There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 298-12-4 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 7, p. 1427 - 1429
[2] Journal of Agricultural and Food Chemistry, 2002, vol. 50, # 19, p. 5394 - 5399
[3] Journal of Medicinal Chemistry, 1978, vol. 21, # 2, p. 165 - 169
[4] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 10, p. 3247 - 3251
[5] Chemical Communications, 2018, vol. 54, # 12, p. 1501 - 1504
2
[ 60-23-1 ]
[ 298-12-4 ]
[ 16310-13-7 ]
Reference：
[1] Bioconjugate Chemistry, 2017, vol. 28, # 2, p. 325 - 329
[2] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 8, p. 1180 - 1183
[3] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1971, vol. 272, p. 1515 - 1517
[4] Comptes rendus hebdomadaires des séances de l'Académie des sciences, 1963, vol. 256, p. 4114 - 4116
3
[ 79-19-6 ]
[ 298-12-4 ]
[ 626-08-4 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 5, p. 423 - 426
[2] Patent: US5591743, 1997, A,
4
[ 614-96-0 ]
[ 298-12-4 ]
[ 52562-50-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
5
[ 95-54-5 ]
[ 298-12-4 ]
[ 3314-30-5 ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydroxyapatite In water at 52℃; for 6 h;
200 mesh hydroxyapatite powder, 0.008g as catalystUse 52 mL of hot water as solvent,The reaction was carried out with 0.1 mol o-phenylenediamine and 0.11 mol glyoxylic acid as raw materials. The reaction time was 6 hours and the reaction temperature was 52°C.After the reaction is over,Hot filter,Cool the filtrate to 2 °CWhite crystals precipitated,Filtered to obtain crystals,35 °C vacuum drying overnight,That is, benzimidazole-2-formaldehyde 11.9g, yield 81percent,Purity 99.6percent,
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 42, p. 13340 - 13344[2] Angew. Chem., 2016, vol. 128, # 42, p. 13534 - 13539,6
7
[ 98-86-2 ]
[ 298-12-4 ]
[ 2166-31-6 ]
Yield
Reaction Conditions
Operation in experiment
15%
Stage #1: at 100℃; for 2 h; Stage #2: With ammonia In water Stage #3: With hydrazine hydrate In water at 100℃; for 2 h;
19.6 g (162.95 mmol) of 1-phenylethanone and 5 g (54.32 mmol) of oxoacetate monohydrate were stirred at 100° C. for 2 hours. The reaction solution was then cooled to 40° C., and 20 ml of water and 4 ml of ammonia were added. The mixture was then twice extracted with 50 ml of dichloromethane. 2.64 ml (53.32 mmol) of hydrazine monohydrate were then added to the aqueous phase obtained, and the mixture was stirred at 100° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature. The precipitated crystals were filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. overnight. This gave 4.3 g (24.97 mmol, 15percent of theory) of the title compound as colorless crystals.LC-MS (method 7): Rt=1.39 min; m/z=173 (M+H)+.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 13.2 (s, 1H), 8.04 (d, 1H), 7.86 (d, 2H), 7.53-7.41 (m, 3H), 7.00 (d, 1H).
15%
Stage #1: at 100℃; for 2 h; Stage #2: With ammonia In water at 40℃;
Example 41A6-Phenylpyridazin-3 (2H)-one 19.6 g (162.95 mmol) of 1-phenylethanone and 5 g (54.32 mmol) of oxoacetic acid monohydrate were stirred at 100° C. for 2 hours. The reaction solution was then cooled to 40° C., and 20 ml of water and 4 ml of ammonia were added. The mixture was then extracted twice with 50 ml of dichloromethane. 2.64 ml (53.32 mmol) of hydrazine monohydrate were then added to the aqueous phase, and the mixture was stirred at 100° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature. The precipitated crystals were filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. overnight. This gave 4.3 g (24.97 mmol, 15percent of theory) of the title compound as colorless crystals.LC-MS (Method 4): Rt=1.39 min; m/z=173 (M+H)+.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 13.2 (s, 1H), 8.04 (d, 1H), 7.86 (d, 2H), 7.53-7.41 (m, 3H), 7.00 (d, 1H).
Reference：
[1] Patent: US2011/34450, 2011, A1, . Location in patent: Page/Page column 103
[2] Patent: US2012/28971, 2012, A1, . Location in patent: Page/Page column 24-25
[3] Synthesis, 1993, # 3, p. 334 - 342
[4] Medicinal Chemistry Research, 2013, vol. 22, # 6, p. 2553 - 2560
[5] Letters in Drug Design and Discovery, 2013, vol. 10, # 6, p. 507 - 514
[6] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 663 - 673
[7] European Journal of Medicinal Chemistry, 2016, vol. 112, p. 48 - 59
8
[ 298-12-4 ]
[ 102-51-2 ]
[ 55686-93-6 ]
[ 55687-11-1 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 9, p. 978 - 984
9
[ 95-83-0 ]
[ 298-12-4 ]
[ 2427-71-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 158 - 175
[2] Patent: US5541324, 1996, A,
10
[ 61-54-1 ]
[ 298-12-4 ]
[ 16502-01-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: With hydrogenchloride In water at 20℃; for 0.25 h; Stage #2: With potassium hydroxide In water at 25℃; for 61.75 h; Inert atmosphere; Cooling; Reflux
Glyoxylic acid monohydrate (12.66 g, 137.6 mmol) was dissolved in 30.0 mL of deionized water. In addition, tryptamine (20.0 g, 124.5 mmol) was mixed with 380.0 mL of deionized water and treated with 3 drops of HCl to assist tryptamine to dissolve in deionized water. The aqueous solution of tryptamine is orange-yellow cloudy at this time. Before tryptamine was completely dissolved in deionized water, the two above aqueous solutions were mixed and stirred about 15 minutes at room temperature. Then, white emulsion is precipitated in the mixed aqueous solution. In addition, KOH (6.8 g) was dissolved in 34.0 mL of deionized water. The aqueous solution of KOH were slowly added in the mixed aqueous solution and then HCl was added until a PH of about 4. The mixture was stirred for one hour at room temperature, and then placed in a refrigerator for 12 hours. After taking out from the refrigerator, a solid was collected by suction filtration. Then, 320.00 mL of deionized water and 60.00 mL of HCl were added and refluxed for 30 minutes. Again, 60.00 mL of HCl was added and refluxed for 15 minutes, then cooled to room temperature. The mixed solution was placed in the refrigerator for 2 days and the precipitate was collected. The precipitate was added in deionized water and heated to 550 so that the precipitate was dissolved and a dark green mixed aqueous solution was obtained. KOH was added in the mixed aqueous solution until a pH of about 12 and then a large amount of light green solid was precipitated. The solid compound 3 ( 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 18.19 g, yield: 84percent) was collected by suction filtration. Spectral data as follow: 1H NMR (400 MHz, d6-DMSO): δ 10.67 (s, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.99 (m, 1H), 6.94-6.93 (m, 1H), 3.86 (s, 2H), 3.08 (br s, 2H), 2.98 (t, J=5.2 Hz, 2H), 2.59 (m, 2H); 13C NMR (100 MHz, d6-DMSO): δ 134.99, 133.68, 126.76, 119.67, 117.60, 116.64, 110.27, 106.42, 42.87, 42.14,
80%
Stage #1: With hydrogenchloride In water at 20℃; for 0.25 h; Stage #2: With hydrogenchloride; potassium hydroxide In water at 20℃; for 1 h;
Firstly, glyoxylic acid monohydrate (12.66 g, 137.6 mmol) was mixed with and dissolved in deionized water (30.00 mL). Tryptamine (20.0 g, 124.5 mmol) was also mixed and stirred with deionized water (380.00 mL), followed by adding several drops of hydrochloric acid. The two water solutions prepared as above were mixed and stirred for 15 minutes at room temperature, and a large amount of white precipitation was formed. In addition, a potassium hydroxide solution was prepared by dissolving potassium hydroxide (KOH, 6.8 g) in deionized water (34.00 mL). The potassium hydroxide solution was slowly added by drops into the mixed solution containing glyoxylic acid monohydrate and tryptamine, followed by adjusting the pH value of the solution to around 4 by hydrochloric acid. The mixture was stirred for one hour at room temperature and was allowed to stand in a freezer for 12 hours. After taken out from the freezer, the mixture was filtered by suction to collect solid, followed by added with deionized water (320.00 mL) and hydrochloric acid (60.00 mL). After refluxed for 30 minutes, the mixture was added with hydrochloric acid (60.00 mL) and refluxed again for 15 minutes, followed by cooling to room temperature. The mixture was allowed to stand in the freezer for two days for precipitation. The solid was collected and then added with deionized water. The mixture was heated to 165° C. to dissolve the solid and a dark green solution was formed. The pH value of the solution was adjusted to 12 by adding potassium hydroxide and a large amount of ligh green precipitation was formed. The solid was filtered by suction and the compound 3 (18.19 g) was obtained. The yield is 80percent. Spectral data as follow: 1H NMR (400 MHz, d6-DMSO) : δ 6 10.67 (s, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.99 (m, 1H), 6.94-6.93 (m, 1H), 3.86 (s, 2H), 3.08 (br s, 2H), 2.98 (t, J=5.2 Hz, 2H), 2.59 (m, 2H) ; 13C NMR (100 MHz, d6-DMSO) : δ 134.99, 133.68, 126.76, 119.67, 117.60, 116.64, 110.27, 106.42, 42.87, 42.14, 21.67. The reaction was shown as the following Equation (5).
78%
Stage #1: With hydrogenchloride In water Stage #2: With potassium hydroxide In water at 20℃; for 1 h;
Example 1; 2-(9-fluorenylmethoxycarbonyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4- b]indolo-1 -carboxylic acid; Tryptamine (8 g; 50 mmol) was dissolved in H2O (155 ml) by addition of 6M HCI solution. A solution (11 .20 ml) of glyoxalic acid (5.06 g; 68 mmol) in H2O was then added to the reaction mixture.The pH of the reaction mixture was then brought to about 3.5-4 with aqueous 3.5M KOH solution.After stirring for 1 hour at room temperature, the formation of a white precipitate was noted.The reaction mixture was filtered and the precipitate was then washed several times with H2O and acetone. 1 ,2,3,4-Tetrahydro-beta- carboline (8.5 g; yield: about 78percent) was thus obtained.HPLC-MS (MH+ 217); LC-UV purity: 99.3percent (λ = 220 nm) 98percent (λ = 254 nm).
Stage #1: With potassium hydroxide In water at 20℃; for 1 h; Inert atmosphere Stage #2: With hydrogenchloride In water for 1 h; Reflux; Inert atmosphere
General procedure: Commercial tryptamine hydrochloride (4.9 g, 24.9 mmol, 1 eq) and glyoxylic acid (2.6 g, 27.4 mmol, 1.1 eq) were dissolved in 78 mL H2O,and then the solution of KOH (1.38 g, 24.9 mmol, 1 eq) in 6 mL H2O was added dropwise. The mixture was stirredfor 1h and the white precipitate was collected by filtration. The precipitate was dissolved in 78 mL H2O and thesolution was added conc. HCl (6.6 mL) at room temperature. After stirring for one hour under reflux, the solutionwas added 6.6 mL conc. HCl again and stirred for another 0.5 h under reflux. After cooling to r.t., the light-greencrystal was obtained and collected by filtration and then dissolved in 78 mL H2O. The solution was basified by 20percentKOH until pH > 13, and the white precipitate was filtered off and washed with water three times to the titlecompound S16a (3.1 g, 73percent). 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.27 (d, J =7.9 Hz, 1H), 7.05 – 6.96 (m, 1H), 6.96 – 6.86 (m, 1H), 3.87 (s, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.60 (t, J = 5.6 Hz,2H). 13C NMR (101 MHz, DMSO) δ 135.9, 134.5, 127.7, 120.6, 118.6, 117.6, 111.2, 107.3, 43.8, 43.1, 22.6.ESI-MS m/z 173 [M + H]+.
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 30 - 38
12
[ 4760-34-3 ]
[ 298-12-4 ]
[ 20572-01-4 ]
Reference：
[1] Journal of the Chemical Society, 1923, vol. 123, p. 1082
13
[ 15861-24-2 ]
[ 298-12-4 ]
[ 17380-18-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
14
[ 98546-51-1 ]
[ 298-12-4 ]
[ 3446-89-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 28, p. 8201 - 8205[2] Angew. Chem., 2017, vol. 129, # 28, p. 8313 - 8317,5
15
[ 298-12-4 ]
[ 102-51-2 ]
[ 55687-30-4 ]
[ 91192-32-4 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 9, p. 978 - 984
16
[ 826-73-3 ]
[ 298-12-4 ]
[ 25823-52-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 17, p. 2707 - 2718
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 28, p. 8201 - 8205[2] Angew. Chem., 2017, vol. 129, # 28, p. 8313 - 8317,5
19
[ 51471-72-8 ]
[ 298-12-4 ]
[ 4892-02-8 ]
Reference：
[1] International Journal of Chemical Kinetics, 1995, vol. 27, # 5, p. 443 - 452
20
[ 298-12-4 ]
[ 98480-38-7 ]
[ 98453-07-7 ]
[ 563-96-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1985, # 1, p. 66 - 74
21
[ 298-12-4 ]
[ 563-96-2 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1959, vol. 24, p. 2532,2539, 2541
[2] Acta Chemica Scandinavica, Series A: Physical and Inorganic Chemistry, 1974, vol. 28, p. 162,167
22
[ 7664-93-9 ]
[ 7732-18-5 ]
[ 298-12-4 ]
[ 563-96-2 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1959, vol. 24, p. 2532,2539, 2541
[2] Acta Chemica Scandinavica, Series A: Physical and Inorganic Chemistry, 1974, vol. 28, p. 162,167
23
[ 332-51-4 ]
[ 371-42-6 ]
[ 298-12-4 ]
Reference：
[1] International Journal of Chemical Kinetics, 1995, vol. 27, # 5, p. 443 - 452
24
[ 17422-33-2 ]
[ 298-12-4 ]
[ 703-82-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
25
[ 6146-52-7 ]
[ 298-12-4 ]
[ 6625-96-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 20, p. 3707 - 3710
26
[ 123-38-6 ]
[ 298-12-4 ]
[ 40834-42-2 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1992, vol. 101, # 7, p. 627 - 640
[2] Patent: WO2012/7814, 2012, A2, . Location in patent: Page/Page column 21-22
Stage #1: With hydroxylamine hydrochloride In water at 20℃; for 24 h; Stage #2: With bromine; sodium hydrogencarbonate In dichloromethane; water at 6 - 20℃; for 3.3 h;
To a stirred solution of glyoxylic acid (4) (10 mmol) in H2O(50 mL) was added hydroxylamine hydrochloride (5) (10 mmol)and the solution was stirred for 24 h at room temperature. Next,NaHCO3 (20 mmol) was added carefully followed by CH2Cl2(60 mL). To the two-phase, well-stirred mixture at 6 C was addedBr2 (1 mL) dropwise over 20 min. Upon completion of the additionof Br2, the solution was stirred for 3 h. The organic layer wasseparated and the aqueous layer was extracted with CH2Cl2(50 mL). The combined organic extract was dried (MgSO4), filtered,and evaporated. The residue was crystallized from n-hexane(50 mL). Yield 1.60 g (81percent), mp 65–66 C (lit.19 mp 63–65 C),white crystals.
22%
Stage #1: With hydroxylamine hydrochloride In water for 1 h; Stage #2: With sodium dihydrogen phosphate monohydrate; bromine; sodium hydroxide In water at 10 - 15℃; Cooling with ice
A solution of glyoxylic acid (37.0 g, 500 mmol) and hydro xylamine hydrochloride (35.1 g, 500 mmol) in water (125 mL) was stirered for 1 h and then sodium hydroxide (50.93 g, 1.27 mmol) added with ice batch cooling. Then a solution of sodium phosphate monobasic H2O (138 g, 1 mol) was added. The reaction mixture was then cooled to 10-15 0C bromine (51.22 mL, 1 mol) was added over 2 h. The resulting reaction mixture was stirred over night at room temperature, then the reaction mixture was dilted with water and extracted with dichloromethane, and the resulting organic phase was dried over sodium sulfate, filtered and evaporated to afford the title compound (22.0 g, 22percent) as an orange solid which was used directly in the next step.
3.5 g
Stage #1: With hydroxylamine hydrochloride In water at 20℃; for 24 h; Stage #2: With bromine; sodium hydrogencarbonate In dichloromethane; water at 0℃; for 2 h;
Glyoxilic acid (10 g; 0.108 mol) and hydroxylamine hydrochloride (9.4 g; 0.138 mol) were dissolved in water (80 mL) and stirred at rt for 24 hs. NaHCO3 (23.5 g; 0.280 mol) was added in small portions, followed by dichloromethane (100 mL). The two phase system was vigorously stirred and cooled to 0 °C; bromine (30 g; 0.187 mol) was added dropwise. After 2 hs, the phases were separated and the organic layer was washed with water. The solvent was removed in vacuum and the resulting solid was crystallized with petroleum ether, obtaining 3.5 g of 22.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 13, p. 1635 - 1637
[2] EJNMMI Research, 2018, vol. 8,
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 13, p. 3703 - 3707[4] Angew. Chem., 2017, vol. 129, # 13, p. 3757 - 3761,5
[5] Patent: WO2010/127978, 2010, A1, . Location in patent: Page/Page column 51
[6] Tetrahedron Letters, 1984, vol. 25, # 5, p. 487 - 490
[7] Tetrahedron Letters, 1992, vol. 33, # 22, p. 3113 - 3116
[8] Tetrahedron, 2012, vol. 68, # 7, p. 1845 - 1852
[9] Org. Process Res. Dev., 2011, vol. 15, # 5, p. 1073 - 1080
[10] Molecules, 2014, vol. 19, # 6, p. 8661 - 8678
[11] Steroids, 2015, vol. 95, p. 88 - 95
[12] European Journal of Organic Chemistry, 2015, vol. 2015, # 10, p. 2205 - 2213
[13] Angewandte Chemie - International Edition, 2017, vol. 56, # 40, p. 12277 - 12281[14] Angew. Chem., 2017, vol. 129, # 40, p. 12445 - 12449,5
[15] Patent: WO2006/129199, 2006, A1, . Location in patent: Page/Page column 54-55
29
[ 107-15-3 ]
[ 298-12-4 ]
[ 24123-14-6 ]
Reference：
[1] Tetrahedron, 1995, vol. 51, # 44, p. 12069 - 12082
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3032 - 3040
30
[ 64-18-6 ]
[ 298-12-4 ]
[ 2491-15-8 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1982, # 16, p. 927 - 929
31
[ 72915-12-9 ]
[ 25561-30-2 ]
[ 298-12-4 ]
[ 354-38-1 ]
[ 55982-15-5 ]
Reference：
[1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
32
[ 298-12-4 ]
[ 71-36-3 ]
[ 105-76-0 ]
[ 2050-60-4 ]
[ 141-03-7 ]
[ 1587-18-4 ]
[ 344268-32-2 ]
[ 38094-11-0 ]
[ 77-94-1 ]
[ 105-75-9 ]
[ 117538-83-7 ]
[ 94086-70-1 ]
Reference：
[1] Chemistry and Biodiversity, 2012, vol. 9, # 4, p. 714 - 726
33
[ 298-12-4 ]
[ 71-36-3 ]
[ 105-76-0 ]
[ 2050-60-4 ]
[ 141-03-7 ]
[ 1587-18-4 ]
[ 344268-32-2 ]
[ 38094-11-0 ]
[ 77-94-1 ]
[ 105-75-9 ]
[ 117538-83-7 ]
[ 94086-70-1 ]
Reference：
[1] Chemistry and Biodiversity, 2012, vol. 9, # 4, p. 714 - 726
34
[ 164461-18-1 ]
[ 298-12-4 ]
[ 3029-19-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 28, p. 8201 - 8205[2] Angew. Chem., 2017, vol. 129, # 28, p. 8313 - 8317,5
Reference：
[1] International Journal of Chemical Kinetics, 1995, vol. 27, # 5, p. 443 - 452
37
[ 75-05-8 ]
[ 298-12-4 ]
[ 71-43-2 ]
[ 14257-84-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1978, vol. <II>, p. 248 - 254
38
[ 298-12-4 ]
[ 71-36-3 ]
[ 105-76-0 ]
[ 2050-60-4 ]
[ 141-03-7 ]
[ 1587-18-4 ]
[ 344268-32-2 ]
[ 38094-11-0 ]
[ 77-94-1 ]
[ 105-75-9 ]
[ 117538-83-7 ]
[ 94086-70-1 ]
Reference：
[1] Chemistry and Biodiversity, 2012, vol. 9, # 4, p. 714 - 726
39
[ 298-12-4 ]
[ 108-95-2 ]
[ 1198-84-1 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 8, p. 1243 - 1248
[2] Tetrahedron Letters, 2003, vol. 44, # 13, p. 2669 - 2672
[3] Agricultural and Biological Chemistry, 1981, vol. 45, # 4, p. 831 - 838
40
[ 298-12-4 ]
[ 108-95-2 ]
[ 1198-84-1 ]
[ 1678-71-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas-Journal of the Royal Netherlands, 1996, vol. 115, # 7-8, p. 353 - 356
[2] Patent: US6359172, 2002, B1, . Location in patent: Page column 6
[3] Recueil des Travaux Chimiques des Pays-Bas-Journal of the Royal Netherlands, 1996, vol. 115, # 7-8, p. 353 - 356
41
[ 298-12-4 ]
[ 108-95-2 ]
[ 1198-84-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas-Journal of the Royal Netherlands, 1996, vol. 115, # 7-8, p. 353 - 356
42
[ 298-12-4 ]
[ 108-95-2 ]
[ 1198-84-1 ]
[ 1678-71-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1988, vol. 107, # 3, p. 242 - 247
43
[ 298-12-4 ]
[ 56990-02-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 28, p. 8201 - 8205[2] Angew. Chem., 2017, vol. 129, # 28, p. 8313 - 8317,5
44
[ 107-15-3 ]
[ 298-12-4 ]
[ 108-95-2 ]
[ 1170-02-1 ]
[ 94770-71-5 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2006, vol. 54, # 12, p. 4355 - 4363
45
[ 298-12-4 ]
[ 41201-62-1 ]
[ 38194-50-2 ]
Reference：
[1] Synlett, 2001, # 1, p. 41 - 44
46
[ 67-48-1 ]
[ 7732-18-5 ]
[ 64-18-6 ]
[ 107-43-7 ]
[ 7664-41-7 ]
[ 298-12-4 ]
Reference：
[1] Nagasaki med. J., 1959, vol. 34, p. 1179
47
[ 95-14-7 ]
[ 621-84-1 ]
[ 298-12-4 ]
[ 124676-19-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 120℃; for 2 h;
To a 250 ml. flask equipped mechanical stirring, was added 2-oxoacetic acid hydrate (9.2 g,0.1 mol), benzyl carbamate (15.1 g, 0.1 mol) and 1H-benzo[dj[1,2,3jtriazole (9.2 g, 0.1 mol), and toluene (300 mL). The resulting solution was stirred for 2 h at 120 °C in an oil bath. The resulting mixture was filtered and the solid residue was washed with petroleum ether (3x), and dried in vacuo to give 2-(1H-benzo[dj[1,2,3jtriazol-1-yl)-2-(benzyloxycarbonylamino)aceticacid (28.6 g, 87percent) as a white solid that was used without further purification. ESI-MS m/z:327 [M+Hf
87%
at 120℃; for 2 h;
To a 250 mL flask equipped mechanical stirring, was added 2-oxoacetic acid hydrate (9.2 g, 0.1 mol), benzyl carbamate (15.1 g, 0.1 mol) and 1H-benzo[d][1,2,3]triazole (9.2 g, 0.1 mol), and toluene (300 mL). The resulting solution was stirred for 2 h at 120° C. in an oil bath. The resulting mixture was filtered and the solid residue was washed with petroleum ether (3*), and dried in vacuo to give 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (28.6 g, 87percent) as a white solid that was used without further purification. ESI-MS m/z: 327 [M+H]+.
134.9 g
for 2 h; Reflux; Dean-Stark
A mixture of benzyl carbamate (82.1 g, 0.54 mol), glyoxylic acid monohydrate (50 g, 0.54 mol) and benzotriazole (64.7 g, 0.54 mol) in toluene (2.5 L) was heated at reflux with Dean and Stark water removal for 2 hours. A total of 23 mL of water was collected during the first hour before water evolution ceased. The mixture was allowed to cool to room temperature and the resulting solid filtered and washed with diethyl ether (200 mL). The damp filter cake was dried at 40 °C/50 mmHg overnight to give a cream coloured powder (134.9 g).
Reference：
[1] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 523 - 527
[2] Patent: WO2017/15449, 2017, A1, . Location in patent: Page/Page column 51
[3] Patent: US2018/193352, 2018, A1, . Location in patent: Paragraph 0205; 0206; 0207
[4] Journal of Organic Chemistry, 1990, vol. 55, # 4, p. 2206 - 2214
[5] Journal of the Chemical Society, Chemical Communications, 1989, # 6, p. 337 - 338
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6389 - 6392
[7] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2311 - 2319
[8] Patent: WO2004/26843, 2004, A1, . Location in patent: Page 54
[9] Patent: WO2007/34127, 2007, A1, . Location in patent: Page/Page column 27
[10] Patent: WO2016/20698, 2016, A1, . Location in patent: Page/Page column 40; 45
To a 4° C. solution of Part A compound (3.08 g, 22.5 mmol) in denatured ethanol (70 mL) was added a solution of glyoxylic acid monohydrate (2.0 g, 22 mmol) in ethanol (10 mL) dropwise. Shortly after the addition of glyoxylic acid, a white precipitate formed. The cooling bath was removed, and the reaction mixture was stirred for 2 h at ambient temperature. Filtration gave the title product (3.1 g, 73percent) as a white solid: LC/MS (electrospray, +ions) m/z 194(M+H).
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 10, p. 1321 - 1325
[2] Patent: US6649606, 2003, B1, . Location in patent: Page/Page column 38
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 47 - 50
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 7, p. 1799 - 1802
51
[ 3458-98-8 ]
[ 298-12-4 ]
[ 91523-50-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
With triethylamine In ethanol at 5 - 20℃; for 1 h;
Triethylamine (0.76 mL, 0.55 g, 5.47 mmol) was added to a stirred solution of 3-(2-aminoethyl)phenol hydrochloride (1:1) 25a (1.00 g, 5.76 mmol) in EtOH (26 mL). The mixture was cooled to 5 °C and a solution of glyoxylic acid (0.53 g, 5.76 mmol) in EtOH (6 mL) was added drop wise. The resulting mixture was stirred for 1 hour with gradual warming to room temperature. The resulting solid was filtered and washed with EtOH to provide the title compound (0.78 g, 70percent yield) as an off-white solid. (ES+) m/z (M+1) 193.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.35 (br s, 1H) 7.50 (d, J = 8.6 Hz, 1H) 6.60 (dd, J = 8.6, 2.0 Hz, 1H) 6.49 (d, J = 2.0 Hz, 1H) 4.33 (s, 1H) 3.42-3.47 (m, 1H) 3.27-3.34 (m, 1H) 3.06-3.14 (m, 1H) 2.81-2.89 (m, 1H) 2.69-2.78 (m, 1H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 19, p. 5833 - 5851
52
[ 38449-59-1 ]
[ 298-12-4 ]
[ 91523-50-1 ]
Reference：
[1] RSC Advances, 2018, vol. 8, # 29, p. 16362 - 16369
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 19, p. 3547 - 3560
53
[ 110-62-3 ]
[ 298-12-4 ]
[ 78920-10-2 ]
Yield
Reaction Conditions
Operation in experiment
96.3%
With morpholine In n-heptane at 40.1 - 41.7℃; for 18 h; Industrial scale
Example of industrial batch. All quantities of material were calculated with respect to the glyoxylic acid content of the 50percent w/w glyoxylic acid solution used. (0050) Heptane (1285kg, 1889L, 4.04vol) and morpholine (595L, 601.3kg, 6902mol, 1.09eq) were charged in the reactor. After addition of morpholine, the equipment was rinsed with heptanes (20L, 0.04vol). The solution was stirred at 22 - 23°C for 10min, before being cooled to 4.4°C. (0051) A 50percent aqueous solution of glyoxylic acid (935kg, 6318mol, 1.0eq) was slowly added while maintaining the temperature below 40°C. After addition of glyoxylic acid, the equipment was rinsed with heptanes (20L, 0.04vol). The medium was stirred for 2 hours at a temperature between 30.9 and 23.8°C. Valeraldehyde (706L, 576.8kg, 6697mol, 1.06eq) was then slowly added to the medium while maintaining the temperature below 40°C. (0052) After addition of valeraldehyde, the equipment was rinsed with heptanes (40L, 0.08vol). The reactor contents were heated between 40.1 and 41 .7°C for 18 hours 04 minutes. The medium was then cooled to 22.8°C and an aqueous solution of hydrochloric acid (1 168L, 1.73eq) was added while keeping the temperature between 23.5 and 25.0°C; the medium was stirred for 4 hours. (0053) The medium was allowed to separate and the organic phase was removed. The aqueous phase was washed with heptanes (3x943L, 3x2vol). Diisopropyl ether (1322kg, 1888L, 4.04vol) was added to the aqueous phase followed by solid sodium carbonate (199kg) until a pH value of 0.4 was reached. The medium was allowed to separate and the organic phase was removed. Compound (II) was extracted from the aqueous phase with diisopropyl ether (2x530kg, 2x756L, 2x1 .6vol). The combined organic phases were washed with a 20percent w/w aqueous solution of sodium chloride (944.2kg, 1.6vol). The organic layer was then dried by azeotropic distillation under vacuum at a jacket temperature of maximum 40°C and filtered. The solution was finally concentrated under vacuum below 40°C and a polish filtration through a 10μηι cartridge filter was performed. The total mass of solution (934.9kg) was corrected for the water content (3.7percent) and the DIPE content (3.8percent) to give 864.8kg of compound (II) (6084mol, 96.3percent yield).
92.5%
at 10 - 45℃; for 7 h; Large scale
50percent aqueous glyoxylic acid (6kg, 41.1mol) was added to a 50L autoclave, n-heptane (10L), water (3L), cooled to below 10 , it quickly added film (3.57kg, 41.1mol), warmed to 25 , the reaction for 2h, n-valeraldehyde (3.53kg, 41.1mol), completion of the addition was warmed to 45 , reaction 5h, cooled to below 10 , rapid concentrated hydrochloric acid (5L), the reaction 3h, liquid separation, washed with 30percent aqueous sodium bicarbonate n-heptane phase is separated off, and washing with n-heptane phase (3L × 3), the aqueous phase was extracted with diisopropyl ether (6L × 3) with, respectively, diisopropyl ether phase concentration (3L × 2), saturated brine (3L × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 45 with isopropyl ether, to give a dark yellow product was 5.387kg, HPLC: 98percent pure, a yield of 92.5percent
55%
With piperidine hydrochloride In 1,4-dioxane; water for 18 h; Inert atmosphere; Reflux
Glyoxilic acid monohydrate (4.55 g, 49.42 mmol) and piperidine hydrochloride (6.30 g, 51.80 mmol) were added to a solution of pentanal (5 mL, 47.02 mmol) in 7:1 dioxane:water (25 mL) under nitrogen. The mixture was heated at reflux for 18 h and, after cooling to room temperature, diluted with 2 M HCl (100 mL) and extracted with diisopropyl ether (3 × 30 mL). The first extract was discharged, while the other two were combined and extracted with 2 M HCl (3 × 30 mL). These three acidic extracts were combined with the reaction mixture, which had been previously diluted with 2 M HCl, and washed with diisopropyl ether, and the whole aqueous layer was extracted with DCM (3 × 80 mL). The DCM extracts were concentrated to give 4a (3.68 g, 55percent) as an oil. 1H NMR (300 MHz, CDCl3) δ 6.00 (s, 1H), 5.84 (t, J = 1.8 Hz, 1H), 4.65 (bs, 1H, exchange with D2O), 2.25–2.52 (m, 2H), 1.52–1.77 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 172.3, 170.3, 117.2, 99.4, 29.6, 19.9, 13.7. Anal. calcd. for C7H10O3: C, 59.14; H, 7.09. Found: C, 58.98; H, 7.13.
To a 250ml reaction flask was added 50percent glyoxylic acid (67ml, 0.61mol) and tetrahydrofuran (130ml), heated to reflux, was added dropwise N- benzyl ethanolamine (41.5g, 0.27mol) in tetrahydrofuran (20ml) solution, to the reaction complete, the tetrahydrofuran was evaporated, water (170ml), cooled with stirring, to precipitate a solid, ice-water bath was stirred for 30 minutes, filtered and washed with ice water, drying in a yellowish solid, i.e. compounds of formula VII (51.8g, 91percent), mp132 ~ 136 .
Reference：
[1] Patent: CN103030668, 2016, B, . Location in patent: Paragraph 0031-0033
[2] Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135
56
[ 20893-30-5 ]
[ 298-12-4 ]
[ 912368-67-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium carbonate In methanol for 2 h; Heating / reflux
Example 1; 2-phenvI-4-f(3S)-piperidin-3-vIaminolthieno[3,2-c1pyridine-7-carboxamide; Step 1:(2Z)-3-cyano-3-(2-thienyl)acrylic acid; To a stirred solution of 2-thienylacetonitrile (24.8 g,0.20 mol) in MeOH (300 mL) is added glyoxylic acid monohydrate (18.5 g, 0.20 mol) and potassium carbonate (25.5 g, 0.20 mol). The reaction slurry is placed under a nitrogen atmosphere and heated to reflux. After 2h the reaction mixture is cooled to rt and the product is obtained by filtration. The filter cake is washed with a large amount of MeOH and then dried in a vacuum oven overnight to give 43.1 g (99percent) of the title compound as a white crystalline potassium salt. 1H NMR δ 7.95 (d, 3H), 7.75 (d, IH), 7.30 (dd, IH), 7.05 (s, IH), 3.0-4.0 (br s, IH). LCMS (ES, M+H=180, M-H=I 78).
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1061 - 1073
[2] Patent: WO2006/106326, 2006, A1, . Location in patent: Page/Page column 53
57
[ 540-72-7 ]
[ 298-12-4 ]
[ 178928-70-6 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 60℃;
In a 100 mL reaction flask was added 0.93 gHydrochloride salt of 2- (1-chlorocyclopropyl) -1- (2-chlorophenyl) -3-hydrazinopropan-2-ol, 15 mL of acetonitrile, 0.55 g of a 50percent glyoxylic acid solution and 0.24 g Sodium thiocyanate,Warmed to 60 ° C, after the reaction was added 10mL of water,Adjust pH = 2 or so,The layers were separated, the aqueous phase was extracted with toluene, the organic phases were combined,0.92 g of a solid product was obtained (yield 89percent).
Reference：
[1] Patent: CN105949137, 2016, A, . Location in patent: Paragraph 0107; 0108
With p-toluenesulfonic acid monohydrate; In water; 1,2-dichloro-ethane; at 83℃; for 4h;
15 g of compound (1 00) (<strong>[36837-50-0]methyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate</strong>), which isprepared in analogy to EP-A-423070, is dissolved in 70 ml 1 ,2-dichloroethane, and10.4 g glyoxylic acid (50 percent in water) as well as 0.445 g p-toluenesulfonic acid monohydrate are added. The mixture is refluxed for 4 h at 83°C. 1 ,2-Dichloroethane is subsequentlyremoved in vacuum. The crude product is dissolved in 100 ml methyl-tert-1 0 butyl ether and washed with water (3 times). The organic phase is dried over sodiumsulfate and subsequently evaporated in vacuum. The obtained crude product is dried at0.3 mbar and 60°C to yield 18.6 g of a material containing compound (1 01 ).151H-NMR (400 MHz, CDCb): 5.03 (lactone).13C-NMR (100 MHz, CDCb): 175.6 (C=O), 173.0 (C=O), 67.7(CHOH).
tert-Butyl 4- {1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1- naphthyl)methoxy]ethyl}piperazine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. After 2h the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (20 mL) and washed with sat. aq. NaHC03 (20 mL). The organic phase was dried over Na2S04, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on Si02 (0- 5% 2 M NH3 in MeOH: DCM) afforded the title compound as an off-white solid (81.6 mg, 79%). The citrate salt was formed by the addition of citric acid (1.0 equivalents) to a methanolic solution of the title compound. Concentration under reduced pressure afforded the desired salt form of the product as an off-white powder. MS m/z 454.4 (M+H) +. ¹H NMR (300.1 MHz, DMSO + TFA) No. 8.64 (s, 1H), 8.08 (t, J= 7.6 Hz, 2H), 7.80 (dd, J= 1.9, 7.1 Hz, 1H), 7.72 (t, J= 7.1 Hz, 1H), 7.64 (t, J= 7.6 Hz, 1H), 7.55 - 7.45 (m, 2H), 5.06 (dd, J= 15.4, 11.0 Hz, 2H), 4.78 (t, J= 5.0 Hz, 1H), 4.20 (d, J= 5.0 Hz, 2H), 3.99 (s, 3H), 3.41 - 3.34 (m, 6H), 3.23 - 3.19 (m, 2H), 2.75 (dd, J= 33.0, 15.4 Hz, 4H), 1.83 (s, 1H). The requisite tert-butyl 4-{1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1- naphthyl)methoxy]ethyl}piperazine-1-carboxylate was synthesized using the following method. tert-Butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate (65 mg, 0.18 mmol) was dissolved in THF (1.8 mL). 4-(Iodomethyl)-3-methoxy-2- naphthonitrile (70 mg, 0.22 mmol) was added followed by NaH (9 mg, 0.36 mmol). After reacting at RT overnight, water (60 mL) was added. The mixture was extracted with EtOAc (40 mL). The organic phase was dried over Na2S04, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on Si02 (0-30% EtOAc: hexane) afforded the title compound (99 mg). MS m/z 554.6 (M+H)+. The requisite tert-butyl 4- [ 1 -(3 -chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine- I - carboxylate was synthesized using the following method. Borane-methyl sulfide complex (2M in THF, 1.07 mL) was added to a solution of [4- (tert-butoxycarbonyl)piperazin-1-yl](3-chloro-4-fluorophenyl)acetic acid (200 mg, 0.54 mmol) in THF (3 mL). After 30 min at RT the reaction was heated to reflux for 4h. After cooling the reaction to RT, MeOH (10 mL) was slowly added. After stirring overnight the volatiles were removed under reduced pressure. Chromatography of the residue on Si02 (0- 50% EtOAc:hexane) afforded the title compound (160 mg, 83%). MS m/z 359.3 (M+H)+, 303.2 (M+H-t-butyl). The requisite [4-(tert-butoxycarbonyl)piperazin-1-yl](3-chloro-4-fluorophenyl)acetic acid was synthesized using the following method. (3-Chloro-4-fluorophenyl) boronic acid (440 mg, 2.52 mmol), tert-butyl piperazine-1-carboxylate (469 mg, 2.52 mmol) and glyoxylic acid monohydrate (232 mg, 2.52 mmol) were reacted together in DCM (10 mL) at reflux overnight. The volatiles were removed under reduced pressure. Chromatography of the residue on Si02 (0-10% MeOH: DCM) afforded the title compound (767 mg, 82%). MS m/z 373.1 (M+H)+, 317.1 (M+H-t-butyl). ¹H NMR (300.1 MHz, DMSO) 6 12.80 (s, 0.6H), 7.59 (d, J= 7.2 Hz, 1H), 7.42 (d, J= 7.2 Hz, 2H), 4.09 (s, 1H), 3.30 (s, 2H), 3.16 (s, 2H), 2.35 (m, 4H), 1.38 (s, 9H).
With sodium tris(acetoxy)borohydride; toluene-4-sulfonic acid; In tetrahydrofuran; dichloromethane; water; acetic acid;
EXAMPLE A6 4-(4-methyl-1-piperazinyl)-1-piperidinoacetic Acid 500 mg of p-toluenesulphonic acid and 12 ml (0.21 mol) of glacial acetic acid were added to a solution of 10.0 g (135.069 mmol) of anhydrous glyoxylic acid and 24.76 g (135.08 mmol) of <strong>[53617-36-0]4-(4-methyl-1-piperazinyl)piperidine</strong> in 500 ml tetrahydrofuran, then 37.2 g (175.555 mmol) of sodium triacetoxyborohydride were added in small portions and the mixture was stirred overnight at room temperature. 60 ml of water were added dropwise with further stirring, the tetrahydrofuran solution was decanted off and the product remaining was digested several times with 20 ml of fresh dichloromethane which was then discarded The product was dissolved in 50 ml water, the resulting solution was extracted three times with 30 ml of dichloromethane and evaporated down in vacuo. The residue was thoroughly washed three times with 20 ml of an acetone-dichloromethane mixture (1/1 v/v) and dried in vacuo. The desired product was obtained in the form of colourless crystals in a yield of 18.8 g (58percent of theory). IR (KBr): 1630 cm-1 (C=O) ESI-MS: (M+H)+=242; (M-H)-=240
EXAMPLE 5 A suspension of 57 g of cyanomethylurea in 45 ml of methanol is heated to boiling under agitation, combined with 3 ml of 8N sodium hydroxide solution, and heated under reflux for 30 minutes. The reaction mixture is then allowed to cool down to 30 C., 550 ml of water and 90 g of 50% strength glyoxylic acid are added thereto, and the mixture is neutralized with 8N sddium hydroxide solution at a temperature of maximally 30 C. until a pH of 6.5 has been attained. The mixture is then heated to 55-60 C., 225 ml of 8N sodium hydroxide solution is added dropwise thereto at this temperature within one hour, and the mixture is stirred for another 2 hours. Then about 150 ml of aqueous methanol is removed by distillation to 95 C.; the mixture is heated for one hour under reflux and gently acidified with concentrated nitric acid. The mixture is allowed to cool down to room temperature, the thus-separated crystallized product is filtered off, washed with water, and dried under vacuum, thus obtaining 72 g of orotic acid (=71.8% of theory).
With sodium hydroxide; for 2h;Reflux; Large scale;
S3: 100 kg of 50% glyoxylic acid is pumped into the reaction kettle, warming up to reflux, then quickly draw 350 kg of 30% sodium hydroxide solution.Boiling reaction for 2h, stop heating,When the temperature drops to 50 C, add concentrated hydrochloric acid dropwise to adjust the pH to 6-7, centrifuge the precipitated solid, that is, crude orotic acid is obtained.
A mixture of <strong>[90555-66-1]3-ethoxyphenylboronic acid</strong> (45 mg, 0.27 mmol), Intermediate 1 (72 mg, 0.20 mmol) and glyoxylic acid monohydrate (26 mg, 0.28 mmol) in 1,2-dichloroethane (2 mL) was heated at 100 C. for 12.5 min. in a microwave reactor. The crude product was purified by flash column chromatography (gradient from 0-20% methanol in dichloromethane) to give 60 mg (56%) of Intermediate 16 as a solid. LC-MS m/z: 538.3 (M+H)+.
In N,N-dimethyl-formamide; acetonitrile; at 100℃; for 0.166667h;
Example 1: methyl 3-((R)-l-((R)-2-(3,4-dimethoxyphenyl)-2-(3-oxoisoindolin-5- ylamino)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate; [00212] A solution of Intermediate 6 (300 mg, 2.0 mmol), 3,4- dimethoxyphenylboronic acid (370 mg, 2.0 mmol) and glyoxylic acid monohydrate (224 mg, 2.4 mmol) in acetonitrile/ DMF (4 mL, 4: 1) was heated in the microwave at 100 0C for 10 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield IA (600 mg, 87%) as a yellow solid. MS (ESI) m/z 343.2 (M+H)+.
In N,N-dimethyl-formamide; acetonitrile; at 20 - 65℃;
To <strong>[854778-31-7]4-fluoro-3-methoxyphenylboronic acid</strong> (100 mg, 0.588 mmol,WO2007002313), Intermediate 5 (95 mg, 0.588 mmol) and glyoxylic acid monohydrate (59.6 mg, 0.647 mmol) was added acetonitrile (2.0 mL) and DMF (1.2 mL). The mixture was sonicated for 2 min, heated at 65 0C for 2.0 h then stirred at rt over night. Solvent was removed by high vacuum and the crude was purified by prep HPLC purification: C18 Phenomenex Luna AXIA column (30 mm x 100 cm, 5mu) with the UV detector set at 254 nm. The separations were performed using a gradient method: 15-80% B in 15 mins; then 80%B in 2 mins with a flow rate of 40 mL/min. Solvent B is 90% acetonitrile - 10% water - 0.1% TFA and solvent A is 10% <n="147"/>acetonitrile - 90% water - 0.1% TFA. The desired fractions were collected to give 22K (68 mg, 34% yield) as a solid after lyophilization. 1H NMR (400 MHz, DMSO- d6) delta ppm 3.83 (s, 3 H) 5.23 (s, 1 H) 7.06 - 7.11 (m, 1 H) 7.13 (d, J=2.20 Hz, 1 H) 7.21 (dd, J=I 1.43, 8.35 Hz, 1 H) 7.37 (td, J=5.60, 2.42 Hz, 2 H) 7.42 - 7.49 (m, 1 H) 8.17 (s, 1 H); LC-MS 343 (M + H)
In N,N-dimethyl-formamide; acetonitrile; at 100℃; for 0.166667h;Microwave irradiation;
Example 4: (/?)-4-Methyl-2-(l-oxo-l,2,3,4-tetrahydro-isoquinolin-7-ylamino)-7- (propane-2-sulfonyl)-4,ll-diaza-tricyclo[14.2.2.1^'1"]henicosa- l(19),6,8,10(21),16(20),17-hexaene-3,12-dione trifluoroacetic acid salt; Intermediate 1 (128 mg, 0.789 mmol),3G (400 mg, 0.751 mmol), and glyoxylic acid monohydrate (69.2 mg, 0.751 mmol) were dissolved in acetonitrile (2.25 mL) and DMF (1.75 mL) to give a yellow solution. The mixture was irradiated in a microwave reactor at 100 0C for 10 min, then was concentrated. The crude product was purified by flash chromatography (1 to 20% MeOH/CH2Cl2 gradient) to afford 380 mg (71.6 %) of 4A as a yellow glass. (ESI) m/z 707 '.2 (M+H)+.
In N,N-dimethyl-formamide; acetonitrile; at 60℃; for 48.0h;
3H:; [00255] Intermediate 2 (164 mg, 1.11 mmol), 3G (535 mg, 1.00 mmol), and glyoxylic acid monohydrate (111 mg, 1.21 mmol) were taken up in CH3CN (3 mL) and DMF (2 ml). The mixture was stirred at 600C for 48 h, then was concentrated. The crude product was purified by flash chromatography (1 to 20% MeOH/CH2Cl2 gradient) to afford 313 mg of 3H as a pale yellow solid. MS (ESI) m/z 693.3 (M+H)+
In N,N-dimethyl-formamide; acetonitrile; at 110℃; for 0.166667h;Microwave irradiation;
[00244] A solution of ID (500 mg, 0.99 mmol), Intermediate 2 (147 mg, 0.99 mmol) and glyoxylic acid monohydrate (91 mg, 0.99 mmol) in acetonitrile (2 mL) and DMF (2 mL) was micro waved at 100 0C for 10 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield IE (540 mg, 0.812 mmol, 82% yield) as a yellow foam. MS (ESI) m/z 665.6 (M+H)+.
Synthesis of (m-Tolyl-hydrazono)-acetic acid3-Methylphenylhydrazine hydrochloride (15.9 g, 100 mmol) was dissolved in water (450 mL) and ethanol (600 mL) with heating at 60 C. A solution of glyoxylic acid (9.21 g, 100 0 mmol) in water (100 mL) was added to the warm solution using water (3 x 15 mL) to rinse. The reaction mixture was stirred at 60 C for 45 minutes and then cooled slightly and concentrated to remove ethanol. The aqueous mixture was neutralized with NaOH and then water was added (800 mL). The precipitate was filtered, washed with water (3 x 100 mL), washed with hexanes (100 mL) and dried to give the subtitle compound as a brown solid 5 (12.2 g, 69 %).
In acetonitrile; at 80℃; for 0.333333h;Microwave irradiation;
Intermediate 33: (+/-H2-fluoro-6-(methyloxy)phenyl1(4-methyl-1-piperazinyl)acetic acid; 200 mg of (+/-)-[2-fluoro-6-(methyloxy)phenyl]boronic acid (0.71 mmole, Aldrich) were added to a suspension of 114 mg of glyoxylic acid hydrate (0.71 mmole, Aldrich) and 130 muL of 1-methylpiperazine (0.71 mmole) in 3 mL of MeCN in a microwave vial. The mixture was irradiated at 8O0C for 20 min to give a thick brown crude which was evaporated to dryness. The final compound was purified on a SPE HLB cartridge (H2O 100% to H2O/MeOH 90/1 ), to give 125 mg (58%) of the title compound; 1H-NMR (500 MHz, CDCI3): delta 2.5 (3H, s), 3.0-3.3 (8H, m), 3.8 (3H, s), 4.9 (1 H, s), 6.8 (1 H, t), 6.9 (1 H, d), 7.4- 7.3 (1 H, q), 10.4 (1 H, br s); m/z (ES): 283 [M+H]+.
Then to the autoclave 0.2 g of the Pd/C was introduced, the air was removed and the reaction was carried out at 50C in the atmosphere of hydrogen gas under the pressure 5 atm for 3 h. When hydrogen absorption ceased the mixture of glyoxylic acid monohydrate (27.6 g, 0.3 mol) and triethylamine (40.4 g, 0.4 mol) in methanol (100 ml) was introduced to the salan compound. The reaction system was heated to 50C and hydrogen was introduced under the pressure of 10 atm. The reductive amination was carried out for 15 h, then the catalyst was filtered and the solvent evaporated by means of a rotary vacuum evaporator. The solid (62 g) obtained was dissolved in water and acidified with 10% hydrochloric acid to pH=2.0. Crystallization was carried out for 12 h at 8C. 37 g of the product N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid monohydrochloride trihydrate was separated with the overall yield 78% with respect to the starting ethylenediamine. The raw product was recrystallized form 85% ethanol. The structure of the product was confirmed by means of 1H NMR and the purity thereof by means of elemental analysis. 1H NMR (DMSO) delta: 7.23-6.78 (m, 8H, ArH), 4.06 (s, 4H, HOOCCH2N), 3.65 (s, 4H, ArCH2N), 3.22 (s, 4H, NCH2CH2) Elemental analysis: Calculated for C20H24N2O6· HCl · 3H2O: C 50.16, H 6.52, N 5.85, Found: C 50.15, H 6.58, N 5.81
Then to the autoclave 0.1 g of the Pd/C was introduced, the air was removed, the autoclave was pressurized with hydrogen and the reaction was carried out at 45-50C under the hydrogen pressure of 6 atm for 14 h. When the absorption of hydrogen ceased, methanol (180 ml) and the mixture of glyoxylic acid monohydrate (27.8 g, 0.3 mol) and triethylamine (40.5 g, 0.4 mol) were introduced to the system. The reaction system was heated to 50C and hydrogen was introduced under the pressure of 10 atm. The reductive amination was carried out for 15 h, then the catalyst was filtered and the solvent evaporated by means of a rotary vacuum evaporator. The solid obtained was dissolved in water and acidified with 10% hydrochloric acid to pH=2.0. Crystallization was carried out for 10 h at 8C. 35.5 g of the product N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid hydrochloride trihydrate was separated with the overall yield 84% with respect to the starting ethylenediamine. The raw product was recrystallized form the 85% ethanol. The structure of the product was confirmed by means of 1H NMR and the purity thereof by means of elemental microanalysis.
With potassium carbonate; In methanol; water; at 20℃;Inert atmosphere;
To a slurry of 5.05 g of <strong>[94952-46-2]2-acetyl-5-chloropyridine</strong> (32.4 mmol) in 36 mL of methanol at room temperature was added 60 mL of water and 4.8 g of 50% glyoxylic acid (32.4 mmol). Potassium carbonate (8.96 g, 2 equivalents) was added carefully (foaming), and the reaction mixture was stirred overnight at room temperature under nitrogen. The next day, the slurry was partially stripped on the rotovap to remove methanol (maximum bath temperature 30 C.). The slurry was transferred to a separatory funnel and extracted twice with methylene chloride. The aqueous phase was transferred back to a round bottom flask and treated carefully with 13.7 mL of acetic acid (foaming) followed by 1.9 g of hydrazine hydrate (38 mmol). The reaction mixture was refluxed for 2 hours. It became very dark. While cooling, potassium carbonate was carefully added until the pH was 7. The reaction mixture was cooled to room temperature, then filtered and washed with water. The solids were dried in a vacuum oven at 50 C. The product was 4.13 g of a fine black solid. The NMR data is as follows: 300 MHz 1H NMR (DMSO d-6, TMS=0 ppm) 7.10 (d, 1H); 7.75 (d, 1H); 8.11 (d, 1H) 8.70 (d, 1H); 13.4 (bs, 1H). The yield of pyridazinone was 61%.
Example 23 Tributylammonium Hydroxy-(4-hydroxy-benzo [b]thiophen-7-yl)-acetate A 2 L reactor equipped with a mechanical stirrer, a thermometer, a dropping funnel, a sensor connected to a pH-meter and an argon inlet was charged under argon with 76.2 g (500 mmol) of 4-Hydroxybenzothiophene and 617.1 g (1100 mmol) of a 10% KOH aqueous solution. To the dark solution were added at 0-5 C. within 30 min ca. 85.91 g (580 mmol) of a 50% glyoxylic acid solution in water. If necessary, more glyoxylic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5 C., 200 ml of tert-butyl methyl ether were added to the reaction mixture followed by ca. 70 ml of 25% HCl solution in water such that the pH was ca. 7.0. The biphasic mixture was filtered through Speedex, then ca. 70 ml of 25% HCl solution in water were added to the aqueous phase such that the pH was ca. 2.0. After addition of 450 ml of tert-butyl methyl ether the organic phase was separated at room temperature and the aqueous phase washed with tert-butyl methyl ether. The combined organic phases were concentrated to a volume of ca. 300 ml and the residue was diluted with 50 ml of tert-butyl methyl ether and 100 ml of acetonitrile. To the resulting clear solution was added portionswise at 20-30 C. within 1 h a solution of 93.6 g (500 mmol) of tributylamine in 100 ml of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 C. and then filtered off. The filter cake was washed with 160 ml of tert-butyl methyl ether/acetonitrile 3:1 and the crystals dried over night at 60 C./10 mbar to afford 108.9 g (53.1%) of tributylammonium hydroxy-(4-hydroxy-benzo[b]thiophen-7-yl)-acetate as white crystals with a m.p. of ca. 200 C. (dec.).
51.3%
A 2 L reactor equipped with a mechanical stirrer, a thermometer, a dropping funnel, a sensor connected to a pH-meter and an argon inlet was charged under argon with 76.2 g (500 mmol) of 4-Hydroxybenzothiophene and 617.1 g (1100 mmol) of a 10% KOH aqueous solution. To the dark solution were added at 0-5 C. within 30 min ca. 85.91 g (580 mmol) of a 50% glyoxylic acid solution in water. If necessary, more glyoxylic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5 C., 200 ml of tert-butyl methyl ether were added to the reaction mixture followed by ca. 70 ml of 25% HCl solution in water such that the pH was ca. 7.0. The biphasic mixture was filtered through Speedex, then ca. 70 ml of 25% HCl solution in water were added to the aqueous phase such that the pH was ca. 2.0. After addition of 450 ml of tert-butyl methyl ether the organic phase was separated at room temperature and the aqueous phase washed with tert-butyl methyl ether. The combined organic phases were concentrated to a volume of ca. 300 ml and the residue was diluted with 50 ml of tert-butyl methyl ether and 100 ml of acetonitrile. To the resulting clear solution was added portionswise at 20-30 C. within 1 h a solution of 93.6 g (500 mmol) of tributylamine in 100 ml of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 C. and then filtered off. The filter cake was washed with 160 ml of tert-butyl methyl ether/acetonitrile 3:1 and the crystals dried over night at 60 C./10 mbar to afford 108.9 g (53.1%) of tributylammonium hydroxy-(4-hydroxy-benzo[b]thiophen-7-yl)-acetate as white crystals with a m.p. of ca. 200 C. (dec.).
A solution of <strong>[38940-62-4]1-(5-bromopyridin-3-yl)ethanone</strong> (2.04 g, 27.5 mmol) in methanol (55 mL) was added slowly to a cold solution of 2-oxoacetic acid (2.04 g, 27.5 mmol) and potassium carbonate (7.22 g, 52.24 mmol) in water (50 mL). The mixture was stirred at room temperature for 2h. The resultant solution was partially evaporated under reduced pressure at 30 C to remove most of the methanol and then extracted three times with ethyl acetate. The cooled aqueous solution was carefully treated with acetic acid (11 mL, 192 mmol) and washed with dichloromethane. Ethylhydrazine oxalate (3.61 g, 26.1 mmol) was added to the aqueous phase, and the mixture heated under reflux for 2 h. A further 3.61 g ethylhydrazine oxalate (26.12mmols) was added and the mixture heated under reflux for 2 d. The solution was neutralised with potassium carbonate to pH 7 and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the crude purified in a 40M column from Biotage on a SP1 automatic purification system using hexane and ethyl acetate as solvents (0-100% ethyl acetate) in 20 column volumes. The appropriate fractions were collected and evaporated to give 3.71 g (47% yield) of the title compound. HPLC/MS (9 min) retention time 5.32 min. LRMS: m/z 282 (M+1)
With triethylamine; In ethanol; at 5 - 20℃; for 1h;
Triethylamine (0.76 mL, 0.55 g, 5.47 mmol) was added to a stirred solution of <strong>[3458-98-8]3-(2-aminoethyl)phenol hydrochloride</strong> (1:1) 25a (1.00 g, 5.76 mmol) in EtOH (26 mL). The mixture was cooled to 5 C and a solution of glyoxylic acid (0.53 g, 5.76 mmol) in EtOH (6 mL) was added drop wise. The resulting mixture was stirred for 1 hour with gradual warming to room temperature. The resulting solid was filtered and washed with EtOH to provide the title compound (0.78 g, 70% yield) as an off-white solid. (ES+) m/z (M+1) 193.9. 1H NMR (500 MHz, DMSO-d6) delta ppm 9.35 (br s, 1H) 7.50 (d, J = 8.6 Hz, 1H) 6.60 (dd, J = 8.6, 2.0 Hz, 1H) 6.49 (d, J = 2.0 Hz, 1H) 4.33 (s, 1H) 3.42-3.47 (m, 1H) 3.27-3.34 (m, 1H) 3.06-3.14 (m, 1H) 2.81-2.89 (m, 1H) 2.69-2.78 (m, 1H).
To a stirred solution of compound AW (4.0 g, 20.83 mmol) in CH3OH (40 mL) was added 2-oxoacetic acid (2.3 mL, 20.83 mmol) at 0 C. The resulting reaction mixture was allowed to warm to RT and stirred for 24 h. After the consumption of starting material (by TLC), the reaction mixture was diluted with H2O (50 mL) and stirred for 5 min. The solid precipitated was filtered and washed with H2O (3×50 mL). The crude solid was purified by silica gel column chromatography (eluting with 30% EtOAc/hexane) to afford compound AX (1.4 g, 6.08 mmol, 29.8%) as pale-yellow solid. 1H NMR (500 MHz, DMSO-d6): delta 12.6 (br s, 1H), 8.25 (s, 1H), 7.78 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H). MS (ESI): m/z 230 [M+H]+.
2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-mesitylacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With iron(III) perchlorate hydrate; In nitromethane; at 80℃; for 24h;
General procedure: A 10 mL screw cap vial was charged with the respective iron salt (1-5 mol%) or Bi(OTf)3 (1-5 mol%), the appropriate amide (1.0 equiv), and MeNO2 (4.0 mL/mmol amide) (or DCE wherever applicable). Ethyl glyoxalate (1.2 equiv) and the appropriate aromatic compound (3.0 equiv) were added under vigorous stirring. Ethyl glyoxalate was used as a 50 wt% solution in toluene (technical form) and used as received for the reactions with iron(III) salts. For the reaction with Bi(OTf)3 toluene was removed in vacuo (1 mbar, 3 h) in order to avoid side reactions. The resulting oil was redissolved in MeNO2. The reaction mixture was heated to 40-100 C and stirred at this temperature. After cooling to r.t., the reaction mixture was diluted with EtOAc and filtered through a short plug of Celite and silica gel. The plug was rinsed with additional EtOAc. The combined filtrates were concentrated under reduced pressure. Purification of the crude residue by column chromatography (cyclohexane/EtOAc, then n-hexane/EtOAc) afforded the analytically pure product.
With tributyl-amine; at 0 - 5℃; for 3.5h;Inert atmosphere;
Step 1: 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[3610-02-4]1-benzothiophen-4-ol</strong> (1.0 g, 6.32 mmol, 1.00 equiv, 95%), potassium hydroxide (821 mg, 1.46 mmol, 2.20 equiv, 10%). This was followed by the addition of 2-oxoacetic acid (592 mg, 4.00 mmol, 1.20 equiv) at 0-5 C. with 30 min. If necessary, more 2-oxoacetic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5 degree C. 20 mL of tert-butyl methyl ether were added to the reacion mixture followed by HCl(25%) solution in water such that the pH was 7. The biphasic mixture was filtered through Speedex, then HCl (25%) solution in water were added to the aqueous phase such that the pH was 2.0. After addition of tert-butyl methyl ether (3*20 mL), the organic phase was separated at 25 C., and 50 mL acetonitrile was added to organic phase. To the resulting clear solution was added portions wise at 20-30 C., a solution of tributylamine (1.23 g, 1.00 equiv) in 20 mL of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 degree C., and then filtered off. The filter cake was dried oven at 60 C. The result afford (1.0 g, 63%) of 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid as gray solid.
63%
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[3610-02-4]1-benzothiophen-4-ol</strong> (1.0 g, 6.32 mmol, 1.00 equiv, 95%), potassium hydroxide (821 mg, 1.46 mmol, 2.20 equiv, 10%). This was followed by the addition of 2-oxoacetic acid (592 mg, 4.00 mmol, 1.20 equiv) at 0-5 C. with 30 min. If necessary, more 2-oxoacetic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5 degree C. 20 mL of tert-butyl methyl ether were added to the reaction mixture followed by HCl(25%) solution in water such that the pH was 7. The biphasic mixture was filtered through Speedex, then HCl (25%) solution in water were added to the aqueous phase such that the pH was 2.0. After addition of tert-butyl methyl ether (3*20 mL), the organic phase was separated at 25 C., and 50 mL acetonitrile was added to organic phase. To the resulting clear solution was added portions wise at 20-30 C., a solution of tributylamine (1.23 g, 1.00 equiv) in 20 mL of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 degree C., and then filtered off. The filter cake was dried oven at 60 C. The result afford (1.0 g, 63%) of 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid as gray solid
63%
With potassium hydroxide; at 0 - 5℃; for 3.5h;pH 11.5;Inert atmosphere;
Into a 100-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1 -benzothiophen-4-ol (1.0 g, 6.32 mmol, 1.00 equiv, 95%), potassium hydroxide (821 mg, 1.46 mmol, 2.20 equiv, 10%). This was followed by the addition of 2-oxoacetic acid (592 mg, 4.00 mmol, 1.20 equiv) at 0-5C with 30 min. If necessary, more 2-oxoacetic acid is added such that the pH of he solution at the end of the addition was 11.5. After stirring for 3h at 0-5 degree C. 20mL of tert-butyl methyl ether were added to the reacion mixture followed by HC1(25%) solution in water such that the pH was 7. The biphasic mixture was filtered through Speedex, then HC1 (25%) solution in water were added to the aqueous phase such that the pH was 2.0. After addition of tert-butyl methyl ether (3*20mL), the organic phase was separated at 25C, and 50mL acetonitrile was added to organic phase. To the resultiong clear solution was added portionswise at 20-30 C, a solution of tributylamine (1.23 g, 1.00 equiv) in 20 mL of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 degree C, and then filtered off. The filter cake was dried oven at 60 C. The result afford (l.Og, 63%) of 2-hydroxy-2-(4-hydroxy-l- benzothiophen-7-yl)acetic acid as gray solid.
2-(diallylamino)-2-(1-methyl-1H-indazol-5-yl)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In acetonitrile; at 60℃;
(Step 1) A solution of <strong>[590418-08-9](1-methyl-1H-indazol-5-yl)boronic acid</strong> (1.0 g, 5.68 mmol), glyoxylic acid monohydrate (0.523 g, 5.68 mmol) and diallylamine (0.699 mL, 5.68 mmol) in acetonitrile (15 mL) was stirred overnight at 60C. The precipitate was collected by filtration, and washed with ethyl acetate to give 2-(diallylamino)-2-(1-methyl-1H-indazol-5-yl)acetic acid (1.41 g, 4.94 mmol, 87%) as a white solid. 1H NMR(300 MHz,DMSO-d6) :delta3.04-3.28(4H,m),4.03(3H,s),4.53(1H,s),5.07-5.21(4H,m),5.70-5.93(2H,m),7.45(1H,dd,J=8.9,1.3 Hz),7.62(1H,d,J=8.7 Hz),7.70(1H,s),8.04(1H,d,J=0.8 Hz),12.53(1H,brs).
<strong>[6972-82-3]5,6-diamino-1-methyluracil</strong> (10g, 64.1mmol) (Synthesis of <strong>[6972-82-3]5,6-diamino-1-methyluracil</strong>, see J. Med. Chem. 2009, 52, 6433-6446) was added to 30 mL of water,Hydroxy acetic acid (4. 87 g, 128.2 mmol) was added,100 ° C Reaction 3. After 5 hours,Sodium hydroxide (4. 3 g, 107.5 mmol) was added and the reaction was carried out at 100 ° C for 5 hours.The solid precipitated to room temperature, filtered and the cake was recrystallized from water to give 6.2 g of a 78.8percent
Z-4-(3-methoxyphenyl)-3-methyl-4-oxo-2-but-enoic acid[ No CAS ]
E-4-(3-methoxyphenyl)-3-methyl-4-oxo-2-but-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In 1,4-dioxane;Reflux;
3'-Methoxypropiophenone (164.8 g, 1.0 mol) and glyoxylic acid (50%, 297 g, 1.5 mol, 1.5 eq.), concentrated H2S04 (50 mL) in dioxane (1 L) was refluxed overnight. After the starting material detected was less than 1 % by HPLC analysis, the mixture was distilled off under vacuum to afford dioxane (1.0-1.2 L, recyclable), and the residue was poured into ice -water (2 L). The solid was collected, washed with H20 and dried under vacuum to give a mixture of intermediate trans-(2) and cis-(2) (trans/cis=3: l), 180.8 g, 81.8% yield with >98% purity
To a solution of mixture of intermediate trans-(2) and cis-(2) (188 g, 0.85 mol) in HOAc (1.7 (0093) L) and H20 (680 mL) was added Zinc dust (67 g, 1.03 mol, 1.2 eq). The resulting mixture was refluxed for 1 h, cooled to rt, diluted with brine (800 mL), and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 L), dried over Na2S04 and concentrated under vacuum to give an oil residue, which was diluted with PE (500 mL). After stirred at 0C for 2 h, the formed solid was collected, washed with PE (500 mL) and dried under vacuum at 40C overnight to give TP2 as a yellow powder. The crude product was recrystallized from Toluene (0.7x) from 80 C to 0 C to give intermediate (3) 140.3 g, >99% pure, 74.6% yield (about 10% product was lost in mother liquor).
200 mesh hydroxyapatite powder, 0.008g as catalystUse 52 mL of hot water as solvent,The reaction was carried out with 0.1 mol o-phenylenediamine and 0.11 mol glyoxylic acid as raw materials. The reaction time was 6 hours and the reaction temperature was 52°C.After the reaction is over,Hot filter,Cool the filtrate to 2 °CWhite crystals precipitated,Filtered to obtain crystals,35 °C vacuum drying overnight,That is, benzimidazole-2-formaldehyde 11.9g, yield 81percent,Purity 99.6percent,
4-(3-chlorophenyl)-5-hydroxy-5-methylfuran-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Ketone or phenyl acetone derivatives (1.0 mmol) was added to a mixture of glyoxylic acid (2.5 mmol) and orthophosphoric acid (10 mL). The reaction mixture was stirred at 75 C for 5 h and then left to stand overnight at room temperature. Ice-cooled brine (20 mL) was added to the reaction mixture. The mixture was extracted in dichloromethane/diethyl ether (1:1, 3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude keto acids or furanones.
With sodium hydroxide; In water; at 115 - 120℃; for 2h;Large scale;
S1. Control the temperature in the reaction channel at 115-120 C, adjust the flow rate of the double pump, and simultaneously pump 1.5 kg of hydantoin 10 kg of water,2.5 kg of 50% mixed solution of glyoxylic acid and 7.5 liters of 8N sodium hydroxide solution, after heating and circulating for 2 hours,Stop heating, and when the temperature drops to 70-80 C, transfer the reaction solution to a 50 liter purification reactor.Maintain the internal temperature at 60-65 C, add concentrated hydrochloric acid dropwise to adjust the pH to 9-9.5, and centrifuge the precipitated solid.A crude white sodium orotate is obtained, and the crude product is added to 6 liters of water.Incubate at 60-65 C, add concentrated hydrochloric acid to adjust the pH to 1-2, stir for half an hour, centrifuge the precipitated solid to obtain 3 kg of crude orotic acid;S2. Add the above crude sodium orotate to 90 liters of water, raise the temperature to 90-95 C, add concentrated ammonia water to adjust the pH to 4-5.To the solid solution, add 50 g of acidic activated carbon, decolorize for 15 minutes, then filter while hot.The filtrate was added with concentrated hydrochloric acid at 80 C to adjust the pH to 1, and after slowly stirring for 2 minutes, the temperature was naturally lowered.The crystal is allowed to stand, and when the temperature is lowered to 50-55 C, centrifugation is started, and the filter cake is washed with water.The air was dried at 100 C to obtain 2.15 kg of anhydrous orotic acid, and the yield was 91.9%.
With nickel(II) triflate; toluene-4-sulfonic acid; for 24h;Inert atmosphere; Heating; Green chemistry;
10 g of 2,4-di-tert-butylphenol was added to a 1000 mL three-necked flask. Glyoxylic acid 80mL, O-xylene 170mL, 250 mg of p-toluenesulfonic acid, 3.57 g of nickel triflate, Vacuuming backfilling nitrogen, The pump is depressurized, the temperature is slowly increased to 1600 C, and the reaction is 24 h. Distilling o-xylene under reduced pressure, Cool down to 70 C, Add 400 mL of methanol dropwise, A deep red solid precipitated while stirring. Filtering, Rinse with methanol, The obtained crude product was dissolved in dichloromethane and then recrystallized by dropwise addition of methanol. Obtained 122 g of a white solid. The yield was 98%.
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