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Product Details of [ 1440-61-5 ]

CAS No. :1440-61-5 MDL No. :MFCD00721939
Formula : C6H10ClNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :YMQRPXBBBOXHNZ-UHFFFAOYSA-N
M.W :163.60 Pubchem ID :74040
Synonyms :

Calculated chemistry of [ 1440-61-5 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.73
TPSA : 29.54 Ų

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) : -7.72 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.54
Log Po/w (XLOGP3) : -0.6
Log Po/w (WLOGP) : -0.3
Log Po/w (MLOGP) : -0.05
Log Po/w (SILICOS-IT) : 1.17
Consensus Log Po/w : 0.35

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.34
Solubility : 74.0 mg/ml ; 0.453 mol/l
Class : Very soluble
Log S (Ali) : 0.45
Solubility : 462.0 mg/ml ; 2.83 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -1.03
Solubility : 15.4 mg/ml ; 0.0942 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.74

Safety of [ 1440-61-5 ]

Signal Word:Danger Class:8
Precautionary Statements:P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P332+P313-P362-P403+P233-P405-P501 UN#:3265
Hazard Statements:H302-H315-H318-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1440-61-5 ]

* 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 [ 1440-61-5 ]
  • Downstream synthetic route of [ 1440-61-5 ]

[ 1440-61-5 ] Synthesis Path-Upstream   1~10

  • 1
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  • [ 79-04-9 ]
  • [ 1440-61-5 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In toluene at 60℃; for 2 h; Step 1
A toluene (30 mL) solution of morpholine (1.00 mL, 11.5 mmol) was added with potassium carbonate (3.17 g, 22.9 mmol) and chloroacetyl chloride (0.91 mL, 11.4 mmol), followed by stirring at 60°C for 2 hours.
The reaction mixture was filtered and the filtrate was concentrated to obtain N-chloroacetylmorpholine (1.87 g, quantitative yield).
1H-NMR (270 MHz, CDCl3) δ 3.51-3.54 (m, 2H), 3.62-3.65 (m, 2H), 3.68-3.74 (m, 4H), 4.07 (s, 2H).
100%
Stage #1: With triethylamine In dichloromethane at 0 - 27℃; for 2 h;
Stage #2: With hydrogenchloride In dichloromethane; water
Chloroacetyl chloride (840 mg, 6.89 mmol) was added to a solution of morpholine (500 mg, 5.74 mmol) in anhydrous CH2CI2 (25 ml_) containing Et3N (1 .74 g, 17.22 mmol) at 0 °C. The mixture was stirred and warmed to 27 °C for 2 h. The mixture was washed with 1 M HCI(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give 2-chloro-1 -morpholinoethanone (1 .13 g, 100percent yield). C6HnCINO2; brown oil; 1H NMR (400 MHz, CDCI3) δ 4.05 (2 H, s), 3.69 (4 H, m), 3.62 (2 H, m), 3.52 (4 H, m); 13C NMR (100 MHz, CDCI3) δ 164.4, 66.5, 66.4, 46.8, 42.5, 40.8; ESI-HRMS calcd for C6Hi2CIN02: 164.0478, found: m/z164.0478 [M + H]+.
99% With triethylamine In dichloromethane at 0 - 20℃; for 6 h; To a solution of morpholine (14a; 4.50 mL, 51.45 mmol) and triethylamine (7.90 mL, 56.68 mmol) in CH2Cl2 (80 mL) was slowly added 2-chloroacetyl chloride (6a; 3.70 mL, 46.45 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h, and then diluted with CH2Cl2, washed with saturated NaHCO3 and brine, dried over MgSO4 and filtered. The residue was concentrated under reduced pressure to afford -chloroamide 15aa (7.55 g, 99percent) as a light yellow liquid: 1H-NMR(CDCl3) δ 3.54 (t, J = 4.5 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H), 3.70–3.74 (m, 4H), 4.07 (s, 2H); 13C-NMR(CDCl3) δ 40.7, 42.5, 46.8, 66.6, 66.7, 165.3; LC-MS (ESI) m/z 164 ([M + 1]+).
96% With triethylamine In dichloromethane at 25℃; for 1 h; To a solution of 2-chloroacetyl chloride (1.0 g, 8.8 mmol) and morpholine (771 mg, 8.85 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.34 g, 13.3 mmol). The reaction was stirred at25 00 for 1 h then concentrated and purified by column chromatography (silica gel, 30percent ethyl acetate/petroleum ether) to give 2-chloro-1-morpholinoethanone (1.1 g, 96percent) asyellow oil. 1H NMR (400 MHz, ODd3) O [ppm] 4.07 (5, 2H), 3.72 (td, J = 4.9,10.0 Hz, 4H), 3.67 - 3.60 (m, 2H), 3.59 - 3.48 (m, 2H).
87% for 2 h; Inert atmosphere; Cooling with ice The precursor, 2-chloro-1-morpholinoethanone was prepared by modified literature report [19] (see Scheme 1 ). 12.35 g (0.143 mol) of morpholine, diluted with 60 mL of diethyl ether was taken into two necked round bottomed flask. To that 8 g (0.072 mol) of chloroacetyl chloride diluted with 20 mL of diethyl ether was added drop wise at ice cooled condition under nitrogen atmosphere. The reaction mixture was stirred for 2 h. The reaction mixture was filtered to remove the white precipitate of morpholine hydrochloride salt and then diluted with 100 mL of ice cold water. The organic layer was separated and the solvent was removed under reduced pressure to afford a viscous yellow liquid. The compound was further dried under high vacuum and subjected to various spectroscopic analyses. The characteristic peaks were compared with the literature values. The isolated yield of the compound was about 87percent. IR (cm-1): 1633.71 (C=O). 1H NMR (400 MHz, CDCl3): δ = 3.46-3.48 (t, N-CH2, 4H), 3.62 (m, O-CH2, 4H), 4.013 (s, C-CH2-Cl, 2H) ppm. 13CNMR (δ, 100 MHz, CDCl3): 40.55, 42.5, 46.73, 66.6, 165.4. Mass (EI, m/z): 163.17 (observed) (calculated: 163.6). A similar procedure was followed for the synthesis of 2-chloro-N,N-diethylacetamide (see Scheme 2 ).
78% at -78 - 20℃; for 3 h; PREPARATION 40; N-chloroacetyl-morpholine; To a solution of chloroacetyl chloride (2.0 mL, 2.5 mmol) in 20 mL CH2CI2 was slowly added a solution of morpholine (2.2 mL, 5.0 mmol) in 20 mL CH2CI2 at-78 °C. The reaction mixture was warmed to rt and stirred for 3 h. A white suspension solution resulted. The white precipitate was filtered off. The filtrate was washed with 1 N HCI, dried over sodium sulphate and concentrated to give the title compound (3.11 g, 78 percent) as colorless oil. 1H NMR (400 MHz, CDCI3) No. 4.12 (s, 2 H), 3.74 (br s, 4 H), 3.61 (br s, 2 H), 3.50 (br s, 2 H). MS m/z 164 [M+1].
76% With triethylamine In dichloromethane at 0 - 20℃; for 0.75 h; d) 2-Chloro- 1 -morpoholin-4-yl-ethanone; A solution of morpholine (0.50 g, 5.7 mmol) in CH2Cl2 (10 mL) was treated with Et3N and cooled to 0 0C. The mixture was treated with chloroacetyl chloride (0.50 mL, 6.3 mmol) as a solution in CH2Cl2 (2 mL). The reaction was stirred at 0 °C for 15 min and then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.72 g, 76 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 4.06 (s, 2H), 3.73-7.67 (m, 4H), 3.62 (app t, 2H, J = 4.0 Hz), 3.52 (app t, 2H, J = 4.0 Hz).
76.6% With triethylamine In tetrahydrofuran Reference Example 116
Triethylamine (4.5 g, 44.5 mmol) was added to a tetrahydrofuran solution (60mL) of morpholine (3g, 32. 7 mmol), and a tetrahydrofuran solution (20 mL) of chloroacetyl chloride (3.9 g, 34.5 mmol) was added dropwise, gradually while the solution was ice-water-cooled.
Ether was added to the residue; the precipitated triethylamine hydrochloride was removed by filtration; and the filtrate was concentrated under reduced pressure.
The residue obtained was purified by distillation under reduced pressure (10 mm Hg, 110 to 112°C), to obtain 4-(chloroacetyl)morpholine (4.1 g, 76.6percent) as a pale yellow oil.
1H-NMR(CDCl3)δ:3.50-3.79(8H,m),4.07(2H,s)ppm
69.2% With triethylamine In dichloromethane for 4 h; To a stirred solution of morpholine (17.4 g,200 mmol) and triethylamine (24.24 g, 220 mmol) in CH2Cl2 (200 mL), acetyl chloride (24.00 g, 210mmol) in CH2Cl2 (volume) was added dropwise. The resulting reaction mixture was stirred at this temperature for a further 4 h, then poured into water, and the aqueous layer extracted twice with methylene chloride. The organic chloride phase was combined, washed with dilute hydrochloric acid and water, and dried over Na2SO4, and evaporated to dryness to give compound 20 (22.66 g, 69.2percentyield) as a pale yellow oil.
68% at 20℃; for 1 h; [0170] To morpholine (466 mg, 5.36 mmol) in DCM (13.4 mL) at 0 °C, was added 2- chloroacetyl chloride (300 mg, 2.68 mmol) in DCM. The mixture was then stirred at r.t. for 1 h. The precipitate was filtered and the filtrate was concentrated to provide the title compound as an oil (300 mg, 68percent). MS (ES+) m/e 164 (M+H)+.
64% With triethylamine In tetrahydrofuran at 0℃; for 0.333333 h; ;4-(Chloroacetyl)morpholine
To a solution of morpholine (3.6 mL, 41 mmol) and triethylamine (5.2 g, 51 mmol) in tetrahydrofuran (100 mL) was added chloroacetyl chloride (3.0 mL, 38 mmol) at 0°C, and the mixture was stirred at 0°C for 20 minutes.
The reaction solution was concentrated and ethyl acetate was added thereto.
The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate.
The solid was filtered off, and the filtrate was concentrated to obtain the title compound (4.0 g, yield 64percent) as an oily matter.
1H NMR (CDCl3) δ 3.52-3.55 (2H, m), 3.62-3.65 (2H, m), 3.69-3.75 (4H, m), 4.07 (2H, s).
64% With potassium carbonate In toluene at 60℃; for 2.5 h; 0.45 mL of chloroacetyl chloride (5.78 mmol, 1.0 eq) was added to a suspension of 0.5 mL of morpholine (5.78mmol, 1.0 eq), 1.60 g of potassium carbonate (11.57 mmol, 2.0 eq) in 15 mL of abs. toluene. The mixture was stirred at 60 °C for 2.5 hours. The suspension was filtered and the solvent was removed under reduced pressure to give 0.78 g (64percent) of a yellow oil.
50% With triethylamine In dichloromethane for 1 h; Cooling with ice Take 870 microliters morpholine in 50ml round bottom flask, add 20ml methylene chloride to make it dissolve, slowly add 820 microliters chloroacetyl chloride slowly under ice-water bath, and slowly add 1.4ml triethylamine slowly, continue stirring 1 hour. The reaction was diluted with water and extracted three times with dichloromethane (15 ml each). The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 827 mg of intermediate A19 in a yield of 50percent
76% With triethylamine In ethyl acetate Preparation 24
4-(Chloroacetyl)morpholine [BM.1]
To a stirring mixture of morpholine (1.00 g) and triethylamine (1.6 mL) in EtOAc (10 mL) at 0° C. is added chloroacetyl chloride (1.83 mL) dropwise.
The mixture is stirred at 0° C. for 35 min., diluted with 10percent HCl (25 mL) and extracted with EtOAc (3*50 mL).
The organic layer is dried over MgSO4, and the solvent removed.
The residue is purified by SiO2 flash column chromatography (eluent 35percent EtOAc/hexane) to afford 1.42 g (76percent) of the title compound as a yellow liquid.
Physical characteristics: 1H NMR (CDCl3) δ 3.54, 3.64, 3.72, 4.07; IR (liq.) 2859, 1654, 1463, 1438, 1302, 1270, 1251, 1233, 1115, 1069, 1040, 965, 790, 657, 604 cm-1; MS (ESI+) m/z 164 (M+H)+. Anal. Found: C, 43.66; H, 6.17; N, 8.58.
46.69 g With triethylamine In dichloromethane at -10 - 20℃; for 3 h; To a solution of chloroacetyl chloride (25 ml) in dry dichloromethane (125 ml) at -10°C was added dropwise a solution of morpholine (30 ml) and triethylamine (47.5 ml) in dry dichloromethane (125 ml) over approximately two hours keeping the internal temperature below 20°C. After addition, the reaction mixture was stirred for one hour then the reaction mixture was washed with 0.5N aqueous hydrochloric acid (200 ml) and water (2 x 200 ml). The combined aqueous was back extracted with dichloromethane (2 x 150 ml); the organic layers were combined, dried (MgS04) and evaporated to afford the title compound (46.69 g) as a brown oil. 1H-NMR (400 MHz, CDC13) δ (ppm): 3.49 - 3.57 (m, 2 H) 3.58 - 3.66 (m, 2 H) 3.71 (dt, J=9.84, 4.86 Hz, 4 H) 4.06 (s, 2 H)

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YieldReaction ConditionsOperation in experiment
95% at 20℃; for 1 h; In a round-bottom flask containing 243 10 mL of chloroform was added morpholine (1 eq.), followed by chloroacetic anhydride 244 (1 eq.) in an ice bath. The reaction mixture was kept under magnetic stirring for one hour at room temperature. The solvent was removed under reduced pressure and the resulting 246 oil was diluted in 20 mL of AcOEt and washed with 15 mL of a saturated solution of 247 NaHCO3. The organic layer was dried with anhydrous magnesium sulfate and the solvent 248 was removed under reduced pressure to yield 4-(chloroacetyl)morpholine 17 as a yellow 249 oil, 95percent yield; IR (neat, cm-1) 1642, 1110; 1H NMR (200 MHz, CDCl3) δ 4.05 (s, 2H), 250 3.76 – 3.65 (m, 4H), 3.65 – 3.57 (m, 2H), 3.56 – 3.47 (m, 2H); 13C NMR (CDCl3, 50 251 MHz) δ 165.2, 66.5, 46.7, 42.4, 40.5.
Reference: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 6, p. 1889 - 1900
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Reference: [1] Patent: US2003/130235, 2003, A1,
[2] Patent: US5707991, 1998, A,
  • 4
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YieldReaction ConditionsOperation in experiment
28.8% With triethylamine In dichloromethane Preparation of 4-(2-chloroacetyl)morpholine
To an ice cold solution of chloroacetyl chloride (1.29 g, 11 mmol) in 10 mL of methylene chloride was added morpholine (1 g, 11 mmol) in 10 mL of methylene chloride containing triethylamine (2.32 g, 23 mmol).
The reaction mixture was stirred at 5° C. for 30 minutes then warmed to room temperature and stirred for 18 hours.
After quenching with water (20 mL) at 5° C., additional methylene chloride (100 mL) was added.
The organic layer was separated, washed with 1N HCl (1*50 mL), saturated aqueous NaHCO3 (1*50 mL), brine (1*50 mL), dried over MgSO4, filtered and concentrated at reduced pressure.
The concentrated residue was dried in vacuo to give 0.52 g (28.8percent) of 4-(2-chloroacetyl)morpholine as a brown oil. 1 H NMR (300 MHz / CDCl3): δ 3.51-3.54 (m, 2H), 3.61-3.64 (m, 2H), 3.68-3.74 (m, 4H), 4.06 (s, 2H). HRMS: calcd for C6 H10 N1 O2 Cl1 164.0478, found 164.0498.
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  • 10
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  • [ 348-57-2 ]
  • [ 51336-94-8 ]
YieldReaction ConditionsOperation in experiment
96.5%
Stage #1: With magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Inert atmosphere
Stage #2: at 40℃; for 2 h;
Prepare a dry, clean 1000mL glass four-port bottle, equipped with a suitable mechanical stirrer, condensing tube and thermometer, check the airtightness before feeding, and add 96.5g to the reaction flask under N2 protection. 2,4-Difluorobromobenzene (0.5mol, 1.0eq),25.5 g (0.525 mol, 1.05 eq) of magnesium bar, 500 mL of tetrahydrofuran, stirring was started, the temperature of the reaction solution was raised to 30-35° C., and the reaction was stirred for 2 h. After the reaction was completed, the reaction solution was slowly added dropwise 163.6 g (1.0 mol). , 2.0 eq.) of 4-(2-chloroacetyl)morpholine (Compound 4) in tetrahydrofuran (163.6 g dissolved in 360 ml of tetrahydrofuran), the temperature controlled during the additionAt 40°C, after the addition is complete, continue incubation at 40°C for 2 hours. After the reaction was completed, the reaction system was quenched with 100 mL of saturated ammonium chloride solution. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and then 500 mL of ethyl acetate was added for extraction. The separated ethyl acetate phase was washed with 300 mL of water and the organic phase was organic. It was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 92.0 g of compound 5 (yield: 96.5percent).
Reference: [1] Patent: CN107746388, 2018, A, . Location in patent: Paragraph 0028; 0030; 0032; 0033; 0034; 0036; 0038; 0040
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[ 2675-89-0 ]

2-Chloro-N,N-dimethylacetamide

Similarity: 0.71

Chemical Structure| 2895-21-8

[ 2895-21-8 ]

N-Isopropyl-2-chloroacetamide

Similarity: 0.64

Chemical Structure| 1440-60-4

[ 1440-60-4 ]

2-Chloro-1-(piperidin-1-yl)ethanone

Similarity: 0.63

Chemical Structure| 96-30-0

[ 96-30-0 ]

2-Chloro-N-methylacetamide

Similarity: 0.62

Amides

Chemical Structure| 1696-20-4

[ 1696-20-4 ]

1-Morpholinoethanone

Similarity: 0.82

Chemical Structure| 51068-78-1

[ 51068-78-1 ]

2-Hydroxy-1-morpholinoethanone

Similarity: 0.78

Chemical Structure| 2675-89-0

[ 2675-89-0 ]

2-Chloro-N,N-dimethylacetamide

Similarity: 0.71

Chemical Structure| 40299-87-4

[ 40299-87-4 ]

2-Bromo-1-morpholinoethanone

Similarity: 0.68

Chemical Structure| 109-11-5

[ 109-11-5 ]

Morpholin-3-one

Similarity: 0.68

Related Parent Nucleus of
[ 1440-61-5 ]

Aliphatic Heterocycles

Chemical Structure| 1696-20-4

[ 1696-20-4 ]

1-Morpholinoethanone

Similarity: 0.82

Chemical Structure| 51068-78-1

[ 51068-78-1 ]

2-Hydroxy-1-morpholinoethanone

Similarity: 0.78

Chemical Structure| 4394-85-8

[ 4394-85-8 ]

Morpholine-4-carbaldehyde

Similarity: 0.74

Chemical Structure| 109-11-5

[ 109-11-5 ]

Morpholin-3-one

Similarity: 0.68

Chemical Structure| 119844-67-6

[ 119844-67-6 ]

(R)-5-Methylmorpholin-3-one

Similarity: 0.61

Morpholines

Chemical Structure| 1696-20-4

[ 1696-20-4 ]

1-Morpholinoethanone

Similarity: 0.82

Chemical Structure| 51068-78-1

[ 51068-78-1 ]

2-Hydroxy-1-morpholinoethanone

Similarity: 0.78

Chemical Structure| 4394-85-8

[ 4394-85-8 ]

Morpholine-4-carbaldehyde

Similarity: 0.74

Chemical Structure| 3647-69-6

[ 3647-69-6 ]

4-(2-Chloroethyl)morpholine hydrochloride

Similarity: 0.71

Chemical Structure| 40299-87-4

[ 40299-87-4 ]

2-Bromo-1-morpholinoethanone

Similarity: 0.68