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CAS No. : | 3687-18-1 | MDL No. : | MFCD00008225 |
Formula : | C3H9NO3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SNKZJIOFVMKAOJ-UHFFFAOYSA-N |
M.W : | 139.17 | Pubchem ID : | 1646 |
Synonyms : |
Tramiprosate;Homotaurine;Tramiprosate, Tramiprosate Na, Tramiprosate sodium, Alzhemed, Homotaurine, NC-758, NC 758, NC758;3-Sulfopropylamine;NSC 77071;NC 758;NC 531;Alzhemed
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 29.78 |
TPSA : | 88.77 Ų |
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) : | -9.81 cm/s |
Log Po/w (iLOGP) : | -0.14 |
Log Po/w (XLOGP3) : | -3.75 |
Log Po/w (WLOGP) : | 0.3 |
Log Po/w (MLOGP) : | -0.99 |
Log Po/w (SILICOS-IT) : | -1.18 |
Consensus Log Po/w : | -1.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.86 |
Solubility : | 10000.0 mg/ml ; 72.0 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 2.48 |
Solubility : | 41600.0 mg/ml ; 299.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.06 |
Solubility : | 122.0 mg/ml ; 0.875 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.59 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 80 - 90% | With dipotassium hydrogenphosphate; In water; dimethyl sulfoxide;pH 8.0; | Preparation of palladium bacteriopheophorbide a 173- (3-sulfopropyl) amide potassium salt (Compound 2 Ten (10) mg of compound 6 in 1 ml of DMSO was mixed with 20 mg of homotaurine (3-AMINO-1-PROPANE-SULFONIC acid) in 1 ml of 0.1 M K-phosphate buffer, pH 8.0 for overnight. Then the reaction mixture was partitioned in CHLOROFORM/WATER. The organic layer was dried over anhydrous sodium sulfate and evaporated. The dry residue was re-dissolved in chloroform-methanol (19: 1) and applied to a chromatographic column with silica. The product 7 was obtained with chloroform- methanol (4: 1) elution. The yield was about 80-90%. ESI-MS (-): 834 (M-K) m/z. NMR (MeOH-d4): 9.16 (5-H, s), 8.71 (10-H, s), 8.60 (20-H, s), 6.05 (132-H, s), 4. 51, 4. 39, 4.11, 3. 98 (7,8, 17,18-H, all M), 3.92 (134-ME, s), 3.48 (21-Me, s), 3.36 (121-Me, s), 3.09 (32-ME, s), 2.02-2. 42 (171 AND 1172-CH2, M), 2.15 (8L-CH2, q), 1.81 (71-ME, d), 1.72 (181-Me, d), 1.05 (82-ME, t), 3.04, 2.68, and 2.32 (CH2'S of homotaurine, M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | 3-amino-1-propanesulfonic acid (2.0 g, 14.4 mmol) was dissolved a NAOH (1.2 g, 30.2 mmol) solution in a mixture of 1, 4-dioxane (SmL) and water (15 mL). The mixture was cooled to 0C before pivaloyl chloride (2. 8 mL, 21.6 mmol) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and it was stirred at 65 C for 4h. The solvent was evaporated under reduced pressure. The resulting solid was dissolved in water (30 mL), and treated with Dowex 50WX8 resin. The suspension was stirred for 5 minutes and the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The residual material was suspended in 20% ETOH/ACETONE. The mixture was stirres at reflux for 30 seconds. The solid product was collected by filtration, and dried in vacuo, to afford compound DT (1.3 g, 41%). 1H NMR (D20,500 MHz) 5 PPM 3. 16 (t, 2H, J= 6. 8 Hz), 2.75 (t, 2H, J= 7. 8 Hz), 1.78 (m, 2H), 1.1 (s, 9H). 13C NMR (D20, 125 MHz) 8 ppm 182. 75,48. 70,38. 57, 38. 18,26. 65,24. 27. ES-MS 222 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium hydroxide; In water; at 70℃; for 1.5h; | 3-AMINO-1-PROPANESULFONIC acid (1.07 g, 7.7 mmol) was dissolved in 1.5N NAOH (5.3 mL). To this solution was added benzyl isothiocyanate (1.02 ML, 7.7 mmol). The reaction mixture was stirred at 70C for 0. 5h ; a second-equivalent of benzyl isocyanate (1.02 ML, 7.7 mmol) was added. The reaction mixture was stirred for LH. The solvent was evaporated under reduced pressure. The residue was suspended in hot acetone. The solid material was collected by filtration, washed with hot acetone, and dried in vacuo. The residual material was recrystallized from MeOH (traces of water), affording compound AM, 1.00 g (42%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium hydroxide; In ethanol; water; at 70℃; for 1.5h; | 3-AMINO-1-PROPANESULFONIC acid (1.06 g, 7.7 mmol) was dissolved in 1. 5N NAOH (5. 3 mL). To this solution was added 1-adamantyl isocyanate (1.36g 7.7 mmol) in hot EtOH (5 mL). The reaction mixture was stirred at 70C for 30min followed by addition (to the mixture) of one-equivalent of 1-adamantyl isocyanate (1.37, 7.7 mmol) in hot EtOH (5 mL). The reaction mixture was stirred for LH. The solvent was removed under reduced pressure. The residue was suspended in hot acetone. The solid material was collected by filtration, washed with hot acetone, and dried in vacuo. The solid was recrystallized from EtOH, affording compound AK, 519.4 mg (20%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide; In water; at 70℃; for 1.5h; | 3-AMINO-1-PROPANESULFONIC acid (1.06 g, 7.7 mmol) was dissolved in 1. 5N NAOH (5. 3 mL). To this solution was added benzyl isocyanate (927 I1L, 7.7 mmol). The reaction mixture was stirred at 70C for 30 min, followed by addition to the mixture one-equivalent of benzyl isocyanate (927 UL, 7.7 mmol). The reaction mixture was stirred for LHOUR. THE solvent was evaporated under reduced pressure. The residue was suspended in hot acetone. The solid material was collected by filtration, washed with hot acetone, and dried in vacuo ; affording compound AH, 2.07 g (92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydroxide; In water; at 70℃; for 2h; | 3-amino-1-propanesulfonic acid (2.0 g, 14.3 mmol) was dissolved in 1.6M NAOH (10 mL). To this solution was added tert-butyl isocyanate (1.1 g, 14.3 MMOL). The reaction mixture was stirred at 70C for lh, followed by addition of one equivalent of tert-butyl isocyanate (1.1 g, 14.3 mmol). The reaction mixture was stirred for LH. The solvent was evaporated under reduced pressure. The residue was suspended in EtOH (30 mL). The solid product was collected by filtration, washed with EtOH (20 mL) and acetone (20 mL). The resulting solid was dried in vacuo, to afford the sodium salt of compound DP (2.1 g, 66%). TH NMR (D20, 500 MHz) 8 ppm 3.03 (t, 2H, J= 6. 6 Hz), 2.76 (t, 2H, J= 7. 6 Hz), 1.72 (m, 2H), 1.12 (s, 9H). 13C NMR (DAL, 125 MHz) 8 PPM 160. 35,50. 26,48. 74,38. 31,28. 86,25. 24. ES-MS 280 (M+NA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium hydroxide; In water; at 0 - 20℃; for 22h; | 3-AMINO-1-PROPANESULFONIC acid (1.0 g, 7.2 mmol) was dissolved in solution of 3M NAOH (7.2 mL). The mixture was cooled to 0C before phenylacetyl chloride (1.4 mL, 10.8 mmol) was added. The reaction mixture was allowed to warm up to room temperature and it was stirred for 22h. The solvent was evaporated under reduced pressure. The residue was suspended in 50% ETOH/ACETONE. The mixture was stirred at reflux for 30 sec. The solid material was collected by filtration and dried in vacuo. The product was recrystallized from 95 % ETOH/H2O and dried in vacuo. This allowed the isolation of compound AG, 880 mg (44%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With sodium hydroxide; In water; at 70℃; | Thionyl chloride (1.6 mL, 21.1 mmol) was added to ibuprofen (1.02 g, 4.9 mmol). The reaction mixture was heated to reflux for 4h. The solvent was evaporated, dried in vacuo, giving corresponding acid chloride. 3-AMINO-1-PROPANESULFONIC acid (308 mg, 2.2 mmol) was dissolved in 1. 5N NAOH (3 mL). To this solution was added dropwise the acid chloride (500.8 mg, 4.4 mmol, prepared above). The reaction mixture was stirred at 70C overnight. The solvent was removed under reduced pressure. The residue was suspended in acetone. The suspension was stirred at reflux for 30 seconds. The solid material was removed by filtration. The filtrate was evaporated to dryness under reduced pressure. The residual material was subjected to separation by flash chromatography (80% CH2CK/MEOH). This allowed the isolation of compound AL, 237 mg (14%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydroxide; In water; at 70℃; for 1.5h; | 3-amino-1-propanesulfonic acid (1.06 g, 7.7 mmol) was dissolved in 1. 5N NAOH (5. 3 mL). To this solution was added n-dodecyl isocyanate (1.7 mL, 7.7 mmol). The reaction mixture was stirred at 70C for 30min followed by addition to the mixture one- equivalent of n-dodecyl isocyanate (1.7 mL, 7.7 mmol). The reaction mixture was stirred for LH. The solvent was removed under reduced pressure. The residual material was suspended in hot acetone. The solid material was collected by filtration, washed with hot acetone, and dried in vacuo ; affording compound AJ, 2.47g (86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | The 3-amino-1-propanesulfonic acid (1.0 g, 7.2 mmol) was dissolved in 3N NAOH (370 mg, 9.4 mmol in 3 mL of water). After the solution was cooled to 0C, diphenylmethyl isocyanate (1.4 mL, 7.2 mmol) was added. The reaction mixture was allowed to warm up to room temperature, stirred for 8h (r. t. ), and followed by addition OF 3N NAOH (3 mL). The reaction mixture was stirred for 18H. The pH of the reaction mixture was brought to 3 with 5N EIC1. The solvent was evaporated under reduced pressure. EtOH (15 mL) was added and the mixture was stirred at reflux for 30 sec. The hot mixture was filtered. The filtrate was evaporated to dryness. This process was repeated 2 more times. The final product was dried in vacuo, affording compound AF, 837 MG (34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; | Compounds I in which Q1 is a sulfonic acid group (or compounds IV) can be synthesized by the reaction of a corresponding geldanamycin compound with a suitable aminosulfonic acid, as shown by procedure of Scheme 3 using 3-amino-1-propanesulfonic acid as an exemplar. The reaction can be performed in DMSO in the presence of a base such as triethylamine. The corresponding sulfonic acid compound derived from 2-amino-1-ethanesulfonic acid is disclosed in Schnur et al., J. Med. Chem. 38 (19), 3806-3812 (1995), the disclosure of which is incorporated herein by reference. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In water; acetone; at 15℃; for 0.166667h;pH 9.5;Heating / reflux; | A solution of 3,4-dicyanobenzenesulphonyl chloride (4.2 g, 0.018 mol, prepared by the method of Negrimovsky et al. Phosphorus, Sulfur, and Silicon 1995, 104, 161-167) in anhydrous acetone (20 ml) was added dropwise to a solution of 3-amino-1- propanesulphonic acid (5 g, 0.036 mol) in water (25 ml) at pH 9.5 (sat. aq. Na2CO3) at 150C (water bath). After completion of the addition the reaction mixture was heated under reflux for 10 min and allowed to cool down to room temperature. The solvent was removed under reduced pressure and a small amount of acetone/water (98:1) was added. The material was passed through a short pad of silica gel and the solvent was removed under reduced pressure. The resulting solid was crystallised from acetonitrile and hot filtered. The product was dried under vacuum over P2O5. Yield 3.8 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; ethylenediamine; | EXAMPLE 7 To a solution of ethylene diamine (30 g; 0.5 mole) in water (100 ml) was added 3-chloro-2-hydroxypropylsulfonic acid (98 g; 10.5 mole) in water (200 ml) and the mixture heated under reflux for 1 hour. Evaporation of the solvent yielded the aminopropyl sulfonic acid of the formula STR24 Analysis: Found N, 11.16; S, 14.81; Calculated N, 11.41; S, 16.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetone; acetonitrile; at 20℃; | A solution of the N-hydroxysuccinimide ester of a N-Boc-protected amino acid or a carboxylic acid (48 mmol, 1.2 eq) in acetonitrile or acetone (50 mL) was added slowly to a solution of 3APS, 3-amino-1-propanesulfonic acid, 40 mmol, 1 eq in 2 N NaOH (sodium hydroxide, 23 mL, 1.2 eq). The reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The residual material was stirred with Et2O (diethyl ether, 150 mL) at reflux for 1 h. After the mixture was cooled to room temperature, the solid material was filtered and dried in vacuo, and further purified according to one of the following work-up procedures |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 13; Synthesis of N-[3-(Chlorosulfonyl)propyl]acetamide (13)Step A: Tetramethylammonium N-acetylhomotaurate (13a)Tetramethylammonium N-acetylhomotaurate was synthesized adapting procedures disclosed in Durlach, U.S. Pat. No. 4,355,043 and U.S. Pat. No. 4,199,601, and DE 3019350. A 250 mL round bottomed flask equipped with a magnetic stir bar was charged with 3-amino-1-propanesulfonic acid (5.0 g, 36 mmol) and 20 mL of water. To the stirred solution, 13.0 g (36.0 mmol) of tetramethylammonium hydroxide ((CH3)4NOH, TMAH) (25 w-% in water) was added. The solution was stirred at room temperature for 1 hour and 4.1 mL of acetic anhydride (4.39 g, 43 mmol) was added. The mixture was stirred overnight at ca. 40 C. (oil bath) to ensure complete conversion. The resulting solution was extracted twice with 30 mL of diethyl ether or tert-butyl methyl ether (MTBE) and residual methanol in the aqueous phase was removed under reduced pressure using a rotary evaporator. The product was isolated from the residual water in the solution by lyophilization to yield 9.1 g (quant.) of the title compound (13a) as a colorless powder that was used without further purification after additional drying under high vacuum. 1H NMR (400 MHz, D2O): delta=1.88-1.95 (m, 2H), 1.97 (s, 3H), 2.88-2.92 (m, 2H), 3.16 (s, 12H), 3.27 (m, 2H) ppm. MS (ESI) m/z 180.04 (M-H)-. | |
100% | Tetramethylammonium N-acetylhomotaurate (1a) was synthesized adapting procedures disclosed in Durlach, U.S. Pat. No. 4,355,043, DE 3019350, and U.S. Pat. No. 4,199,601. A 250 mL round bottomed flask equipped with a magnetic stir bar was charged with 3-amino-1-propanesulfonic acid (5.0 g, 36.0 mmol) and 20 mL of water. To the stirred solution, 13.0 g (36.0 mmol) of tetramethylammonium hydroxide (25 w-% in water) was added. The solution was stirred at room temperature for 1 hour and acetic anhydride 4.1 mL (4.39 g, 43.0 mmol) was added. The mixture was stirred overnight at ca. 40 C. (oil bath) to ensure complete conversion. The resulting solution was extracted twice with 30 mL of diethyl ether or tert-butyl methyl ether (MTBE), and residual methanol in the aqueous phase was removed under reduced pressure using a rotary evaporator. The extract was isolated from the residual water in the solution by lyophilization to yield 9.1 g (quant.) of the title compound (1a) as a colorless powder that was used without further purification after additional thorough drying under high vacuum. 1H NMR (400 MHz, D2O): delta=1.88-1.95 (m, 2H), 1.97 (s, 3H), 2.88-2.92 (m, 2H), 3.16 (s, 12H), 3.27 (in, 2H) ppm. MS (ESI) m/z 180.04 (M-H)-. | |
100% | Tetramethylammonium N-acetylhomotaurate (1a) was synthesized adapting procedures disclosed in Durlach, U.S. Pat. No. 4,355,043, DE 3019350, and U.S. Pat. No. 4,199,601. A 250 mL round bottomed flask equipped with a magnetic stir bar was charged with 3-amino-1-propanesulfonic acid (5.0 g, 36.0 mmol) and 20 mL of water. To the stirred solution, 13.0 g (36.0 mmol) of tetramethylammonium hydroxide (25 w-% in water) was added. The solution was stirred at room temperature for 1 hour and acetic anhydride (4.1 mL, 4.39 g, 43.0 mmol) was added. The mixture was stirred overnight at ca. 40 C. (oil bath) to ensure complete conversion. The resulting solution was extracted twice with 30 mL of diethyl ether or tert-butyl methyl ether (MTBE) and residual methanol in the aqueous phase was removed under reduced pressure using a rotary evaporator. The extract was isolated from the residual water in the solution by lyophilization to yield 9.1 g (quant.) of the title compound (1a) as a colorless powder that was used without further purification after additional thorough drying under high vacuum. 1H NMR (400 MHz, D2O): delta=1.88-1.95 (m, 2H), 1.97 (s, 3H), 2.88-2.92 (m, 2H), 3.16 (s, 12H), 3.27 (m, 2H) ppm. MS (ESI) m/z 180.04 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With acetic acid; | potassium 3-phthalimidopropane-1-sulfonate; Starting from 3-amino-1-propanesulfonic acid (3.0 g) this compound was prepared according to a procedure described for 3-phthalimidoethanesulfonylchloride in literature: Winterbottom, R.; Clapp, J., W.; Miller, W., H.; English, J., P.; Roblin, R., O. Studies in chemotherapy. XV. Amides of pantoyl turine. JACS, (1947), 1393-1401.Yield: 6.09 g (98%). 1H-NMR (D2O) delta (ppm) 7.74 (s, 4H), 3.71 (t, J= 6.9 Hz, 2H), 2.97-2.89 (m, 2H), 2.12-1.98 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; for 20h;Inert atmosphere; Reflux; | Example 23; Potassium diacetyl-/?/s-(N'4-3-aminopropane-sulfonate, N"4- methylthiosemicarbazone), KL9H2; To a stirring suspension of L1H2 (0.07 g, 0.3 mmol) in acetonitrile (7 ml_) was added 3-aminopropane-sulfonic acid (0.04 g, 0.3 mmol) and K2CO3 (0.04 g, 0.3 mmol). The resulting yellow suspension was heated at reflux for 20 h under an atmosphere of N2. The resulting white suspension was cooled to room temperature and the white solid was collected by filtration, washed with acetonitrile (x1 ) and diethyl ether (x3) and dried to give an impure white powder (0.09 g). 1H NMR (d6-DMSO, 500 MHz): £ 1.84, 2H, m, CH2-CH2-CH2; £ 2.18, 6H, s, CH3; £ 2.45, 2H, t, CH2-SO3K; £ 3.01 , 3H, d, NH-CH3; £3.64, 2H, m, NH-CH2; £8.21 , 1 H, br, NH; £8.51 , 1 H, br, NH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In methanol; at 20℃; for 0.5h; | Preparation (2-hydroxyethyl)trimethylammonium 3-amino-1-propanesulfonate(choline homotaurinate). Procedure 1:At room temperature, homotaurine (69.6 g, 0.50 moles) was added in one portion to a stirred choline hydroxide solution (143 g of 45 wt.% solution in methanol, 0.53 moles of choline). An additional portion of methanol (50 ml.) was added to wash the inner wall of the flask. The mixture was stirred at room temperature for 30 min and a clear solution was obtained (note: in some cases, trace amounts of insoluble materials if any may be removed by filtration before the next step).The solution obtained was concentrated to dryness under reduced pressure (rotary evaporator) and the solid residual material was further dried at 70 C (water bath), to give a white solid (between 126 and 129 g).To the above solid was added isopropanol (300 mL), and the mixture obtained was heated (with effective stirring) to reflux to a clear solution. The solution was allowed to cool to room temperature. The mass of crystals formed was broken into slurry with a metal rod. The slurry was stirred in an ice-water bath for 0.5 to 1 hour. The crystalline solid was collected by filtration, washed with isopropanol (5 x 25 mL) and dried in a vacuum oven at 60 C overnight (or 24 to 72 hours), to give a white crystalline powder product, 110.5 to 111 g (91 to 92% yield): mp., 110-111 "C; 1H NMR (D2O, reference to DOH at 4.80 ppm) 1.87 (br-pent, 2H), 2.74 (br-t, 2H), 2.95 (br-t, 2H), 3.21 (s, 9H), 3.53 (br-m, 2H), 4.07 (br, 2H); ES-MS (m/z, positive mode) 104, 346; ES-MS (m/z, negative mode) 138, 380. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Preparation of the organic nutrient salt of carnitine and homotaurine: L-camitine inner salt (10.6 g, 0.066 mole) was dissolved in water (15 ml.) with brief heating. To the solution was added homotaurine (9.16, 0.066 mole) with constant stirring.More water (10 mL) was added to give a clear solution. Solvent was evaporated under reduced pressure. The residual solid was suspended in isobutanol (30 mL); and the mixture was concentrated to dryness under reduced pressure. The isobutanol treatment was repeated with a second portion of 15 mL isobutanol. The residual material (18.0 g) was suspended in acetone (200 mL) and the mixture was stirred overnight at room temperature.The solid material was collected by filtration, dried at 60 C under vacuum, giving a white crystalline powder (17.8 g). 1H-NMR spectrum of the product was recorded in D2O (seeFigure 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Into a 50-mL round-bottom flask, was placed a solution of 3-aminopropane-l -sulfonic acid (180 mg, 1 29 mmol, 1 00 equiv) in tetrahydrofiiran/water (10/10 niL) with sodium bicarbonate (430 mg, 5 12 mmol) This was followed by the addition of 3-(6, 8-dichloro-2-methyl-l, 2,3,4- tetrahydroisoquinohn-4 yl)benzene-l-sulfonyl chlonde (500 mg, 1 29 mmol, 099 equiv) in several batches The resulting solution was stirred for 4 h at room temperature The reaction progress was monitored by LCMS The pH value of the solution was adjusted to 6 with IM hydrogen chlonde The resulting mixture was concentrated under vacuum The crude product (500 mg) was purified by preparative HPLC to give 26 7 mg of the title compound (4%) as a TFA salt 1H-NMR (300MHz, DMSO, pprri) 10 28(s, IH), 7 53-7 79(m, 6H), 6 83(s, IH), 4 74(s, 2H), 4 51(s, IH), 3 90(s, IH), 3 06 (s, 3H), 2 86-2 93(m, 2H), 2 33-2 44(m, 2H), 1 58-1 63(m, 2H) MS (ES, m/z) 493 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With lithium hydroxide; In water;pH 9.3 - 9.9; | Synthesis of Compound 8: 3-amino-l -propane sulfonic acid (36.9 mmol, 5.14 g) was dissolved in 100 mL of water. The solution was brought to pH 9.9 with 18 mL of 1 M LiOH. The bis-acid chloride (Compound 6) was added to the solution and the mixture stirred for 3 hours. Another 7 mL of IM LiOH was added to raise the pH from 8.8 to 9.4 and the mixture continued stirring overnight. The pH dropped to 1.6 overnight. Another 18 mL of 1 M LiOH was added to raise the pH to 9.3, and the mixture stirred for 2 more hours. The pH was adjusted to 2.5 with IM HCl, and the solids were removed by filtration. Excess salts were removed via a RO membrane, and the solution concentrated under vacuum to 7.5 wt%. Yield (4.9 g as solid, 70%). LCMS (M-H = 741). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 ml glass flask was charged with 0.84 g of lithium hydroxide monohydrate (manufactured by Wako Pure Chemical Industries, Ltd.), 18.21 g of ion exchanged water, 18.21 g of isopropyl alcohol, and 2.87 g (0.02 mol) of 3-aminopropanesulfonic acid (Sigma-Aldrich Japan), and the mixture was heated to 78C. To this mixture, 15.34 g (0.04 mol) of the compound (3-1) was added dropwise for 2 hours, and the reaction was allowed to proceed for 24 hours to obtain a water / isopropyl alcohol solution containing 33.7% of the reaction product mainly comprising the compound (1-7). The reaction solution was analyzed by gas chromatography, and conversion rate of the compound (3-1) was 99.1%. To confirm the identity of the reaction product, a portion of the reaction solution was dried at 110C for 2 hours, and the resulting solid was analyzed by NMR. 1H-NMR and 13C-NMR spectrum data for the compound (1-7) were as shown below. 1H-NMR (300 MHz, solvent: CD3OD, standard substance: hexamethyldisiloxane), ? (ppm) : 1.8 to 1.9 (2H), 2.0 to 2.4 (2H), 2.4 to 2.8 (10H), 4.0 to 4.1 (2H) 13C-NMR (300 MHz, solvent: CD3OD standard substance: hexamethyldisiloxane) ? (ppm): 23.2, 36.4 to 37.0 (t), 50.3, 55.4, 55.7, 62.1, 63.0, 63.8, 64.8 The gas chromatographic analysis and the NMR spectrum data indicated substantial absence of the non-reacted compound (3-1), namely, that most of the compound (3-1) had been converted to the intended product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 ml glass container was charged with 0.80 g of sodium hydroxide, 18.2 g of ion exchanged water, 18.2 g of isopropyl alcohol, and 2.87 g (0.02 mol) of 3-aminopropanesulfonic acid (manufactured by Sigma-Aldrich Japan), and the mixture was heated to the reflux temperature. To this mixture, 15.33 g (0.04 mol) of the compound (3-1) was added dropwise for 2.5 hours, and the reaction was allowed to proceed for 36 hours to obtain a water / isopropyl alcohol solution containing 32.7% of the reaction product mainly comprising the compound (1-5). The reaction solution was analyzed by gas chromatography, and conversion rate of the compound (3-1) was 99.6%. To confirm the identity of the reaction product, a portion of the reaction solution was dried at 110C for 2 hours, and the resulting solid was analyzed by NMR. 1H-NMR and 13C-NMR spectrum data for the compound (1-5) were as shown below. 1H-NMR (300 MHz, solvent: CD3OD standard substance: hexamethyldisiloxane) ? (ppm) : 1.8 to 1.9 (2H), 2.0 to 2.4 (2H), 2.4 to 2.8 (10H), 4.0 to 4.1 (2H) 13C-NMR (300 MHz, solvent: CD3OD standard substance: hexamethyldisiloxane) ? (ppm): 23.2, 36.4 to 37.0 (t), 50.3, 55.4, 55.7, 62.1, 63.0, 63.8, 64.8 The gas chromatographic analysis and the NMR spectrum data indicated substantial absence of the non-reacted compound (3-1), namely, that most of the compound (3-1) had been converted to the intended product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | A mixture of acid example 1 .51 (360 mg; 0.427 mmol), BOC-anhydride (247 mg; 1 .13 mmol) and triethylamin (230 muIota; 1.17 mmol) in THF (100 ml) is stirred at 60 C for 3d. Volatiles are evaporated and the crude BOC-protected intermediate is further reacted without purification as follows: A mixture of the intermediate, triethylamine (170 muIota; 1 .23 mmol) and HATU (147 mg; 0.387 mmol) in DMF (6 ml) and ACN (6 ml) is stirred at ambient temperature for 30 min. The amino component 3-Amino-propylsulphonic acid (98 mg; 0.702 mmol) is added and the mixture is stirred overnight. The mixture is evaporated and the residue is purified by RP-HPLC (modifier: TFA) to yield the BOC-protected amide intermediate which is taken up in DCM and TFA and stirred overnight. Volatiles are evaporated and the residue is taken up in HCl in methanol and evaporated again. The latter is repeated for further two times to yield the title compound. Yield: 31 mg (15% of theory) C22H30ClN9O5S x 2 HCl. ESI Mass spectrum: m/z = 568 [M+H]+; m/z = 566 [M-H]-. RP-HPLC: Rt = 0.93 min (HPLC method 7). | |
Example 2.1 A mixture of acid example 1.51 (360 mg; 0.427 mmol), BOC-anhydride (247 mg; 1.13 mmol) and triethylamine (230 mul; 1.17 mmol) in THF (100 ml) is stirred at 60 C. for 3d. Volatiles are evaporated and the crude BOC-protected intermediate is further reacted without purification as follows: A mixture of the intermediate, triethylamine (170 mul; 1.23 mmol) and HATU (147 mg; 0.387 mmol) in DMF (6 ml) and ACN (6 ml) is stirred at ambient temperature for 30 min. The amino component 3-Amino-propylsulphonic acid (98 mg; 0.702 mmol) is added and the mixture is stirred overnight. The mixture is evaporated and the residue is purified by RP-HPLC (modifier: TFA) to yield the BOC-protected amide intermediate which is taken up in DCM and TFA and stirred overnight. Volatiles are evaporated and the residue is taken up in HCl in methanol and evaporated again. The latter is repeated for further two times to yield the title compound. Yield: 31 mg (15% of theory) C22H30ClN9O5S*2HCl ESI Mass spectrum: m/z=568 [M+H]+; m/z=566 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium hydroxide; In N,N-dimethyl-formamide; at 125℃; for 3h;Darkness; | General procedure: 2 (50mg, 0.095m mol) in DMF (10mL) was mixed with 3-amino-1-propane-sulfonic acid (500mg, 3.60m mol) in the presence of solid sodium hydroxide (100mg, 2.50mmol) and allowed to react at 125C in dark for 3h. Evaporated under vacuum to get rid of the solvent, the dark brown solid residue was obtained and applied to a 1% citric acid-silica gel column with dichloromethane:methyl alcohol:acetic acid=250:50:1(v/v/v) as the eluant. The brown-black constituent was collected and applied to 1% citric acid-silica gel plate with ethyl acetate:methyl alcohol=3:1 (v/v) used as the eluant. C-18 reversed phase column chromatography was used for the further purification of 3 with methanol:water=6:4 used as the eluant. The grey-brown constituent was the derivative in a yield of 36%, characterized as below. UV-vis (DMSO, lambdamax, log epsilon): 459nm (4.27), 580nm (4.29), 635nm (4.22); IR (KBr, numax, cm-1): 3444, 3363, 2935, 1610; 1H NMR (400MHz, D2O, delta): 6.50, 6.45 (s, 2H, 5,8-H), 6.11 (s, 1H, 15-H), 5.85 (s, 1H, 13-H), 4.18, 4.14, 4.10, 4.07 (m, 12H, 2,6,7,11-OCH3), 3.82 (m, 2H, 17-CH2), 3.15 (m, 2H, 19-CH2), 2.73 (s, 3H, 16-CH3), 2.43-2.45 (m, 2H, 18-CH2); 13C NMR (100MHz, CDCl3, delta): 185.52, 185.48, 168.02, 167.68, 164.60, 163.17, 149.23, 146.44, 144.48, 134.17, 134.00, 133.77, 123.89, 123.77, 123.72, 122.92, 121.68, 120.84, 108.37, 107.12, 102.91, 102.84, 61.01, 60.81, 43.63, 31.27, 30.80, 20.43, 18.12; ESI-MS (m/z): 622.2 (M-1). Anal. Calcd for C31H29NO11S: C, 59.70; H, 4.69; N, 2.25; S, 5.14; Found: C, 59.49; H, 4.98; N, 2.05; S, 4.79. HPLC (methanol/water=8:2): retention time: 10.064min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 0 - 25℃; for 18h; | To a suspension of 3-aminopropan-1-sulfonic acid (homotaurine) (1.5 g, 10.88 mmol)and NaHCO3 in H20/DMF (1:1 v/v, 30 mL) is added at 0 C a solution of compound Iin DMF (20 mL). The mixture is heated at room temperature (20-25 C) and stirred for18 hours. After several washings with AcOEt, the acqueous phase is evaporated and the yellow solid is dissolved in methanol and filtered over silica gel (dichloromethane/methanol 2:1). This way, compound 2 is obtained as a pure solid with a 59% yield.1H NMR (D20): d 1.20-1.25 (m), 1.4-1.6 (m), 1.65-1.85 (m), 2.05 (t), 2.2-2.4 (m), 2.6-2.8 (m), 3.0-3.2 (m), 3.4-3.6 (m), 7.8 (bs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.2 mg, 0.37 mumol) and diisopropylethylamine (0.11 muL, 0.65 mumol) were added to a solution of complex 70c (0.35 mg, 0.25 mumol) in dimethylformamide (50 muL). The mixture was stirred at room temperature for 5 min. A solution of homotaurine (0.05 mg, 0.37 mumol) in water (10 muL) was added to this solution, and then the solution was stirred at room temperature under inert atmosphere for 16 h. The progress of the reaction was monitored by LC-MS. After this time, reaction was complete. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (95 muL) under inert atmosphere at 4 C. and trifluoroacetic acid was added to this solution. The mixture was stirred for 20 min and then the solvent was removed under reduced pressure. The reaction mixture was purified by semipreparative HPLC to give compound 93 (0.3 mg, 85%). HRMS (ESI-) calculated for C62H69EuN8O13P3S [M]-, m/z 1409.3120 found: 1409.3110. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 1h;Inert atmosphere; | <strong>[3687-18-1]Homotaurin</strong>e (4.0 mg, 28.8 mumol), (O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate) (5.4 mg, 14.4 mumol) and diisopropylethylamine (9 muL, 48 mumol) were added successively to a solution of compound 113 (7.1 mg, 4.8 mumol) in anhydrous dimethylsulfoxide (1 mL). The mixture was stirred at room temperature for 1 h under inert atmosphere. The crude product was purified by preparative HPLC to give compound 114 in the form of a white solid (6.6 mg, 70%); HRMS (ESI+) calculated for C75H94N10O23P3S3Eu [M+2H]2+, m/z 922.2040 found: 922.2045. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium hydroxide; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere; | HypocrellinB (HB) 150mg (2.8X10 4 mol), 3-amino-1-propanesulfonicacid 1500mg(1.1X103mol) with solid sodium hydroxide1040mg (9. 8X103 moles) added into 20ml 1,4- dioxane, After thorough mixing, under a Argongas atmosphere the reaction was heated to 100 C and Mechanical stirring for 3 hours. Aftercompletion of the reaction, the solvent drained under reduced pressure, the suitableamount of deionized water was used to dissolve the residue, and then added withan equal amount of deionized water and ethyl acetate was used for extractionand extracted six times, after water layer was drained of , by chromatographicmethods carried out separation, first with dichloromethane, methanol and aceticacid with a volume ratio of 125: 25: 1 mixture and the obtained mixture wassubjected to expansion. The collected Brown product composition Rf value is 0.5, and then the brown product composition Rf value of 0.5 with ethyl acetate andmethanol with volume ratio of 3: 1mixture and obtained expanded solution was subjected to expansion, The collected gray-blackproduct composition Rf value is 0.4,obtained present invention provided formulaI represents 15 position deacetylation13 position 3-amino-1-propanesulfonic acid substituted Hypocrellinderivatives (n=3) 61mg, yield 35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium hydroxide; In acetonitrile; at 80℃; for 2h;Inert atmosphere; | Hypocrellin A (HA) 100mg (1.8X104mol), 3-amino-1-propanesulfonic acid1200mg(8.6X103mol) with solid sodium hydroxide300mg (5. 4X10 3moles) added into 20ml of acetonitrile, After thorough mixing, under a Argongas atmosphere the reaction was heated to 80 C and Mechanical stirring for 2 hours. Aftercompletion of the reaction, the solvent drained under reduced pressure, the suitableamount of deionized water was used to dissolve the residue, and then added withan equal amount of deionized water and ethyl acetate was used for extractionand extracted four times, after water layer was drained of , by chromatographicmethods carried out separation, first with dichloromethane, methanol and aceticacid with a volume ratio of 250: 50: 1 mixture and the obtained mixture wassubjected to expansion. The collected Brown product composition Rf value is 0.5, and then the brown product composition Rf value of 0.5 with ethyl acetate andmethanol with volume ratio of 3: 1mixture and obtained expanded solution was subjected to expansion, The collected gray-blackproduct composition Rf value is 0.4,obtained present invention provided formulaI represents 15 position deacetylation13 position 3-amino-1-propanesulfonic acid substituted Hypocrellinderivatives (n=3) 40mg, yield 36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In dichloromethane; at 0℃; | At 0 C, 1.39 g of a compound of formula a, 27.9 mL of triethylamine, 26.2 g of di-tert-butyl dicarbonate (BOC) 2O and 1.2 g of 4-dimethylaminopyridine was added 150 mL of dichloromethane, stirred, and after completion of the reaction, Washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, Filtering and concentrating to obtain a compound of formula b; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; | Example 4 (0066) Preparation of Compound (34) (0067) (0068) 1 g (4 mmol) of compound 33 was dissolved in 5 mL DMF C. 835 mg (6 mmol) of 3-aminopropanesulfonic acid was added, followed by addition of triethylamine (1.4 mL, 10 mmol). The reaction mixture was stirred at room temperature until TLC shows the reaction is complete. Ethyl acetate (40 mL) was added to the stirring mixture. The resulting precipitate was collected by filtration, and washed with ethyl acetate, and dried under high vacuum to give compound 34. | |
With triethylamine; In N,N-dimethyl-formamide; at 20℃; | 1 g (4 mmol) of compound 33 was dissolved in 5 mL of DMF, and 835 mg (6 mmol) of 3-aminopropanesulfonic acid was added.Triethylamine (1.4 mL, 10 mmol) was then added.The reaction mixture was stirred at room temperature until TLC showed the reaction was completed.Ethyl acetate (40 mL) was added to the stirred mixture.The resulting precipitate was collected by filtration and washed with ethyl acetate.Drying under high vacuum gave compound 34. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of Compound 28 (530 mg, 0.97 mmol) in DCM (7 mL) were added sequentially l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (224 mg, 1.17 mmol), N- hydroxybenzotriazole (145 mg, 1.07 mmol), taurine (128 mg, 1.02 mmol) and diisopropylethylamine (0.43 mL, 2.5 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (reverse phase C-18 column, 0-42% aceonitrile/ water containing 0.25% formic acid) and then further purified by MS-HPLC to afford Compound 56 (270 mg, 43%). LCMS (method A): m/z 652.6 (M+H)+. XH NMR (CD3OD) delta 7.59 (d, 2H), 7.37 (d, 2H), 4.49 (br s, 1H), 4.37 (t, 2H), 3.62 (t, 3H), 3.50-3.34 (m, 3H), 3.00-2.83 (m, 6H), 2.30 (m, 2H), 2.18 (m, 1H), 2.01 (m, 3H), 1.82 (d, 2H), 1.60 (t, 3H), 1.18 (m, 2H); Using the procedure as described in Example 7 and using DMF as solvent, (1383) Compound 231 (80 mg, 0.15 mmol) was converted to Compound 248 (20 mg, 20%). LCMS (Method A): m/z 666.7 (M+H)+. 'H NMR (DMSO-d6) delta 8.20 (m, IH), 7.83-7.80 (m, IH), 7.70-7.68 (m, 2H), 7.40-7.38 (m, 2H), 5.57 (s, IH), 4.60-4.57 (dd, IH), 4.29-4.23 (m, 2H), 3.98-3.68 (m, 4H), 3.39-3.33 (m, 2H), 3.09-3.04 (m, 2H), 3.25-2.79 (m, 4H), 2.46-2.38 (m, 2H), 2.18-2.13 (m, IH), 2.04-2.01 (m, 2H), 1.73-1.63 (m, 4H), 1.55-1.47 (m, 3H), 1.20-1.14 (m, 2H), 1.04-0.94 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 3h; | To a 50 mL round-bottom flask '.vas added 4-[(lS,4S,5R)-5-[[5-cydopropyl-3-(2,6-25 dichorophenyl)-1 ,2-oxazol-4-yllmethoxy ]-2-azabicydo[2.2.l]hepta.n-2-y l]benzoic acid I-52(200 mg, 0.40 rnmol, LOO equiv.), DIEA (206 mg, 1.59 mmol, 4.00 equiv.), N,Ndimethyltormamide(10 mL), PyBOP (312 mg, 1.30 equiv.), and 3-aminopropane-1-sulfonicacid (75 mg, 0.54 mmol, 1.50 equiv.). The resulting mixture was heated at 80C for Jh withsiirreing. After cooling to room temperature, the mixture was diluted with 100 mL ofEA, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated undervacuurn. 1l1e crude product was purified by Prep-HPLC using the following conditions:Column, XBridge Prep C18 OBD Column, l9jA150mm Sum .SumC-0013: mobile phase,Water (0.05~oTFA) and ACN (48.0%; ACN up to 62.0%; in 8 min); Detector, UV 254nm.5 After purification 2-([ 4-[(1 S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)- L2-oxazol-4-yl]methoxy ]-2-azabicyclo[2.2.1 ]heptan-2-yl]phenyl]formamido )ethane-1-sulfonic acid I-166(79.4 mg, 33%) as a light yellow solid. 1H-NMR (300 MHz, CD30D): o 7.69 (d, J = 8.5 Hz,2H), 7.60---7.44 (m, 3H), 6.68 (d, J "' 8.4 Hz, 2H), 4.32 (s, 2H), 4.19 (s, lH), 3.80 (t, J '" 6.2Hz, 2H), 3.52 (d, J '" 6.1 Hz, lH), 3.42 (dd, J '" 9.8, 4.1 Hz, HI), 3.08 (t, J" 6.5 Hz, 2H), 2.7110 (d, J = 9.8 Hz, 1H), 2.53 (s, 1H), 2.26 (p, J = 6.9 Hz, 1H), 1.92- 1. 78 (m, lH), 164 (s, 2H),1.32 (d, J = 13.5 Hz, lH), 1.22-- 1.11 (m, 4H): MS (ES, mlz): [M+ l] = 606.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35 mg | With N-ethyl-N,N-diisopropylamine; In water; at 20℃; for 4h; | (3-Aminopropane-1-sulfonic acid, 151 mg, 1.084 mmol, 2 eq) was dissolved completely in 5 ml of distilled water. Hunig base (472 ul, 2.71 mmol, 5 eq) To prepare a mixed solution. The compound 2-1 synthesized in Preparation Example 1(0.542 mmol, 1 eq) was added a mixed solution of 3-aminopropane-1-sulfonic acid The reaction proceeds at room temperature for 4 hours. After the reaction was completed, Obtained as a white solid and then subjected to silica gel chromatography to obtain pure compound 1-2(35 mg, 14.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | The probe 4 (0.581 g, 1.0 mmol) and 4-dimethylaminopyridine (0.146 g, 1.2 mmol) were dissolved in 20 ml of anhydrous dimethylformamide.Under argon protection, a solution of phenyl p-nitrochloroformate (0.242 g, 1.2 mmol) in 10 ml of anhydrous dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, 3-amino-propanesulfonic acid was added. Add sodium (0.168 g, 1.2 mmol), add anhydrous triethylamine (0.16 ml, 1.2 mmol), and stir at room temperature for 30 min under Ar-protection conditions. After completion of the reaction, the solvent is evaporated to dryness and the residue is separated by reverse phase column to obtain a probe. 0.397 g, yield 50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To Compound 24 (80 mg, 0.16 mmol) in DCM (1 mL) was added CDI (32 mg, 0.2 mmol) and the reaction was stirred at room temperature for 45 minutes. After the solvent was removed in vacuo, half of the residue was dissolved in DMF (1 mL), followed by the addition of Intermediate 18C (24 mg, 0.1 mmol) and DIEA (0.02 mL, 0.12 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (0 - 5% MeOH/DCM) to afford Compound 28A (42 mg, 68%). LCMS (method A): m/z 770.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In water; acetone; at 20℃; | 3-Amino-1-propanesulfonic acid (300 mg, 2.15 mmol) was dissolved in water (3 mL) followed by the addition of tetrabutylammonium hydroxide (0.2 M, 11 mL). A solution of Boc20 (759 mg, 2.15 mmol) in acetone (8 mL) was then added to dropwise. The reaction mixture was stirred at room temperature overnight. The acetone was removed in vacuo and the remaining aqueous mixture was extracted with dichloromethane and the combined organic layers were dried and concentrated under vacuum to obtain the product as an oil (912 mg, 88%). dH (400 MHz, CDCIs) 3.31 (m, 10H, CH2), 2.87 (t, 2H, CH2), 1.99 (m, 2H, CH2), 1.65 (m, 8H, CH2), 1.45 (m, 8H, CH2), 1.41 (s, 9H, CH3), 1.01 (t, 12H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium hydroxide; In water; N,N-dimethyl-formamide; | Toa mixture of amine or hydroxylamine derivatives (128 mmol) and NaOH (3.8 g,96mmol) in DMF (50 mL) and H2O (10 mL) was added 4-(3-bromo- 4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(12 g, 32 mmol) in DMF (30 mL). The reaction mixture was stirred at roomtemperature and the reaction progress was monitored by TLC. After fullconversion, the mixture was diluted with water and the solution was filtered togive product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: Homotaurin In N,N-dimethyl-formamide at 20℃; | 56 Monomethyl isophthalate 56a (500mg, 2.77mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 1023mg, 3.32mmol) and triethylamine (561mg, 5.54mmol) were sequentially added to N,N-dimethylformamide (6mL), stirred at room temperature and reacted for 1 hour, then 3-amino-1-propanesulfonic acid (579mg , 4.16mmol), continue to stir the reaction at room temperature.After the completion of the reaction was detected by TLC, ethyl acetate (20 mL) was added to dilute the reaction solution, the reaction solution was extracted with water (20 mL), and the aqueous phase was washed with ethyl acetate (20 mL).After the solvent was evaporated from the aqueous phase under reduced pressure, it was purified by silica gel column chromatography (dichloromethane: methanol = 15:1) to obtain compound 56b (white solid, 420 mg, yield 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide In water at 50℃; for 3h; | 14 Example 14 Sodium 3-((((2,2-dipentyl-1,3-dioxolan-4-yl)methoxy)carbonyl)amino)propane-1-sulfonate (JZ-0177) To a round bottom flask with (2,2-dipentyl-1,3-dioxolan-4-yl)methyl (4-nitrophenyl) carbonate (205 mg, 0.5 mmol), 3-aminopropane-1-sulfonic acid (104 mg, 0.75 mmol) and 5 mL can, 1M NaOH aq solution (1 mL) at RT was added. The reaction was stirred at 50°C for 3h. The crude mixture was then concentrated on vacuum, purified by flash column. A white color solid product was obtained (210 mg, 97%). 1H NMR (400 MHz, DMSO-d6): d 7.24 (t, J = 5.8 Hz, 1H), 4.19 (qd, J = 6.7, 4.2 Hz, 1H), 4.09 - 3.97 (m, 2H), 3.87 (dd, J = 11.4, 6.5 Hz, 1H), 3.57 (dd, J = 8.2, 6.9 Hz, 1H), 3.01 (q, J = 6.7 Hz, 2H), 2.43 - 2.35 (m, 2H), 1.68 (m, 2H), 1.52 (m, 4H), 1.36 - 1.15 (m, 12H), 0.90 - 0.80 (m, 6H). MS m/z 408 [M - Na - H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | Stage #1: propan-1-ol-3-amine With sulfur trioxide; sodium iodide at 110℃; for 0.75h; Inert atmosphere; Stage #2: With hydrogenchloride In water at 20℃; | 1-7; 1 Add 20g of tetrabutyl titanate and 150mL of absolute ethanol into a round bottom flask and mix well, then add 100mL of deionized water and stir for 30min at room temperature, then heat to 80, stir for 30min, and then add 20wt% HNO3 dropwise. During the addition process, the solution will gradually become turbid. When the ratio of n(HNO3) to n(tetrabutyl titanate) is 4, stop adding nitric acid; after stirring for 3h, the colloidal solution will be generated according to the doping amount of molybdenum Add 2.8ml of ammonium molybdate solution containing 0.25g/mL of molybdenum, and continue to stir for 10h, and filter to obtain a stable molybdenum-doped nano-TiO2 sol. After washing and drying, it is calcined in a muffle furnace at 400 for 8h to obtain molybdenum-doped sol. Hybrid nano-titanium dioxide.Add 500g of 3-aminopropanol with a concentration of 25wt%, 12.5g of sodium iodide, and 30.0g of molybdenum-doped titanium dioxide into the reactor. The stirring speed of self-priming slurry is 800r/min. The temperature is increased to 110°C and diluted with nitrogen. 45% concentration of standard gas SO3, maintain the pressure at 8.0MPa, after 45 minutes of reaction, reduce to room temperature, discharge excess SO3; add 20wt% hydrochloric acid dropwise to the reaction kettle until the system pH=6; take 500g of mother liquor after pickling , Add 562.5g of ethanol and 187.5g of isopropanol to the mother liquor, adjust the speed to 100r/min and fully stir, set the cooling program of 1.0/min, the end of the cooling is -15, and after the crystal is cultivated for 60min, add the mother liquor to the centrifuge In the machine, centrifuge at 1500r/min, centrifuge for 10min, add 25g of anhydrous ethanol and methanol mixture at -15 to rinse, centrifuge again for 1min, and dry at 80 to obtain qualified 3-aminopropanesulfonic acid. The yield is 96.5%, and the purity is 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In 1-methyl-pyrrolidin-2-one; water at 160 - 180℃; for 10h; Inert atmosphere; Autoclave; | 1-7 Example 7 Add 4.0L of NMP/water (4:1) mixed solvent to a stainless steel autoclave equipped with a water trap, and then phenolphthalein (2mol, 636g) and 3-aminopropanesulfonic acid (2.04mol, 284g) are suspended in In the solvent, a weak base potassium carbonate (1.02 mol, 141 g) was added under stirring conditions. Subsequently, vacuum degassed three times, heated to 160°C under nitrogen protection, and reacted for 4 hours. After the water output stabilized, the water separator valve was closed. The temperature was increased to 180°C, while the pressure was adjusted to 1.0 MPa, and the reaction was continued for 6 hours. After cooling to room temperature, dichloromethane was added and filtered. Washed with dichloromethane several times to obtain a solid powder. The conversion rate tested by proton nuclear magnetic resonance spectrum was 87.0%. Finally, the solid powder obtained by filtration is recrystallized with ethanol to obtain the target product, and the separation yield reaches more than 80%. |
[ 14650-46-5 ]
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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