ChemicalBook CAS DataBase List Carbamic acid, [(1S,2R)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI)

Carbamic acid, [(1S,2R)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI) synthesis

6synthesis methods

Product Name:Carbamic acid, [(1S,2R)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI)
CAS Number:365996-30-1
Molecular formula:C11H22N2O2
Molecular Weight:214.3

Triphenylphosphine (14.3 g) was added to a THF (190 ml) solution containing tert-butyl S,2S)-2-hydroxycyclohexyl) carbamate (10.0 g), followed by ice cooling. Diethyl azodicarboxylate (40% in toluene) (24.3 g) and DPPA (15.3 g) were added dropwise to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was left overnight. The solvent was distilled away under reduced pressure. Water was added, and then a 20% sodium hydroxide aqueous solution was added. Then, the organic layers were collected. Water (30 ml) was added to the obtained organic layers, followed by heating to 60 C. A THF (40 ml) solution containing triphenylphosphine (14.3 g) was added dropwise, followed by reflux for 2.5 hours. The solvent was distilled away under ordinary pressure. Toluene was added, and the pH was adjusted with 3M hydrochloric acid to pH=1 or less. Then, the resulting aqueous layers were collected, ethyl acetate was added, and the pH was adjusted with a 20% sodium hydroxide aqueous solution to pH 12. The organic layers were collected and dried over anhydrous sodium sulfate. Light yellow oily matter of tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (Carbamic acid, [(1S,2R)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI))was thus obtained.

364385-54-6 Synthesis

Carbamic acid, [(1R,2S)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI)

364385-54-6
83 suppliers
$36.00/250mg

Carbamic acid, [(1S,2R)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI)

365996-30-1
161 suppliers
$34.00/100mg

Yield:365996-30-1 34%

Reaction Conditions:

Stage #1:(1S,2R)-2-tert-Butoxycarbonylamino-cyclohexylamine with (R)-Mandelic Acid in ethyl acetateLarge scale;
Stage #2: with potassium carbonate in water;ethyl acetate at 20 - 30; for 3 h;Large scale;

Steps:

6.3; 6.4
To a 1000L reactor was added racemate 6.3 (13 1.3kg, 613mo1) in EtOAc and Dmandelic acid (0.5 eq). The reaction mixture was stirred for overnight and then resulting solid was filtered and washed with EtOAc. 96% e.e. of the salt was obtained with 34% yield. The mother liquor was reacted with K2C03 (aq.) and free-diamine was prepared. The free-diamine isolated was reacted with L-mandelic acid. 98% e.e. of the opposite salt 6.5 was obtained with 39% yield. The same operation was repeated four times. 89.8kg of (1S,2R)-salt 6.4 were obtained with high e.e. This salt was recrystallized from isopropanol. 77.7kg of(1S,2R)-salt 6.4 with 98% e.e. was obtained in 69% yield. To the 1000L reactor was added (1S,2R)-salt 6.4, (77.7kg, 212mo1) and ethyl acetate. And then K2C03 aq. (35.1kg, 254mo1) was added. The mixture was stirred for 3hrs at 20-30°C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with sat. NaC1 aq. The organic layer was dried by Na2504 and then inorganic residue was removed by filtration. The filtrate was concentrated at approximately 40°C under reduced pressure. The crude product (42.1kg) was purified by distillation and the desired product (1S,2R)-N-Boc-1,2-cyclohexanediamine 6.6 (35.4kg, 147-150°C 1-2 mm Hg) was collected. Its purity was 99.5%, 98.0%e.e. by GC analysis.

References:

PORTOLA PHARMACEUTICALS, INC.;PANDEY, Anjali WO2014/152768, 2014, A1 Location in patent:Paragraph 0101; 0102

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