Preparation method of ((1R, 3S)-3-hydroxycyclopentyl) tert-butyl carbamate

Abstract

The invention provides a preparation method of ((1R, 3S)-3-hydroxycyclopentyl) tert-butyl carbamate, which comprises the following steps: (1) mixing (R)-3-oxocyclopentane carboxylic acid with alkali, diphenyl azide phosphate and tert-butyl alcohol for reaction to obtain an intermediate; and (2) mixing the intermediate with a chiral catalyst and borane for reaction to obtain ((1R, 3S)-3-hydroxycyclopentyl) tert-butyl carbamate. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, simple process operation, safe and controllable production and high optical purity of the target product, and can meet the requirements of industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate. Background Technology

[0002] The main use of ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester is as an organic intermediate, widely applied in the research and production of pharmaceuticals, pesticides, and optoelectronic materials. Its hydroxyl and amino functional groups can participate in esterification and amidation reactions, generating active groups for subsequent drug molecule design. Currently, there is relatively little research on the synthesis of ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester.

[0003] Building upon previous research, Barrow, JC, et al. reported the following synthetic route: starting with cyclopentene monoepoxide (A), the intermediate (B) was rapidly purified by TMSN3 reaction at 0°C under palladium catalysis. This step yielded approximately 62% with 9% dihydroxy byproduct. Intermediate (B) was then deprotected with dilute hydrochloric acid to obtain intermediate (C). Intermediate (C) was then reacted with 10 equivalents of vinyl acetate and 0.5 g / mmol of trypsin. The crude product was directly reduced with 10% palladium on carbon without purification, yielding compound (D) and the product in a reaction system containing Boc anhydride. Both were then separated by column purification to obtain the target product with an optical purity of 88-92%, and the calculated overall yield was approximately 23%. This synthetic method uses expensive tetra-triphenylphosphine palladium and palladium on carbon. The obtained intermediates have poor optical purity, require rapid purification, and exhibit chemical instability. The target product also requires purification, and its optical purity does not meet pharmaceutical requirements, making it completely unsuitable for industrial production.

[0004]

[0005] WO2009023269 utilizes (1R,3S)-3-aminocyclopentanol or its hydrochloride protected with Boc anhydride to obtain the target compound. Tracing its precursor (1R,3S)-3-aminocyclopentanol or its hydrochloride, as a key intermediate in the AIDS treatment drug Bictegravir, its synthetic reports are very limited. WO2015195656 reports a lengthy eight-step synthesis using vinslide as a substrate, with expensive starting materials and reagents, an optical purity of only 90% after resolution, and a low overall yield. CN110668959 uses L-camphor sulfonamide as a starting material, undergoing amidation with solid phosgene, asymmetric diene addition with cyclopentadiene under oxidative conditions, followed by alkaline or acidic hydrolysis and final hydrogenation on palladium carbon to obtain (1R,3S)-3-aminocyclopentanol. While this method shortens the synthetic steps, each step requires harsh reaction conditions and also uses expensive palladium carbon. Even if this precursor is obtained, it still needs to be reacted with Boc anhydride to obtain the target product, which makes the whole process relatively long and results in a low overall yield.

[0006] To address the shortage of existing synthetic methods for tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate, there is an urgent need to develop a new method that is simple to operate, has a high yield, and high optical purity to meet the needs of large-scale industrialization. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate. The preparation method provided by the present invention uses inexpensive and readily available raw materials, has a simple process operation, ensures safe and controllable production, and produces a high-purity target product, meeting the needs of industrial production.

[0008] To achieve this objective, the present invention adopts the following technical solution:

[0009] On one hand, the present invention provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, the preparation method comprising the following steps:

[0010] (1) React (R)-3-oxocyclopentanecarboxylic acid 1 with a base, an azide reagent, and tert-butanol to obtain intermediate 2;

[0011] (2) Intermediate 2 is mixed with a chiral catalyst and borane to react and obtain the ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester™;

[0012] The reaction route is as follows:

[0013] .

[0014] The above method uses (R)-3-oxocyclopentanecarboxylic acid as the starting material, obtains an intermediate through the Curtiss rearrangement reaction, and then obtains the highly optically active target product by Corey-Baksh-Shibata reduction of the carbonyl group. The overall method uses inexpensive and readily available raw materials, has simple process operation, safe and controllable production, and the target product has high optical purity, which can meet the needs of industrial production.

[0015] The raw material (R)-3-oxocyclopentanecarboxylic acid used in this invention is commercially available or can be prepared according to the method in WO201722296A1.

[0016] Preferably, the base in step (1) includes any one or a combination of at least two of triethylamine, N,N-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0017] Preferably, the azide reagent in step (1) includes any one or a combination of at least two of diphenyl azidophosphate, sodium azide, or potassium azide.

[0018] Preferably, the molar ratio of (R)-3-oxocyclopentanecarboxylic acid to base, azide reagent, and tert-butanol in step (1) is 1:(1.2-2.5):(1-2):(1.2-10), wherein the amount of base can be 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5, the amount of azide reagent can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2, and the amount of tert-butanol can be 1.2, 2, 3, 4, 5, 6, 7, 8, 9, or 10, but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0019] Preferably, the specific process of the mixing reaction in step (1) is to mix (R)-3-oxocyclopentanecarboxylic acid with a base and an azide reagent for a preliminary reaction, and then mix with tert-butanol for further reaction.

[0020] Preferably, the initial reaction time is 1-3 hours, and the continued reaction time is 6-20 hours. The initial reaction time can be 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours, etc., and the continued reaction time can be 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0021] Preferably, the temperature of the mixing reaction in step (1) is 90-120℃, such as 90℃, 95℃, 100℃, 105℃, 110℃, 115℃ or 120℃, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0022] Preferably, the chiral catalyst in step (2) comprises any one or a combination of at least two of (S)-CBS ((S)-2-methyl-CBS-oxazolylborane), (-)-DIP-Cl ((-)-diisopinepinelchloroborane), or (S)-Alpine-Hydride (B-isopinepinel-9-boronabicyclo[3.3.1]nonane hydride), with (S)-CBS being the most preferred.

[0023] The aforementioned specific chiral catalysts can effectively improve the optical purity of the product and enhance the effectiveness of the preparation method.

[0024] Preferably, the molar ratio of the intermediate to the chiral catalyst and borane in step (2) is 1:(0.1-0.2):(1-1.5), wherein the amount of chiral catalyst can be 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.2, etc., and the amount of borane can be 1, 1.1, 1.2, 1.3, 1.4 or 1.5, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0025] Preferably, the reaction temperature in step (2) is -30~-10℃ and the time is 0.5-3 h. The temperature can be -30℃, -25℃, -20℃, -15℃ or -10℃, etc., and the time can be 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h or 3 h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0026] Preferably, the reaction in step (2) is followed by a quenching reaction, and then the mixture is stirred with acid.

[0027] Preferably, the acid includes hydrochloric acid.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] This invention provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester. Starting from (R)-3-oxocyclopentanecarboxylic acid, an intermediate is obtained via the Curtiss rearrangement reaction, followed by carbonyl reduction via Corey-Bakshi-Shibata to obtain the highly optically active target product. The overall method uses inexpensive and readily available raw materials, has a simple process operation, and is safe and controllable in production. The target product has high optical purity and can meet the needs of industrial production. Detailed Implementation

[0030] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0031] Example 1

[0032] This embodiment provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, the specific steps of which are as follows:

[0033] Step 1 (Refer to WO201722296A1)

[0034] Water (75 L) was pumped into a reactor equipped with a mechanical stirrer and heater. Then, 3-oxo-1-cyclopentanecarboxylic acid (5.0 kg, 39.03 mol) and strychnine (16.9 kg, 42.93 mol) were added. After the addition was complete, the stirring and heating were turned on and the mixture was brought to reflux. Once the mixture was completely dissolved, the temperature was gradually lowered to 25°C. The precipitated solid was filtered and washed with water. The resulting solid was further purified by crystallization with water (50 L), and this crystallization process was repeated three times. The resulting solid was then mixed with water (50 L) again and heated until clear. Then, 25% (w / w) ammonia solution was added dropwise until the pH reached 12. The system was gradually cooled to 25°C, and the solid was removed by filtration. The pH of the filtrate was adjusted to between 1 and 2 with 5% dilute hydrochloric acid. The filtrate was then extracted three times with 5 L of methyl ether each time. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50-55°C to obtain 1780 g of white solid (R)-3-oxocyclopentanecarboxylic acid, with a yield of 35.6% and an optical purity ee of 99.47%.

[0035] Step 2

[0036] (R)-3-oxocyclopentanecarboxylic acid (200 g, 1.56 mol) was dissolved in toluene (2 L). Triethylamine (325 mL, 2.34 mol) and diphenyl azide phosphate (DPPA, 515 g, 1.87 mol) were then added dropwise to the reaction system. After the additions were complete, the reaction system was heated to 100 °C and reacted for 2 h, during which exothermic and gas-releasing phenomena were observed. The temperature was then lowered to approximately 80 °C, and tert-butanol (224 mL, 2.34 mol) was slowly added dropwise. After the addition was complete, the reaction was continued at 100 °C for 12 h, at which point the reactants were almost completely reacted. The reaction system was then cooled to 25 °C, and then 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L) were added. After stirring and allowing the mixture to stand, the organic phase was separated. The separated organic phase was washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 55°C. The residue was dissolved in hexane and filtered through a silica gel pad. The eluent was a mixed solvent of hexane and ethyl acetate (v / v, 30 / 1-20 / 1). The collected filtrate was concentrated under reduced pressure at 45°C to obtain 265 g of intermediate product, with a yield of 85.2%.

[0037] Step 3

[0038] At -30°C, a borane-tetrahydrofuran complex (600 mL, 0.60 mol, 1.0 M tetrahydrofuran solution) was slowly added dropwise to a (S)-CBS solution (60 mL, 0.06 mol, 1.0 M tetrahydrofuran solution). This mixture was stirred at -30°C for 30 min. Then, a tetrahydrofuran solution (400 mL) of the aforementioned intermediate (100 g, 0.50 mol, 1.0 eq) was slowly added dropwise to the mixture, maintaining the reaction temperature between -30°C and -20°C. After the addition was complete, the reaction was continued at this temperature for 1 h, and then slowly restored to 10°C. The reaction was quenched by slowly adding 100 mL of methanol, followed by the addition of 1 L of 5% dilute hydrochloric acid solution. The entire mixture was then stirred for 30 min. The reaction solution was filtered through diatomaceous earth and then extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The crude product was purified by slurrying with n-hexane to obtain 88 g of the target product as a white solid, with a yield of 87.1% and an optical purity ee of 99.99%. 1 HNMR (CDCl3-d6) ppmδ: 1.48 (s, 9H), 1.58 - 1.72 (m, 1H), 1.74- 1.81 (m, 3H), 1.92 - 2.14 (m, 3H), 3.96 - 4.08 (m, 1H), 4.32 -4.38 (m, 1H),5.06 (bs, 1H).

[0039] Example 2

[0040] This embodiment provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, the specific steps of which are as follows:

[0041] first step

[0042] Refer to Example 1.

[0043] Step 2

[0044] (R)-3-oxocyclopentanecarboxylic acid (200 g, 1.56 mol) was dissolved in toluene (2 L). Triethylamine (434 mL, 3.12 mol) and diphenyl azide phosphate (DPPA, 645 g, 2.34 mol) were then added dropwise to the reaction system. After the additions were complete, the reaction system was heated to 100 °C and reacted for 2 h, during which exothermic and gas-releasing phenomena were observed. The temperature was then lowered to approximately 80 °C, and tert-butanol (523 mL, 5.46 mol) was slowly added dropwise. After the addition was complete, the reaction was continued at 100 °C for 16 h, at which point the reactants were almost completely reacted. The reaction system was then cooled to 25 °C, and then 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L) were added. After stirring and allowing the mixture to stand, the organic phase was separated. The separated organic phase was washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 55°C. The residue was dissolved in hexane and filtered through a silica gel pad. The eluent was a mixed solvent of hexane and ethyl acetate (v / v, 30 / 1-20 / 1). The collected filtrate was concentrated under reduced pressure at 45°C to obtain 270 g of intermediate product, with a yield of 86.8%.

[0045] Step 3

[0046] At -30°C, a borane-tetrahydrofuran complex (500 mL, 0.50 mol, 1.0 M tetrahydrofuran solution) was slowly added dropwise to a (S)-CBS solution (50 mL, 0.05 mol, 1.0 M tetrahydrofuran solution). This mixture was stirred at -30°C for 30 min. Then, a tetrahydrofuran solution (400 mL) of the aforementioned intermediate (100 g, 0.50 mol, 1.0 eq) was slowly added dropwise to the mixture, maintaining the reaction temperature between -30°C and -20°C. After the addition was complete, the reaction was continued at this temperature for 3 h, and then slowly restored to 10°C. The reaction was quenched by slowly adding 100 mL of methanol, followed by the addition of 1 L of 5% dilute hydrochloric acid solution. The entire mixture was then stirred for 30 min. The reaction solution was filtered through diatomaceous earth and then extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 45°C. The crude product was purified by pulping with n-hexane to obtain 83 g of the target product as a white solid, with a yield of 82.2% and an optical purity ee of 99.16%.

[0047] Example 3

[0048] This embodiment provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, the specific steps of which are as follows:

[0049] first step

[0050] Refer to Example 1.

[0051] Step 2

[0052] (R)-3-oxocyclopentanecarboxylic acid (200 g, 1.56 mol) was dissolved in toluene (2 L). Triethylamine (525 mL, 3.90 mol) and diphenyl azide phosphate (DPPA, 859 g, 3.12 mol) were then added dropwise to the reaction system. After the additions were complete, the reaction system was heated to 100 °C and reacted for 3 h, during which exothermic and gas-releasing phenomena were observed. The temperature was then lowered to approximately 80 °C, and tert-butanol (1269 mL, 13.27 mol 8.5 eq) was slowly added dropwise. After the addition was complete, the reaction was continued at 100 °C for 8 h, at which point the reactants were almost completely reacted. The reaction system was then cooled to 25 °C, and then 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L) were added. After stirring and allowing the mixture to stand, the organic phase was separated. The separated organic phase was washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 55°C. The residue was dissolved in n-hexane and filtered through a silica gel pad. The eluent was a mixed solvent of n-hexane and ethyl acetate (v / v, 30 / 1-20 / 1). The collected filtrate was concentrated under reduced pressure at 45°C to obtain 260 g of intermediate product, with a yield of 83.6%.

[0053] Step 3

[0054] At -30°C, a borane-tetrahydrofuran complex (750 mL, 0.75 mol, 1.5 eq, 1.0 M tetrahydrofuran solution) was slowly added dropwise to a (S)-CBS solution (100 mL, 0.10 mol, 1.0 M tetrahydrofuran solution). This mixture was stirred at -30°C for 30 min. Then, a tetrahydrofuran solution (400 mL) of the aforementioned intermediate (100 g, 0.50 mol, 1.0 eq) was slowly added dropwise to the mixture, maintaining the reaction temperature between -30°C and -20°C. After the addition was complete, the reaction was continued at this temperature for 1 h, and then slowly restored to 10°C. The reaction was quenched by slowly adding 100 mL of methanol, followed by the addition of 1 L of 5% dilute hydrochloric acid solution. The entire mixture was then stirred for 30 min. The reaction solution was filtered through diatomaceous earth and then extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The crude product was purified by slurrying with n-hexane to obtain 85 g of the target product as a white solid, with a yield of 84.2% and an optical purity ee of 99.38%.

[0055] Example 4

[0056] This embodiment provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, the specific steps of which are as follows:

[0057] first step

[0058] Refer to Example 1.

[0059] Step 2

[0060] Refer to Example 1.

[0061] Step 3

[0062] At -30°C, the hand-reducing reagent (-)-DIP-Cl (310 mL, 0.53 mol, 1.7 M n-hexane solution) was slowly added dropwise to a tetrahydrofuran (500 mL) solution of the above intermediate (100 g, 0.50 mol). During the addition, the temperature of the entire reaction system did not exceed -20°C. After the addition was complete, the reaction continued for 2 hours, then the reaction system was allowed to return to room temperature (20°C) and stirred for another 1 hour. Thin-layer chromatography (TLC) monitoring showed that the reactants had almost completely reacted. Methanol (100 mL) was slowly added dropwise to quench the reaction, followed by the addition of 5% dilute hydrochloric acid solution (1 L). The entire system was then stirred for 30 minutes. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure at 45°C to obtain most of the solvent. Then, it was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated again under reduced pressure at 45°C. The crude product was purified by slurrying with n-hexane to obtain 72 g of the target product as a white solid, with a yield of 71.3% and an optical purity ee of 99.42%.

[0063] Example 5

[0064] This embodiment provides a method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, the specific steps of which are as follows:

[0065] first step

[0066] Refer to Example 1.

[0067] Step 2

[0068] Refer to Example 1.

[0069] Step 3

[0070] At -30°C, a borane-tetrahydrofuran complex (500 mL, 0.50 mol, 1.0 M tetrahydrofuran solution) was slowly added dropwise to a (S)-Alpine-Hydride solution (100 mL, 0.10 mol, 1.0 M tetrahydrofuran solution). This mixture was stirred at -30°C for 30 min. Then, a tetrahydrofuran solution (400 mL) of the aforementioned intermediate (100 g, 0.50 mol, 1.0 eq) was slowly added dropwise to the mixture, maintaining the reaction temperature between -30°C and -20°C. After the addition was complete, the reaction was continued at this temperature for 2 h. Thin-layer chromatography (TLC) showed that the reactants had almost completely reacted. Subsequently, a 5% dilute hydrochloric acid solution (1 L) was slowly added dropwise to quench the reaction, and the entire system was stirred for another 30 min. The reaction solution was filtered through diatomaceous earth and then extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The crude product was purified by slurrying with n-hexane to obtain 80 g of the target product as a white solid, with a yield of 79.2% and an optical purity ee of 95.78%.

[0071] Comparative Example 1

[0072] This comparative example provides a method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate, the specific steps of which are as follows:

[0073] first step

[0074] Refer to Example 1.

[0075] Step 2

[0076] Refer to Example 1.

[0077] Step 3

[0078] The intermediate (50 g, 0.25 mmol) was dissolved in methanol (500 mL). Then, NaBH4 (14 g, 0.38 mol) was added in portions to the reaction system at 0 °C. After the addition was complete, the temperature was gradually restored to 25 °C, and the reaction was stirred for 2 h. The reaction was then quenched by adding 5% dilute hydrochloric acid solution (500 mL), and the system was stirred for another 30 min. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure at 55 °C, and then extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by slurrying with n-hexane to obtain 41 g of the target product as a white solid, with a yield of 81.2% and an optical purity of de: 71.15%.

[0079] Comparative Example 2

[0080] This comparative example provides a method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate, the specific steps of which are as follows:

[0081] first step

[0082] Refer to Example 1.

[0083] Step 2

[0084] Refer to Example 1.

[0085] Step 3

[0086] At -70°C, diisobutylaluminum hydride (300 mL, 0.30 mol, 1.0 M n-hexane solution) was slowly added dropwise to a tetrahydrofuran solution (350 mL) of the above intermediate (50 g, 0.25 mol). After the addition was complete, the reaction system was maintained at -70°C and stirred for 2 h. Subsequently, methanol (50 mL) was slowly added dropwise to quench the reaction, followed by the addition of 5% dilute hydrochloric acid solution (500 L). The entire system was then stirred for 30 min. The reaction solution was filtered through diatomaceous earth and then extracted with ethyl acetate (250 mL × 2). The combined organic phases were washed with brine (250 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The crude product was purified by slurrying with n-hexane to obtain 46 g of the target product as a white solid, with a yield of 91.1% and an optical purity of de: 28.91%.

[0087] The data above show that the raw materials used in the preparation method provided by the present invention are cheap and readily available, the process is simple, the production is safe and controllable, and the target product has high optical purity. Comparing Examples 1-5 and Comparative Examples 1-2, it can be seen that the present invention can effectively improve the optical purity of the product and improve the effect of the preparation method by selecting a specific chiral catalyst.

[0088] The applicant declares that this invention illustrates the preparation method of ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester through the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials of this invention, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

[0089] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0090] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester, characterized in that, The preparation method includes the following steps: (1) The (R)-3-oxocyclopentanecarboxylic acid was reacted with a base, an azide reagent, and tert-butanol to obtain an intermediate; (2) The intermediate is mixed with a chiral catalyst and borane to react and obtain the ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester; The reaction route is as follows: 。 2. The method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester according to claim 1, characterized in that, The base in step (1) includes any one or a combination of at least two of triethylamine, N,N-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene; Preferably, the azide reagent in step (1) includes any one or a combination of at least two of diphenyl azidophosphate, sodium azide, or potassium azide.

3. The method for preparing ((1R,3S)-3-hydroxycyclopentyl)carbamate tert-butyl ester according to claim 1 or 2, characterized in that, The molar ratio of (R)-3-oxocyclopentanecarboxylic acid to base, azide reagent, and tert-butanol in step (1) is 1:(1.2-2.5):(1-2):(1.2-10).

4. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-3, characterized in that, The specific process of the mixed reaction in step (1) is to mix (R)-3-oxocyclopentanecarboxylic acid with a base and an azide reagent for a preliminary reaction, and then mix it with tert-butanol for further reaction; Preferably, the initial reaction time is 1-3 hours, and the continued reaction time is 6-20 hours.

5. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-4, characterized in that, The temperature of the mixing reaction in step (1) is 90-120℃.

6. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-5, characterized in that, The chiral catalyst in step (2) includes any one or a combination of at least two of (S)-CBS, (-)-DIP-Cl, or (S)-Alpine-Hydride, preferably (S)-CBS.

7. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-6, characterized in that, The molar ratio of the intermediate to the chiral catalyst and borane in step (2) is 1:(0.1-0.2):(1-1.5).

8. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-7, characterized in that, The reaction in step (2) is carried out at a temperature of -30 to -10°C for 0.5 to 3 hours.

9. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-8, characterized in that, The reaction described in step (2) also includes a quenching reaction, followed by mixing and stirring with acid.

10. The method for preparing tert-butyl ((1R,3S)-3-hydroxycyclopentyl)carbamate according to any one of claims 1-9, characterized in that, The acid includes hydrochloric acid.

Images