[ CAS No. 899809-64-4 ] {[proInfo.proName]}

Name: 899809-64-4|(E)-3-(5-Nitrocyclohex-1-en-1-yl)acrylic acid|97%
Brand: Ambeed
SKU: A110881
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Quality Control of [ 899809-64-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 899809-64-4 ]

Product Details of [ 899809-64-4 ]

CAS No. :	899809-64-4	MDL No. :	MFCD16877199
Formula :	C₉H₁₁NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PEYXGOWSKLZBEO-SNAWJCMRSA-N
M.W :	197.19	Pubchem ID :	44224960
Synonyms :

Calculated chemistry of [ 899809-64-4 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.44
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.19
TPSA :	83.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.08
Log Po/w (XLOGP3) :	1.07
Log Po/w (WLOGP) :	1.38
Log Po/w (MLOGP) :	0.32
Log Po/w (SILICOS-IT) :	-0.76
Consensus Log Po/w :	0.62

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.54
Solubility :	5.7 mg/ml ; 0.0289 mol/l
Class :	Very soluble
Log S (Ali) :	-2.41
Solubility :	0.772 mg/ml ; 0.00392 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	0.08
Solubility :	239.0 mg/ml ; 1.21 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.58

Safety of [ 899809-64-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 899809-64-4 ]

* 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.

Upstream synthesis route of [ 899809-64-4 ]
Downstream synthetic route of [ 899809-64-4 ]

[ 899809-64-4 ] Synthesis Path-Upstream 1~3

1
[ 900186-90-5 ]
[ 899809-64-4 ]

Yield	Reaction Conditions	Operation in experiment
76.5%	Stage #1: With sodium hydroxide In methanol; water at 5 - 20℃; for 24 h; Stage #2: With acetic acid In methanol; water	To a solution of 10 (67 g, 432 mmol) in 1 L of methanol at 0 ⁰C was added 144.4 g (432 mmol) of the Wittig reagent. The resulting mixture was agitated at 0 ⁰C for 3 hrs. The solvent was removed under reduced pressure. The residue was extracted with MeOBu -t twice. The extract was filtered to remove any solid, washed with brine, and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate (10/ 1) to give 9.2 g cis and 55.1 g (60.4percent) trans product. ¹H NMR (CDCl₃) d 7.31 (d, J = 11.3 Hz, IH), 6.18 (m, IH), 5.84 (d, J = 15.9 Hz, IH), 4.74-4.68 (m, IH), 3.76 (s, 3H), 2.81-2.74 (m, 2H), 2.50-2.04 (m, 4H).Next, to a flask were added 2.1 g of the methyl ester, 9.6 ml of MeOH and 2.4 ml of water. To the mixture at about 5 ⁰C was added dropwise 0.96 ml of 50percent NaOH. The mixture was allowed to warm to room temperature and stirred at this temperature for about 24 hrs. The reaction mixture was neutralized with HOAc to pH between 4 and 5 and the methanol was removed under reduced pressure. The residue was extracted with 3 X 50 ml EtOAc. The EtOAc layer was concentrated to EPO <DP n="39"/>give 1.5 g of nitroacid 6 (76.5percent).

Reference： [1] Patent: WO2006/76415, 2006, A2, . Location in patent: Page/Page column 35-37

2
[ 900186-75-6 ]
[ 141-82-2 ]
[ 899809-64-4 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: at 60℃; for 7 h; Stage #2: With hydrogenchloride In pyridine; water at 15 - 25℃;	To a solution of S-nitro-cyclohex-l-enecarbaldehyde (18g, 0.116 mol) in pyridine (36 ml) was added malonic acid (41 g, 0.394 mol). The resulting suspension was heated to 60 ⁰C for about 7 hours. After cooling to a temperature between 15⁰C and 20⁰C, 6N HCl (72 ml) was slowly added into the reaction mixture to adjust the pH to between 1.5 and 2 while maintaining the temperature between 20⁰C and 25⁰C. The mixture was then extracted with methylene chloride three times (1X180 ml, 2X90 ml). The combined extracts were washed with IN HCl (48 ml), water (48 ml) and concentrated to a volume of 36 ml. The concentrate suspension was cooled to O⁰C and 5⁰C for 1 hour. Light yellow solid was obtained after filtration and drying under vacuum. Yield: 1Og, 60percent. Mp 158-160 ⁰C. ^IHNMR (400 MHz, DMSOd₅): δ 2.10 - 2.33 (m, 4H), 2.73 (m, 2H), 4.96 (m, IH), 5.83 (d, J = 20 Hz, IH), 6.28 (s, IH), 7.27 (d, J = 20 Hz, IH), 12.3 (s, IH).

Reference： [1] Patent: WO2006/76415, 2006, A2, . Location in patent: Page/Page column 35

3
[ 18350-46-4 ]
[ 899809-64-4 ]

Yield	Reaction Conditions	Operation in experiment
98.1 - 98.9 % ee	at 35℃; for 96 h; Enzymatic reaction; Resolution of racemate	The coupling was carried out by the scheme outlined in Example 12. In the coupling, 2.52 g of (VIIId), 4.31 g of (DIb), and 1.2 g of chirazyme L-9 were mixed in 75 ml of dry TBME. The reaction was agitated at 35 ⁰C. After 96 h, the conversion reached 95.4percent, giving approximately 70percent of the product (Ie), and 30percent of the corresponding acid (VIIc). To remove the remaining (IHb), 50 ml iPrOAc and 4.3 g of SO₃-Pyr in 5 ml DMF were added to the mixture. The agitation was continued for 2 h to complete the sulfonation. The insoluble was then removed by filtration. The organic solution was washed with 5percent acetic acid, 8percent KHCO3, and brine, 150 ml each. After concentration, the crude oil (2.6 g) was purified over a silica gel column. It gave 2.15 g product (Ie) in >99percent purity. NMR analysis indicated that the product was a mixture of two diastereomers. The ee with the respect of (IHb) moiety was determined to be 98.1percent for R enantiomer.

Reference： [1] Patent: WO2006/76565, 2006, A2, . Location in patent: Page/Page column 42-44

[ 899809-64-4 ] Synthesis Path-Downstream 1~16

1
3-(5-oximecyclohex-1-enyl)acrylic acid [ No CAS ]
[ 899809-64-4 ]

Yield	Reaction Conditions	Operation in experiment
69 - 89.4%		Preparation of 3-(5-nitrocyclohex-1-enyl) acrylic acid (6) To a 3 three-neck flask equipped with an agitator, thermometer and a nitrogen inlet, was added 730 mL of water and 100 g (0.72 mol) of sodium phosphate monobasic monohydrate. The pH of the reaction mixture was adjusted to 6.4 by the addition of 25% sodium hydroxide aqueous solution. 73 g of (2) (0.40 mol), 97.8 g of sodium molybdate dihydrate (0.40 mol) and 730 mL of CH3CN were added to the reaction mixture. The resulting mixture was heated to 50 C. followed by slowly adding 62 mL of 30% hydrogen peroxide aqueous solution while maintaining the temperature at 50 C. The reaction mixture was agitated at 50 C. for 1 to 2 hours and then cooled to 20 C. Next a solution of 10.22 g of sodium sulfite in 73 mL of water was added to the reaction mixture. The reaction mixture was then agitated for 30 minutes at 20 C. and concentrated under vacuum. To the reaction mixture was added 365 mL water, and the reaction mixture was cooled to 5 C. and the pH was adjusted to 2-3 by the addition of 37% hydrochloric acid aqueous solution. Compound 6 precipitated out and was then filtered, washed and dried to provide 55 g of a light brown colored solid; yield 69%, m.p. 162.8 C. 1H-NMR (DMSO-d6) delta 12.2 (s, 1H), 7.22 (d, J=15.8 Hz, 1H), 6.28 (s, 1H), 5.78 (d, J=15.8 Hz,1H), 4.97 (s,1H), 2.74 (m, 2H), 2.33 (brs 2H), 2.08-2.22 (m, 2H). Procedure 2 Into a 2 L three neck flask equipped with an agitator, thermometer, and a nitrogen inlet, was added 69 g of sodium phosphate monobasic monohydrate and 500 mL of water. An aqueous 25% sodium hydroxide solution (27.5 mL) was added to adjust pH to 6.5. To above solution was added 50.0 g of Compound 6 and 350 mL of acetonitrile. The pH was adjusted to 7.0 with additional 25% sodium hydroxide aqueous solution. The mixture was heated to 40 C. and stirred for 15 minutes. At the end of 15 minutes the mixture was cooled to a temperature of less than 10 C. To the cooled solution was added 60 mL of 37% hydrochloric acid aqueous solution to adjust solution pH to pH 2 to pH 3. Purified compound 6 began to precipitate from the solution forming a suspension. The suspension was cooled to a temperature of less than 5 C. and stirred for one additional hour while maintaining the suspension at a temperature below 5 C. At the end of one hour the solid compound 6 was collected via filtration. The collected compound 6 was washed with cold water and dried in an air-draft oven set at a temperature of 45 to provide 44.7 g of Compound 6 as off-white solid (89.4% w/w yield, purity 98.1% w/w). The purified compound 6 thus obtained was characterized by. m.p. 162.8 C. (DSC onset point) and 1H-NMR (DMSO-d6) 12.2 (s, 1H), 7.22 (d, J =15.8 Hz, 1H), 6.28 (s, 1H), 5.78 (d, J =15.8 Hz, 1H), 4.97 (s, 1H), 2.74 (m, 2H), 2.33 (brs, 2H), 2.08-2.22 (m, 2H).

Reference： [1]Patent: US2008/9651,2008,A1 .Location in patent: Page/Page column 12

2
[ 899809-64-4 ]
[ 3282-30-2 ]
C₁₄H₁₉NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In toluene; at 0 - 5℃; for 1h;	To a flask were charged sequentially Compound 6 (90 g, 0.46 mole) and toluene (500 mL). The suspension was cooled to about 0 0C, and N- methylmorpholine (91 mL, 0.83 mole) and trimethylacetyl chloride (56 mL, 0.46 mole) were slowly added while keeping the reaction temperature below 5 0C. The reaction mixture was agitated for 1 hour at 0 0C and assayed for completion of formation of mixed anhydride (< 10% of UB remains). A solution of 3a (100 g, 0.38 mole) in toluene (400 mL) and THF (220 mL) was added while keeping the reaction temperature below 5 0C. This was followed by addition of a solution of 4- dimethylaminopyridine (5.5 g, 0.046 mole) in THF (45 mL). The mixture was agitated at about 0 0C for 8-12 hours until reaction completion (<0.2% EB remains). Reaction was quenched by adding a solution of 2.0 EPO <DP n="41"/>N H2SO4 (400 mL), warmed up to 25 0C and filtered through a pad of celite. The layers were separated and the organic layer was washed with 5% K2CO3 solution (3x300 mL) to remove excess 6 (<1% of 6 remains). The mixture was washed with 5% NaCl solution (300 mL), filtered through a pad of celite, and concentrated to about 500 mL final volume. Solution yield 90-95%. *H NMR (CDCl3, 400 MHz) delta 7.05-7.35 (m, HH), 6.13 (br, IH), 5.62 (dd, J = 16, 4 Hz, IH), 5.31 (q, J = 7 Hz, IH), 4.67 (m, IH), 2.62-2.78 (m, 2H), 2.58 (br, 2H), 2.05 (m, 2H), 1.22 (d, J = 7 Hz, 3H).
	With 4-methyl-morpholine; In toluene; at 0 - 5℃; for 1h;	Step 2: Preparation of 3 from (S)-1; Compound 2 (90 g, 0.46 mole) was added to toluene (500 mL) and the suspension was cooled to about 0 C. N-methylmorpholine (91 mL, 0.83 mole) and trimethylacetyl chloride (56 mL, 0.46 mole) were slowly added while keeping the reaction temperature below 5 C. The reaction mixture was agitated for 1 hour at 0 C. and assayed for completion of formation of mixed anhydride (>90% complete). A solution of (S)-1 (100 g, 0.38 mole) in toluene (400 mL) and tetra hydro furan (220 mL) was added while keeping the reaction temperature below 5 C. This was followed by addition of a solution of 4-dimethylaminopyridine (5.5 g, 0.046 mole) in THF (45 mL). The mixture was agitated at about 0 C. for 8-12 hours until reaction completion (<0.2% (S)-23 remained). The reaction was quenched by adding a solution of 2.0 NH2SO4 (400 mL), warmed up to 25 C. and filtered through a pad of celite. The layers were separated and the organic layer was washed with 5% K2CO3 solution (3×300 mL) to remove excess 2 (<1% remained). The mixture was washed with 5% NaCl solution (300 mL), filtered through a pad of celite, and concentrated to about 500 mL final volume. Solution yield 90-95%. 1H NMR (CDCl3, 400 MHz) delta 7.05-7.35 (m, 11H), 6.13 (br, 1H), 5.62 (dd, J=16, 4 Hz, 1H), 5.31 (q, J=7 Hz, 1H), 4.67 (m, 1H), 2.62-2.78 (m, 2H), 2.58 (br, 2H), 2.05 (m, 2H), 1.22 (d, J=7 Hz, 3H).

Reference： [1]Patent: WO2006/76415,2006,A2 .Location in patent: Page/Page column 38-39
[2]Patent: US2008/85923,2008,A1 .Location in patent: Page/Page column 30

3
[ 900186-75-6 ]
[ 141-82-2 ]
[ 899809-64-4 ]

Yield	Reaction Conditions	Operation in experiment
60%		To a solution of S-nitro-cyclohex-l-enecarbaldehyde (18g, 0.116 mol) in pyridine (36 ml) was added malonic acid (41 g, 0.394 mol). The resulting suspension was heated to 60 0C for about 7 hours. After cooling to a temperature between 150C and 200C, 6N HCl (72 ml) was slowly added into the reaction mixture to adjust the pH to between 1.5 and 2 while maintaining the temperature between 200C and 250C. The mixture was then extracted with methylene chloride three times (1X180 ml, 2X90 ml). The combined extracts were washed with IN HCl (48 ml), water (48 ml) and concentrated to a volume of 36 ml. The concentrate suspension was cooled to O0C and 50C for 1 hour. Light yellow solid was obtained after filtration and drying under vacuum. Yield: 1Og, 60%. Mp 158-160 0C. IHNMR (400 MHz, DMSOd5): delta 2.10 - 2.33 (m, 4H), 2.73 (m, 2H), 4.96 (m, IH), 5.83 (d, J = 20 Hz, IH), 6.28 (s, IH), 7.27 (d, J = 20 Hz, IH), 12.3 (s, IH).

Reference： [1]Patent: WO2006/76415,2006,A2 .Location in patent: Page/Page column 35

4
C₁₂H₁₆N₂O₄ [ No CAS ]
[ 18350-46-4 ]
[ 899809-64-4 ]
C₁₈H₂₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	CHIRAZYME L-9; In tert-butyl methyl ether; at 35℃; for 96h;Enzymatic reaction; Resolution of racemate;	The coupling was carried out by the scheme outlined in Example 12. In the coupling, 2.52 g of (VIIId), 4.31 g of (DIb), and 1.2 g of chirazyme L-9 were mixed in 75 ml of dry TBME. The reaction was agitated at 35 0C. After 96 h, the conversion reached 95.4%, giving approximately 70% of the product (Ie), and 30% of the corresponding acid (VIIc). To remove the remaining (IHb), 50 ml iPrOAc and 4.3 g of SO3-Pyr in 5 ml DMF were added to the mixture. The agitation was continued for 2 h to complete the sulfonation. The insoluble was then removed by filtration. The organic solution was washed with 5% acetic acid, 8% KHCO3, and brine, 150 ml each. After concentration, the crude oil (2.6 g) was purified over a silica gel column. It gave 2.15 g product (Ie) in >99% purity. NMR analysis indicated that the product was a mixture of two diastereomers. The ee with the respect of (IHb) moiety was determined to be 98.1% for R enantiomer.

Reference： [1]Patent: WO2006/76565,2006,A2 .Location in patent: Page/Page column 42-44

5
[ 226915-53-3 ]
[ 899809-64-4 ]
[ 900186-79-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pivaloyl chloride; triethylamine;dmap; In toluene; at 0 - 5℃; for 18h;	To a flask under nitrogen were added 1.48g of nitro acid 6 and 9 ml of toluene. To this mixture was added dropwise 2.4 ml of Et3N to dissolve all solid. To the cooled mixture at between 0 and 5 0C were added 0.9 ml of pivaloyl chloride and 30mg of 4-dimethylaminopyridine (DMAP). The resulting mixture was stirred at between 0 and 50C for 18 hrs. The reaction mixture was poured into 10 ml of water. The layers were separated and the organic layer was washed with NaHCCb and water and concentrated under reduced pressure. The residue was chromatographed EPO <DP n="53"/>on a silica gel column, eluting with Hexane/EtOAc to give 1.56g of 19a (81%). 1H NMR (CDCl3) delta 7.45-7.31 (m, 6H), 6.28-6.18 (m, IH), 5.81 (d, J = 15.9 Hz, IH)3 5.62 (q, J = 6.8 Hz, IH), 5.20 (s, 2H), 4.78-4.68 (m, IH), 3.88-3.70 (m, 2H), 2.52-2.15 (m, 4H), 1.57 (d, J = 6.8 Hz, 3H).

Reference： [1]Patent: WO2006/76415,2006,A2 .Location in patent: Page/Page column 50-51

6
[ 900186-90-5 ]
[ 899809-64-4 ]

Yield	Reaction Conditions	Operation in experiment
76.5%		To a solution of 10 (67 g, 432 mmol) in 1 L of methanol at 0 0C was added 144.4 g (432 mmol) of the Wittig reagent. The resulting mixture was agitated at 0 0C for 3 hrs. The solvent was removed under reduced pressure. The residue was extracted with MeOBu -t twice. The extract was filtered to remove any solid, washed with brine, and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate (10/ 1) to give 9.2 g cis and 55.1 g (60.4%) trans product. 1H NMR (CDCl3) d 7.31 (d, J = 11.3 Hz, IH), 6.18 (m, IH), 5.84 (d, J = 15.9 Hz, IH), 4.74-4.68 (m, IH), 3.76 (s, 3H), 2.81-2.74 (m, 2H), 2.50-2.04 (m, 4H).Next, to a flask were added 2.1 g of the methyl ester, 9.6 ml of MeOH and 2.4 ml of water. To the mixture at about 5 0C was added dropwise 0.96 ml of 50% NaOH. The mixture was allowed to warm to room temperature and stirred at this temperature for about 24 hrs. The reaction mixture was neutralized with HOAc to pH between 4 and 5 and the methanol was removed under reduced pressure. The residue was extracted with 3 X 50 ml EtOAc. The EtOAc layer was concentrated to EPO <DP n="39"/>give 1.5 g of nitroacid 6 (76.5%).

Reference： [1]Patent: WO2006/76415,2006,A2 .Location in patent: Page/Page column 35-37

7
[ 899809-64-4 ]
(x)C₄H₆O₅*C₁₁H₁₇NO₂ [ No CAS ]