1152134-45-6|(1R,2R)-1-((tert-Butoxycarbonyl)amino)-2-(difluoromethyl)cyclopropanecarboxylic acid| Ambeed

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Quality Control of [ 1152134-45-6 ] Purity: 98% SDS Specification

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Product Details of [ 1152134-45-6 ]

CAS No. :	1152134-45-6
Formula :	C₁₀H₁₅F₂NO₄
M.W :	251.23
SMILES Code :	O=C([C@]1(NC(OC(C)(C)C)=O)[C@H](C(F)F)C1)O
MDL No. :	MFCD29920658

Safety of [ 1152134-45-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P210-P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P370+P378-P403+P233-P403+P235-P405-P501

Application In Synthesis of [ 1152134-45-6 ]

* 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.

Downstream synthetic route of [ 1152134-45-6 ]

[ 1152134-45-6 ] Synthesis Path-Downstream 1~35

1
[ 154350-29-5 ]
[ 1152134-45-6 ]
[ 1152134-46-7 ]

Yield	Reaction Conditions	Operation in experiment
45%		The acid (0.6 g) was dissolved in DCM (10 mL)Cooling to 0 degrees,DMAP (0.73 g) was added sequentially,Cyclopropylsulfonamide (0.36 g) was stirred for 5 min,Then EDCI (1.14 g) was added to the reaction system,0 degrees reaction 1h,Room temperature reaction 24h,TLC detection of raw materials reaction is complete,There are new points generated,Add water (20mL),DCM (3 * 40 mL) was extracted with anhydrous sodium sulfate,The organic phase was concentrated and the column was chromatographed on a white solid (0.4 g, 45%).
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 49h;	Step 2B; <n="185"/>Carboxylic acid 2a (~ 132 mmol) was dissolved in DCM (400 mL) then cooled to 0 C. DMAP (40.3 g, 330 mmol), sulfonamide (16.0 g, 132 mmol), and EDC (63.3 g, 330 mmol) were added and reaction was stirred at 0 C for 1 h, warmed to rt, then stirred an additional 48 h. Reaction was diluted with EtOAC (1.5 L) and extracted with IN HCl (2 x 750 mL). Combined aqueous layers were back-extracted with EtOAc, and the combined EtOAc layers were washed with brine (1 L). Organic portions were dried (Na2SO4), filtered, and concentrated. Crude oil was purified via SiO2 chromatography using a 60% EtOAc/hexanes to yield the desired sulfonimide 2b (40 g, 85%, two steps).

References: [1]Patent: CN107074876,2017,A .Location in patent: Paragraph 0398; 0399; 0400; 0406.
[2]Patent: WO2009/64975,2009,A1 .Location in patent: Page/Page column 183-184.

2
[ 1152134-42-3 ]
[ 1152134-45-6 ]

Yield	Reaction Conditions	Operation in experiment
95%		A mixture of (1R,2R)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(difluoromethyl)cyclopropanecarboxylate (540 mg, 1.423 mmol) in Tetrahydrofuran (7 mL) and MeOH (7.00 mL) was added 2M LiOH (3.56 mL, 7.12 mmol) in water and stirred at rt over the weekend. It was then extracted with ether, the aqueous layer was acidified with 1N HCl until pH=3. It was then extracted with ethyl acetate, dried over MgSO4, filtered and concentrated to yield W=340 mg (95%) off-white solid. 1HNMR (500 MHz, MeOD) δ ppm 1.39-1.54 (m, 10H,) 1.64-1.87 (m, 1H), 1.88-2.11 (m, 1H,) 5.91 (t, J=55.85 Hz, 1H).
80%	With water; lithium hydroxide; In tetrahydrofuran; ethanol; at 50℃; for 10h;	The starting material 53 as a solution in heptane is concentrated, chased with EtOH, and then dissolved in EtOH (6 mL/g of 53) and THF (6 mL/g of 53). The solution is heated to 50 C. and then a 5.5% aqueous solution of LiOH (5 eq) is added and the mixture stirred at 50 C. until the reaction is complete by high-performance liquid chromatographic (HPLC) analysis (approximately 10 h). The mixture is cooled to rt and formic acid (3.5 eq) is added and the mixture concentrated to approximately 7 mL/g. To this mixture is added isopropyl acetate (IPAc) (10 mL/g of 53) and formic acid (2.5 eq) to adjust the pH to 4.5. The mixture is filtered, rinsing with IPAc and the aqueous layer is separated. The upper product containing layer is washed with water, and then brine. The IPAc solution is concentrated and the product crystallized from IPAc/heptanes. The yield of 54 is typically 80%.
60.4%	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 8h;	The difluoro compound (0.5 g)Was dissolved in THF (6 mL)MeOH (2 mL) andH2O (2 mL)Lithium hydroxide (0.27 g) was then added to the reaction system,Reaction at room temperature for 8 h,TLC detection has product formation,Raw material reaction is complete,The reaction solution was diluted with 15 mL of water,Then 1NHCl adjusted to pH 3-4,Ethyl acetate was extracted three times,Dried over anhydrous sodium sulfate,The organic phase was concentrated and the column was chromatographed (0.2 g, yield: 60.4%) as a white solid.

Step 2A; Ethyl ester 11 (50 g, 132 mmol) was dissolved in THF (400 mL), then further diluted with MeOH (160 mL) and water (160 mL). LiOH-H2O (27.6 g, 660 mmol) was added and the reaction mixture was stirred at rt overnight. The solution was acidified to pH ~ 2 using 1 M HCl, then extracted with DCM (3 x 500 mL). The combined organic portions were dried (Na2SO4), filtered, and concentrated. The crude carboxylic acid 2a was carried directly on without any further purification.

References: [1]Patent: US2010/150866,2010,A1 .Location in patent: Page/Page column 12.
[2]Organic Process Research and Development,2020,vol. 24,p. 183 - 200.
[3]Patent: US9809576,2017,B1 .Location in patent: Page/Page column 94.
[4]Patent: CN107074876,2017,A .Location in patent: Paragraph 0398; 0399; 0400; 0405.
[5]Patent: WO2009/64975,2009,A1 .Location in patent: Page/Page column 183.

3
[ 1152134-45-6 ]
[ 1229446-97-2 ]
[ 1229446-98-3 ]

Yield	Reaction Conditions	Operation in experiment
25.09%		To a solution of <strong>[1152134-45-6](1R,2R)-1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylic acid</strong> (100 mg, 0.398 mmol) in Tetrahydrofuran (4 mL) was added CDT (84 mg, 0.517 mmol) and the formed solution was stirred at r.t. for 3 h. 1-(hept-6-enyl)cyclopropane-1-sulfonamide (104 mg, 0.478 mmol) and DBU (0.120 mL, 0.796 mmol) were added and the reaction continued at r.t. overnight. The reaction was diluted with EtOAc. Washed with 5% citric acid, brine, dried over MgSO4, filtered and concentrated. The residue was purified by Biotage column, eluted with gradient 5%70% EtOAc-Hexane to afford the desire produce tert-butyl (1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamate (45 mg, 0.100 mmol, 25.09% yield). 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.95 (s, 2H) 1.28-1.36 (m, 2H) 1.36-1.47 (m, 6H) 1.52 (s, 9H) 1.58-1.67 (m, 2H) 1.72 (d, J=10.54 Hz, 1H) 1.78-1.95 (m, 2H) 1.97-2.12 (m, 3H) 4.88-5.05 (m, 2H) 5.23 (b, NH) 5.65-5.92 (m, 2H) 9.20 (b, NH).

References: [1]Patent: US2010/150866,2010,A1 .Location in patent: Page/Page column 13.

4
[ 1108658-19-0 ]
[ 1152134-45-6 ]
[ 1535210-08-2 ]

Yield	Reaction Conditions	Operation in experiment
0.73 g		Step 1. Preparation of A12-1: A vessel containing a solution of carboxylic acid A9-1 (1 g, 4 mmol) in THE (15 mL) was treated with CDI (0.84 g, 5.2 mmol), sealed and heated to 75 00 for 2 h. The clear tan colored solution is divided in half and used subsequently without further purification for the remainder of Step 1 in the preparation of Intermediate A12 as well as the preparation ofIntermediate A13 as detailed below. This solution is treated with 1- fluorocyclopropane-1 -sulfonamide (0.42 g, 3 mmol; prepared according to Steps 1, 4, and 9 of Example 7 of International Patent Publication No. WO 2009/1 4730, p. 107-110) and DBU (0.6 mL, 4 mmol) and allowed to stir overnight at rt. The solution was acidified to pH -1 with 1 M HCI and concentrated in vacuo toremove the majority of THE. The aqueous layer was extracted with EtOAc and the combined organics washed with brine, dried over anhydrous Mg504 and concentrated in vacuo to dryness to afford 0.73 g of the A12-1 that was used without further purification.

References: [1]Patent: WO2014/8285,2014,A1 .Location in patent: Page/Page column 127.

5
[ 1152134-45-6 ]
C₈H₁₁F₃N₂O₃S*(x)ClH [ No CAS ]

References: [1]Patent: WO2014/8285,2014,A1 .

6
[ 1152134-45-6 ]
[ 1360828-80-3 ]

References: [1]Patent: WO2014/145095,2014,A1 .
[2]Patent: US9809576,2017,B1 .
[3]Organic Process Research and Development,2020,vol. 24,p. 183 - 200.

7
[ 1152134-45-6 ]
(1aS,2aR,6S,9S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-15-fluoro-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexa-decahydro-1H,9H-8,11-methanocyclopropa[4',5']cyclopenta[1',2':18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide trifluoroacetate [ No CAS ]