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CAS No. : | 623-57-4 | MDL No. : | MFCD00004714 |
Formula : | C5H13NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QCMHUGYTOGXZIW-UHFFFAOYSA-N |
M.W : | 119.16 | Pubchem ID : | 79078 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 31.37 |
TPSA : | 43.7 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) : | -7.77 cm/s |
Log Po/w (iLOGP) : | 1.69 |
Log Po/w (XLOGP3) : | -1.04 |
Log Po/w (WLOGP) : | -1.1 |
Log Po/w (MLOGP) : | -0.65 |
Log Po/w (SILICOS-IT) : | -0.9 |
Consensus Log Po/w : | -0.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.27 |
Solubility : | 224.0 mg/ml ; 1.88 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.61 |
Solubility : | 486.0 mg/ml ; 4.08 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.35 |
Solubility : | 267.0 mg/ml ; 2.24 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.53 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P280-P303+P361+P353-P301+P330+P331-P304+P340+P310-P305+P351+P338+P310 | UN#: | 2735 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
EXAMPLE 7 Synthesis of poly(monooleoylglyceride co succinate) liquid containing 5percent 3-dimethylamino-1,2-propanediol 40.1 g (112.5 mmoles) of glyceryl monooleate, 12.5 g (125 mmoles) of succinic anhydride and 1.5 g of 3-dimethylamino-1,2-propanediol (12.5 mmoles) were added to a dry 100 mL, single neck, round bottom flask along with 25 mul of stannous octoate. A stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed in a room temperature oil bath and a nitrogen blanket was started. The temperature was raised to 150° C. and maintained for 6 hours. After 6 hours, the flask was removed from the oil bath to cool to room temperature. The polymer was a brown, transparent viscous liquid. | ||
EXAMPLE 8 Synthesis of poly(monooleoylglyceride co succinate) liquid containing 10percent 3-dimethylamino-1,2-propanediol 36.7 g (100 mmoles) of glyceryl monooleate, 12.5 g (125 mmoles) of succinic anhydride and 3.0 g of 3-dimethylamino-1,2-propanediol (25 mmoles) were added to a dry 100 mL, single neck, round bottom flask along with 25 mul of stannous octoate. A stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed in a room temperature oil bath and a nitrogen blanket was started. The temperature was raised to 150° C. and maintained for 6 hours. After 6 hours, the flask was removed from the oil bath to cool to room temperature. The polymer was a brown, transparent viscous liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1H-imidazole; In chloroform; at 20℃; for 16h; | To a solution of <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (50.0 mg, 0.419 mmol, Aldrich Chemical Company) in 2 ML chloroform was added dimethyloctadecyl chlorosilane (328 mg, 0.944 mmol, Aldrich Chemical Company) and imidazole (68.1 mg, 0.944 mmol, Aldrich Chemical Company).After 16 hrs at ambient temperature, the solution was partitioned in EtOAc/H2O with 10percent sodium bicarbinate.The organic layer was washed with water, and brine.The solvent was removed (aspirator) to afford 266 mg (86percent) of 3-(dimethylaminopropyl)-1,2-dimethyloctadecyl silyl ether as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,3-dimethylaminopropanediol (Aldrich) was alkylated with tetradecylmethane sulfonate (NuChekPrep) to afford the tertiary amine DMP-DMA. This amine was quatranized by treatment with 3-bromopropylphthalimide (Aldrich). Deprotection of the primary amine by phthalimide cleavage using hydrazine afforded GAP-DMRIE. Two equivalents of GAP-DMRIE were reacted with 1,4-diisocyanatobutane (Aldrich) to afford SBGU-DMRIE. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | EXAMPLE 2 The procedure of Example 1 was repeated, but starting from a 0.2 M solution of dihydroxybutene together with 10 g of decanol in methanol and using as catalyst 10 g of 10percent platinum on activated carbon support (ex Merck) until 80 mmoles of dihydroxybutene were converted. 20 g of dimethylamine were precharged into the autoclave and the reduction or the reductive amination was performed at 40° C. GC analysis of the product material revealed the 3-dimethylamino-1,2-dihydroxypropane yield to be 94percent. | |
80% | EXAMPLE 3 The procedure of Example 1 was repeated, but starting from a 0.2 M solution of dihydroxybutene and 10 g decanol in methanol and using as catalyst 20 g of 5percent ruthenium type 97 (ex Johnson Matthey) until 80 mmoles of dihydroxybutene were converted. 12 g of dimethylamine were precharged into the autoclave and the reduction or the reductive amination was performed at 30° C. GC analysis of the product material revealed a yield of 80percent 3-dimethylamino-1,2-dihydroxypropane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; ethyl acetate; | Example 1 2,3 -dioleyloxy-1-(N,N-dimethylamino)propane (1). To a three-necked, 2-liter round bottom flask equipped with a Dean-Stork trap were added 3 -dimethylamino-1,2 -propanediol (6.08 g, 51.1 mmoles), xylene (1300 ml) and KOH (8.0 g). The solution was refluxed for 2 hours while removing water azeotropically via the Dean-Stork trap. Oleyl mesylate (40.0 g, 115.6 mmoles) in 100 ml xylene was added to the reaction mixture drop-wise in 30 minutes. Refluxing was continued for 3 hours and the reaction mixture concentrated to a gum. The gum was triturated with 400 ml hexane and filtered. The solid was washed with 100 ml hexane followed with 200 ml ethyl acetate. The filtrates were combined, concentrated and subjected to f lash chromatography. 2,3-dioleyloxy-1- (N, N-dimethylamino) propane was obtained as a colorless oil in 76percent yield, TLC: Rf =0.37 (Silica gel: 5percent EtOAc: hexane); IR: 2925, 2850, 1469, 1120, 1040 cm-1; H-NMR (CDCl3) delta 5.35 (t, 4H), 4.13 (q, 1H) 3.4-3.65 (m, 6H), 2.35-2.45 (m, 2H), 2.25 (S, 6H), 1.95-2.05 (m, 8H), 1.5-1.65 (m, 4H), 1.2-1.45 (m, 4H) 0.9 (t, 6H). |
95 g | [0217] 1,2-Dioleyloxy-3-dimethylaminopropane (DODMA) DLinDMA was synthesized in the same manner, exceptthat oleyl mesylate was replaced with linoley mesylate.[0218] Benzene (800 mL) was added to sodium hydride (52g, 95percent, 2.06 mol) in a 3L pear-shaped round bottom flaskwith a stir bar under argon. A solution of N,N-dimethylaminopropane-1,2-diol (28.1g, 234.8 mmol) in benzene (200mL)was slowly added to the reaction flask under argon, rinsing with a further 50mL of benzene and allowed to stir for 10minutes. [0219] Oleyl mesylate (200.3g, 578.9 mmol) in benzene (200mL) was added to the reaction mixture under argon andrinsed with a further 1200mL of benzene. The reaction mixture was allowed to reflux under argon overnight. [0220] The reaction mixture was transferred to 4L erlenmeyer flask and ethanol (100 mL) was added slowly underargon to quench unreacted sodium hydride. Additional ethanol (1300 mL) was added to give a total ethanol content of1400mL such that benzene:ethanol is 1:1. The reaction mixture (800mL) was aliquoted to a 2L separatory funnel and240mL water was added (benzene:ethanol:water 1:1:0.6 v/v). The organic phase was collected and the aqueous layerwas re-extracted with benzene (100mL).[0221] Oleyl mesylate (200.3g, 578.9 mmol) in benzene (200mL) was added to the reaction mixture under argon andrinsed with a further 1200mL of benzene. The reaction mixture was allowed to reflux under argon overnight. This stepwas repeated again. [0222] The combined organic fractions were dried with anhydrous magnesium sulphate (30g) and filtered under vacuumusing a sintered glass funnel. Solvent was removed on a rotovap (water bath 50 - 60hC). The viscous oily product wasredissolved in dichloromethane (300 mL) and vacuum filtered through a sintered glass funnel with a filter paper andsilica gel 60 (80g, 230 - 400 mesh). Dichloromethane was removed on a rotovap at 50 - 60hC. [0223] The product was purified by column chromatography. A total of 151 g product was divided into two ?75g aliquotsand loaded onto two 600g silica gel 60 columns. The product was dissolved in 2percent MeOH in dichloromethane (?1:1 w/v)prior to loading onto the column. 2percent MeOH in dichloromethane (?1 L) was used until product came out. Approximately1 L of 5percent, 7.5percent and then 10percent MeOH in dichloromethane were used to elute the columns collecting ?200 mL fractions.[0224] Fractions with a top or bottom spot on TLC (impurity) and product were rotovaped separately from the purefractions. Impure DODMA was collected from other batches, added together, and put down a column a second time topurify. The yield of DODMA was 95g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.92 g (84%) | With pyridine; In methanol; diethyl ether; hexane; water; benzene; | A. Synthesis of +-1,2-dioleoyl-3-N,N-dimethylamino-propane (AL-1). This compound was prepared by the method of Leventis et al. (Biochim. Biophys. Acta 1029:124-132, 1990). Three ml (35 mmol) of oxalyl chloride was added to 1.0 g (3.5 mmol) oleic acid dissolved in 10 ml benzene and stirred at room temperature for 1 h. After removal of solvent and excess oxalyl chloride under vacuum, the acid chloride was dissolved in 5 ml diethyl ether, and a further 5 ml of ether containing 0.20 g (1.7 mmol) of 3-N,N-dimethylamino-1,2-propanediol and 0.15 g pyridine was added. The resulting mixture was stirred at room temperature for 30 minutes before quenching with 1 ml methanol and removing solvents under vacuum. The crude product was dissolved in 50 ml hexane and washed with 2*25 ml 0.1M potassium hydroxide in methanol/water (1:1) followed by 25 ml 0.1M aqueous sodium chloride. Drying over anhydrous sodium sulphate and removal of hexane under vacuum gave a slightly yellow oil. Column chromatography on silica gel (70-230 mesh), eluding with ethyl acetate, gave 0.92 g (84percent) of pure product (TLC, Rf =0.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; benzene; | A. Synthesis of 1-stearoyl-2-hydroxy-3-N,N-dimethylaminopropane (SHDAP) STR19 A solution of stearic acid (1 g) in benzene (100 mL) was treated with oxalyl chloride (6 mL) at room temperature for one hour. The solvent was removed under reduced pressure and the residue was dissolved in dry THF. The solution was cooled to 0° C. and slowly added to a solution of 3-N,N-dimethylaminopropan-1,2-diol, with stirring. The reaction mixture was stirred at 0° C. for 0.5 hour and then warmed to room temperature for two hours. The resulting solution was diluted with water, made basic with sodium hydroxide and extracted with methylene chloride. The organic extract was concentrated and chromatographed to provide SHDAP (0.39 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | (2,3-Diacetoxy-propyl)-trimethyl-ammonium; iodide 36 A mixture of 3-dimethyl-amino-propane-1,2-diol (0.30 mL, 2.5 mmol), acetyl anhydride (2 mL, excess) and DCM (5 mL) was stirred overnight at room temperature. Then MeI (2 mL, excess) was added to the solution and the stirring was continued for 4 hours. Then the solution was concentrated and ethyl ether (20 mL) was added to the residue to precipitate the product (0.73 g, 85percent yield). The characterization data were consistent with the chemical structure and formula. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 48h; | Dodecanedioic acid 2-dimethylamino-1-[11-(2-nitro-benzyloxycarbonyl)-undecanoyloxymethyl]-ethyl ester 2-nitro-benzyl ester (29b) To an ice-cold solution of 2 (2.0 g, 5.5 mmol), 3-dimethylamino-propane-1,2-diol (0.3 mL, 2.5 mmol) and DMAP (catalytic amount) in DCM (15 mL) was slowly added a solution of DCC (1.1 g, 5.5 mmol) in DCM (5 mL). After the addition, the solution was warmed to room temperature and stirred for 2 days. The reaction mixture was then filtered to remove the insoluble DCU. Concentration of the filtrate followed by chromatography (50percent EtOAc/DCM to 100percent EtOAC) afforded 0.95 g (50percent yield) product as colorless oil. The characterization data were consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 48h; | 12-Benzyloxy-dodecanoic acid 2-(12-benzyloxy-dodecanoyloxy)-3-dimethylamino-propyl ester 39 To an ice-cold solution of 12-Benzyloxy-dodecanoic acid (0.82 g, 2.67 mmol), 3-dimethylamino-propane-1,2-diol (0.11 mL, 1 mmol) and DMAP (catalytic amount) in DCM (10 mL) was slowly added a solution of DCC (0.66 g, 3.2 mmol) in DCM (5 mL). After the addition, the solution was warmed to room temperature and stirred for 2 days. The reaction mixture was then filtered to remove the insoluble DCU. Concentration of the filtrate followed by chromatography (50percent EtOAc/DCM to 100percent EtOAC) afforded 0.21 g (30percent yield) product as colorless oil. The characterization data were consistent with the chemical structure and formula. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; | (B) DOTMA Synthesis and Liposome Preparation STR7 DOTMA (N-(1-(2,3,-Diolelyloxy)propyl)-N,N,N-trimethylammonium chloride) was prepared as outlined in FIG. 1. A mixture of <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (Aldrich Chemical Co., 1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl p-toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature and reduced pressure (30 Torr) for 30 min, and was then heated to 50° C. with stirring for an additional 15 min. The reaction vessel was purged with nitrogen, and the mixture was heated to reflux (approximately 140° C.) for 3 hrs. After cooling, the reaction mixture was diluted with hexane (100ml), and the resulting solution was extracted with water (2*50 ml). The organic layer was concentrated, and the residue was chromatographed over silica gel by elution with a mixture of hexanes and ether (1:2) to afford the intermediate 2,3-dioleyloxy-1-(dimethylamino)-propane as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dimethyl amine; In nitrogen; | EXAMPLE 34 Production of N,N-dimethyl-N-(2,3-dihydroxypropyl)glycine A reactor was charged with 180 g (2.0 mol) of 50 percent dimethylamine aqueous solution, and 74 g (1.0 mol) of glycidol was added thereto in dropwise manner over 40 minutes. After reaction at room temperature for additional 1 hour, temperature of the reaction solution was gradually elevated to 50°C, and water and excess dimethylamine were distilled off at the same temperature in a stream of nitrogen gas, followed by drying under a reduced pressure to obtain crude N,N-dimethyl-N-(2,3-dihydroxypropyl)amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 60℃; for 6h; | 309.00 parts of 3-(2-aminoethylamino)-propyldimethoxymethylsilane were mixed with 505.40 parts of freshly prepared organic phase from 1.1 with stirring and heated to 60° C. A slightly exothermic reaction took place. After about 2 hours, the exothermic reaction subsided, and the mixture was left to react further at 60° C. for 4 hours. It was then cooled to room temperature. Glycidyl groups could no longer be titrated. This was because alkylation of the primary amino group had taken place. 814.4 parts of a silane mixture (I) were thus obtained with the following main components: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
298.00 parts of diethylamine were combined with 12.25 parts of water. Then, with stirring, at 20° C., 377.60 parts of epichlorohydrin were added dropwise over the course of 10 hours. The mixture was then further stirred for a further 10 hours at 20° C., and then 506.7 parts of sodium hydroxide solution, aqueous, 30percent strength by weight, were added dropwise. After 3 hours (15-20° C.), the stirrer was switched off. An organic phase (501.5 parts) formed which was separated off. It consisted of about 384.0 parts glycidyldiethylamine, 60.0 parts N,N,N',N'-tetraethyl-1,3-diamino-2-hydroxypropane, 25.0 parts water, 24.5 parts N,N-diethyl-2-hydroxy-3-chloropropanamine, 1.0 part sodium chloride and 7.0 parts 3-dimethylamino-2-hydroxy-1-propanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With pyridine;dmap; In dichloromethane; at 0 - 20℃; for 6h; | To a mixture of 3-(dimethylamino)propane-l,2-diol (0.5g, 4.2mmoles), pyridine (1.7OmL, 21mmoles) and 4-dimethylaminopyridine (catalytic amount) in 1OmL of dry dichloromethane was added myristoyl chloride (2.6g, 10.5mmoles) at 0°C. The reaction was allowed to proceed from 00C to room temperature for 6 hours. The reaction mixture was extracted with chloroform (50 mL), washed with 5percent sodium bicarbonate (3x25 mL), followed by water (2x25 mL) and brine solution (2x25 mL). The chloroform extract was evaporated on a rotary evaporator and the residue was loaded on a silica gel (230-400 mesh), eluted with 0.2percent methanol in chloroform to afford a waxy white solidAnother batch of (+/-)-N,N-Dimethyl-N-[2,3-bis(tetradecanoyloxy)-propyl]amine was prepared, and yielded the following NMR spectra coordinates: 1H NMR (CDCl3): delta 5.24-5.15 (m, IH), 4.35 (dd, J= 12.0, 3.2 Hz, IH), 4.08 (dd, J= 11.6, 6.0 Hz, IH), 2.52-2.38 (m, 2H), 2.30 (dt, J= 7.2, 3.6 Hz, 4H), 2.61 (s, 6H), 1.67-1.53 (m, 4H), 1.36- 1.17 (m, 40H), 0.87 (t, J= 6.4 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5 - 20℃;Inert atmosphere; Large scale; | 3-dimethylamino-1,2-propanediol 500 g,1600 g of diisopropylethylamine and 15 L of tetrahydrofuran are added to the reaction vessel.Cool down to minus 5°CThe gas in the replacement axe is nitrogen,A solution of 2800 g of oleic acid chloride in tetrahydrofuran was slowly added dropwise.Keep the temperature in the reactor not higher than 10°C,Then slowly warm up to room temperature,Continue to react for 2-3 hours,Concentrate under reduced pressure,Add Ethyl Acetate and Cold Water,Liquid separation,The organic phase is washed with saturated saline solution.Liquid separation,The organic phase is dried over anhydrous magnesium sulfate,filter.The organic phase is concentrated and dried under reduced pressure to obtain1,2-Dioleoyl-3-diamino-propane2580 g, yield 95percent. |
72% | With pyridine;dmap; In dichloromethane; at 0 - 20℃; for 6h; | An alternative synthesis is as follows: to a solution of 3-(dimethylamino)-l,2- propandiol (0.2 mL, 1.68 mmol), pyridine (0.55 mL, 6.72 mmol) and DMAP (20 mg, 0.17 mmol), in CH2CI2 (10 mL) at 00C was added dropwise oleoyl chloride (1.38 mL, 4.2 mmol). The reaction mixture was allowed to warm up slowly to room temperature. After stirring for 6 hours at room temperature, the reaction mixture was diluted with CH2Cl2 (50 mL), washed sequentially with 5percent aqueous sodium bicarbonate (15 mL), water (15 mL), and saturated aqueous NaCl (15 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 0.2percent MeOH in CHCl3) furnished compound II (0.782 g, 72percent) as oily liquid. NMR spectra coordinates are as follows: 1H NMR (CDCl3): delta 5.47-5.32 (m, 4H), 5.28-5.18 (m, IH), 4.40 (dd, J= 11.8, 3.0 Hz, IH)5 4.13 (dd, J= 12.0, 6.8 Hz, IH)5 2.56-2.42 (m, 2H)5 2.35 (dt, J= 7.6, 2.8 Hz, 4H), 2.30 (s, 6H), 2.12-1.97 (m, 8H), 1.71- 1.58 (m, 4H), 1.44-1.23 (m, 40H), 0.92 (t, J= 7.0 Hz, 6H).Another crop of of (+/-)-N,N-Dimethyl-N-[2,3-bis(9-(2)-octadecanoyloxy)- propyl] amine (II) was prepared and had the following 1H NMR characteristics: (400 |
With pyridine; In chloroform; at 4℃;Product distribution / selectivity; | In the herein reproduced experiment of Feigner et al., all experimental conditions have been chosen to stay in close accordance with US5,264,618 (Feigner et al.), Example 5, column 27, lines 15 to 47. 31.5 g of oleoylchloride (FLUKA 0733IAH) dissolved in 125 ml chloroform was added dropwise at 4°C under cooling over a period of 11/2 hour to 5.0 g of 3-(dimethylamino)-1 ,2-propanediol, dissolved in 37.5 ml chloroform and 25 ml of pyridine. The yellow solution was stirred overnight. Then 125 ml of cold water and 125 ml diethylether was added. The organic phase was washed twice with 100 ml of 0.5N HCL and also twice with 100 ml 0.5N sodium bicarbonate solution. 39 g anhydrous sodium sulfate was added and the so obtained suspension was filtrated and washed with 100 ml chloroform. The filtrate was then concentrated under reduced pressure at 40°C. 40.1 g of a brown liquid (SM-0318-A) having a (2R,S)-DODAP content of 24.3percent w/w measured by HPLC resulted. A further drying under reduced pressure at 60°C resulted in a reduction of weight to 31.2 g.31.0 g of this material was purified by silicic acid column chromatography as follows:Silica gel: 129 g (the amount of silica gel was calculated relative to the amount (2R,S)-DODAP) Merck 60 F 63-200umColumn: diameter 4 cm, height 60 cmFlow: about 8 ml/minAs mobile phase first 1 ,500 ml methylene chloride (fractions 1-27), then 1 ,000 ml methylene chloride/methanol 95:5 (fractions 28-47) and finally 1 ,000 ml methanol was used. Fractions were collected and combined according to their TLC analysis. So fractions 4-33 were concentrated together under reduced pressure. 10.8 g of a brown oil (SM-0318-B) having a (2R,S)-DODAP content of 65.6percent w/w measured by HPLC resulted. And fractions 34-42 resulted in 12.6 g of a brown oil (SM 0318-D) having a (2R,S)-DODAP content of 54.2percent w/w measured by HPLC.10.4 g Methylene chloride was added to 9.6 g of the compound obtained out of the fractions 4-33 (SM-0318-B) in a high pressure glass tube. The glass tube was then closed and the brownish solution was heated over night at 50°C to form an emulsion. Then the tube was opened and residual methylene chloride was removed by evaporation. 8.0 g of a yellow wax (SM-0318-E) having a (2R,S)-DOTAP chloride content of 65.0percent w/w and 1.3percent w/w (2R,S)-DODAP both measured by HPLC resulted.14.0 g acetonitrile was added to this wax (SM-0318-E). The so obtained emulsion was transferred with 80 ml acetonitrile (to obtain a ratio solid to solvent of about 1 :12) into a flask and cooled down to 20°C. Nocrystallisation could be observed. At 20°C a solidified honey like yellow- brownish material resulted which even when only slightly warming it up tended to become a sticky viscous brownish material.ConclusionThe data demonstrate that 1 ,2-dioleoyl-3-propyltrimethylammonium chloride ((2R,S)-DOTAP chloride) prepared according to the above procedure, which is in accordance with US 5,264,618 (Feigner et al), Example 5, column 27, lines 15 to 47 cannot be obtained in a crystalline form.See also Figures 6 and 7 illustrating (2R,S)-DOTAP chloride emulsion (SM- 0318-E) in acetonitrile when cooling down and (2R,S)-DOTAP chloride emulsion (S -0318-E) in acetonitrile after having been cooled it down to - 20°C, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20 - 60℃; for 4h; | 286.50 parts of 3-aminopropyldiethoxymethylsilane were mixed with 505.40 parts of the freshly prepared organic phase from 1.1 with stirring at room temperature and heated to 60° C. An exothermic reaction took place, during which the temperature was kept at 60° C. by cooling. As soon as the exothermic reaction had passed, the mixture was left to react further for 4 hours at 60° C. and only then cooled to room temperature. Glycidyl groups could no longer be titrated. This was because alkylation of the primary amino groups of the silane had taken place. This thus gave 791.9 parts of a silane mixture (II) with the following main components: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 6.25h;Product distribution / selectivity; | To a solution of 3-dimethylamino-l,2-propanediol (0.5g, 3,6 mmoles) in 10 mL dichloromethane was added cholesterylhemisuccinic acid (1.75g, 3.6 mmoles) and DCC (1.48g, 7.2 mmoles) at 0°C. The reaction was allowed to proceed from 0°C (15 mins) to room temperature for 6 hours. DCU was filtered off and the filtrate was evaporated on a rotary evaporator and loaded on a silica gel (230-400 mesh). The desired product was EPO <DP n="57"/>eluted with 4-5percent methanol in chloroform (v/v) to give a colorless thick liquid (0.834g, Rf -0.5 in 10percent methanol in chloroform, yield 34percent).1HNMR (400 MHz, CDCl3): delta 5.36 (d, J= 4.0 Hz, IH), 4.67-4.56 (m, IH), 4.19 (dd, J= 11.6, 3.6 Hz, IH), 4.04 (dd, J= 11.6, 6.0 Hz, IH), 3.97-3.89 (m, IH), 2.70-2.56 (m, 4H), 2.44 (t, J= 10.0 Hz, IH), 2.36-2.23 (m, 9H), 2.05-1.75 (m, 5H), 1.66-0.80 (m, 33H), 0.67 (s, 3H). |
34% | With dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 6.08333h;Product distribution / selectivity; | An alternative synthesis procedure is as follows: to an ice-cooled solution of cholesteryl hemisuccinate (4.09 g, 8.42 mmol) in DMF (35 mL) 3-(dimethylamino)-l,2- propandiol (1.0 mL, 8.42 mmol) was added N,N'-dicyclohexylcarbodiimide (3.47 g, 16.84 mmol). After 5 min., the ice bath was removed and the solution was stirred for an additional 6 h at room temperature. The resulting precipitation of dicyclohexylurea was removed by filtration. The filtrate was transferred to a 100 mL round bottom flask and concentrated to dryness under vacuum. The pasty mass was dissolved in CHCl3 (200 mL) and washed with H2O (30 mL), saturated aqueous NaCl (30 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 5percent MeOH in CHCl3) furnished IV (1.68 g, 34percent) as wax. NMR spectra coordinates are as follows: 1H NMR (CDCl3): delta 5.36 (d, J= 4.0 Hz, IH), 4.67-4.56 (m, IH), 4.19 (dd, J = 11.6, 3.6 Hz, IH), 4.04 (dd, J= 11.6, 6.0 Hz, IH), 3.97-3.89 (m, IH), 2.70-2.56 (m, 4H), 2.44 (t, J= 10.0 Hz, IH), 2.36-2.23 (m, 9H), 2.05-1.75 (m, 5H), 1.66-0.80 (m, 33H), 0.67 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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99.7% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.33333h; | 3 -Dimethyl amino- 1,2 -propanediol (5), (50.1 g, 420.4 mmol) was weighed into a 2 L round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with N1N- <n="254"/>dimethylformamide (750 mL) and N,N-diisopropylethylamine (111 mL, 630.7 mmol) and cooled to 0 0C. t-Butyldimethylchlorosilane (67.0 g, 1.05 equiv.) was weighed into a 500 mL round bottomed flask, sealed and then dissolved in N.TV-dimethylformamide (250 mL). The t- butyldimethylchlorosilane solution was transferred to a pressure equalizing dropping runnel and added to the stirring reaction mixture slowly over 20 minutes. The reaction was allowed to come to room temperature while stirring over 3 hours. The reaction was concentrated in vacuo. Saturated bicarbonate (1500 mL) was added to the residue and the mixture transferred to a 4L separatory funnel. The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 97.8 Ig (99.7percent) of clear, colorless oil that was used without further purification. |
87% | With 1H-imidazole; In dichloromethane; for 2.5h;Cooling with ice; Inert atmosphere; | Solid TBSC1 (1.36 g, 9.00 mmol, 1.00 equiv.) was added to a stirring, ice-cold CH2C12 (11 mL) solution of 3-dimethylaminopropane-i,2-diol (1.07 g, 9.00 mmol) and imidazole (613 mg, 9.00 mmol, 1.00 equiv.) in a round bottom flask under argon. After 2.5 h, the reaction mixture was diluted with CH2C12 and washed with distilled water (1x25 mL). The aqueous layer was extracted with CH2Cl2 (1x15 mL) and the combined organic layers washed with brine (1x15 mL), dried over Na2S04 and concentrated to afford a clear, colourless oil as silyl ether 1 (1.83 g, 87percent yield), which was used without further purification. (0308) Rf = 0.09 (Si02, 50:50 EtOAc/hexanes); (0309) NMR (300 MHz, CDCI3): delta 3.80-3-68 (m, lH), 3.60 (m, lH), 2.39 (dd, J = 12.3, 9.0 Hz, lH), 2.34-2.24 (m, lH), 2.29 (s, 6H), 0.90 (s, 9H), 0.07 (s, 6H). |
A dry dichloromethane (10 mL) solution of <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (98percent, 1.00 g, 8.39 mmol, 1.0 equiv) and imidazole (0.57 g, 8.39 mmol, 1.0 equiv) was stirred at 0° C. under argon for 15 minutes. Solid tert-butyldimethylsilyl chloride (1.26 g, 8.39 mmol, 1.0 equiv) was added to the mixture and the resultant was stirred for 2 hours at 0 °C. The mixture was then diluted with 20 mL of dichloromethane and poured into deionized water (15 mL). The organic layer was separated and the aqueous layer was extracted with two additional portions of dichloromethane (20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to afford crude 1-(tert-butyldimethylsilyloxy)-3-(dimethylamino)propan-2-ol, a thick clear oil, which was used without further purification. 1H NMR: 3.72-3.80 (m, 1H), 3.63 (d, 2H, J=5.19), 2.34-2.46 (m, 2H), 2.33 (s 6H), 0.91 (2, 9H), 0.08 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; at 0 - 20℃; | 3-Dimethylamino-l,2-propanediol (6.0 g, 50 mmol) was weighed into a 1 L round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with pyridine and cooled to 0 0C. 4,4'-Dimethoxytrityl chloride (17.9 g, 1.05 equiv.) was weighed into a 100 mL round bottomed flask, sealed and then dissolved in pyridine (80 mL). The 4,4'- dimethoxytrityl chloride solution was transferred to the stirring reaction mixture slowly, using additional fresh pyridine (20 mL) to effect the transfer of residual 4,4'-dimethoxytrityl chloride. The reaction was allowed to come to room temperature while stirring overnight. The reaction was concentrated in vacuo and re-dissolved in dichloromethane (300 mL). The organic phase was washed with saturated bicarbonate (2 x 200 mL) and brine (I x 200 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 22.19g of a yellow gum that was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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22% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of the linoleic acid (25 g, 89.1 mmol) in anhydrous DMF (60 mL), diisopropyl ethylamine (17 mL, 100 mml) was added at room temperature with stirring followed by <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (4.8 g , 40.5 mmol) and EDCI (17.25 g, 89.9 mmol) and the mixture was stirred at room temperature overnight. The TLC of the reaction mixture (eluent 20percent EtOAc in hexanes) showed the completion of the reaction. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 x <n="133"/>100 mL). The combined organic layers were washed with water (100 mL), saturated NaHCO3 (100 mL) and dried over Na2SO4. Concentration of the organic layer provided the crude product which was purified by column chromatography (silica gel, eluent: 20percent EtOAc in hexanes). The fractions containing pure product was pooled and concentrated. The pure ester was isolated as a clear liquid (5.7 g, 22percent). MS m/z 645 (M+H). 1H NMR CDCl3 delta 0.88 (t,J= 6.3Hz, 6H), 1.20-1.39 (m, 28H), 1.61 (t, J = 4.9 Hz, 12H), 2.03-2.08 (m, 8H), 2.26-2.38 (m, 10H), 2.44-2.56 (m, 2H), 2.76 (t, J= 6.3 Hz, 4 H), 4.09 (dd, J= 6.1 Hz 11.9 Hz, 1H), 4.36 (dd, J= 3.3 11.9 Hz, 1H), 5.29-5.34 (m, 1H), 5.34-5.41 (m, 8H). 13C NMR CDCl3 delta 14.30, 22.79, 25.08, 25.10, 25.83, 27.40, 29.26, 29.30, 29.34, 29.42, 29.55, 29.83, 31.73, 34.32, 34.58, 46.01, 59.37, 64.02, 128.08, 128.24, 130.21, 130.42, 173.39, 173.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example I: Synthesis of (+)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(myristoleyloxy)- 1-propanaminium bromide (GAP-DMORIE, formula I)[0310] Racemic l-dimethylamino-2,3-propanediol (0.96 g; Janssen Chimica) was converted to the disodium salt in situ by treatment with sodium hydride (60percent in oil, 0.8 g) in tetrahydrofuran (70 mL). Condensation with myristoleyl methane sulfonate (5.3 g; NuChek Prep) afforded crude (+)-N,N-dimethyl-(2,3-bis(myristoleyloxy))propylamine (DMOP-DMA). |
Yield | Reaction Conditions | Operation in experiment |
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60% | Synthesis of 1, 2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA) and 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA) (0249) 3-(Dimethylamino)-1,2-propanediol (714 mg, 6 mmol) and 95% sodium hydride (NaH, 1.26 g, 50 mmol) are stirred in benzene (30 mL) under nitrogen for 30 minutes. Linoleyl mesylate (5.0 g, 15 mmol) is added and the reaction refluxed under nitrogen for 3 hours. The reaction mixture is then cooled in an ice bath while quenching via the slow addition of ethanol. Following dilution with a further 150 mL of benzene, the mixture is washed with distilled water (2×150 mL) and brine (150 mL). The organic phase is dried over magnesium sulphate and evaporated to give the crude product. (0250) The crude product is purified on a silica gel (Kiesel Gel 60) column eluted with 0-5% methanol in chloroform. Column fractions are analyzed by thin layer chromatography (TLC) (silica gel, chloroform/methanol 9:1 v/v, visualized with molybdate dip) and fractions containing purified product (Rf=0.5) are pooled and concentrated. (0251) Decolorization and further purification of DLinDMA is effected with a second column, this time eluting with 20-50% ethyl acetate in hexane. Column fractions are analyzed by TLC (silica gel, ethyl acetate/hexane 1:1 v/v, visualized with molybdate) and fractions containing pure product (Rf=0.4) are pooled and concentrated. The procedure described herein typically yields 2.2 g (60%) of pure product. | |
EXAMPLE 2SYNTHESIS OF 1 ,2-DILINOLEYLOXY-N1N-DIMETHYL-S-AMINOPROPANE (DLINDMA) DLinDMA was synthesized as described below.1 ,2-Dilinoleyloxy-3-dimethylaminopropane (DLinDMA)To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,N-dimethyl-3-aminopropane-1 ,2- diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, the resulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75 mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred at room temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspension was treated dropwise with 250 ml_ of 1 :1 (V:V) ethanol-benzene solution. The organic phase was washed with water (150 ml_), brine (2 x 200 ml_), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9 g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by column chromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1 H NMR (400 MHz, CDCI3) delta: 5.35 (8H, m, CH=CH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2 x CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2 x NCH3), 2.05 (8H, q, vinyl CH2), 1.56 (4H, m, 2 x CH2), 1.28 (32H, m, 16 x CH2), 0.88 (6H, t, 2 x CH3) ppm. | ||
To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,N-dimethyl-3-aminopropane-1,2-diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, the resulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75 mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred at room temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspension was treated dropwise with 250 mL of 1:1 (V:V) ethanol-benzene solution. The organic phase was washed with water (150 mL), brine (2×200 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9 g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by column chromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1H NMR (400 MHz, CDCl3) delta: 5.35 (8H, m, CHCH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2×CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2×NCH3), 2.05 (8H, q, vinyl CH2), 1.56 (4H, m, 2×CH2), 1.28 (32H, m, 16×CH2), 0.88 (6H, t, 2×CH3) ppm |
10.4 g | [0211] To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,Ndimethyl-3-aminopropane-1,2-diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, theresulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred atroom temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspensionwas treated dropwise with 250 mL of 1:1 (V:V) ethanol-benzene solution. The organic phase was washed with water(150 mL), brine (2 x 200 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by columnchromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1 H NMR (400 MHz, CDCl3)delta: 5.35 (8H, m, CH=CH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2 x CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2 x NCH3), 2.05 (8H,q, vinyl CH2), 1.56 (4H, m, 2 x CH2), 1.28 (32H, m, 16 x CH2), 0.88 (6H, t, 2 x CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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27% | In methanol; dichloromethane; acetone; | (2,3-Bis-octadec-9-enyloxypropyl)-(8-hydroxy-3,6-dioxooctyloxycarbonylbutyl)-dimethylammonium bromide (ME42) A mixture of (2,3-bis-octadec-9-enyloxypropyl)-dimethylamine 4 (378 mg, 0.61 mmol) (synthesised from octadec-9-enyl mesylate and 3-dimethylamino-1,2-propanediol as described previously by Hurley et al., J. Org. Chem., 2004, 69, 980-984) and 3 (335 mg, 1.07 mmol) in acetone (5 ml) was stirred in a sealed-tube at 80° C. for 48 h. After cooling, the solvent was evaporated in vacuo. Purification by flash chromatography on silica (gradient; 5percent to 10percent methanol in dichloromethane) gave ME42 as an orange oil (140 mg, 27percent). deltaH (300 MHz; CDCl3) 0.89 (6H, t, J 6.7 Hz, 2*CH2CH3), 1.25 (44H, m), 1.53 (4H, m, 2*OCH2CH2CH2), 1.72 (2H, m, COCH2CH2), 1.85 (2H, m, CH2CH2N+), 1.99 (8H, m, 2*CH2CH=CHCH2), 2.45 (2H, t, J 6.8 Hz, COCH2), 3.36-3.43 (11H, m, 2*CH3N+, CHOCH2, CHCH2OCH2, 1H of N+CH2CH), 3.54-3.72 (14H, m, 8*CH2CH2O, HOCH2, CH2NCH2CH, CHCH2OCH2), 3.88 (1H, d, J 13.2 N+CH2CH), 4.06 (1H, m, CH), 4.23 (2H, t, J 4.6 Hz, CH2OCO), 5.32 (4H, m, 2*CH=CH); deltaC (75 MHz; CDCl3) 14.10 (2*CH2CH3, overlap), 21.52 (COCH2CH2), 22.06 (CH2CH2N+), 22.66, 26.03, 26.22, 27.20, 29.14-30.17 (signal overlap), 32.59, 33.20 (COCH2), 52.25 (2*CH3N+, overlap), 61.39 (HOCH2), 63.44 (CH2OCO), 65.14 (N+CH2CH) 65.73 (CH2CH2N+), 68.44 (CHCH2O), 68.96 (CH2CH2OCO), 69.28 (CHOCH2), 70.16 (HOCH2CH2OCH2), 70.49 (CH2OCH2CH2OCO), 71.99 (CHCH2OCH2), 72.50 (HOCH2CH2), 73.31 (CH), 129.72 (2*CH=CH, overlap), 129.95 (2*CH=CH, overlap) 172.74 (C=O); m/z (ES+) 852.76483 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Example 183; {4-[4-(4-Bromo-phenylcarbamoyl)-2-(7-isopropyl-pyrido[2,3^d]pyrimidin-4-ylamino)- phenylsulfanyl]-phenyl}-carbamic acid 3-dimethylamino-2-hydroxy-propyl ester; [0646] The product from Example 100 (76 mg, 0.1 mmol), 3-dimethylamino-propane-l,2-diol (59 muL, 0.5 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (15 muL, 0.1 mmol) in tetrahydrofuran (5 mL) was heated at 60 0C for 1 hour. The mixture was added saturated sodium carbonate, extracted with ethyl acetate, dried with magnesium sulfate, filtered and evaporated. The residue was purified by <n="179"/>reverse phase preparative HPLC with TFA method to give the title compound as a trifluoroacetic acid salt (42 mg, 43 percent). 1H NMR (300 MHz, DMSOd6) delta ppm: 1.36 (d, J=6.99 Hz, 6 H) 2.80 (d, JM4.41 Hz3 3 H) 2.84 (d, J=4.41 Hz, 3 H) 3.15 (m, 2 H) 3.28 (m, 1 H) 4.10 (m, 3 H) 7.08 (d, J=8.09 Hz, 1 H) 7.41 (d, J=8.82 Hz, 2 H) 7.54 (m, 4 H) 7.72 (d, J=8.82 Hz, 2 H) 7.89 (m, 2 H) 7.99 (s, 1 H) 8.87 (s, 1 H) 9.00 (d, J=8.46 Hz, 1 H) 9.33 (s, 1 H) 10.01 (s, 1 H) 10.40 (s, 1 H) 11.70 (s, 1 H); MS (ESI+) m/z 730 732 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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DAraDMA (Compound 21) having the structure shown below was synthesized as described below.C45H77O2NMoI. Wt.: 664.1[0494] A 250 mL round bottom flask was charged with 3-(dimethylamino)-l ,2-propanediol (0.3 g, 2.5 mmol), tetrabutylammonium hydrogen sulphate (0.4 g), arachidonyl methane sulfonate (2 g, 5.4 mmol), and 30 mL toluene. After stirring for 15 minutes, the reaction was cooled to 0-50C. A solution of 40percent sodium hydroxide (15 mL) was added slowly. The reaction was left to stir for approximately 48 hours. After 48 hours of stirring, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes. The mixture was then transferred to a 500 mL separatory funnel, quantitatively transferred with (2 x 5 mL toluene) and allowed to separate. The lower aqueous phase was run off and the organic phase was washed with saturated sodium chloride (50 mL). Approximately 20 minutes were allowed for phase separation. The two aqueous phases were separately and consecutively back extracted with chloroform (50 mL). The organic phase was subsequently dried with MgSO4, filtered, and the solvent evaporated. The crude product (2.6 g) was purified on column chromatography using silica gel (60 g) with 0-2 percent methanol gradient in dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.7% | Sodium hydride (2.5 g, 100 mmol) was added to a 250 mL round bottom flask, along with benzene (40 mL) and a stir bar. In a 50 mL beaker, a solution was made from the iV,iV-Dimethyl-3-aminopropane-l,2-diol (1.42 g, 12 mmol) and benzene (60 mL). This was added to the reaction vessel and the reaction stirred for 10 minutes (effervescence). Phytanyl Mesylate (23) (10.52 g, 28 mmol) was added and the flask fitted with a condenser, flushed with nitrogen, and heated to reflux. After 18 hours, the flask was removed from the heat and allowed to cool. The volume was made up to 200 mL with benzene. EtOH was added slowly to quench unreacted sodium hydride. Once quenching was complete, the reaction mixture was washed twice with EtOH/H2psi, in a ratio to the benzene of 1 : 1 :0.6 benzene:water:ethanol. The aqueous phases were combined and extracted with CHCl3 (2 x 100 mL). Finally, the organic phase was dried (MgSO4), filtered, and concentrated (rotovap). Purification by column chromatography yielded DPanDMA as a pale yellow oil (6.1 g, 8.97 mmol, 74.7percent). |
Yield | Reaction Conditions | Operation in experiment |
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C49H77NO2 MoI. Wt: 712.1[0509] A 250 mL round bottom flask was charged with 3-(dimethylamino)-l ,2-propanediol (0.28 g, 2.36 mmol), tetrabutylammonium hydrogen sulphate (0.4 g), docosahexaenoyl methane sulfate (2.0 g, 5.1 mmol), and 30 mL toluene. After stirring for 15 minutes, the reaction was cooled to 0-50C. A solution of 40percent sodium hydroxide (15 mL) was added slowly. The reaction was left to stir for approximately 40 hours. After 40 hours of stirring, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes. The mixture was then transferred to a 500 mL separatory funnel, quantitatively transferred with (2 x 5 mL toluene) and allowed to separate. The lower aqueous phase was run off and the organic phase was washed with saturated sodium chloride (50 mL). Approximately 20 minutes were allowed for phase separation. The two aqueous phases were separately and consecutively back extracted with chloroform (50 mL). The organic phase was subsequently dried with MgSO4, filtered, and the solvent evaporated. The crude product (4.8 g) was purified on column chromatography using silica gel (60 g) with 0-2 percent methanol gradient in dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
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gamma-DLenDMA (Compound 1) having the structure shown below was synthesized as described below.C41H73O2NMoI. Wt: 612.04 [0467] A 250 mL round bottom flask was charged with 3-(dimethylamino)-l,2-propanediol (0.8 g, 6.7 mmol), tetrabutylammonium hydrogen sulphate (1 g), gamma linolenyl mesylate (cis-6,9,12-octadecatriene sulphonic acid) (5 g, 14.6 mmol), and 30 mL toluene. After stirring for 15 minutes, the reaction was cooled to 0-5°C. A solution of 40percent sodium hydroxide (15 mL) was added slowly. The reaction was left to stir for approximately 48 hours. An additional 15 mL of toluene was then added to the reaction vessel, along with 40percent sodium hydroxide (15 mL). After the reaction was stirred for an additional 12 hours, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes. The mixture was then transferred to a 500 mL separatory funnel and allowed to separate. The lower aqueous phase was run off and the organic phase was washed with saturated sodium chloride (2 x 50 mL). Since the aqueous and organic phases resulting from the saturated sodium chloride washes could not be completely separated after 20 minutes, the lower aqueous phase (slightly yellow) was run off and back extracted with chloroform (-45 mL). The organic phase was dried with MgSO4, filtered, and the solvent evaporated.[0468] The crude product, an orange liquid, was purified on column chromatography using silica gel (6Og) with 0-3percent methanol gradient in dichloromethane to yield 3.19 g. The product was further purified via column chromatography on silica gel (50 g) with 10-30percent ethyl acetate gradient in hexanes to yield 1.26 g pure product. | ||
A 250 mL round bottom flask was charged with 3-(dimethylamino)-l,2-propanediol (0.8 g, 6.7 mmol), tetrabutylammonium hydrogen sulphate (1 g), gamma linolenyl mesylate (cis-6,9,12-octadecatriene sulphonic acid) (5 g, 14.6 mmol), and 30 mL toluene. After stirring for 15 minutes, the reaction was cooled to 0-5°C. A solution of 40percent sodium hydroxide (15 mL) was added slowly. The reaction was left to stir for approximately 48 hours. An additional 15 mL of toluene was then added to the reaction vessel, along with 40percent sodium hydroxide (15 mL). After the reaction was stirred for an additional 12 hours, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes. The mixture was then transferred to a 500 mL separatory funnel and allowed to separate. The lower aqueous phase was run off and the organic phase was washed with saturated sodium chloride (2 x 50 mL). Since the aqueous and organic phases resulting from the saturated sodium chloride washes could not be completely separated after 20 minutes, the lower aqueous phase (slightly yellow) was run off and back extracted with chloroform (-45 mL). The organic phase was dried with MgS04, filtered, and the solvent evaporated.[0326] The crude product, an orange liquid, was purified on column chromatography using silica gel (60g) with 0-3percent methanol gradient in dichloromethane to yield 3.19 g. The product was further purified via column chromatography on silica gel (50 g) with 10-30percent ethyl acetate gradient in hexanes to yield 1.26 g pure product | ||
1.26 g | Example 38 Synthesis of gamma-DLenDMA gamma-DLenDMA (Compound 61) having the structure shown below was synthesized as described below. A 250 mL round bottom flask was charged with <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (0.8 g, 6.7 mmol), tetrabutylammonium hydrogen sulphate (1 g), gamma linolenyl mesylate (cis-6,9,12-octadecatriene sulphonic acid) (5 g, 14.6 mmol), and 30 mL toluene. After stirring for 15 minutes, the reaction was cooled to 0-5° C. A solution of 40percent sodium hydroxide (15 mL) was added slowly. The reaction was left to stir for approximately 48 hours. An additional 15 mL of toluene was then added to the reaction vessel, along with 40percent sodium hydroxide (15 mL). After the reaction was stirred for an additional 12 hours, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes. The mixture was then transferred to a 500 mL separatory funnel and allowed to separate. The lower aqueous phase was nm off and the organic phase was washed with saturated sodium chloride (2×50 mL). Since the aqueous and organic phases resulting from the saturated sodium chloride washes could not be completely separated after 20 minutes, the lower aqueous phase (slightly yellow) was run off and back extracted with chloroform (45 mL). The organic phase was dried with MgSO4, filtered, and the solvent evaporated. The crude product, an orange liquid, was purified on column chromatography using silica gel (60 g) with 0-3percent methanol gradient in dichloromethane to yield 3.19 g. The product was further purified via column chromatography on silica gel (50 g) with 10-30percent ethyl acetate gradient in hexanes to yield 1.26 g pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In methanol; dichloromethane; Isopropyl acetate; water; ethyl acetate; toluene; | Example 3Synthesis of 1,2-Di-gamma-linolenyloxy-N,N-dimethylaminopropane (gamma-DLenDMA)gamma-DLenDMA having the structure shown below was synthesized as described below.A 250 mL round bottom flask was charged with <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (0.8 g, 6.7 mmol), tetrabutylammonium hydrogen sulphate (1 g), gamma linolenyl mesylate (cis-6,9,12-octadecatriene sulphonic acid) (5 g, 14.6 mmol), and 30 mL toluene.After stirring for 15 minutes, the reaction was cooled to 0-5° C. A solution of 40percent sodium hydroxide (15 mL) was added slowly.The reaction was left to stir for approximately 48 hours.An additional 15 mL of toluene was then added to the reaction vessel, along with 40percent sodium hydroxide (15 mL).After the reaction was stirred for an additional 12 hours, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes.The mixture was then transferred to a 500 mL separatory funnel and allowed to separate.The lower aqueous phase was run off and the organic phase was washed with saturated sodium chloride (2*50 mL).Since the aqueous and organic phases resulting from the saturated sodium chloride washes could not be completely separated after 20 minutes, the lower aqueous phase (slightly yellow) was run off and back extracted with chloroform (~45 mL).The organic phase was dried with MgSO4, filtered, and the solvent evaporated.The crude product, an orange liquid, was purified on column chromatography using silica gel (60 g) with 0-3percent methanol gradient in dichloromethane to yield 3.19 g.The product was further purified via column chromatography on silica gel (50 g) with 10-30percent ethyl acetate gradient in hexanes to yield 1.26 g pure product. | |
With sodium hydroxide; In methanol; dichloromethane; Isopropyl acetate; water; ethyl acetate; toluene; | Example 4Synthesis of 1,2-Di-gamma-linolenyloxy-N,N-dimethylaminopropane (gamma-DLenDMA)gamma-DLenDMA having the structure shown below was synthesized as described belowA 250 mL round bottom flask was charged with <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (0.8 g, 6.7 mmol), tetrabutylammonium hydrogen sulphate (1 g), gamma linolenyl mesylate (cis-6,9,12-octadecatriene sulphonic acid) (5 g, 14.6 mmol), and 30 mL toluene.After stirring for 15 minutes, the reaction was cooled to 0-5° C. A solution of 40percent sodium hydroxide (15 mL) was added slowly.The reaction was left to stir for approximately 48 hours.An additional 15 mL of toluene was then added to the reaction vessel, along with 40percent sodium hydroxide (15 mL).After the reaction was stirred for an additional 12 hours, water (50 mL) and isopropyl acetate (50 mL) were added and stirred for 15 minutes.The mixture was then transferred to a 500 mL reparatory funnel and allowed to separate.The lower aqueous phase was run off and the organic phase was washed with saturated sodium chloride (2*50 mL).Since the aqueous and organic phases resulting from the saturated sodium chloride washes could not be completely separated after 20 minutes, the lower aqueous phase (slightly yellow) was run off and back extracted with chloroform (~45 mL).The organic phase was dried with MgSO4, filtered, and the solvent evaporated.The crude product, an orange liquid, was purified on column chromatography using silica gel (60 g) with 0-3percent methanol gradient in dichloromethane to yield 3.19 g.The product was further purified via column chromatography on silica gel (50 g) with 10-30percent ethyl acetate gradient in hexanes to yield 1.26 g pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis ofl. Cholesteryl hemisucciriate (3 g, MW 486.2) and N, N- dimethylaminopropanediol (0.73 g, MW 120) were combined in 50 mL CH2CI2 and stirred until dissolved. Next, 0.5 g DMAP and 2.2 g of DCC were added sequentially to the reaction and it was stirred for 10 h. The reaction was then vacuum-filtered to remove the precipitated DCU. The filtrate was dried by rotary evaporation. The white solid was taken up into chloroform and purified on a Horizon Flash Chromatography system with achloroform/methanol elution system (0-3percent MeOH over 360 mL, 9mL/fraction). The product was collected with minor impurities in fractions 45-60 and moved on to the next step. |
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