* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With pivaloyl chloride In isopropyl alcohol at 20℃; for 12 h; Inert atmosphere
(3) Under the protection of nitrogen, 82 g of isopropanol was charged into the reaction flask.The stirring device was turned on, the temperature was controlled at 5 ° C, and 93.4 g of pivaloyl chloride was added dropwise.After the completion of the dropwise addition, the esterification reaction was carried out at 25 ° C for 30 min;To the resulting system, a solution of compound III in isopropanol (formulated by dissolving 52 g of compound III in 53 g of isopropanol) was added dropwise.After the completion of the dropwise addition, the deprotection reaction was carried out at room temperature for 12 h;After the end of the GC monitoring reaction, the temperature of the reaction system was controlled at 0 ° C after 1 h.After stirring and precipitating the solid, the mixture was kept for 1 hour to ensure that the solid was fully analyzed.Then filter under nitrogen,The obtained filter cake was rinsed with isopropanol at 5 ° C, and evacuated to a drop without dropping.Mixing the filter cake obtained after rinsing with 40 g of acetone, stirring,Heating to 50 ° C, stirring for 2 h;Cool down to 0 ° C, filter under nitrogen,The obtained filter cake was rinsed with acetone at 5 ° C, and depressurized until no droplets were dropped.Then dried under vacuum at 40 ° C for 12 h.Got 25.4g(1R,3S)-3-aminocyclopentanol hydrochloride (GC detectionThe purity of (1R,3S)-3-aminocyclopentanol hydrochloride is 99.75percent.The optical isomer impurity <0.01percent; the total yield was 69.8percent based on the compound I).
58.6%
With hydrogenchloride In water; isopropyl alcohol at 0 - 20℃; for 4 h;
400 mL of isopropanol was added to the reaction flask, and the temperature was lowered to 0 ° C, and hydrogen chloride gas was slowly introduced into the isopropanol until the weight of the solution was increased by 70 g.A hydrogen chloride-isopropanol solution was obtained; 201 g of the compound III was dissolved in 200 mL of isopropanol, and the temperature was lowered to 0 ° C, and the hydrogen chloride-isopropanol solution was added dropwise to the obtained mixed solution. After the dropwise addition, the room temperature was obtained. Stirring for deprotection for 4 h;To the obtained system, 600 mL of isopropyl acetate was added, stirred for 30 min, and filtered with a Buchner funnel under nitrogen atmosphere. The filter cake was washed with isopropyl acetate and dried to give 32.2 g (1R, 3S) -3-amino ring. The pentanol hydrochloride salt yield was 58.6percent and the purity was 96.2percent.
Reference：
[1] Patent: CN108774145, 2018, A, . Location in patent: Paragraph 0080; 0083; 0085; 0088; 0089; 0092; 0093; 0096
[2] Patent: CN108774145, 2018, A, . Location in patent: Paragraph 0104
At OX 36 mg (0.26 mmol) (1/?,3S)-3-aminocyclopentanol hydrochloride were added to 16 mg (0.39 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF. After 15 min of stirring on the ice bath, 129 mg (0.26 mmol) of 6-chloro-3-(4- methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1 ,2-b]pyridazine were added. The ice bath was removed and the mixture was stirred for 15 h at 40C. 0.07 mL (0.53 mmol) of triethylamine were added and the mixture was stirred at 40 for another 7 h. In a separate flask, 19 mg (0.13 mmol) of (1 /?,3S)-3-aminocyclopentanol hydrochloride were added at OX to 8 mg (0.2 mmol) sodium hydride (60% in mineral oil) in 1 mL anhydrous DMF. This mixture was added to the reaction and the resulting mixture was stirred at 40X for another 16 h. In a separate flask, 19 mg (0.13 mmol) of (1 /?,3S)-3-aminocyclopentanol hydrochloride were added at OX to 8 mg (0.2 mmol) sodium hydride (60% in mineral oil) in 1 mL anhydrous DMF. Again, this mixture was added to the reaction and the resulting mixture was stirred at 40X for another 16 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by HPLC to give 54 mg of the title compound as solid material. 1H-NMR (400 MHz, DMSO-d6), delta [ppm]= 1.65 (1 H), 1.72-1.81 (1 H), 1.97 (1H), 2.06- 2.15 (2H), 2.52-2.61 (1 H), 3.46 (1 H), 4.04 (3H), 5.37-5.44 (1 H), 7.02 (1H), 7.38 (1H), 7.48 (1H), 8.06 (1 H), 8.14-8.19 (2H). LC-MS (Method 3): Rt = 0.77 min; MS (ESIpos) m/z = 366 [M+H]+.
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2h;
10 g of the compound of formula V is dissolved in 20 mL of dioxane,Add 50 mL of dioxane hydrochloride (4M) and stir at room temperature for 2 h. Spin the reaction solution,100 mL of acetonitrile was beaten, suction filtered, and the filter cake was rinsed with 100 mL of acetonitrile.Dry blast to give 6.4 g of a white solid.The yield was 95%.
75%
With hydrogenchloride; In tert-butyl methyl ether; water; at 0℃;
Add 4.2 g of (1S, 3R) -3-hydroxycyclopentyl-1-carbamic acid tert-butyl ester to the reaction flask,30 ml of methyl tert-butyl ether was completely dissolved by stirring, the temperature was lowered to 0 C, hydrogen chloride gas was passed until the reaction was completed, filtered, the filter cake was collected, and 2.16 g of a white solid was obtained after drying, with a yield of 75.0%.
69.8%
With pivaloyl chloride; In isopropyl alcohol; at 20℃; for 12h;Inert atmosphere;
(3) Under the protection of nitrogen, 82 g of isopropanol was charged into the reaction flask.The stirring device was turned on, the temperature was controlled at 5 C, and 93.4 g of pivaloyl chloride was added dropwise.After the completion of the dropwise addition, the esterification reaction was carried out at 25 C for 30 min;To the resulting system, a solution of compound III in isopropanol (formulated by dissolving 52 g of compound III in 53 g of isopropanol) was added dropwise.After the completion of the dropwise addition, the deprotection reaction was carried out at room temperature for 12 h;After the end of the GC monitoring reaction, the temperature of the reaction system was controlled at 0 C after 1 h.After stirring and precipitating the solid, the mixture was kept for 1 hour to ensure that the solid was fully analyzed.Then filter under nitrogen,The obtained filter cake was rinsed with isopropanol at 5 C, and evacuated to a drop without dropping.Mixing the filter cake obtained after rinsing with 40 g of acetone, stirring,Heating to 50 C, stirring for 2 h;Cool down to 0 C, filter under nitrogen,The obtained filter cake was rinsed with acetone at 5 C, and depressurized until no droplets were dropped.Then dried under vacuum at 40 C for 12 h.Got 25.4g(1R,3S)-3-aminocyclopentanol hydrochloride (GC detectionThe purity of (1R,3S)-3-aminocyclopentanol hydrochloride is 99.75%.The optical isomer impurity <0.01%; the total yield was 69.8% based on the compound I).
58.6%
With hydrogenchloride; In water; isopropyl alcohol; at 0 - 20℃; for 4h;
400 mL of isopropanol was added to the reaction flask, and the temperature was lowered to 0 C, and hydrogen chloride gas was slowly introduced into the isopropanol until the weight of the solution was increased by 70 g.A hydrogen chloride-isopropanol solution was obtained; 201 g of the compound III was dissolved in 200 mL of isopropanol, and the temperature was lowered to 0 C, and the hydrogen chloride-isopropanol solution was added dropwise to the obtained mixed solution. After the dropwise addition, the room temperature was obtained. Stirring for deprotection for 4 h;To the obtained system, 600 mL of isopropyl acetate was added, stirred for 30 min, and filtered with a Buchner funnel under nitrogen atmosphere. The filter cake was washed with isopropyl acetate and dried to give 32.2 g (1R, 3S) -3-amino ring. The pentanol hydrochloride salt yield was 58.6% and the purity was 96.2%.
With hydrogenchloride; acetyl chloride; In methanol; water; ethyl acetate; for 3h;Cooling with ice;
The intermediate product II of the previous step was mixed with potassium hydroxide and methanol in a dry reaction flask A, and stirred for 3 hours; then all the solvents were removed under vacuum, and then extracted with water-ethyl acetate; over anhydrous sodium sulfate, filtered and concentrated to give a brown oil, i.e. (1R,3S)-3-aminocyclopentanol; 2-3 aqueous phase after extraction with ethyl acetate recovered R-mandelic pH was adjusted with dilute hydrochloric acid acid (3.6 g); was added anhydrous methanol (20 mL) and dried in a further reaction flask B, and acetyl chloride (3.5 mL, 50.0 mmol) under ice-cooling conditions B, was added dropwise to the reaction flask, the original bit generation of hydrogen chloride in methanol; good after preparation methanolic hydrogen chloride, then the previously described brown oil (1R, 3S) -3- amino cyclopentanol, dissolved in a small amount of methanol and added dropwise to a solution of hydrogen chloride in methanol Finally, all volatile components were removed under reduced pressure to give a final product (1R,3S)-3-aminocyclopentanol hydrochloride solid 4.6 g, yield about 85%
(R)-2-hydroxy-N-((1S,3R)-3-hydroxycyclopentyl)-2-phenylacetamide[ No CAS ]
[ 1279032-31-3 ]
Yield
Reaction Conditions
Operation in experiment
61.4%
With hydrogenchloride; In methanol; at 50℃;
Example 1: Add 1.2 g of C1, 10 mL of anhydrous hydrogen chloride in methanol to a reaction bottle, and heat to 50 C for reaction. After the raw materials disappear, the remaining hydrogen chloride and methanol are removed under reduced pressure, and the residue is washed with methyl tert-butyl ether slurry. After filtering and drying, 0.43 g of white solid D was obtained with a yield of 61.4%.
(R)-2-hydroxy-N-((1S,3R)-3-hydroxycyclopentyl)propanamide[ No CAS ]
[ 1279032-31-3 ]
Yield
Reaction Conditions
Operation in experiment
68.9%
With hydrogenchloride; In methanol; at 25℃;
Add 1.5g of C2, 20mL of anhydrous hydrogen chloride in methanol to the reaction bottle, and react at 25 C until the raw materials disappear. The residual hydrogen chloride and methanol are removed by concentration under reduced pressure. The residue is washed with methyl tert-butyl ether slurry, filtered and dried to obtain White solid D0.82g, yield 68.9%.
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