characterized in that, A 3,3-difluorocyclopentylamine hydrochloride is synthesized by using 2-cyclopentenone and phthalimide as raw materials, sequentially performing Michael addition reaction, deoxy-fluorination, removal of phthaloyl protecting group, Boc protection and deprotection reaction. The reaction route is as follows:

2. The process for the synthesis of 3,3-difluorocyclopentylamine hydrochloride according to claim 1, characterized in that, The Michael addition reaction comprises: dissolving 2-cyclopentenone of formula 1 and phthalimide of formula 2 in a solvent, controlling the temperature to be 0-5 DEG C, slowly adding a base, stirring at 20-25 DEG C after the addition is completed, adding water, filtering, and obtaining a compound shown in formula 3.

3. The method for synthesizing 3,3-difluorocyclopentanamine hydrochloride according to claim 2, characterized in that, The deoxy-fluorination reaction comprises: dissolving the compound of formula 3 in a solvent, controlling the temperature of the system to be 0-5 DEG C, slowly adding a fluorinating agent diethylamine sulfide, adding saturated sodium bicarbonate after the reaction is completed, separating phases, and drying to obtain a compound of formula 4.

4. The method of claim 3, wherein the 3,3-difluorocyclopentylamine hydrochloride is synthesized by the process of: ###0002### 3,3-difluorocyclopentylamine hydrochloride ###0003### 3,3-difluorocyclopentylamine hydrochloride The removal of phthaloyl protecting group and Boc protection comprises: dissolving the compound of formula 4 in acetic acid, adding hydrochloric acid, stirring while controlling the temperature of the system to be 100-110 DEG C, drying the solvent after the reaction is completed, dissolving in an alcohol, adding Boc anhydride, drying the solvent, and obtaining a compound of formula 6. ​ 5. The method for synthesizing 3,3-difluorocyclopentanamine hydrochloride according to claim 4, characterized in that, The deprotection of Boc and salt formation comprises: dissolving the compound of formula 6 in a solvent, controlling the temperature to be 0-5 DEG C, slowly adding a hydrogen chloride solution, stirring to react, filtering, washing, and drying to obtain a pure compound of formula 7.

6. The synthesis method of claim 5, wherein the molar ratio of 2-cyclopentenone of formula 1, phthalimide of formula 2 and the base is 1.0:1.0-1.5:0.1-0.2; and / or the base is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium tert-butoxide or potassium tert-butoxide; and / or the solvent is N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

7. The synthesis method of claim 6, wherein the deoxy-fluorination reaction is performed in the presence of a fluorinating agent and a solvent, wherein the molar ratio of the compound of formula 3 and the fluorinating agent is 1.0:2.0-4.0; and / or the fluorinating agent is diethylamine sulfide (DAST) or sulfurous trifluoride morpholine; and / or the solvent is tetrahydrofuran, dichloromethane or 1,2-dichloroethane; and / or the temperature of the deoxy-fluorination reaction is 0-5 DEG C. The removal of phthaloyl protecting group and Boc protection comprises: dissolving the compound of formula 4 in acetic acid, adding hydrochloric acid to perform reflux, the mass-volume ratio of the compound of formula 4, acetic acid and hydrochloric acid is 1.0:5-10:5-10; and / or dissolving in an alcohol, adding Boc anhydride, the molar ratio of the compound of formula 5 and Boc anhydride is 1:1.1-1.5; the concentration of the hydrochloric acid is 5N or 10N; and / or the alcohol is methanol or 95% ethanol. ​ ​ ​ ​ ​ 8. The method of claim 7, wherein the 3,3-difluorocyclopentylamine hydrochloride is synthesized by the process of: ###0002### 3,3-difluorocyclopentylamine hydrochloride ###0003### 3,3-difluorocyclopentylamine hydrochloride ​ ​ ​ ​ 9. The method for synthesizing 3,3-difluorocyclopentanamine hydrochloride according to claim 8, characterized in that, The deprotection of the tert-butyloxycarbonyl (Boc) is carried out in the presence of a compound of formula 6, a hydrogen chloride solution and a solvent, the molar ratio of the compound of formula 6 to the hydrogen chloride being 1.0:1.5-2.0; and / or, The hydrogen chloride solution is a hydrogen chloride ethanol solution or a hydrogen chloride ethyl acetate solution or a hydrogen chloride dioxane solution or a hydrogen chloride tetrahydrofuran solution; and / or, The solvent is water or tetrahydrofuran or dioxane or ethyl acetate.

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