| 73% |
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine at 20℃; for 18h; Inert atmosphere;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 2℃; for 2h; |
1.A Step A. 4-Benzylmorpholine-2-carbonitrile.
Step A. 4-Benzylmorpholine-2-carbonitrile. 2-(Benzylamino)ethanol (46 g, 304 mmol) and 2-chloroacrylonitrile (26.5 g, 304 mmol) were stirred at rt for 18 h. THF (300 mL) was added followed by t-BuOK (38.9 g, 330 mmol) protionwise over 1 h, keeping the reaction temperature at < 2 C. After 1 h post-stirring at 0 °C, the mixture was quenched with sat. aq. NaHC03. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure. Purification (FCC, Si02, (PE/EtOAc = 5/1) provided the title compound (45 g, 73%) as an oil. 1H NMR (CDC13, 400 MHz) δ 7.36-7.27 (m, 5H), 4.63-4.60 (m, 1H), 4.15-4.00 (m, 1H), 3.82-3.75 (m, 1H), 3.64- 3.53 (m, 2H), 2.80-2.75 (m, 1H), 2.67-2.54(m, 2H), 2.46-2.39 (m, 1H). |
| 70% |
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 12h;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran; toluene at -5℃; for 0.833333h; |
1.1
In a 1L flask, 2-chloroacrylonitrile (39.6 g, 453 mmol) was dissolved in toluene (105ml). In another vessel, N-benzylethanolamine (66.5 g, 440 mmol) was dissolved in toluene (35 ml), and this solution was added to the above mentioned 1L flask. The resultant mixture was stirred for 12 hours at room temperature, further added with toluene (205 ml), and cooled to -5. Then, the mixture was slowly added with t-BuOK (50.84g, 444 mmol) dissolved in THF (202 ml). The resultant mixture was stirred for 50 minutes while the temperature was maintained at -5. The resultant mixture was washed with salt water once, and dried and filtered with MgSO4. After the solvent was removed by vacuum distillation, through column chromatography, 4-benzylmorpholine-2-carbonitrile compound (64.1 g, 316.9 mmol, 70 %) was obtained.[104] 1H NMR (400 MHz, CDCl3) δ7.39-7.28 (m, 5H), 4.62 (t, J = 3.6 Hz, 1H), 4.05 (m, 1H), 3.79 (dt, J = 3.6, 11.6 Hz, 1H), 3.59 (dd, J = 9.2, 25.2 Hz, 2H), 2.78 (dd, J = 3.6, 12.0 Hz, 1H), 2.66 (m, 1H), 2.58 (dd, J = 3.6, 12.0 Hz, 1H), 2.43 (m, 1H). |
| 65% |
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine at 0 - 29℃;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at -5 - 2℃; for 2h; |
8.2.i
A one-liter reactor with mechanical stirring, cooled by ice bath, was charged with [N-BENZYLETHANOLAMINE] (172.2 g, 1.14 mol). [2-CHLOROACRYLONITRILE] [(LOOG,] 1.14 mol) was added dropwise over a period of 2 minutes. The temperature was kept between [23°C] and [29°C] using an ice bath, progressively replaced by a water bath at [15°C.] After stirring at room temperature over night the mixture was dissolved in THF and transferred into a 21 reactor cooled to-5°C by an ice/NaCl bath. The total volume of THF equalled 1.351. Potassium tert-butoxide [(148G,] 1.1 eq. ) was added in portions over lhour, while maintaining the temperature at [02°C.] After 1 hour stirring at [0°C] the mixture was quenched by saturated [NAHC03] [(500ML).] The aqueous layer was extracted with diethyl ether. The organic layers were dried over MgS04 and evaporated to dryness. After percolation of the 250 g dry residue on 1 kg [SI02] (eluent: ethyl acetate/n-heptane gradient 5/95 to 80/100 [v/v] ) 4-benzyl-morpholine-2-carbonitrile was obtained as a clear oil (149.8g, 65%). |
| 65% |
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine at 0 - 29℃; Neat (no solvent); Cooling with water bath;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at -5 - 0℃; for 2h; Cooling with ice/NaCl bath;
Stage #3: With water; sodium hydrogencarbonate In tetrahydrofuran at 0℃; |
Preparation of Intermediates for the Synthesis of Examples 1-32 4-Benzyl-morpholine-2-carbonitrile; A one-litre reactor with mechanical stirring, cooled by an ice bath, is charged with N-benzylethanolamine (172.2 g; 1 equiv. available from Aldrich Chemical Company). 2- Chloroacrylonitrile (100 g; 1 equiv. available from Aldrich Chemical Company) is added dropwise over 2 minutes. The temperature is maintained between 23 °C and 29 °C by means of the ice bath and subsequently a water bath at 15 °C. After one night stirring at room temperature (water bath), the mixture is dissolved in tetrahydrofuran and transferred to a 2 L reactor which is cooled to-5 °C by ice/NaCl bath. The total volume of tetrahydrofuran is 1.35 L. Potassium tert-butoxide (148 g; 1.1 equiv. ) is added by portions over 1 hour, keeping the reaction temperature at 02 °C. After 1 hour post-stirring at 0 °C, the mixture is quenched with saturated NaHCO3 (500 mL). The aqueous layer is extracted with diethyl ether (500 mL). Organic layers are dried over MgSO4 and evaporated to dryness. The title compound (149. 8 g; 65%) is obtained after percolation of the 250 g dry residue on 1 kg of Si02, eluting with the following gradient: 5% AcOEt-95% n-heptane 2.5 L 10% AcOEt-90% n-heptane 2 L 15% AcOEt-85% n-heptane 2 L 20% AcOEt-80% n-heptane 5 L |
| 65% |
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine at 0 - 29℃;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 2h; |
A one-litre reactor with mechanical stirring, cooled by an ice bath, is charged with N-benzylethanolamine (172.2 g; 1 equiv. available from Aldrich Chemical Company). 2- Chloroacrylonitrile (100 g ; 1 equiv. available from Aldrich Chemical Company) is added dropwise over 2 minutes. The temperature is maintained between 23 °C and 29 °C by means of the ice bath and subsequently a water bath at 15 °C. After one night stirring at room temperature (water bath), the mixture is dissolved in tetrahydrofuran and transferred to a 2 L reactor which is cooled to-5 °C by ice/NaCl bath. The total volume of tetrahydrofuran is 1. 35 L. Potassium tert-butoxide (148 g ; 1.1 equiv. ) is added by portions over 1 hour, keeping the reaction temperature at 02 °C. After 1 hour post-stirring at 0 °C, the mixture is quenched with saturated NaHCO3 (500 mL). The aqueous layer is extracted with diethyl ether (500 mL). Organic layers are dried over MgS04 and evaporated to dryness. The title compound (149.8 g ; 65%) is obtained after percolation of the 250 g dry residue on 1 kg of Si02, eluting with the following gradient: 5% AcOEt-95% n-heptane 2.5 L 10% AcOEt-90% n-heptane 2 L 15% AcOEt-85% n-heptane 2 L 20% AcOEt-80% n-heptane 5 L |
|
With potassium <i>tert</i>-butylate Yield given. Multistep reaction; |
|
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 17h;
Stage #2: With potassium <i>tert</i>-butylate In toluene at 0℃; for 2.5h; |
Preparation of Intermediates (2S)- (4-BENZYL-MORPHOLIN-2-YL)-PHENYL-METHANONE (1) A 1600 L GL reactor under N2 is successively loaded with 2-CHLOROACRYLONITRILE (33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) is added and the reaction mixture is post-agitated at room temperature for about 17 h. Then, the mixture is diluted with toluene (336 L), cooled down to-12. 4 °C and potassium t-butoxide (42.3 kg, 377 moles) is added in portions (10) maintaining-13. 7 °C < Tmass |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 17h;
Stage #2: With potassium <i>tert</i>-butylate In toluene at -13.7 - 0℃; for 2.5h; |
A 1600 L GL reactor under N2 is successively loaded with 2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) is added and the reaction mixture is post-agitated at room temperature for about 17 h. Then, the mixture is diluted with toluene (336 L), cooled down to-12. 4 °C and potassium t-butoxide (42.3 kg, 377 moles) is added in portions (10) maintaining-13.7 °C < Tmass |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In diethyl ether at 40℃;
Stage #2: With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane Heating; Further stages.; |
|
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine at 20℃; for 24h;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1h; |
3.3-1
A mixture of N-benzylethanolamine (intermediate 23, 44.8 ml, 314 mmol) and 2-chloroacrylonitrile (intermediate 24, 25 ml, 314 mmol) was stirred at room temperature for 24 hours. After the mixture was cooled to O C, tetrahydrofuran (300 ml)and then potassium fertf-butoxide was added to the mixture, and the mixture was stirred at O C for one hour. The mixture was diluted by ethyl ether, and then washed with water and brine and dried over magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; 5% ethyl acetate in hexane) to afford 4"benzylmorpholine-2-carbonitrile (intermediate 25) as colorless oil. iH NMR (400 MHz, CDCl3) ? : 2.4l(lH, ddd, J=3.1, 8.8, 11.8 Hz), 2.56(lH, dd, J=3.2, 11.9 Hz), 2.64(1H, d, J=11.8 Hz), 2.76(1H, dd, J=3.8, 11.8 Hz), 3.57(2H, q, J=12.9 Hz), 3.77(1H, dt, J=3.6, 11.7 Hz), 4.03(1H, ddd, J=2.7, 8.9, 11.7 Hz), 4.6O(1H, t, J=3.6 Hz), 7.26-7.36(5H, m) MS: [MH-H]+ = 203 |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine at 20℃; for 24h;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1h; |
3.3-1
A mixture of N-benzylethanolamine (intermediate 23, 44.8 ml, 314 mmol) and 2'chloroacrylonitrile (intermediate 24, 25 ml, 314 mmol) was stirred at room temperature for 24 hours. After the mixture was cooled to 0 0C, tetrahydrofuran (300 ml)and then potassium fer^-butoxide was added to the mixture, and the mixture was stirred at 0 0C for one hour. The mixture was diluted by ethyl ether, and then washed with water and brine and dried over magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; 5% ethyl acetate in hexane) to afford 4-benzylmorpholine-2-carbonitrile (intermediate 25) as colorless oil. 1H NMR (400 MHz, CDCl3) δ : 2.4l(lH, ddd, J=3.1, 8.8, 11.8 Hz), 2.56(lH, dd, J=3.2, 11.9 Hz), 2.64(1H, d, J=11.8 Hz), 2.76(lH, dd, J=3.8, 11.8 Hz), 3.57(2H, q, J=12.9 Hz), 3.77(1H, dt, J=3.6, 11.7 Hz), 4.03(lH, ddd, J=2.7, 8.9, 11.7 Hz), 4.60(lH, t, J=3.6 Hz), 7.26-7.36(5H, m) MS: [M+H]+ = 203 |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20 - 21℃; for 17h;
Stage #2: With potassium <i>tert</i>-butylate In toluene at -13.7 - 0℃; for 2.5h; |
A 1600 L GL reactor under N2 was successively loaded with 2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) was added and the reaction mixture was post-agitated at room temperature for about 17 h. Then, the mixture was diluted with toluene (336 L), cooled down to-12.4 °C and potassium t-butoxide (42.3 kg, 377 moles) was added in portions (10) maintaining - 13. 7 °C |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 17h;
Stage #2: With potassium <i>tert</i>-butylate In toluene at -13.7 - 0℃; for 2.5h;
Stage #3: With water In toluene at 2.1 - 15℃; for 0.583333h; |
A 1600 L GL reactor under N2 was successively loaded with 2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) was added and the reaction mixture was post-agitated at room temperature for about 17 h. Then, the mixture was diluted with toluene (336 L), cooled down to-12.4 °C and potassium t-butoxide (42. 3 kg, 377 moles) was added in portions (10) maintaining - 13. 7 °C _< Tmass 5-2. 8 OC. The mixture was post-agitated at about 0°C for 2.5 h, quenched by adding ultra pure water (142.5 L) maintaining 2. 1 °C < Tmass No. 8. 7 °C. The aqueous layer (176 kg) was separated after 35 minutes of post-stirring allowing the mixture to reach 15 °C and the toluene layer was washed with ultra pure water (142.5 L) and the aqueous layer (162 kg) was separated. The organic layer was then concentrated under reduced pressure (150 mbars) maintaining Tmass : 60 °C in order to distill 162 kg of toluene. The filtrates were then diluted with toluene (114 L) and treated with Si02 (MERCK silica gel 60,0. 063-0.1 mm, 74.1 kg) under agitation at room temperature for 1.25 h. SI02 was filtered and rinsed with toluene (2X114 L). Then, the filtrates were concentrated under reduced pressure (150 mbars) maintaining Tmass < 60 °C in order to distill 351. 8 kg OF TOLUENE (KF : 0. 01 % w/w H20). The SOLUIONXOF4-BENZYL-MORPHOLINE-2-CARBONITRILE (169.2 kg) was diluted with toluene (157 L) and was cooled to 0°C and phenylmagnesiumchloride (25 wt. % solution in THF, 213 kg, 389 moles, 1.36 molar equiv. ) was slowly added (over 3.5 h) to the reaction mixture, maintaining the temperature AT-3 °C < Tmass < 7 °C. The reaction mixture was post-stirred for 2 hours at Tmass = 0°C. Then, the quench was performed by adding acetic acid (8.55 L, Tmass = 5- 17. 2 °C), post stirring 10 minutes and cooling to 5 °C before adding an acetic acid/water mixture (229 L, 33/67 v/v). During the quench, addition was performed at such a rate that Tmass did not exceed 20°C (typical Tmass = 4. 6 °C to 10. 4 °C). The mixture was post-agitated overnight at RT and the aqueous layer (285. 8 kg) was extracted. The toluene layer was cooled to 0°C and a 5 N NAOH aqueous solution (420.1 kg) was slowly added maintaining the temperature at-2.4 °C < Tmass No. 11 °C. The reaction mixture was post-stirred for lh and the aqueous layer (494.8 kg) was extracted. The toluene layer was concentrated under reduced pressure (50 mbars) maintaining Tmass No. 60 °C in order to distill 356.2 kg of toluene and isopropanol (180. 4 kg) was added. The toluene was stripped off under reduced pressure (100 mbars) maintaining Tmass No. 60 °C in order to distill 186.4 kg of toluene and isopropanol (135 kg) was added again to the mixture. A last distillation of toluene was performed under reduced pressure (50 mbars) maintaining Tmass < 60 °C in order to distill 131 kg of toluene and isopropanol (49.4 kg) was finally added to the mixture and the solution was stirred at RT until crystallization (17 minutes). Ultra pure water was added (125.4 L) and the mixture was stirred overnight at RT and cooled down to about 0 °C for 1 hour. The precipitate was filtered and rinsed with a cooled water/isopropanol 50/50 v/v solution (76.6 kg). The wet precipitate was dried under vacuum at TJACK = 35°C for 96 hours to obtain the title compound as an off-white powder with 59 % overall yield. The title compound can be resolved by the fractional crystallisation process described above. |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 16.0833h;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran; toluene at -5 - 0℃; for 1.5h;
Stage #3: With water In tetrahydrofuran; toluene |
4-Benzyl-morpholine-2-carboxylic acid hydrochloride (91); A 500 mL reactor under N2 is successively loaded with toluene (36. 72 mL) and 2- chloroacrylonitrile (10.7 g, 122.23 mmol) at room temperature. Then, N-benzyl ethanolamine (18. 36 g, 121.14 mmol) is added over 5 min and the reaction mixture is post-agitated at room temperature for 16h. Then, the mixture is diluted with toluene (110.16 mL), cooled to-5°C and 2M potassium tert-butoxide solution in THF (121.14 mmol) is slowly added over 30 min, maintaining the temperature at-5 °C to 0 °C. The mixture is post-agitated at about-5°C to 0°C for lh, then quenched by adding water (45.9 mL). The aqueous layer is separated and the toluene layer is washed with water (45.9 mL) and then the mixture is allowed to warm to room temperature. The organic layer is then concentrated under reduced pressure at 40°C. Then, the mixture is diluted with toluene (100 mL) and extracted with 6N HClaq (162 mL). This aqueous layer is heated up to the reflux for lh30, then the mixture is allowed to stir at room temperature overnight. After crystallization of 91, the solid is filtered, rinsed with 6N HClaq (40 mL) and dried under reduce pressure at 40°C (19 g, yield = 61%). |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20 - 21℃; for 17h;
Stage #2: With potassium <i>tert</i>-butylate In toluene at -13 - 0℃; for 2.5h;
Stage #3: With water In toluene at 2 - 8℃; for 0.583333h; |
Alternatively, this intermediate may be prepared as follows: A 1600 L glass-lined reactor under N2 is successively loaded with 2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) is added and the reaction mixture is post-agitated at room temperature for about 17 h. Then, the mixture is diluted with toluene (336 L), cooled down to about-12 °C and potassium t-butoxide (42.3 kg, 377 moles) is added in portions (10) maintaining about-13 °C < Tmass < about-2 °C. The mixture is post-agitated at about 0°C for 2.5 h, then quenched by adding water (142.5 L) maintaining about 2 °C 5 Tmass < about 8 °C. The aqueous layer is separated after 35 minutes of post-stirring allowing the mixture to reach 15 °C and the toluene layer is washed with water (142.5 L) and the aqueous layer is separated. The organic layer is then concentrated under reduced pressure (150 mbars) maintaining Tmass < 60 °C in order to distill 162 kg of toluene. The filtrates are then diluted with toluene (114 L) and treated with SiOa (Merck silica gel 60,0. 063-0.1 mm, 74.1 kg) under agitation at room temperature for 1.25 h. Si02 is filtered and rinsed with toluene (2x114 L). Then, the filtrates are concentrated under reduced pressure (150 mbars) maintaining Tmass < 60 °C in order to distill 351. 8 kg of toluene |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 17h;
Stage #2: With potassium <i>tert</i>-butylate In toluene at -13.7 - 0℃; for 2.5h; |
A 1600 L GL reactor under N2was successively loaded with 2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21°C. Then, N-benzylethanolamine (57 kg, 377 moles) was added and the reaction mixture was post-agitated at room temperature for about 17 h. Then, the mixture was diluted with toluene (336 L), cooled down to-12.4 °C and potassium t-butoxide (42.3 kg, 377 moles) was added in portions (10) maintaining - 13. 7 °C < Tmass 17. 2'C), post stirring 10 minutes and cooling to 5 °C before adding an acetic acid/water mixture (229 L, 33/67 v/v). During the quench, addition was performed at such a rate that Tmass did not exceed 20°C (typical Tmass = 4. 6 °C to 10. 4 °C). The mixture was post-agitated overnight at RT and the aqueous layer (285.8 kg) was extracted. The toluene layer was cooled to 0°C and a 5 N NaOH aqueous solution (420.1 kg) was slowly added maintaining the temperature at-2. 4 °C Tmass < 11 °C. The reaction mixture was post-stirred for lh and the aqueous layer (494. 8 kg) was extracted. The toluene layer was concentrated under reduced pressure (50 mbars) maintaining Tmass < 60 °C in order to distill 356.2 kg of toluene and isopropanol (180.4 kg) was added. The toluene was stripped off under reduced pressure (100 mbars) maintaining Tmass < 60 °C in order to distill 186.4 kg of toluene and isopropanol (135 kg) was added again to the mixture. A last distillation of toluene was performed under reduced pressure (50 mbars) maintaining Tmass < 60 °C in order to distill 131 kg of toluene and isopropanol (49.4 kg) was finally added to the mixture and the solution was stirred at RT until crystallization (17 minutes). Ultra pure water was added (125.4 L) and the mixture was stirred overnight at RT and cooled down to about 0 °C for 1 hour. The precipitate was filtered and rinsed with a cooled water/isopropanol 50/50 v/v solution (76.6 kg). The wet precipitate was dried under vacuum at Tjack = 35°C for 96 hours to obtain the title compound as an off-white powder with 59 % overall yield. The title compound can be resolved by the fractional crystallisation process described above. |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 25℃; for 16.25h; Inert atmosphere;
Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran; toluene at -5 - 0℃; for 1.5h; |
152
Intermediate 152; 4-(Phenylmethyl)-2-morpholinecarbonitrile; A 500 mL reactor under nitrogen was successively loaded with toluene (50 mL) and 2- chloro-2-propenenitrile (14.26 mL, 179 mmol) at 25 0C, and then 2- [(phenylmethyl)amino]ethanol (25.4 ml_, 179 mmol) was added over 15 minutes. The reaction mixture was post-agitated at 25 0C for 16 hours. The mixture was diluted with toluene (100 ml_), cooled to -5 0C, and potassium tert-butoxide (20.04 g, 179 mmol) in THF (90 ml.) was slowly added over 30 minutes, maintaining the temperature at -5 0C to 0 0C. The mixture was post-agitated at about -5 0C to 0 0C for 1 hour, then quenched by the addition of water (150 ml_), and the mixture was allowed to warm to 25 0C. The aqueous was extracted with EtOAc (4 x 150 ml_), dried (Na2SO4), filtered, and concentrated to afford the title compound (36 g) as a brown solid. LC-MS (ES) m/z = 203 [M+H]+. |
|
Stage #1: 2-Chloroacrylonitrile; N-Benzylethanolamine In toluene at 20℃; for 18h;
Stage #2: With potassium <i>tert</i>-butylate at 0℃; for 3h; |
|
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
